Neurological Associations Of Covid-19

Introduction

A novel coronavirus termed as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) which is responsible for the disease COVID-19 (coronavirus disease 2019), which was first seen in Wuhan, China since December 2019. From then onwards, it has spread rapidly to almost all the continents causing a global pandemic and it has become the current emerging health problem worldwide. Over 57 million cases and 1.37 million deaths due to SARS-CoV-2 have been reported globally.¹ The virus was confirmed to have reached Myanmar on March 2020 and a rapid increase in COVID-19 infection was reported. A total of 79,246 cases including 1,739 fatalities and 58,6758 recoveries have been confirmed across the country.² New para is an enveloped positive-stranded RNA virus and current evidence suggests that transmission of SARS-CoV-2 occurs between people through direct or indirect contact, or close contact with infected people through respiratory secretions, or droplets. Although the respiratory system complications have been the most frequent and life-threatening, there is growing evidence of neurological manifestations of COVID-19.

Neuropathogenesis ³

The proposed mechanisms include, either direct viral toxicity of nervous tissues or secondary inflammatory or immune-mediated response to infection such as hypoxemia, ischemia, or effect of metabolic derangements with multiorgan failure, renin-angiotensin system dysfunction, immune dysfunction with release of proinflammatory cytokines and inflammatory markers, microvascular pathology, thrombophilia etc.

Neurological symptoms and signs as presenting features

Approximately 40% to 45% of COVID-19 infected patients can be asymptomatic.⁴ Among the symptomatic patients, fever, cough, dyspnea, and bilateral peripheral infiltrates on chest imagingwere most frequent presentations. Other features such as sore throat, rhinorrhea, nausea, vomiting, diarrhea and abdominal pain were also reported⁵. Despite the wide range of presentations, neurological manifestations of SARS-CoV2 such as headache, dizziness, myalgia, anosmia (smell disorders), dysgeusia (taste disorders), altered consciousness, confusion, weakness, seizures, diffuse corticospinal tract signs, neuralgia and paraesthesia, were not unexpected. Liotta et.al, reported that the frequency distribution of neurological manifestations as myalgias (44.8%), headaches (37.7%), encephalopathy (31.8%), dizziness (29.7%), dysgeusia (15.9%), and anosmia (11.4%), in COVID-19.⁶

Associated neurological syndromes of COVID-19 and their case definitions ^{7, 8, 9}

Recent evidence describes the emerging spectrum of neurological complications in COVID-19 infection and these have included,
1. Meningitis/meningism¹⁰
2. Encephalitis/encephalopathy including delirium^{11, 12}
3. Myelitis/myelopathy^13,14
4. Acute disseminated encephalomyelitis (ADEM)¹⁵
5. Guillain-Barré Syndrome¹⁶
6. Cerebrovascular diseases¹⁷
7. Other neurological diseases or syndromes

1. Meningitis/ Meningism

Meningism: Suspected meningitis with headache, vomiting, neck stiffness or positive Kernig’sor Brudzinsky’s sign with no other apparent diagnosis andno evidence of fever, CSF abnormalities or imaging features of meningitis.

Meningitis: Presence of fever and CSF total white cell count >5 cells/mm³ or altered signal intensity and corresponding contrast enhancement of meninges on imaging in a patient with meningism.

2. Encephalitis/encephalopathy including delirium

Encephalopathy: Acute or subacute (<4 weeks) alteration in consciousnessorcognition (with a clinical presentation of delirium or coma), personality or behavior disorder,which are persisting for more than 24 hours in the absence of fever, clinical or electrophysiological (EEG) evidence of focal neurological findings and withoutevidence in CSF and imaging abnormalitiesfor an alternative diagnosis.

Encephalitis (inflammation of brain parenchyma): New onset seizure, new focal neurological signs or movement disorder, with the presence of fever or abnormal EEG consistent with focal brain abnormality and CSF total white cell count>5 cells/mm3 or imaging compatible with encephalitis in a patient with encephalopathy.

3. Myelitis and myelopathy

Myelopathy: Presence of weakness or sensory symptomson upper and/or lower limbs, which is worsening to maximum severity within 4 hours to 21 days form the onset of symptoms in the presence of any of upper motor neurone signs, such as brisk reflexes, extensor plantar response, bladder or bowel dysfunction, clearly defined sensory level, in the absence of an alternative diagnosis for these symptoms.

Myelitis: Absence of extra-axial compressive etiology on neuroimaging and absence of flow voids on the surface of the spinal cord suggestive of arteriovenous malformation in MRI, and also with the presence of CSF abnormality (total white cell count >5 cells/mm3) or MRI changes consistent with myelitis (gadolinium enhancement or T2 hyperintensity) in a patient with myelopathy.

4. Acute Disseminated Encephalomyelitis (ADEM)

Probable ADEM: Suspected ADEM with new onset multifocal clinical CNS events and alteration in consciousness or behavior (encephalopathy),without other possible diagnoses which could be explained by fever/systemic illness/postictal symptoms, and abnormal brain MRI with typical diffuse, poorly demarcated lesions >1cm.

Confirmed ADEM: No new clinical events or stable MRI findings for >3 months after onset of symptoms in a patient with probable ADEM.

5. Guillain-Barré Syndrome (GBS)

Suspected GBS: Monophasic illness pattern with bilateral flaccid weakness of the limbs with it speak between 12 hours and 28 days, which was followed by clinical plateau in the absence of an alternative apparent diagnosis.

Probable GBS: A suspected GBS patient with CSF total white cell count <50 cells/mm³ or electrophysiological (nerve conduction study) findings consistent with GBS.

Confirmed GBS: A suspected GBS patient with CSF total white cell count < 50 cells/mm³ and electrophysiological (nerve conduction study) findings consistent with GBS.
6. Cerebrovascular diseases that have been reported to be associated with COVID-19 are silent infarction, silent cerebral hemorrhage, ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, cerebral venous sinus thrombosis, transient ischemic attack (TIA) and central nervous system (CNS) vasculitis.

7. Other neurological syndromes

Any new onset neurological diseases which were suspected by the clinician to be associated with recent COVID-19 infection, including neuropsychiatric disease (psychosis, affective disorders), complications of critical illness (myopathy, neuropathy), and olfactory dysfunction (anosmia, ageusia etc).

Decision on association with COVID-19 (confirmed, probable or possible)⁸

In case of meningitis, encephalitis, myelitis and CNS vasculitis, in the absence of other explanatory causes, when SARS-CoV-2 PCR in CSF or its specific intrathecal antibody was detected, it can be reported as confirmed association. But if SARS-CoV-2 is detected only in respiratory specimen, it will be termed as probable association.

In other cases such as ADEM or GBS, if the neurological symptoms onset is less than 6 weeks after acute COVID-19 infection and SARS-CoV-2 RNA is detected in any of specimens or presence of antibody of acute SARS-CoV-2 infection, in the absence of other commonly associated causes, it is called confirmed association. If other commonly associated causes are present, it will be postulated as possible association.

Cerebrovascular diseases have probable association with COVID-19 infection, when the SARS-CoV-2 was detected in CSF or other sample or antibody in serum indicating acute infection, in the absence of well-known cardiovascular risk factors. If any of cardiovascular risk factors such as hypertension, current smoker, diabetes, hypercholesterolemia, and atrial fibrillation is present, it will be just possible association with COVID-19.

Timeline of spectrum of neurological diseases due to COVID-19 ¹⁸

The spectrum of neurological presentations such as myalgia, headache, dizziness, anosmia, dysguesia can occur at acute stage of COVID-19 infection within 1 week of symptom onset, and other associated neurological syndromes such as stroke, encephalitis, encephalopathy, meningitis, myelitis etc. can mostly occur as post-infectious hyperinflammatory illness from week 2 to week 4. As early sequel, ADEM and GBS can occur as para-infectious or post-infectious period of COVID-19. Late neurological complications of COVID-19 after week 4 and its pathological pathways are not well-documented yet but researches are still undergoing.

Impact of COVID-19 on neurological interventions/services ¹⁹

Neurological interventions/services including level of diagnostics and management were found to be affected partially or completely because of direct and indirect consequences of COVID-19. WHO has studied the impact of COVID-19 on mental and neurological services and 93% of countries reported that presence of disruptions in their services. They defined complete disruption as > 50% of users not served as usual, and partial disruption as between 5% and 50%. 33% of responding countries reported complete or partial disruption in at least 75% of specific mental and neurological services. An important finding was that 35% of countries reported some disruption of management of life-saving emergency formental and neurological manifestations (including status epilepticus, delirium and severe substance withdrawal syndromes) and 30% reported disruption in supply of medications for people with mental and neurological diseases.
The main causes of disruption identified were decrease in outpatient volume due to patients not attending, travel restrictions hindering access to health facilities and a decrease in inpatient volume due to cancellation of elective care. In addition, community-based services were also limited in availability. Fortunately, most are responding to the disruption in multiple innovative ways, including telemedicine, teletherapy interventions, hotlines and training for health care providers.

Impact of COVID-19 on chronic neurological diseases

Moreover, individuals with chronic neurological diseases such as dementia, parkinsonism, epilepsy and neuroimmune diseases, such as multiple sclerosis and myasthenia gravis, who require immunotherapy might also be impacted because of services disruptions as mentioned above as well as their vulnerability to COVID-19.

Conclusion

Understanding COVID-19 is still evolving and its effect on nervous system is an important source of morbidity and mortality. Therefore, expanding list of research regarding the neurological complications as a consequence of COVID-19 is ongoing.

Disclosure

There is no conflict of interest and no financial grant from any organization or individual.

References

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    Ohnmar¹, Zarni Myint Shwe², Kyawt Oo Kay ThiHtay³, Kyaw Phyo Hlaing⁴, Yin Minn Aye⁵, Phyu Phyu Lay⁶
    1. Associate Professor, Department of Neurology, University of Medicine 1
    2. Consultant Neurologist, Department of Neurology, Yangon General Hospital
    3. Consultant Physician, Department of Neurology, Yangon General Hospital
    4. Specialist Assistant Surgeon, Department of Neurology, Yangon General Hospital
    5. Associate Professor, Department of Neurology, Yangon General Hospital
    6. Professor/Head, Department of Neurology, Yangon General Hospital

Primary author’s information:
Dr Ohnmar, Associate Professor, Department of Neurology, University of Medicine 1.
M.B.,B.S (Ygn), M.Med.Sc (Int Med), MRCP (UK), FRCP (Edin), Dr.MedSc (Neurology), Fellowship in Neuromuscular (NNI, Singapore)
Email: dr.maohmar@gmail.com, Phone: 095198124