Neurological manifestation and recent advances with on going trials in COVID19

1. BY DR VAIBHAV SOMVANSHI
DM NEUROLOGY RESIDENT
GMC KOTA
Neurological Manifestation of
COVID19

2. INTRODUCTION
SARS-COV-2 SS mRNA (30kb) virus belongs to Beta corona family
At the end of 2019, a novel coronavirus identified as cause of a cluster of pneumonia cases in
Wuhan, a city in the Hubei Province of China.
Acronym – CO(corona) VI(virus) D(diasease) 19(year of identification)
Neurologic implication common – around 80% in hospitalized patients at some point.
Liotta EM, Batra A, Clark JR, Shlobin NA, Hoffman SC, Orban ZS, Koralnik IJ. Frequent neurologic manifestations and encephalopathy-associated morbidity in
Covid-19 patients. Ann Clin Transl Neurol. 2020 Nov;7(11):2221-2230. doi: 10.1002/acn3.51210. Epub 2020 Oct 5. PMID: 33016619; PMCID: PMC7664279.

3. Pathogenesis

4. Pathophysiology
Viral entry receptor :
ACE-2
Entry dependent on
interaction between
spike protein,
TMPRSS2 and ACE2.
Portal of entry:
Respiratory tract
mucosa

8. Neuropathology
of COVID-19 –
Schematic
Representaion
Olfactory
neurons, neural
stem cells, and
Sustentacular
cells
Virus bind
to ACE2
Cytokine
storm in
vasculature
ACE2 on
respiratory
epithelium
BBB and ACE2
expressing
pericytes
cerebral microinfarcts from
vascular plugging and
vasoconstriction
Transsynaptic
spread

9. NEUROPATHOGENESIS
Mechanisms of neurologic complications in patients with COVID-19 - Diverse and multifactorial
Neurologic injury from
systemic dysfunction
Renin-angiotensin system
dysfunction
Immune dysfunction
Proinflammatory
state
Parainfectious and
postinfectious
triggers
Direct viral invasion of the
nervous system
 Post-hypoxic
leukoencephalopathy
 Encephalopathy due to
metabolic
derangements  Cytokine storm
 Capillary
endothelitis
 coagulopathy
 ADEM
 GBS
 Olfactory
 Vagus nerve
 Neurotropis
m
 Transcytosis
 Endocytosis
 Transynaptic
transmission

10. SARS-CoV2 Infection

11. Interaction of the viral and host response
in patients with COVID-19

14. Risk factors for more severe COVID-19 illness in
patients with pre-existing neurological
disorders
Age >=60 years
Pre-existing neurological disorders
Long-term facility or nursing home residents
Swallowing or breathing difficulty
Immunosuppressants-drugs
Comorbidities
Stroke
Chronic lung disease
Asthma
Serious heart diseases
Obesity
Diabetes
Hypertension
Renal disease
Liver disease
Immunocompromised

15. Prevalence of
Neurological
Manifestations
in COVID-19
Patients
Saniasiaya J, Islam MA, Abdullah B. Prevalence of Olfactory Dysfunction in Coronavirus Disease 2019 (COVID-19): A Meta-analysis of 27,492 Patients. Laryngoscope.
2021 Apr;131(4):865-878. doi: 10.1002/lary.29286. Epub 2020 Dec 5. PMID: 33219539; PMCID: PMC7753439

16. 0
5
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Series1

17. Neurology in COVID-19 : Etiopathogenesis
and clinical aspects

18. SMELL AND TASTE DISORDERS
Anosmia and dysgeusia - common early symptoms in patients with COVID-19.
meta-analysis of 83 studies involving more than 27,000 patients, olfactory dysfunction - 48 %
Transient anosmia - d/t inflammatory changes in sustentacular cells
In a survey of nonhospitalized patients with olfactory dysfunction from Italy,
83 % - complete recovery at a mean of 37 days after symptom onset.
Saniasiaya J, Islam MA, Abdullah B. Prevalence of Olfactory Dysfunction in Coronavirus Disease 2019 (COVID-19): A Meta-analysis of 27,492
Patients. Laryngoscope. 2021 Apr;131(4):865-878. doi: 10.1002/lary.29286. Epub 2020 Dec 5. PMID: 33219539; PMCID: PMC7753439.

19. ENCEPHALOPATHY
Encephalopathy is common in critically ill patients with COVID-19.
 Delirium and agitation requiring sedation or may manifest somnolence and a decreased level
of consciousness.
Spectrum of neuroimaging abnormalities –
Hyperintensities in the medial temporal lobe, multifocal white matter lesions on FLAIR
isolated white matter micro-hemorrhages
Cytotoxic lesions in the splenium of the corpus callosum
Periventricular ischemic changes
EEG – non-specific
CSF- some case report shows + RTPCR for COVID19 otherwise WNL
Encephalopathy is a risk factor for poor outcome in COVID pts.

20. CEREBROVASCULAR DISEASE
incidence of ischemic stroke associated with COVID-19 in hospitalized patients- 0.4 to 2.7%
incidence of intracranial hemorrhage - 0.2 to 0.9%
incidence of CVT - 0.08%
Risk of stroke may vary according to the severity of COVID-19.
Due to the close association between COVID-19 and cerebrovascular disease, all patients
presenting with stroke need to be screened for SARS-CoV-2 infection,
COVID-19 is mainly associated with LVO strokes rather than the small vessel occlusion strokes.
Infection induced hypercoagulable state and embolisms d/t COVID-19-related myocarditis may
both result in strokes.
Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, Chang J, Hong C, Zhou Y, Wang D, Miao X, Li Y, Hu B. Neurologic Manifestations of Hospitalized Patients With Coronavirus
Disease 2019 in Wuhan, China. JAMA Neurol. 2020 Jun 1;77(6):683-690. doi: 10.1001/jamaneurol.2020.1127. PMID: 32275288; PMCID: PMC7149362.

21. CEREBROVASCULAR DISEASE
Mostly stroke occurs 1 - 3weeks after onset of COVID-19 symptoms but can be initial
presentation.
Similar ischemic treatment protocol IV rTPA, aspirine, mechanical thrombectomy, with
unambiguous indication for full-dose anticoagulation.
Patients receiving ACE inhibitors or ARBs should continue treatment with these agents
PRES syndrome- Low availability of ACE 2 receptor leads to labile blood pressure results into
PRES like picture.
Widespread capillary endothelitis or a cytokine storm can also cause a diffuse
leukoencephalopathy with confluent posterior predominant white matter T2/FLAIR
hyperintensities and scattered microhemorrhage
Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, Chang J, Hong C, Zhou Y, Wang D, Miao X, Li Y, Hu B. Neurologic Manifestations of Hospitalized Patients With Coronavirus
Disease 2019 in Wuhan, China. JAMA Neurol. 2020 Jun 1;77(6):683-690. doi: 10.1001/jamaneurol.2020.1127. PMID: 32275288; PMCID: PMC7149362.

22. NEUROMUSCULAR DISEASE
GBS associated with COVID 19 infection with low incidence.
Cases of GBS have been observed with the Ad26.COV2.S (Janssen/Johnson & Johnson) COVID-
19 vaccine.
AIDP more prevalent than other variants.
COVID-19 GBS seems to be more severe than non-COVID-19 GBS,
CSF and electrodiagnostic studies unremarkable.
Management remains the same.
Malik GR, Wolfe AR, Soriano R, Rydberg L, Wolfe LF, Deshmukh S, Ko JH, Nussbaum RP, Dreyer SD, Jayabalan P, Walter JM, Franz CK. Injury-prone: peripheral nerve injuries associated with prone
positioning for COVID-19-related acute respiratory distress syndrome. Br J Anaesth. 2020 Dec;125(6):e478-e480. doi: 10.1016/j.bja.2020.08.045. Epub 2020 Sep 4. PMID: 32948295; PMCID: PMC7473147.

23. NEUROMUSCULAR DISEASE
Myositis – prevalence 11% , myalgia and fatigue common symptoms.
HCQS, Azathioprine, dexamethasone induced iatrogenic myopathy and neuropathy
Focal and multifocal neuropathies - Ocular motor neuropathies , 7th , 10th , 11th, 12th, Tapia
syndrome, Neuralgic amyotrophy.
Critical illness neuropathy and myopathy
Peripheral nerve injuries after prone positioning- MC brachial plexus (lower trunk) – 14.5%
Malik GR, Wolfe AR, Soriano R, Rydberg L, Wolfe LF, Deshmukh S, Ko JH, Nussbaum RP, Dreyer SD, Jayabalan P, Walter JM, Franz CK. Injury-prone: peripheral nerve injuries associated with prone positioning for
COVID-19-related acute respiratory distress syndrome. Br J Anaesth. 2020 Dec;125(6):e478-e480. doi: 10.1016/j.bja.2020.08.045. Epub 2020 Sep 4. PMID: 32948295; PMCID: PMC7473147.

24. Seizure
Prevelence in COVID pts – 4.1%
Risk factors - metabolic alterations, and potential changes related to encephalitis.
Reported in patients with severe COVID-19 infection. Neuroimaging - abnormal in
approximately half of patients.
Saniasiaya J, Islam MA, Abdullah B. Prevalence of Olfactory Dysfunction in Coronavirus Disease 2019 (COVID-19): A Meta-analysis of 27,492 Patients. Laryngoscope. 2021 Apr;131(4):865-878. doi:
10.1002/lary.29286. Epub 2020 Dec 5. PMID: 33219539; PMCID: PMC7753439

25. Covidnosomnia
Risk factors -
Sleep disorders related to Anxiety, depression, poor sleep quality
Physical and social isolation, psychosocial disturbance
Quarantine, stress related to financial loss, loss of loved ones
Both insomnia and hypersomnia is prevalent.

26. Critical illness polyneuropathy/myopathy
Long stay admissions - post intensive care syndrome (PICS) - critical illness polyneuropathy and
myopathy (CIPNM)
SARS-CoV can infiltrate brainstem via trans-synaptic transfer - lead to dysfunction of the
cardiorespiratory centres of brainstem – need of long duration ventilation.
Risk factors for PICS - long durations of mechanical ventilation, hypoxia and sepsis,
Pro-inflammatory cytokines and free radicals - affect the microcirculation of both CNS & PNS by
reducing oxygen and nutrient delivery.

27. ACUTE NEUROLOGIC MANIFESTATIONS
Meningoencephalitis - Both viral (CSF RTPCR +ve for COVID19) and apparent
autoimmune(NMDA) meningoencephalitis have been reported in patients with COVID-19.
Rhombencephalitis - Brainstem encephalitis or isolated cerebellitis have been reported in adults
and children with COVID-19 infection. Patients with fulminant disease and brainstem
compression develop hydrocephalus.
ADEM and ANE - Hemorrhagic lesions in bilateral thalami, medial temporal lobes, and
subinsular lesions.
MS - might potentially experience both true and pseudorelapses.

28. ACUTE NEUROLOGIC MANIFESTATIONS
Multisystem inflammatory syndrome in children - illness similar to incomplete Kawasaki
disease- neurocognitive symptoms- headache, lethargy, confusion with MRI revealed signal
abnormality in the splenium of the corpus callosum .
Movement disorders reported in COVID-19 patients- tremors, myoclonus, and nonspecific
psychomotor agitation.
Posterior reversible encephalopathy syndrome (PRES) –due to hypertension and renal failure

29. Neurologic Manifestations of COVID-19 in
Children
Pathophysiology similar in pediatric population as well.
Pediatric patients shows prevalence of headache (4%), anosmia (2%), seizures (0.7%), and
cerebrovascular stroke(0.7%)
The pooled estimates frequency of seizure (3.1%) and encephalopathy (12.6% ) in children
with severe COVID 19.
Immune profiling suggests that autoantibodies in (MIS-C) shared sequence similarity between
SARS-CoV-2 and sialic acid residues on neural tissue.
Management - steroids and IV immunoglobulin in MIS-C, autoantibody depletion with
plasmapheresis.
Future potential immunologic interventions include blocking agents (against interleukin-1 and -
6), anti-CD20 monoclonal antibodies to ameliorate neurologic complications of COVID-19
Ranabothu S, Onteddu S, Nalleballe K, et al: Spectrum of COVID-19 in children. Acta Paediatr 2020; 109:1899–1900

30. PERSISTENT NEUROLOGIC SYMPTOMS
AFTER COVID-19 INFECTION
Constellation of persistent symptoms after acute COVID-19 infection described by various
terms- long COVID/post-COVID syndrome/post-COVID conditions.
Persists >6/6 weeks after SARS-CoV-2 infection, which have been reported to range between 5
and 80 percent of patients.
Umbrella term covers fatigue, dyspnea, brain fog" (81%), headache (68%), numbness/tingling
(60%), dysgeusia (59%), anosmia (55 %), and myalgias (55%)
Dysexecutive syndrome has been noted in around 30% of patients who have survived severe
life-threatening COVID-19 which encompasses emotional, motivational and behavioural
symptoms, as well as cognitive deficits.
It is unclear which, if any, part the neuroaxis or brain networks would be susceptible to
degeneration in the long-term, after acute COVID-19 illness. Long-term population follow-up
studies are needed to monitor for increased incidence of neurodegenerative problems
Graham EL, Clark JR, Orban ZS, Lim PH, Szymanski AL, Taylor C, DiBiase RM, Jia DT, Balabanov R, Ho SU, Batra A, Liotta EM, Koralnik IJ. Persistent neurologic symptoms and cognitive dysfunction in non-
hospitalized Covid-19 "long haulers". Ann Clin Transl Neurol. 2021 May;8(5):1073-1085. doi: 10.1002/acn3.51350. Epub 2021 Mar 30. PMID: 33755344; PMCID: PMC8108421.

31. PERSISTENT NEUROLOGIC SYMPTOMS
AFTER COVID-19 INFECTION
Extensive use of steroids/monoclonal antibodies/broad-spectrum antibiotics may lead to the
development/exacerbation of a preexisting fungal disease .
Rhino-oculo-cerebral mucormycosis (ROCM) is a rare disorder in which the olfactory system and brain become
infected with aerosolized spores from the Mucorales genus of fungi, which
includes Rhizopus, Apophysomyces, Mucor, Cunninghamella and Lichtheimia.
Spores  nasal cavity necrosis nasal stuffiness and discharge, which can contain blood. mucor fungus -
highly angioinvasive- spreads to maxillary and ethmoidal sinuses, the orbits, the cavernous sinuses, the meninges
and, finally, the brain
Large multicentre study, 87% COVID-19-associated ROCM had used corticosteroids as a standard regimen to
treat the viral infection, diabetes mellitus in 78% of cases , diabetic ketoacidosis in 15% of cases
When routed through the cavernous sinuses  maxillary and mandibular nerve palsies and internal carotid
artery thrombosis, pseudoaneurysm carotid cavernous fistula. From the sphenoid sinus  clivus to the basal
meninges and basilar artery  thrombosis or rupture with subarachnoid haemorrhage. nasal cavity or the
paranasal sinuses brain parenchyma, leading to cerebritis and abscesses.
Graham EL, Clark JR, Orban ZS, Lim PH, Szymanski AL, Taylor C, DiBiase RM, Jia DT, Balabanov R, Ho SU, Batra A, Liotta EM, Koralnik IJ. Persistent neurologic symptoms and cognitive dysfunction in non-
hospitalized Covid-19 "long haulers". Ann Clin Transl Neurol. 2021 May;8(5):1073-1085. doi: 10.1002/acn3.51350. Epub 2021 Mar 30. PMID: 33755344; PMCID: PMC8108421.

33. Pathological Studies of Brains of Patients
Who Died from Covid-19

34. Mycoses, First published: 07 June 2021, DOI: (10.1111/myc.13334)

37. MANAGEMENT OF COVID 19: OVERVIEW
Dexamethasone 6mg/d X 10d
Neucleotide analogue – Ramdesevir 200mg  100mg
Mab Cocktail – Bamlanivimab (cost – 1250$ per vial (700mg)
Estesevimab ( cost – 610$ (1400mg)
Tocilizumab 400mg (cost 40600 INR) 8mg/kg infusion

38. MANAGEMENT OF PATIENTS WITH
NEUROLOGIC CONDITIONS
Vaccination against COVID-19
Managing immunosuppressive therapy - At present there is no evidence to suggest that patients
with neurologic disease who are treated with immunosuppressive therapy are at increased risk of
COVID-19
Infection is a trigger for myasthenic crisis but has not been reported to be particularly prevalent in
patients with COVID-19
Alternative treatments may also be considered for patients who develop COVID-19 while taking
immunosuppressive therapy. As examples, immunoglobulin therapy, complement inhibitor therapy,
and plasma exchange are not expected to increase the risk of COVID-19
Conditions with features of raised ICP - treatment protocol comprises decongestants like mannitol,
hypertonic saline and hyperventilation to maintain target PCO2 around 30mmHg.
In ischemic stroke, with a high D-Dimer level, preventive anticoagulation is recommended.
In patients of intracranial hemorrhage, optimal blood pressure control is targeted using calcium
channel blockers and diuretics.

39. COVID-19 vaccination
Thromboembolic events with thrombocytopenia – CVT with and without hemorrhage, reported
in patients immunized - adenovirus-vector ChAdOx1 nCoV-19/AZD122 (AstraZeneca COVID-19)
and Ad26.COV2.S (Janssen COVID-19) vaccines
DNA from adenovirus vectors may bind to platelet factor 4 and trigger the production of
autoantibodies
Autoimmune vaccine-induced thrombotic thrombocytopenia (VITT) syndrome likely occurs
between 5 and 30 days post-vaccination
Benefits of vaccination to prevent the morbidity and mortality associated with COVID-19
infection greatly outweigh the risk of VITT
Management- anticoagulation, IVIG, hydration, plasma Exchange in refractory cases
Furie KL, Cushman M, Elkind MSV, Lyden PD, Saposnik G; American Heart Association/American Stroke Association Stroke Council Leadership. Diagnosis and Management of Cerebral Venous Sinus
Thrombosis With Vaccine-Induced Immune Thrombotic Thrombocytopenia. Stroke. 2021 Jul;52(7):2478-2482. doi: 10.1161/STROKEAHA.121.035564. Epub 2021 Apr 29. PMID: 33914590.

40. COVID-19 in Patients with Pre-Existing
Neurological Disorders
A review of 17.5 million NHS patient records in England found that patients with strokes,
dementia, and neurological disorders had a hazard ratio of COVID-19 related hospital death 2 to
3, after adjusting for age, sex, ethnicity, and other co-morbidities.
Population with neurological disease - older, on immunomodulators, social-distancing, and
frequent hand washing are challenging for patients with significant physical or cognitive
impairment, or behavioural issues. So more frequent screening needed.
Apart from the direct effects of the virus itself, changes in daily-routine and the additional
personal, familial, and social stress that the pandemic has caused have led to increased
prevalence of anxiety, depression, and obsessive-compulsive disruptive behaviours in the
general population

41. Practice of Neurology
Out-patient services for non-COVID-19 patients have been Crippled, travel restrictions,
patients’ fear of venturing to medical centers, re-allocation of medical services to care for
COVID-19 patients.
Access and availability of medication has also suffered - Developing e-pharmacies would also
help ease patients’ access to medicines.
Global disruption of various routine new-born, early childhood and other population-based
vaccination programs - may result in re-emergence or surge in neurological illnesses such as
polio, diphtheria, and sub-acute-sclerosing-panencephalitis.
Vaccination status of all children should be checked when they visit a medical facility.
Telemedicine could be the suportive role for wide availability of experts without facing health
hazards and could be alternative to conventional learning.

42. Neuroimaging in COVID-19
Encephalitis including limbic encephalitis radiological acute disseminated encephalomyelitis,
cytotoxic lesions of the corpus callosum, and radiological acute hemorrhagic necrotizing
encephalopathy.
Detection of acute stroke can be a strong prognostic marker of the poor patient outcome as it is
the most common neuroimaging finding among the COVID-19 patients.
Magnetic resonance imaging of COVID-19 patients with GBS showed enhancement of caudal
nerve roots and enhancement of facial nerve bilaterally.

54. Study trials
Going

55. Take Home Message
SARS CoV-2 has potential to affect almost all organs but whether it does so, is still fully understood.
Extra-pulmonary manifestations of COVID-19 must be managed as per existing guidelines based on other
etiologies.
Telemedicine should be encouraged and infrastructure strengthening to concur future waves is best shot to
manage covid neurological complications as well as non-covid neurological diseases safely.
Vaccination against COVID-19 is now strong combatting tool available. Whenever possible mRNA based vaccine
specially those who already experienced any GBS episode.
Development of novel therapies- combatting RAS disequilibrium induced by ACE2 loss using MasR agonists. In
this regard, a clinical trial (NCT04452435) of the MasR agonist C21 for treating nonneurologic complications of
COVID-19 was recently completed.
Long term degenerative neurological complications should also be monitored as having similar basic
mechanisms of neural inflammation, demyelination, vascular or fibrinogen leakage, astrocytes modulations.
Successful treatment of rodent stroke after nasal delivery of C21, suggesting the potential for future trials for
treating or preventing neurologic complications of COVID-19
Bennion DM, Jones CH, Dang AN, et al: Protective effects of the angiotensin II AT2 receptor agonist compound 21 in ischemic stroke: A nose-to-brain delivery
approach. Clin Sci (Lond) 2018; 132:581–593

56. Quiz Time !

57. Q. 56-year-old woman with encephalitis,
experienced headache, confusion, facial
palsy, ophthalmoparesis, refractory status
epilepticus and pleocytosis. SARS-CoV-2
PCR results were positive in respiratory
sample but negative in CSF. Diagnosis?
A. Encephalopathy
B. Encephalitis
C. Ischemic Stroke
D. ADEM

58. Q. 76-year-old man, developed altered
mental status 14 days after severe
respiratory symptoms. SARS-CoV-2 PCR
results were positive in nasopharyngeal
sample and negative in CSF; no pleocytosis
was noted. Diagnosis?
A. Encephalopathy
B. Encephalitis
C. Ischemic Stroke
D. ADEM

59. Q. 60-year-old woman, experienced
sudden right haemiparesis 11 days after
severe respiratory symptoms. SARS-CoV-2
PCR results were positive in
nasopharyngeal sample. Diagnosis?
A. Encephalopathy
B. Encephalitis
C. Ischemic Stroke
D. ADEM

60. Q. 60-year-old woman experienced sudden
right haemiparesis and aphasia after
withdrawal of sedation. SARS-CoV-2 PCR
results were positive in nasopharyngeal
sample. Diagnosis?
A. Encephalopathy
B. Encephalitis
C. Hemorrhagic Stroke
D. ADEM

61. Q. 49-year-old man whose CT revealed
interstitial pneumonia and with real-time
polymerase chain reaction (RT-PCR) was
positive for SARS-CoV-2. Endotracheal
intubation and mechanical ventilation with
prolonged sedation were required because
of severe respiratory failure. He presented
with delayed recovery of consciousness
after protracted sedation. Diagnosis?
A. Encephalopathy
B. Encephalitis
C. Hemorrhagic Stroke
D. ADEM

62. Q. 59-year-old woman with a background
of transfusion-dependent aplastic anemia
presented with seizures and reduced level
of consciousness 10 days after the onset of
subjective fever, cough, and headache.
Nasopharyngeal swab testing for severe
acute respiratory syndrome coronavirus
(SARS-CoV-2) was positive. Diagnosis?
A. Encephalopathy
B. Encephalitis
C. Hemorrhagic Stroke
D. ANE

64. References
Dhamne, et al.: Guillian--Barre Syndrome and COVID-19 - http://www.annalsofian.org
UpToDate
Bradley and Daroff's Neurology in Clinical Practice, 2-Volume Set, 8th Edition
Vitalakumar D, Ankita Sharma, Anoop Kumar,and S. J. S. Flora ; Neurological Manifestations in
COVID-19 Patients: A Meta-Analysis; https://doi.org/10.1021/acschemneuro.1c00353 ACS
Chem. Neurosci. 2021, 12, 2776−2797