Acute Ce re bral Edema: A Le thal Neu ro log i cal Com pli ca tion in A Pa tient with COVID-19 In fec tion. Case Re port and Lit er a ture Re view

dys func tion, cytokine re lease syn drome, and hypoxic dam age from pul mo nary dys func tion.

shape and had a nor mal body mass in dex (BMI), he was diag nosed with pri mary ar te rial hy per ten sion.The lat ter was ef fec tively con trolled with a fixed dose of an gio ten sincon vert ing en zyme in hib i tor (ACEI) perindopril.The patient de vel oped gen eral fa tigue, fe brile fe ver, and cough.A cou ple of days later he tested pos i tive for SARS-CoV-2 poly mer ase chain re ac tion in a na so pha ryn geal swab test per formed on the out pa tient ba sis.The pa tient was not vacci nated and con tracted the vi rus from one of his un vac cinated fam ily mem bers.Within a few days his symp toms de te ri o rated as his cough in ten si fied and se vere dyspnea pre sented.The am bu lance took him to the emer gency room as the pa tient de vel oped acute re spi ra tory dis tress syn drome (ARDS) with prom i nent tachypnea (the re spi ratory rate was ap prox i mately 22 times per min ute) and desaturation (SpO 2 was 86-88%).Ox y gen ther apy was admin is tered us ing a non-rebreathing mask with ox y gen flow rate of 10 L/min.Chest X-ray re vealed bi lat eral in filtrates (Fig. 1A).Blood tests showed mi nor thrombocytopenia at 102×10 9 /L (ref er ence range: 130-400×10 9 /L) and in creased in flam ma tory mark ers with CRP of 146.3 mg/L (ref er ence range: 0-10 mg/L) and white-cell count of 8.53×10 9 /L (ref er ence range: 4-10×10 9 /L) with neutrophilia (80%).The neutrophil-to-lym pho cyte ra tio was 4. In ad di tion, other prog nos tic mark ers were also poor with ferritin be ing as high as 1892.47 mg/L (ref er ence range: 30-400 mg/L) and the lac tate dehydrogenase (LDH) 702.86 mg/L (ref er ence range: 135-225 mg/L).For fur ther treat ment, the pa tient was ad mit ted to the Covid-19 unit of our hos pi tal.The pa tient was treated with in tra ve nous an tibi ot ics (1.2 g of amoxiclav 3 times a day), dexa meth a sone (8 mg once a day given in tra ve nously), and a pro phy lac tic dose of nadroparin (5700 IU/0.6 ml given sub cu ta neously).As the pa tient had nor mal re nal and liver func tion, the 5-day course of remde sivir was ini ti ated.In flam ma tory mark ers de creased with the course of an ti bi ot ics and an ti -vi ral treat ment, how ever, the se ver ity of re spi ra tory distress pro gressed, thus ox y gen de mand in creased sharply.There upon, the pa tient was started ox y gen ther apy through a re-breath ing mask with a flow rate of 15 L/min.Ar te rial blood gas test de picted se vere hypoxemia with pO2 of 54 mmHg and ar te rial sat u ra tion of 88%.Chest com puted to mog ra phy (CT) was per formed in sus pi cion of pul monary em bo lism, but no fill ing de fects were dis cov ered.CT re vealed a large ex tent of lung dam age, as ground-glass opac i ties char ac ter is tic of COVID-19 were seen in around 80% of the lung tis sue (Fig. 1B).
Sud denly, the med i cal staff found the pa tient in his ward ex pe ri enc ing a sei zure ep i sode.The lat ter was ter minated by 10 mg of di az e pam given in tra ve nously.Af ter the sei zure ep i sode, the pa tient re mained un con scious, re acting to a pain ful stim u lus by bend ing arms up, so the Glasgow Coma Scale (GCS) score at that mo ment was es timated to be 6 ut most (M-4, E-1, S-1).The pu pils were equal in size, re ac tive to light.In creased mus cle tone in the lower ex trem i ties and pos i tive Babinski sign on both sides were also pres ent.Ur gent head CT scan was per formed, which re vealed signs of brain stag na tion, dif fuse ce re bral edema, and subarachnoid hem or rhage (SAH) on both sides (Fig. 2).Due to the ther a peu tic con di tion, signs of brain stag na tion, and loss of dif fer en ti a tion be tween white and grey mat ter, neu ro sur geons did not rec om mend urgent sur gery, there fore, con ser va tive treat ment of brain edema was rec om mended.Shortly af ter, the GCS score de creased to as low as 3 (M-1, E-1, S-1), and for fur ther treat ment, due to pro gress ing ce re bral edema and re spi ratory fail ure, the pa tient was ad mit ted into in ten sive care unit (ICU) where he was im me di ately intubated.Brain stem re flexes on sub se quent clin i cal neu ro log i cal ex am ina tion were ab sent.Given the infaust prog no sis, fur ther treat ment was con sid ered fu tile, and the pa tient died shortly af ter wards.

DIS CUS SION
There are sev eral dif fer ent mech a nisms in volved in COVID-19-as so ci ated dam age to the cen tral ner vous system (CNS), in par tic u lar ac ti va tion of in flam ma tory and throm botic path ways and a di rect vi ral ef fect on the en dothe lium and the pa ren chyma.Around 40% of pa tients with COVID-19 de velop neu ro log i cal symp toms.Ce re bral edema has been de tected in au topsy stud ies of brain tis sue of COVID-19 pa tients [4,5].Sev eral iden ti fied risk fac tors pre dis pose pa tients with COVID-19 for hav ing neu ro log ical com pli ca tions: pa tient age (se verely ill pa tients were sig nif i cantly older (58.2±15 vs. 48.9±14.7 years) and comorbid con di tions, es pe cially hy per ten sion (36.4% vs. 15.1%)[6].
The coronavirus uses an gio ten sin-con vert ing enzyme 2 (ACE-2) re cep tors in the ep i the lial cells of the re spi ra tory and gas tro in tes ti nal tract for pen e tra tion [7,8].
The vi rus can en ter the CNS by hematogenous dis sem i nation (us ing en do the lial ACE-2 re cep tors ex pressed in brain ves sels or cross ing a leaky blood-brain bar rier (BBB) affected by sys tem i cally pro duced cytokines) or by neuronal and ol fac tory path ways [1,7,9,10].More over, the high avail abil ity of ACE-2 re cep tors in the enterocytes cells of the gas tro in tes ti nal tract and the di rect con nec tion of the en teric ner vous sys tem with the brain via the af fer ent endings of the vagus nerve from the lungs pro vides an ad ditional route for the vi rus to en ter the brain [10].
The pos si ble course of the COVID-19 dis ease can be di vided into three "NeuroCovid Stages" based on the analy sis of the po ten tial pathophysiological mech a nisms involved in neu ro log i cal man i fes ta tions of SARS-Cov-2 (Ta ble) [11].
Pa tients in fected with COVID-19 may have a mas sive in flam ma tory re ac tion due to the rapid ac cu mu la tion of T-cells and macrophages re leas ing cytokines into the blood stream, which aim to de stroy the vi rus, re sult ing in cytokine storm syn drome (CSS), char ac ter ized by increased IL-1, IL-2, IL-6, granulocyte-col ony stim u lat ing fac tor, in ter feron-g in duc ible pro tein 10, macrophage inflam ma tory pro tein 1a, and tu mor ne cro sis fac tor (TNF)-a [1,12].This hyperinflammatory re sponse can man i fest with high lev els of C-re ac tive pro tein, coagulopathy (el evated D-dimer lev els, low platelet count, and fibrinogen The re sul tant edema and brain in jury lead to de lir ium, encephalopathy, and/or sei zures.High titers of vi rus occupy a higher por tion of ACE-2 and there fore lev els of an gio ten sin II in crease.Then, height ened pe riph eral vas cu lar re sis tance and hy per ten sion in crease the risk of intracranial hem or rhage.lev els), tis sue dam age (el e vated LDH and alanine aminotransferase and aspartate aminotransferase lev els), macrophage/hepatocyte ac ti va tion (el e vated ferritin levels), and cytopenias (thrombocytopenia and lymphopenia) [1,13].Fur ther more, im mune dysregulation with hyperinflammatory re sponse con trib ute to the dam age of lym phocytes, es pe cially T-lym pho cytes, there fore an in creased neutrophil-to-lym pho cyte ra tio may be pres ent.These labo ra tory biomarkers are used to pre dict dis ease se ver ity.In se vere cases, the cytokine storm re sults in ARDS, char acter ized by a se ri ous short ness of breath and hypoxemia, and is the prin ci pal cause of death [8,[14][15][16].
Based on the clin i cal symp toms and lab o ra tory test results (high level of C-re ac tive pro tein, el e vated D-dimer, LDH, ferritin lev els, low platelet count), our pa tient had a se vere form of COVID-19 in fec tion with CSS.Acute clin ical de te ri o ra tion could be re lated to pathophysiological mech a nisms de scribed in "NeuroCovid Stage" III.De spite this, it re mains un clear whether dif fuse ce re bral edema was the re sult of an oxia in duced by se vere vi ral lung dam age (80% ac cord ing to chest CT scan data) and cytokine storm, or an other cause (pri mary SAH, vasculitis, or en ceph a li tis) be cause ce re bral CT angiography and lum bar punc ture were not per formed due to the poor over all con di tion of the pa tient: he de vel oped re spi ra tory fail ure, which re quired ur gent intubation and ICU ad mis sion.
One of the po ten tial mech a nisms for neu ro log i cal com pli ca tions can be re lated to SARS-CoV-2-in duced ARDS and hypoxia.Nor mal blood ox y gen level is around 95%, and the brain may not re ceive suf fi cient ox y gen if this level falls be low 90% [10].Dif fuse al ve o lar dam age in COVID-19 leads to im paired gas ex change by the re spi ratory sys tem and to gen eral hypoxia.An aer o bic me tab olism in the mi to chon dria of brain cells re sults in ac i do sis.It causes BBB dis rup tion which can con trib ute to CNS compli ca tions: intracerebral vasodilation, brain edema, obstruc tion of ce re bral blood flow.As a re sult of con tin u ous hypoxia, intracranial hy per ten sion can ap pear [1,4,8].This can cause a change in the level of con scious ness and even coma.Brain edema is as sumed to be sec ond ary to the COVID-19-re lated cytokine storm, ARDS, and ei ther leads to the sei zure.In this case, se vere hypoxic brain damage may ex plain rapid clin i cal de te ri o ra tion of our pa tient.On the other hand, an acute sei zure ep i sode can re sult from men in geal ir ri ta tion due to the CNS in fec tion or SAH.Accord ing to sev eral pub li ca tions, SARS-CoV-2 bind ing to the ACE-2 re cep tor may raise blood pres sure in the brain, en hance the per me abil ity of BBB, and in crease the risk of hem or rhage.Hy per ten sion, es pe cially with the pres ence of thrombocytopenia and bleed ing dis or ders, is a fac tor that may con trib ute to ce re bral hem or rhage in pa tients with COVID-19 [17][18][19].In ad di tion, crit i cally ill pa tients with se vere SARS-CoV-2 in fec tion of ten show el e vated lev els of D-dimer and se vere platelet re duc tion, which puts these pa tients at higher risk for acute cerebro vascular events [20].COVID-19 has been as so ci ated with coagulopathies such as dis sem i nated intravascu lar co ag u lation (DIC), thrombocytopenia, el e vated D-dimer, and pro -longed prothrombin time, which can re sult in hem or rhage [21].In our case, the pa tient had a re duced platelet count, and this may be a fac tor pre dis pos ing bleed ing com pli cation.
Vi ral en ceph a li tis and di rect in va sion of the vi rus to the CNS can cause sei zures.The ac cu mu la tion of in flam matory mark ers as so ci ated with SARS-CoV-2 in fec tion, can cause a lo cal cor ti cal ir ri ta tion that pre cip i tates sei zures [1,5,10,14].In crit i cally ill COVID-19 pa tients, met a bolic and elec tro lyte im bal ances, on go ing hypoxia, and in flamma tory/in fec tious pro cesses may con trib ute to sei zure [21].Un for tu nately, in our case, cerebrospinal fluid (CSF) anal y sis in or der to ex clude CNS in fec tion was not performed due to se vere brain edema and SAH.On the other hand, COVID-19 in fec tion has been sug gested as a cause of in fec tious toxic encephalopathy, also known as acute toxic en ceph a li tis.It is a rare type of re vers ible brain dysfunc tion syn drome caused by fac tors such as sys temic toxemia, met a bolic dis or ders, and hypoxia dur ing the pro cess of acute in fec tion and is as so ci ated with ce re bral edema with no ev i dence of in flam ma tion on CSF anal y sis.Patients with a mild form may de velop head ache, dysphoria, or de lir ium, while more se vere forms may lead to dis ori enta tion, pa ral y sis, loss of con scious ness, and even coma [4,5].
More re cently, re vers ible ce re bral vasoconstriction syn drome has been de scribed as one of po ten tial mech anism of CNS in jury in COVID-19 pa tients.En do the lial dys func tion can re sult in microcirculatory vasoconstriction lead ing to pos te rior re vers ible encephalopathy syndrome (PRES).SARS-Cov-2 slows the con ver sion of angio ten sin II to an gio ten sin.Higher lev els of an gio ten sin II are as so ci ated with vasoconstriction and pe riph eral vas cular re sis tance.PRES has been re ported in 10 pa tients with COVID-19 from 8 stud ies and it usu ally pres ents with acute im pair ment of con scious ness, head ache, vi sual distur bance, and sei zures.It is as so ci ated with cor ti cal or subcortical vasogenic edema, in volv ing pre dom i nantly the pa ri etal and oc cip i tal re gions bi lat er ally.In COVID-19, en do the lial dys func tion in com bi na tion with hemodynamic in sta bil ity and im mu no log i cal ac ti va tion with release of cytokines can in crease the vas cu lar per me abil ity in the brain tis sue.Dis rup tion of BBB in these cases may cause vasogenic edema and PRES [21,22].
Fur ther more, SARS-CoV-2-in duced de crease in ACE-2 ac tiv ity can lead to vasoconstriction and dys function of ce re bral autoregulation and, sub se quently, blood pres sure spikes, which can cause ar te rial wall rup ture and hem or rhage [4,21,[23][24][25].Intracranial hem or rhage (includ ing SAH) has been re ported in 0.3-1.2% of pa tients with COVID-19 based on a re view of 9 co hort stud ies (N=13,741 pa tients) [26].In a ret ro spec tive study of 3,403 pa tients who were con firmed pos i tive for SARS-CoV-2 in fec tion, Sawlani et al. re ported that neuroimaging showed ab nor mal i ties in 23% of pa tients: the most con sis tent neuroradiological find ing was microhaemorrhage (60%) while SAH ac counts for only 5% [27].A po ten tial mech a nism for non-aneurysmal SAH may be vasculitis in volv ing the me dium and small-sized ar ter ies in the brain di ag nosed by neuroimaging in pa tients with COVID-19 [28].In an other study, Büttner et al. ret rospec tively an a lyzed brain CT and mag netic res o nance imag ing (MRI) scans of 34 hos pi tal ized COVID-19 pa tients.Patho log i cal find ings were de tected in 38.2% of pa tients.The most com mon find ings were microbleeds (20.6%) and signs of hypoxic brain in jury (11.8%).Fur ther more, cor tical SAH, typ i cal and atyp i cal ce re bral hematomas, ischemic strokes, and gen er al ized brain edema were doc umented.All neuroimaging find ings oc curred in pa tients who were ei ther intubated or treated by extracorporeal mem brane ox y gen a tion (ECMO).Patho log i cal neuroimaging find ings seem to be rel a tively rare in gen eral, but do oc cur in a sub stan tial pro por tion of pa tients with se vere COVID-19 dis ease need ing intubation or ECMO [29].
Only a few clin i cal cases with dif fuse ce re bral edema in COVID-19 pa tients have been re ported.Van den Enden et al. de scribed a case of mas sive and rap idly fa tal ce re bral edema in a 57-year-old pa tient (with out comorbidities) who was ad mit ted to the ICU with se vere ARDS due to COVID-19-in duced bi lat eral pneu mo nia.Af ter 2 weeks at the ICU, with re spi ra tory con di tions im prov ing, the pa tient de vel oped le thal ce re bral edema.The ab sence of histopathological ev i dence or CSF anal y sis com pli cates de termi na tion of a cer tain di ag no sis.There fore, in this case, differ en tial di ag no sis in cludes: (mas sive) ce re bral ve nous sinus throm bo sis, hem or rhagic/necro tizing (vi ral) en ceph ali tis (and thereby de vel op ing re ac tive ce re bral edema), and (mas sive) vasculitis [30].Acute fulminant ce re bral edema was pre vi ously more of ten re ported in chil dren (4 cases of pre vi ously healthy chil dren) with COVID-19.It is a rec ognized phe no type with high mor tal ity both in adults and chil dren usu ally as so ci ated with other vi ral causes [29] as men tioned above.
Ac cord ing to these find ings, ce re bral edema in COVID-19 pa tients may ei ther re sult from di rect vi ral effects on the brain or sec ond ary ef fects due to pul mo nary dis tur bances (hypoxia due to COVID-19 pneu mo nia and ARDS), or from treat ment con se quences (in va sive ven ti lation, ECMO, or var i ous med i ca tions), as well as a com bina tion of these fac tors.
Ap ta ri mas.Ner vø sis te mos pa þei di mà COVID-19 in fek cijos me tu le mia daug pa to fi zio lo gi niø me cha niz mø: ACE-2 recep to riø pa þei di mas, ci to ki nø aud ra, hi pok si ja, krau jo ir sme genø bar je ro funk ci jos su tri ki mas ir be si vys tan tis CNS uþ de gimas.Neu ro lo gi niø simp to mø ið reikð tu mas pri klau so nuo COVID-19 in fek ci jos sun ku mo ir ga li va ri juo ti nuo asimp to mës in fek ci jos ir vë liau at si ran dan èiø neu ro lo gi niø nu si skun di mø iki sun kiø ir le ta liø kom pli ka ci jø.Mû sø ap ra ðy tu at ve ju stai gø CNS pa þei di mà su di fu zi ne sme ge nø ede ma ga li mai lë më SARS-CoV-2 su kel tas krau ja gys liø en do te lio pa þei di mas, ci toki nø aud ra ir imu ni nës sis te mos ak ty va ci jos nu lem tas dau gi nis or ga nø pa þei di mas bei hi pok si ja dël ryð kios plau èiø au di nio disfunk ci jos.

Fig. 1 .
Fig. 1.Chest X-ray on ad mis sion dem on strates bi lat eral pul mo nary in fil trates (A).Chest CT scan show ing typ i cal CT find ings of COVID-19: bi lat eral pe riph eral ground-glass opac i ties in the lungs (B, cir cle).

Acute
Ce re bral Edema: A Le thal Neu ro log i cal Com pli ca tion in A Pa tient with COVID-19 In fec tion.Case Re port and Lit er a ture Re view Ta ble."NeuroCovid Stages" Stage I SARS-Cov-2 bind ing to ACE-2 re cep tors is lim ited to the na sal and gas tro in tes ti nal tract ep i the lial cells.The cytokine storm ac ti vated by the vi rus re mains low and con trolled.Pa tients may have only smell or taste impairments and of ten re cover.Stage II SARS-Cov-2 ac ti vates a strong im mune re sponse with high lev els of cytokines, which in crease the lev els of ferritin, C-re ac tive pro tein, D-dimer.The hypercoagulable state trig gers the for ma tion of blood clots.Im mune re sponse also causes vasculitis in mus cles or CNS.Stage III SARS-Cov-2 cytokine storm dam ages the BBB and re sults in in fil tra tion of in flam ma tory fac tors in the CNS.

Fig. 2 .
Fig. 2. Non con trast head CT scan dem on strates dif fuse ce re bral edema with subarachnoid hem or rhage (A and B).