NEUROLOGICAL COMPLICATIONS OF COVID-19 INFECTION IN EGYPTIAN POPULATION, A MULTI-CENTER STUDY

NEUROLOGICAL COMPLICATIONS OF COVID-19 INFECTION IN EGYPTIAN POPULATION, A MULTI-CENTER STUDY

By

Mohamed Saad Ahmed Ghaly, Mohamed Al-Bahay M.G. Reda and Ahmed Hasan El-Shishiny

Neurology Department, Faculty of Medicine, Al-AzharUniversity, Cairo, Egypt

E-mail: saadghaly90@gmail.com

ABSTRACT

Background: COVID-19 infection can cause a variety of symptoms, including neurologic symptoms like anosmia, ageusia, or dysgeusia, as well as neurologic complaints like stroke, Guillain-Barre syndrome, encephalopathy, and a variety of others.

Objective: To detect the neurological complications of definite covid-19 infection patients, the relation with the onset and evolution of the infection, and compare these data with probable covid-19 infection patient.

Patients and methods: This were a multi-center observational retrospective – prospective study. Data were obtained from the archived files of the selected Covid-19 patients, in addition to patients admitted at Isolated ICU and inpatient rooms at Al-AzharSpecializedHospital, PoliceHospitals and ArabContactorMedicalCenter. The duration of the recruiting period was from February 2021 till August 2021.

Results: Neurological complication was found in 97(33.2%) patients out of 292 covid-19 patients included in our study. Headache was the most prevalent neurological outcome. That present in 44 patients (16.9%). The presence of neurological complications was significantly associated with female gender (25.8 vs 15.9%), presence of comorbidities (40.2 vs 9.2%), hypertension (53.6 vs 20.5%), diabetes mellitus (DM) (44.3 vs 11.3%), HCV (7.2 vs 0.5%), and history of cerebrovascular stroke (CVS) (7 vs 0%). D-dimer, ferritin, C-reactive protein (CRP), platelets, international randomization ratio (INR) were noticeably higher among patients presented with neurological complications comparing to those who have not had any neurological issues. In prediction of stroke, two significant predictors including hypertension and CRP were found. Neurological involvement in Covid-19 patients carried a bad prognostic indication. It was associated with more frequent need for mechanical ventilation and higher risk of mortality. The neurological defects between the suspected and confirmed Covid-19 patients did not show significant differences except in cranial nerves affection that was higher among confirmed cases.

Conclusion: Patients with Covid-19 frequently have neurological symptoms. There was a significant association between the presence of neurological manifestations and mortality.

Keywords: COVID-19 infection, Neurologic, Complication, Mortality, Multi-center.

INTRODUCTION

     SARS-CoV-2, an unusual coronavirus outbreak, is wreaking havoc on the world's population's health and, as a result, the worldwide economy. Although Fever, cough, and lethargy are the most prevalent symptoms of COVID-19. Other symptoms of the condition include headache, dyspnea, and diarrhea. In the most serious cases, pneumonia, acute respiratory distress syndrome, and multi-organ failure may occur Asadi-Pooya and Simani (2020).

     The novel SARS-CoV-2 virus infects cells via the viral structural spike (S) protein, which attaches to the angiotensin converting enzyme 2 (ACE2) receptor and down-regulates ACE-2, resulting in increased synthesis of the vasoconstrictor Ang II and decreased production of the vasodilator angiotensin 1-7. Angiotensin II also acts as a proinflammatory cytokine when it binds to the angiotensin receptor 1. (AT1R). The Ang II – AT1R axis also activates NF-kB and metalloprotease 17, causing the mature form of epidermal growth factor receptor ligands and TNF-a to be produced. Lung alveolar epithelial cells, small intestine enterocytes, vascular endothelial cells, airway epithelia cells, and kidney cells all express the ACE2 receptor. Glial cells, neurons, the cerebral cortex, striatum, posterior hypothalamic area, substantia nigra, paraventricular nucleus, and the brain stem all have ACE2 receptors (South et al., 2020).

     Coronaviruses exhibit a number of characteristics in common, including neurotropism. The neurological system might be affected directly by the viruses or indirectly by the stimulation of immune-mediated processes. While the first effect can be seen during the acute phase of the sickness, the second can take days, weeks, or even months to appear after the acute phase has passed. (Li et al., 2020) Coronaviruses can infect immune-functioning macrophages, microglia, and astrocytes in the nervous system, causing nerve damage by direct infection (circulatory and neuronal), hypoxia, immunological injury, ACE2 assault, and other methods (Obaidi et al., 2020).

     Neurological manifestations were found in 78/214 patients (36.4 %) during the COVID-19 outbreak in Wuhan, China, and were divided into three categories: central nervous system (dizziness, headache, impaired consciousness, acute Cerebrovascular disease, encephalitis, and seizure), cranial and peripheral nervous system (taste impairment, smell impairment). The most prevalent symptoms in seriously impacted patients were stroke, ataxia, seizures, and a low level of awareness (Mao, 2020).

     Ischemic strokes believed to be induced by three basic processes in COVID-19: hypercoagulability, vasculitis, and cardiomyopathy with a global reduction in blood flow (Beyrouti, 2020). While the etiology of hemorrhagic strokes in the existence of COVID-19 is unknown, it's likely that SARSCoV-2's affinity for ACE2 receptors, which are located in endothelial and arterial smooth muscle cells in the brain, permits the virus to injure intracranial arteries and burst vessel walls. Furthermore, hemorrhagic strokes may be caused by the cytokine storm that promotes the development of this sickness (Corad-Artal, 2020).

     Furthermore, many neurological illnesses (multiple sclerosis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy [CIDP], myasthenia) have an immunological etiology and may be aggravated or induced by COVID Mao (2020). For all of these causes, the neurologic community must maintain a watchful eye on any potential neurological manifestations that may occur at the outset, during, or after COVID19.

     The present work aimed to detect the neurological complications of definite covid-19 infection patients, and the relation with the onset and evolution of the infection, and compare these data with probable covid-19 infection patient.

PATIENTS AND METHODS

     Multi-center observational retrospective – prospective study, data was attained from the archived files of the selected Covid-19 cases, in addition to patient who was admitted at Isolated ICU and inpatient rooms at Al-Azhar specialized Hospital, PoliceHospitals and Arab contactor medical centers. The duration of the recruiting period was from February 2021 to August 2021.

Inclusion criteria: All participants age above 18 years and may be classified into definite covid-19 infection (positive PCR test) and probable covid-19 infection (clinical, laboratory and chest radiology highly suggestive for covid-19 infection).

Exclusion criteria: Patients below 18 years and patients not fulfilling criteria of diagnosis of covid-19 infection.

Ethical issues: Approval was obtained from the ethical committee of the Faculty of Medicine, Al-AzharUniversity. At the time of the enrolment, written informed consents were obtained from the enrolled patients.

Data collection: I-data related to covid-19 infection: Demographic data including age, sex and BMI, Life style habits, comorbidities, concomitant therapies, clinical characteristics, chest imaging (High resolution thorax CT), laboratory tests for COVID-19 (CBC, CRP, D dimer, serum ferritin, LDH) and outcome of COVID-19 infection.

     II-data related to neurological manifestation; Full neurological history, neurological examination, folstein Mini-MentalState examination, neurological imaging: - CT brain, MRI brain. - Neurophysiological assessment and EEG if needed and CSF study if needed.

Statistical analysis: All data were gathered, tabulated and statistically analyzed.

     Qualitative data were presented as numbers and percentages and tested for in-between groups difference significance with Chi-square test if its assumptions were met, otherwise Fisher exact test or Monte-Carlo method were performed. Quantitative data were presented as mean ± standard deviation and tested for in-between groups difference significance with t-test assuming normality of the data distribution after confirmation of normality tests, otherwise nonparametric Mann Whitney U test was used.

     Logistic regression and discriminant analysis models were built to predict mortality and stroke among Covid-19 patients after ensuring model fitness.

     Receiver operating characteristics (ROC) curves were drawn for each predictive logistic regression model, then the area under the ROC curves was tested against the area obtained by chance which equal 0.5.

     P-value< 0.05 was considered significant.

     Statistical Package for the Social Sciences (SPSS) v 26 was used.

RESULTS

     The study comprised 292 hospitalized individuals who had been diagnosed with covid-19. (263 males + 56 females). Ninety-seven patients had neurological abnormalities (33.2%). The most common neurological outcome was headache, with 44 patients reporting it (16.9%). This headache was usually characterized by bilateral frontal moderate to severe headache.

     The presence of neurological complications was significantly associated with female gender (25.8 vs 15.9%), presence of comorbidities (40.2 vs 9.2%), hypertension (53.6 vs 20.5%), DM (44.3 vs 11.3%), HCV (7.2 vs 0.5%), and history of CVS (7 vs 0%). Patients with neurological manifestations were older than those without neurological affection (Table 1).

Table (1):   Demographic data and baseline factors of the patients

     D-dimer, ferritin, CRP, platelets, when comparing covid-19 patients were with neurological difficulties to covid-19 patients without neurological complications. INR were considerably higher (Table 2).

Table (2):   Demographic data and baseline factors of the patients

Independent samples t-test was used to compare between the two groups assuming normality of the variables' distribution. ¥: Mann Whitney U test was used assuming the distribution was not normal.

     The reported neurological manifestations included headache in 44 patients (16.5%), taste impairment in 22 patients (8.27%), smell impairment in 22 patients (8.27%). Besides the headache, trigeminal neuralgia was detected in 6 patients (2.3%). Seizures occurred in 13 patients (4.9%), 7 of those patients (2.6%) were generalized Tonic-Clonic seizures, three patients (1%) with focal seizures, and 3 patients (1%) with focal to generalized seizures. Cranial nerve affection in 23 patients (8.7%), trigeminal nerve was the most common affected cranial nerve 6 (2.26%). speech abnormalities in 18 patients (6.8%). Thirteen of those patients with dysarthria (4.9%) and 5 presents with dysphasia (1.9%). Cerebrovascular disease (CVD) was found in 26 patients (9.7%), 20 patients with arterial infarction (7.5%), 4 patients were evaluated as hemorrhagic CVD (1.5%), and 2 as venous infarction (0.8%). Guillain-Barre syndrome present in 7 patients (2.6%). CNS infection present in 13 patients (4.9%). six of those patients were evaluated as viral infection (2.1%), 3 patients with bacterial infection (1.1%), and four patients with fungal infection (1.5%) (Table 3).

Table (3):   Covid-19 individuals have a wide range of neurological symptoms

     The neurological defects outcomes between suspected and confirmed Covid-19 patients did not show significant differences, except cranial nerve affection that was higher among confirmed cases. The patients with confirmed Covid-19 infection had higher platelets and ferritin, than suspected cases (Table 4).

Table (4):   Neurological defects among suspected and confirmed Covid-19 patients.

     In the regression model, we found two significant predictors including hypertension and CRP after adjusting for all predictors of the model. Hypertensive patients were 2.8 times more likely to get acute ischemic stroke after Covid-19 infection compared to normotensive patients. Additionally, for every one-point increase in CRP, the odds of stroke increased by 0.4% (Table 5).

Table (5):   Prediction of stroke among Covid-19 patients (suspected and confirmed) using logistic regression model

     In comparison between outcome of covid-19 patients with neurological complications and without neurological complications, we found that 40% of patients with neurological complications have died, while only 12% of patients without neurological complications have died.

DISCUSSION

         Although SARS-CoV-2 is primarily a respiratory virus that causes pneumonia, it also affects the nervous system, severe cases are likely to result in multi-organ dysfunction and failure. Coronaviruses have been shown to infect brain tissue, according to new research, causing a variety of neurological symptoms and problems (Pleasure et al., 2020).

     The primary goal of this study was to describe any neurological complications seen by definite covid-19 infection patients, as well as their relationship to the beginning and progression of the illness, and to compare these findings to those experienced by probable covid-19 infection patients. The recruiting phase lasted for six months.

     Neurological symptoms in hospitalized COVID-19 patients were assessed in this retrospective – prospective investigation. Ninety-seven patients out of 292 were found to have neurological involvement (33.2%). CNS, PNS, and skeletal muscles were among the neurological symptoms. The most prevalent usual symptom was headache (16.5%).

     Our results showed that the presence of neurological complications was significantly associated with female gender, presence of comorbidities, hypertension, DM, HCV, and history of CVS. Patients with neurological manifestations were older than those without neurological affection. In agreement with the study of Essmat (2021), it has been shown that patients with neurological affection were significantly older. In addition, they had significantly higher frequency of previous pulmonary morbidities. However, in the study of (Romagnolo et al., 2020) they noted that Covid-19 patients with neurological disorders are significantly older than those without neurological affection.

     The present study showed that headache is the most common symptom that present in 16.5%, taste impairment in 8.2%, smell impairment in 8.2%, trigeminal neuralgia was detected in 2.3%, seizures occurred in 4.9%, cranial nerve affection in 8.7%, speech abnormalities in 6,8%, cerebrovascular disease (CVD) in 9.7%. four of those patients were evaluated as hemorrhagic CVD (1.5%), and 2 as venous infarction (0.8%). Guillain-Barre syndrome present in 1.5%, CNS infection present in 4.5%, (6 were evaluated as viral infection 2.1%, 1% patients with bacterial infection and 1.4% with fungal infection). However, in the study of Yassin et al. (2021), myalgia was in 22.2%, a problem with taste 19.6%, a problem with odor 18.3%, headache 12.1%, dizziness 11.3%, encephalopathy or cognitive dysfunction 9.4%, and ataxia or abnormal gait 2.1%. Nearly, 2.5% of COVID-19 patients had acute cerebrovascular diseases (CVD); which included ischemic stroke (IS), intracerebral hemorrhage (ICH), and cerebral venous sinus thrombosis (CVT).

     In our study, headache the most common CNS manifestation. Taste and smell impairment were the most common manifestations affecting PNS. The severity of headache was reported to be moderate to severe. Headaches were reported to have tension-type quality and mostly located in the forehead region. Present on average, 2 days from onset of covid-19 symptoms. In the study of Essmat (2021), headache was the most common central CNS manifestation while smell and taste impairment were the commonest manifestations affecting the peripheral nervous system (PNS). These findings were in agreement with the study of Agarwal et al. (2020). However, in the study of Makda et al. (2020), the most common CNS manifestation was dizziness. In one meta-analysis, the commonest symptom affecting the CNS was headache while the commonest symptoms affecting the PNS was smell disturbance in agreement with our conclusions (Bolay et al., 2020). The prevalence of anosmia and ageusia varies greatly between research, ranging from 5% in a China (Mao et al., 2020), to over 80% in an Italian study (Lee et al., 2020). Anosmia was found to be more common in females, younger patients, and those who were not hospitalized in multiple investigations. Anosmia cleared up on its own in most cases within 3 weeks, according to (Lechien and Chiesa-Estomba, 2020).

     Several possible underlying pathophysiological mechanisms have been proposed, particularly for headaches in the forehead and periorbital regions; one possibility is that SARS-CoV-2 has infected the trigeminal nerve terminals in the nasal cavity directly. The participation of endothelial cells of the artery walls with high expression of angiotensin-converting enzyme 2 is another potential underlying mechanism for trigemino-vascular activation (ACE2). The release of pro-inflammatory mediators and cytokines during COVID-19, according to a third theory, may stimulate perivascular trigeminal nerve ends, causing headache (Khatoon et al., 2020).

     Cerebrovascular disease (CVD) was discovered in 26 participants in our investigation (9.7 percent). Four of these patients were diagnosed with hemorrhagic CVD (1.5%) and two with venous infarction (0.8 percent). According to recent research, venous and arterial thromboembolic consequences occur in 5–15 percent of patients with severe COVID-19 during the present pandemic (Speeckaert et al., 2020). On average, 10 days after the onset of covid-19 symptoms, this symptom appears. The reason could be a combination of low-grade DIC and a localized pulmonary thrombotic micro-angiopathy. A considerable rise in D-dimers, elevated fibrinogen levels, mildly prolonged prothrombin time, and slight thrombocytopenia are all symptoms of COVID-19 coagulopathy. Furthermore, patients with COVID-19 have a transitory increase in antiphospholipid antibodies, which could play a role in thrombosis pathogenesis. Another probable cause is cytokine storm, which occurs frequently in COVID-19 patients who are extremely unwell. It inhibits anticoagulant pathways and causes the release of von Willebrand factor, which can lead to thrombosis in these patients (Yaghi et al., 2020).

     In our study, CNS infection present in 4.5%. Symptoms of viral encephalitis started to appear on average 7 days from onset of covid-19 symptoms. Two virus entry routes have been proposed: the first was through the trigeminal and olfactory nerve terminals. The enhanced FLAIR signal in the medial temporal lobe could be explained by infiltration through the olfactory system. Furthermore, signal alterations in the brainstem and thalamus could indicate a central invasion via the trigeminal system (Virhammar, 2020). Increased permeability of the Blood Brain Barrier (BBB) due to high levels of pro-inflammatory cytokines in the CSF could be the second route of viral invasion (Poyiadji and Colleagues, 2020).

     Seizures occurred in 4.9%. Seizures usually started on average 12 days from onset of covid-19 symptoms. However, Essmat (2021) stated that, the frequency of seizures was 18% of patients with neurological affection. Infections of the central nervous system (CNS) and subsequent activation of neuro-inflammatory pathways have been shown to lower the seizure threshold and perhaps facilitate epileptogenesis in some people (Elgamasy et al. 2020). Furthermore, the increase of inflammatory markers linked to SARS-CoV-2 infection could result in local cortical irritation, which could lead to seizures (Hepburn et al., 2020).

     In our study, Guillain-Barre syndrome present in 2.3%. Patients were diagnosed as Guillain-Barre Syndrome (GBS) on average 3 weeks after discharging with COVID-19 and re hospitalized. The possible framework is molecular mimicry, in which the pathogen has epitopes that are identical to those found in peripheral nerve components. Antibodies generated by the host immune system to resist the virus cross-react with peripheral nerves, resulting in neuronal dysfunction (Zubair et al., 2020).

     In the trying to predict all possible predictors of death among the Covid-19 patients. The regression model found three significant predictors including SpO2, hypertension, and d-dimer after adjusting for all predictors of the model. Hypertensive patients were 4.45 times more likely to die after Covid-19 infection compared to normotensive patients. Additionally, for every one-point decrease in oxygen saturation, the odds of death increased by 5%. Neurological involvement in Covid-19 patients carries a bad prognostic indication. It was associated with more frequent need of mechanical ventilation and higher risk of mortality (Shekhar et al., 2020).

     In the trying to predict all possible predictors of stroke among the Covid-19 patients, a multivariate binary logistic regression model found two significant predictors including hypertension and CRP after adjusting for all predictors of the model. Hypertensive patients were 2.8 times more likely to get acute ischemic stroke after Covid-19 infection compared to normotensive patients. Additionally, for every one-point increase in CRP, the odds of stroke increased by 0.4%. However, Essmat's study (2021) stated that the existence of neurological signs was found to be an independent predictor of mortality in the individuals investigated. (Jain et al., 2020) found a link between neurological symptoms and poor outcome in Covid-19 patients. Chua et al. (2020) identified the existence of neurological symptoms as a negative prognostic factor in Covid-19 patients in their systematic review and meta-analysis.

     According to Dorjee et al. (2020), the overall prevalence of death [percentage (95 percent confidence interval)] from COVID-19 was 20% in the United States and Europe, and 23% in China. 85 percent of individuals who died were over 60 years old, 66 percent were men, and 66 percent, 44 percent, 39 percent, 37 percent, and 27 percent, respectively, had hypertension, smoking history, diabetes, heart disease, and chronic kidney disease (CKD). all had increased sRRs of death. The prevalence of hypertension (55 percent), diabetes (33 percent), smoking history (23 percent), and heart disease (17 percent) among COVID-19 hospitalized patients in the United States was significantly higher than that of the general US population, implying that those with comorbidities are more susceptible to infection or disease progression.

     Furthermore, Khamis et al. (2021) indicated that the multivariable logistic regression demonstrated that in-hospital mortality in admitted COVID-19 patients was associated with old age, heart diseases, liver diseases, those with higher ferritin levels, acute respiratory distress syndrome (ARDS), sepsis, and those that had ICU admission.

     The neurological defects between the suspected and confirmed Covid-19 patients did not show significant differences except in cranial nerves affection that was higher in confirmed cases.

CONCLUSION

     Neurological manifestations were communal in Covid-19 patients, with a significant relationship between the presence of neurological manifestations and mortality.

CONSENT FOR PUBLICATION

     I confirm that all authors accept the manuscript for submission.

REFERENCES

1. Agarwal P, Ray S, Madan A and Tyson B (2020): Neurological manifestations in 404 COVID-19 patients in WashingtonState. Journal of Neurology, 1-3.
2. Asadi-Pooya AA and Simani L (2020): Central nervous system manifestations of COVID-19: A systematic review. J Neurol Sci., 413: 116832.
3. Beyrouti R, Adams ME, Benjamin L, Cohen H Farmer SF and Goh YY (2020): Characteristics of ischemic stroke associated with COVID-19. Journal of Neurology, Neurosurgery & Psychiatry, 91(8): 889-891.‏
4. Bolay H, Gül A and Baykan B (2020): COVID‐19 is a Real Headache! Headache: The Journal of Head and Face Pain, 60(7): 1415-1421.‏
5. Chua TH, Xu Z and King NKK (2020): Neurological manifestations in COVID-19: a systematic review and meta-analysis. Brain Injury, 1-20.
6. Corad-Artal FG (2020): Neurological complication of coronavirus and COVID-19. Rev Neurol., 70(9): 311-22.
7. Dorjee K, Kim H, Bonomo E, and Dolma R (2020): Prevalence and predictors of death and severe disease in patients hospitalized due to COVID-19: A comprehensive systematic review and meta-analysis of 77 studies and 38,000 patients. PloS one, 15(12): e0243191.
8. Elgamasy S, Kamel M. G, Ghozy S, Khalil A, Morra M. E, and Islam S. M (2020): First case of focal epilepsy associated with SARS‐coronavirus‐2. Journal of medical virology, 92(10): 2238-2242.‏
9. Essmat, A. (2021): Neurological Manifestations in Egyptian Covid-19 Patients. Al-Azhar International Medical Journal, 1-3.
10. Hepburn M, Mullaguri N, George P, Hantus S, Punia V and Bhimraj A (2020): Acute Symptomatic Seizures in Critically Ill Patients with COVID-19: Is There an Association? Neurocrit Care, 28: 1–5.
11. Jain R, Young M, Dogra S, Kennedy H, Nguyen V, Jones, S and Horwtiz L (2020): COVID-19 related neuroimaging findings: a signal of thromboembolic complications and a strong prognostic marker of poor patient outcome. Journal of the neurological sciences, 414: 116923.‏
12. Khamis F, Memish Z, Al Bahrani M, Al Dowaiki S, Pandak N, Al Bolushi Z and Al-Zakwani I, (2021): Prevalence and predictors of in-hospital mortality of patients hospitalized with COVID-19 infection. Journal of Infection and Public Health. 14(6): 759-765.
13. Khatoon F, Prasad K and Kumar V (2020): Neurological manifestations of COVID-19: available evidences and a new paradigm. Journal of Neurovirology, 26(5):619-30.
14. Lechien J.R. and Chiesa-Estomba C.M (2020): Features of Mild-to-Moderate COVID-19 Patients with Dysphonia. J Voice, 20:30183-1.
15. Lee Y, Min P, Lee S and Kim S.W (2020): Prevalence and Duration of Acute Loss of Smell or Taste in COVID-19 Patients. J Korean Med Sci.,35(18): e174-6.
16. Li YC, Bai WZ and Hashikawa T (2020): The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. Journal of Medical Virology, 92(6): 552-555.‏
17. Makda A, Kumar S, Kumar A, Kumar V and Rizwan A (2020): The Frequency of Neurological Symptoms in COVID-19 Patients at a TertiaryCareHospital in Pakistan. Cureus, 12(9): e10360-3.
18. Mao L, Wang M, Chen S, He Q, Chang J, Hong, C and Hu B (2020): Neurological manifestations of hospitalized patients with COVID-19 inWuhan, China: a retrospective case series study, 1-25.
19. Obaidi MMJ, Bahadoran A, Wang SM, Manikam R, Raju CS and Sekaran SD (2020): Disruption of the blood brain barrier is vital property of neurotropic viral infection of the central nervous system. Act Virol: 62(1):16-27.
20. Pleasure SJ, Green AJ and Josephson SA (2020): The spectrum of neurologic disease in the severe acute respiratory syndrome coronavirus 2 pandemic infections: neurologists move to the frontlines: neurologists move to the frontlines. JAMA Neurol., 77(6):679–80.
21. Poyiadji N, Shahin G, Noujaim D, Stone M, Patel S and Griffith B (2020): COVID-19-associated acute hemorrhagic necrotizing encephalopathy: Imaging Features. Radiology, 296 (2): E119–E120, S.
22. Romagnolo A, Balestrino R, Imbalzano G, Ciccone G, Riccardini F, Artusi C.A and Lopiano L (2021): Neurological comorbidity and severity of COVID-19. Journal of Neurology, 268(3): 762-769.‏
23. Shekhar R, Sheikh AB, Suriya SS, Upadhyay S and Zafar A (2020): Neurological Complications Among Native Americans with COVID-19: Our Experience at a TertiaryCareAcademicHospital in the U.S. Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association, 29(12):105260-8.
24. South A.M, Tomlinson L, Edmonston D, Hiremath S and Sparks M.A (2020): Controversies of renin–angiotensin system inhibition during the COVID-19 pandemic. Nature Reviews Nephrology, 16(6): 305-307.‏
25. Speeckaert M.M, Speeckaert R and Delanghe J.R (2020): Potential underlying mechanisms of cerebral venous thrombosis associated with COVID-19. J Neuroradiol., (20):30206-6.
26. Virhammar J, Kumlien E, Fällmar D, Frithiof R, Jackmann S and Sköld M.K (2020): Acute necrotizing encephalopathy with SARS-CoV-2 RNA confirmed in cerebrospinal fluid, Neurology, 95(10): 445-449.‏
27. Yaghi S, Ishida K, Torres J, Mac Grory B, Raz E and Humbert K (2020): SARS2-CoV-2 and Stroke in a New York Healthcare System. Stroke. 51(7):2002–2011.
28. Yassin A, Nawaiseh M, Shaban A, Alsherbini K, El-Salem K, Soudah O and Abu-Rub M (2021): Neurological manifestations and complications of coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis. BMC Neurology, 21(1): 1-17.
29. Zubair A.S, McAlpine L.S, Gardin T, Farhadian S, Kuruvilla D.E, and Spudich S (2020): Neuropathogenesis and neurologic manifestations of the coronaviruses in the age of coronavirus disease 2019: a review. JAMA neurology, 77(8): 1018-1027.‏