Case Series


https://doi.org/10.5005/jp-journals-10025-1123
International Journal of Keratoconus and Ectatic Corneal Diseases
Volume 8 | Issue 2 | July–December 2019

Neurological Manifestations of COVID-19: A Series of Seven Cases

Kavya Goel1https://orcid.org/0000-0002-5427-5347, Kumar Ajay2https://orcid.org/0000-0001-5643-7955, Diwan Sahil3https://orcid.org/0000-0002-6489-802X, Kohli Santvana4https://orcid.org/0000-0003-1410-6933, C Sachdeva Harish5https://orcid.org/0000-0003-4476-0506, Ganapathy Usha6https://orcid.org/0000-0001-5472-5769, Mustafi Saurav M7https://orcid.org/0000-0003-0893-2155, Kumar Pravin8https://orcid.org/0000-0002-4827-6650

1–8Department of Anaesthesia and Intensive Care, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India

Corresponding Author: Santvana Kohli, Department of Anaesthesia and Critical Care Medicine, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India, Phone: +91 7838434398, e-mail: dr.santvana.kohli@gmail.com

How to cite this article: Goel K, Kumar A, Diwan S, Kohli S, Sachdeva HC, Usha G, et al. Neurological Manifestations of COVID-19: A Series of Seven Cases. Indian J Crit Care Med 2021;25(2):219–223.

Source of support: Nil

Conflict of interest: None

HIGHLIGHTS

There is no dearth of literature on pulmonary involvement in COVID-19 infection. However, extra-pulmonary manifestations are rare and can be easily missed during this pandemic. Our case series hopes to highlight the fact that neurological manifestations of COVID-19 infection are likely to be overlooked. Hence, a low threshold of clinical suspicion and testing for COVID-19 infection is needed in cases presenting with primary neurological symptoms. This will facilitate quicker detection, isolation of cases to prevent further transmission, and provision of early treatment.

ABSTRACT

Identification of neurological manifestations associated with SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) in patients with no or mild pulmonary infection proves to be a challenge. The incidence of neurological associations of COVID-19 may be small as compared with respiratory disease; however, in the present scenario with an increasing number of cases each day, the overall incidence of patients with neurological manifestations and their health-related socioeconomic impact might be large. Hence it is important to report such cases so that healthcare providers and concerned authorities are aware of and may prepare for the growing burden. The literature on primary neurological manifestations of COVID-19 is limited, and hence our case series is relevant in the current scenario. The most commonly reported neurological complications are cerebrovascular accidents, encephalopathy, encephalitis, meningitis, and Guillain-Barr é syndrome (GBS). We present a series of seven cases with various neurological presentations and possible complications from this novel virus infection.

Keywords: Cerebrovascular accident, COVID-19, Encephalitis, Guillain-Barré syndrome, Neurological, SARS-CoV-2

INTRODUCTION

The coronavirus disease (COVID-19) outbreak due to SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) first originated from Wuhan city, China in December 2019 and has rapidly spread as a global health pandemic.1,2 This infection has been demonstrated to produce a mild flu-like illness encompassing fever, cough, breathlessness, and other mild symptoms, such as headache, lethargy, and generalized weakness in a majority of patients.3 Originally considered a primarily respiratory disease,4 new facts have emerged regarding extra-pulmonary complications of the COVID-19 illness. Neurological manifestations are common in the advanced stages of the disease.5 Although the exact mechanism by which SARS-CoV-2 penetrates the central and peripheral nervous system (CNS and PNS) is not yet known, the two most likely theories are (1) hematogenous spread of SARS-CoV-2 from systemic circulation to the cerebral circulation and (2) dissemination through the cribriform plate and olfactory bulb.6 Angiotensin-converting enzyme 2 (ACE 2) receptors that are present on endothelial cells of the cerebral vasculature act as the cell entry points of the virus.7 It may also induce certain microvascular/macrovascular changes leading to nervous system involvement.8 We have compiled a case series of confirmed COVID-19 patients who presented with or developed primary neurological manifestations, to better understand the neurological aspect of this disease. The neurological manifestations of COVID-19 are described in Figure 1.

Fig. 1: Neurological manifestations of COVID-19 infection

CASE DESCRIPTION

A total of seven RT-PCR (real-time reverse transcriptase-polymerase chain reaction) confirmed COVID-19 patients presented to our institute primarily with neurological manifestations (Tables 1 and 2). Two of these cases presented with altered sensorium and a recent history of fever, whereas another two presented with paraparesis. One case presented with hemiplegia and two cases presented with loss of consciousness. Out of the two unconscious patients, one had a history of generalized weakness and the other had dyspnoea one day prior to admission. Apart from dyspnea in this patient, no respiratory symptoms were noted in any of the other cases. None of these patients had a history of travel to a foreign country or contact with a confirmed case of COVID-19. Out of all the seven patients, only two had chest X-ray changes, i.e., homogenous opacities and partial one-sided lung collapse in one and fluffy infiltrates in the other. Five of the patients tested positive in the initial tests while two (case numbers 6 and 7) were initially negative and tested positive after admission in non-COVID ICU. Neurology consultation was sought for patient management at every stage.

Table 1: Clinical findings of cases
No. Age/sex Clinical presentation Classical COVID-19 symptoms Comorbidities Final diagnosis Treatment Outcome
1 55 years/M Left hemiparesis × 1 day None Hypertension T2DM COVID-19 with CVA Antibiotics
Phenytoin, mannitol
Antithrombosis
Steroids
Expired
2 56 years/M Unconsciousness × 1 day
Generalized weakness
× 1 week
None T2DM COVID-19 with CVA Antibiotics
Phenytoin, mannitol
Antithrombosis
Steroids
Expired
3 59 years/F Unconsciousness × 1 day Dyspnea × 1 day T2DM
Hypertension
COVID-19 with influenza-like illness with CVA Antibiotics
Phenytoin, mannitol
Antithrombosis
Steroids
Expired
4 37 years/F Altered sensorium × 1 day
Fever × 6 days
Seizure × 1 episode
Fever × 6 days None COVID-19 associated CNS infection Antibiotics
Thromboprophylaxis
Steroids
Levetiracetam
Expired
5 19 years/F Altered sensorium
× 10 days
Vomiting × 5 days
Fever × 10 days None COVID-19 associated CNS infection Antibiotics
Levetiracetam
Thromboprophylaxis
Steroids
Critically ill
6 55 years/F Paraparesis × 6 days
Low backache x 6 days
None Hypertension COVID-19 with GBS, complicated by PRES IVIG
Antibiotics
Thromboprophylaxis
Steroids
Expired
7 17 years/M Progressive ascending quadriparesis × 2 days Fever at presentation None COVID-19 with GBS with septic shock Antibiotics
IVIG
Thromboprophylaxis
Steroids
Expired
CVA, cerebrovascular accident; T2DM, type 2 diabetes mellitus; GBS, Guillain-Barré syndrome; IVIG, intravenous immunoglobulins
Table 2: Laboratory and radiological findings of cases
Case no. Age/sex Neuroradiology CSF study/
neurophysiology
Chest X-ray RT-PCR Relevant blood investigations
1 55 years/M NCCT: Right MCA
territory subacute infarct with no
hemorrhagic transformation
Not performed Bilateral
homogeneous
opacities with partial right lung collapse
Positive Day 2 Leukocytosis
Neutrophilia
Lymphopenia
Hyponatremia
2 56 years/M MRI: Left MCA (massive) and Right ACA infarct Not performed Unremarkable Positive Day 2 Lymphopenia
Neutrophilia
Raised CRP
Deranged liver function
D-dimer: 3250 ng/mL
3 59 years/F NCCT: Multiple
subacute cortical infarcts
Not performed Bilateral infiltrates Positive Day 2 Anemia
Thrombocytopenia
D-dimer: 4018 ng/mL
Serum ferritin: 226 ng/mL
4 37 years/F NCCT: Normal CSF: Normal protein and cell count Unremarkable Positive Day 6
Negative Day 11
Leukocytosis
Neutrophilia
Lymphopenia
D-dimer: 2994 ng/mL
5 19 years/F NCCT: Diffuse cerebral edema CSF: Raised proteins and cell count Unremarkable Positive Day 10 Leukocytosis
Lymphopenia
Neutrophilia
Hyponatremia
D-dimer: 2348 ng/mL
6 55 years/F MRI: features of PRES CSF: Raised proteins, normal cell count
NCV: Axonal and
demyelinating
sensorimotor polyneuropathy
Unremarkable Positive Day 10
Negative Day 19 and 21
Anemia
Lymphopenia
Thrombocytopenia
Hyponatremia
D-dimer: 1804 ng/mL
Serum procalcitonin: 2.02
7 17 years/M MRI brain: Normal
MRI spine: Normal
CSF: Raised proteins, normal cell count
NCV: demyelinating
sensorimotor polyneuropathy
Unremarkable Negative Day 1
Negative Day 3
Positive Day 8
Mild leukocytosis
Lymphopenia
Neutrophilia
Hyponatremia
D-dimer: 890 ng/mL
NCCT, non-contrast computed tomography; MCA, middle cerebral artery; ACA, anterior cerebral artery; MRI, magnetic resonance imaging; CRP, C-reactive protein; NCV, nerve conduction velocity; CSF, cerebrospinal fluid

DISCUSSION

This case series was observed in a single center, catering to COVID as well as non-COVID patients, from June to August 2020. At the onset of the pandemic, the main focus was on patients presenting with respiratory symptoms. So a higher threshold of suspicion of COVID-19 disease was maintained for patients presenting with clear-cut neurological manifestations, without any pulmonary involvement. However, with an increasing number of cases, the focus was shifted towards the possibility of neurological association of COVID-19, and an attempt was made to gather more data in this direction.

It may be remarkable to note that all patients in this case series were less than 60 years of age (mean age 40.1 years), with two of these patients less than 20 years. The patients had a relatively even sex distribution in this case series with three male and four female patients. Four out of seven patients had comorbidities usually associated with a worse outcome, i.e., hypertension and type 2 diabetes mellitus. Table 3 shows the consolidated data from various studies that have contributed to a better understanding of our cases.

Table 3: Review of literature on neurological manifestations in COVID infection
Reference Country Clinical features COVID RT-PCR Neuroimaging,
CSF findings
Blood investigations Treatment and
outcome
Oxley et al. 9
5 cases
(CVA)
USA Hemiplegia, altered consciousness, sensory deficits, dysarthria All positive Single territory infarcts on imaging
No CSF studies
One patient had
thrombocytopenia,
two had deranged clotting parameters, three had raised fibrinogen, D-dimer, and ferritin
Four had clot retrieval, one thrombolysis, and hemicraniectomy, one stent insertion
Three discharged, two in hospital
Beyrouti et al. 10
6 cases
(CVA)
UK Hemiparesis,
dysphasia,
dysarthria, altered consciousness
Presented with a median of 13 days after respiratory symptoms
All positive Unifocal infarcts in 4 patients, Bilateral infarcts in 2 patients One had leukocytosis and three had lymphopenia, all had raised D-dimers and lactate dehydrogenase,
5 had raised ferritin
and CRP
One had dual
antiplatelets and LMWH (low-molecular-weight heparin), one had extra-ventricular
drain placement and LMWH, one had apixaban
One died and the rest outcome unknown
Mao et al. 11
16 cases
(CNS infection)
China Unconsciousness
Seizures
All positive Not reported Lymphocytopenia
Thrombocytopenia
Raised blood urea
nitrogen (BUN)
13 out of 16 had severe dyspnea
Toscano et al.12
5 cases
(GBS)
Italy 3 had quadriparesis, 1 had paraparesis
1 had facial diplegia and limb paresthesia
Presented after a median of 7 days of respiratory symptoms
4 positive by nasopharyngeal swabs, 1 positive serologically, all negative in CSF RT-PCR MRI: enhancement of caudal nerve roots in two patients and facial nerve in one
NCV: axonal pattern in three patients and demyelinating in two
Not reported All treated with IVIG, one also had plasma exchange
Three required mechanical ventilation

USA and UK have also reported multiple cases of COVID patients presenting with CVA, mostly older patients with the majority being ischemic strokes. Oxley et al.9 reported five such cases which notably consisted of patients younger than 50 years. In our series, all three cases were under 60 years with known risk factors for CVA and diagnosed as ischemic stroke. The first patient in our case series expired within a day of admission and was later found to be COVID positive. This gave us a reason to search for literature on the neurological presentation of COVID infection. Going forward, we have found more cases and evidence of hypercoagulability in COVID patients presenting with stroke. The first patient did not survive long enough to allow D-dimer testing, but the second and third patients showed high values. Beyrouti et al.10 reported six patients with large cerebral infarcts with elevated D-dimer levels indicating a hypercoagulable state. The third case in our series is different from the first two, as he had associated shortness of breath on presentation, which led to a quicker diagnosis of COVID-19. This patient had NCCT head changes suggestive of embolism or vasculitis associated infarcts which may be considered a complication rather than a manifestation of COVID-19.

The next two cases in our series had altered sensorium at presentation and encephalitis/meningitis was suspected based on a history of fever with neurological signs. When tested, they were found to be COVID-19 positive. Moriguchi et al.13 reported the first confirmed case of COVID-19 associated viral encephalitis from Japan. A 24-year-old man presented with fever followed by seizures and unconsciousness. He had neck stiffness and underwent a CT scan brain which was normal. There was patchy pneumonia on the CT chest. PCR assay from nasopharyngeal swab was negative but the CSF sample was positive for COVID-19. This presentation may justify the inclusion of the fourth and fifth cases, which had similar initial CNS findings but without any pulmonary involvement. Although it is difficult to diagnose COVID-19 associated CNS infection in such cases, it becomes prudent to keep a high index of suspicion, especially in the middle of a pandemic and absence of any other definitive cause.

There have been several cases reported from China and Italy of GBS associated with COVID-19. The first such case was reported from China of a 61-year-old lady with a history of return from Wuhan but no respiratory symptoms.14 She was however infective as two of her relatives caring for her during her hospital stay were found positive for SARS-CoV-2. She later developed fever and cough during her hospital stay. In contrast, the 55-year-old lady, the sixth case in our series, had no history of travel or contact with a confirmed case, or the classical presentation of a febrile illness. She presented to us with paraparesis only and her hospital stay was complicated by PRES. Whether this neurological involvement was causal or coincidental is difficult to say as the patient presented late to the hospital, having gone to a secondary health center previously and there was a further delay in COVID testing due to the complete absence of usual respiratory symptoms. The last case of a 17-year-old boy presented with a relatively faster progression of the disease and developed high-grade fever during his illness, possibly due to sepsis with no response to high-grade antibiotics.

CONCLUSION

As initially perceived, the SARS-COV-2 virus is not only responsible for respiratory and cardiovascular diseases but also neurological morbidity. This may be secondary to micro/macrovascular changes in the CNS or the PNS or due to a direct invasion of the cerebral endothelium/parenchyma by the virus hematogenously. To make a clear distinction, further studies need to be undertaken with the help of multidisciplinary teams of critical care, neurology, internal medicine, pathology, microbiology, and radiology departments. A low threshold of COVID-19 testing needs to be kept in cases with neurological presentations, particularly in areas with higher COVID-19 infection rates to improve quicker detection, provide early treatment, and isolate such cases to prevent further transmission in highly susceptible critical patients.

JUSTIFICATION OF STUDY

Our case series hopes to highlight the fact that extrapulmonary manifestations of COVID-19 infection are likely to be missed. Hence, a low threshold of testing must be kept in such cases to improve quicker detection, isolation of cases to prevent further transmission, and provision of early treatment.

ORCID

Kavya Goel https://orcid.org/0000-0002-5427-5347

Ajay Kumar https://orcid.org/0000-0001-5643-7955

Sahil Diwan https://orcid.org/0000-0002-6489-802X

Santvana Kohli https://orcid.org/0000-0003-1410-6933

Harish C Sachdeva https://orcid.org/0000-0003-4476-0506

Usha Ganapathy https://orcid.org/0000-0001-5472-5769

Saurav M Mustafi https://orcid.org/0000-0003-0893-2155

Pravin Kumar https://orcid.org/0000-0002-4827-6650

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