COVID-19 Encephalopathy with Se vere Neu ro log i cal Symp toms: A Clin i cal Case Pre sen ta tion with Lit er a ture Re view

in some se verely ill patients.

fec tion are of an ex tremely wide spec trum, rang ing from asymp tom atic to acute re spi ra tory, re nal or other or gan fail ure.The most com mon symp toms are fe ver, cough, short ness of breath, head ache and mus cle aches, nau sea, ab dom i nal pain, and di ar rhea [3].It is es ti mated that approx i mately 50% of pa tients with COVID-19 in fec tion may have neu ro log i cal symp toms [4].One of the no ta ble neu ro log i cal com pli ca tions is encephalopathy.Acute encephalopathy is a non-spe cific term used to de scribe an acute dis or der of the brain that oc curs clin i cally as a change in the level of con scious ness [5].Most re cent stud ies have shown that up to 36% of hos pi tal ized pa tients with COVID-19 ex pe ri ence encephalopathy symp toms such as con fu sion, de lir ium, or som no lence [6].Some pa tients may ex pe ri ence ad di tional symp toms such as cog ni tive or mem ory im pair ment, con vul sions, head aches, incoordination, or myoclonias [4,6].The pathogenesis of COVID-19 encephalopathy may be multifactorial.Currently, most of the data sug gest hypoxic, met a bolic damage caused by the cytokine storm as well as char ac ter is tics of the vi rus's own neurotropism.
In this ar ti cle, we pres ent a rare clin i cal case in which a young pa tient di ag nosed with COVID-19 in fec tion with mild pri mary re spi ra tory symp toms pro gressed and de veloped new neu ro log i cal symp toms.COVID-19 encephalopathy was di ag nosed af ter a de tailed ex am i na tion and exclu sion of other pos si ble causes.

CASE RE PORT
On May 12, 2021, a 37-year-old man ar rived at the emergency unit for in fec tious dis eases com plain ing of dou ble vi sion, diz zi ness, im paired gait and mem ory; the per son could not re mem ber the day's events or the ex act date.The pa tient's anamnesis showed that on May 2, 2021, he was de ter mined as COVID-19 pos i tive.At that time, blood tests showed a mod er ate in crease in C-re ac tive pro tein (16.5 mg/L) and pul mo nary ra di og ra phy re vealed bi lat eral vi ral pneu mo nia but with a sta ble course, so the pa tient was treated and iso lated at home.The pa tient had pri mary ar terial hy per ten sion, ir reg u larly used antihypertensive drugs, and had no other chronic con di tions.There was no al co hol or drug use, no tick bites were ob served.On May 8, new symp toms ap peared -dou ble vi sion, mem ory im pair ment, the pa tient did not feel like him self, it be came dif fi cult to walk and talk.On May 12, the pa tient felt a fur ther wors ening of his over all con di tion and there fore sought med i cal at ten tion.
In the emer gency unit, the pa tient's blood tests showed el e vated cytolytic liver en zymes (ALT 127 U/L), while other tests were within nor mal range.The pa tient was exam ined by a neu rol o gist, he was par tially ori ented in place and time (did not know the ex act date, nor events of the day, nor where he ar rived), showed signs of dysarthric speech, and had dou ble vi sion.No ob vi ous pa re sis and sensory dis tur bances were ob served, but dur ing the Romberg test, the pa tient was un sta ble, his gait was ataxic, he spread his legs wide when walk ing, and could not walk with out as sis tance or per form limb co or di na tion tests ac cu rately.No acute ab nor mal i ties were ob served af ter ur gent head computered to mog ra phy (CT).The pa tient was hos pi talized for a more de tailed ex am i na tion for acute fo cal neu rolog i cal symp toms.Dur ing hos pi tal iza tion, the pa tient under went a lum bar punc ture, his cerebrospinal fluid (CSF) was ex am ined (leu ko cytes 6/µL, pro tein 0.526 g/L) and head mag netic res o nance im ag ing (MRI) with MRI angiography was per formed.The ob tained im ages were eval u ated for the pos si bil ity of dif fuse changes in the white mat ter (Fig. 1), it was rec om mended to re peat the vi sual exam i na tion, but no sig nif i cant changes were found af ter repeated im ag ing.
To ex clude a pos si ble au to im mune pro cess, mo saic stud ies of au to im mune en ceph a li tis were per formed with a neg a tive re sult.Anti-neuronal an ti bod ies were tested, posi tive (++) non-spe cific anti-amphiphysin was de tected, other an ti bod ies were neg a tive.An ti bod ies to HIV and tick-borne en ceph a li tis were also neg a tive.Dur ing in patient treat ment, the pa tient un der went re peated elec tro enceph a log ra phy (EEG) -the find ings sug gested gen eral changes in bioelectrical ac tiv ity (pos si bly encephalopathic) with un sta ble lateralization in both the left and right fron tal-tem po ral ar eas, reg u lar al pha ac tiv ity, re cur rent syn chro nized in ter mit tent theta-delta ac tiv ity; epileptiform ac tiv ity was not re corded (Fig. 2).
Due to the per sis tent dis ori en ta tion and emo tional lability, the pa tient was con sulted by a psy chi a trist, however, men tal dis or ders were con sid ered to be sec ond ary, caused by a neu ro log i cal dis ease.Af ter a de tailed ex am i nation of the pa tient, an in ter dis ci plin ary med i cal concilium was held which con cluded that the di ag no sis of COVID-19 encephalopathy was con firmed by ex clud ing ischemic, auto im mune, and toxic encephalopathies.Since there is no spe cific treat ment for this dis ease, the pa tient was given symp tom atic treat ment.Dur ing the course of treat ment, the pa tient's con di tion im proved -mem ory im pair ment regressed, co or di na tion im proved.The pa tient could walk with the help of walk ing aids, how ever, dur ing the Romberg test, he re mained un sta ble, anx i ety and decreased phys i cal ca pac ity were also ob served.In the absence of biopsychosocial func tion, the pa tient con tin ued re ha bil i ta tion treat ment af ter which he be came fully mobile and was dis charged home with a Barthel score of 95 and MMSE score of 30.
In the next sec tion, we will dis cuss pos si ble the o ries of the pathogenesis of COVID-19 encephalopathy, clin i cal man i fes ta tions, rec om mended di ag nos tic tests and in terpre ta tion of find ings, treat ment op tions, and dis ease progno sis.

PATHOGENESIS
The pathogenesis of COVID-19 encephalopathy may be multifactorial.Neu ro log i cal com pli ca tions are thought to be caused by both the di rect ef fects of the vi rus to the nervous sys tem and the sys temic re sponse of the or gan ism to the in fec tion [7].The vi rus is cur rently known to cause a cytokine storm syn drome which is char ac ter ized by high pro duc tion of anti-in flam ma tory mark ers such as tu mor ne cro sis fac tor al pha (TNF al pha), interleukin-6 (IL-6), and interleukin-1beta (IL-1b) [8].The sys temic in flam matory re sponse can lead to the in creased blood-brain bar rier per me abil ity, al low ing pe riph eral cytokines to en ter the cen tral ner vous sys tem (CNS).High lev els of cir cu lat ing anti-in flam ma tory cytokines can cause a change in the state of con scious ness.In ad di tion to the cytokine storm, hypoxia and met a bolic dis tur bances are also caused which dis rupt the nor mal func tion ing of the brain [9].Coronavirus has also been shown to have neurotropism through the renin-an gio ten sin sys tem [10].The sur face of the SARS-CoV-2 vi rus con tains spike pro teins the vi rus uses to bind to an gio ten sin-con vert ing en zyme 2 (ACE2) re ceptors in host cells.In hu mans, ACE2 re cep tors are found in the cells of var i ous or gans, in clud ing the ner vous sys tem and skel e tal mus cles, and play an im por tant role in both reg u lat ing blood pres sure and mech a nisms of ath ero sclero sis.One of the pos si ble mech a nisms of neurotropism is the di rect spread of the vi rus through the blood-brain barrier via ACE2 re cep tors lo cated in the cerebrovascular endo the lial cells [11].By bind ing to the ACE2 re cep tors, SARS-CoV-2 vi rus can dam age vas cu lar en do the lial cells by im pair ing mi to chon drial func tion and en do the lial ni tric ox ide synthetase ac tiv ity, lead ing to sec ond ary ef fects on 145 COVID-19 Encephalopathy with Se vere Neu ro log i cal Symp toms: A Clin i cal Case Pre sen ta tion with Lit er a ture Re view Fig. 2. Elec tro en ceph a lo gram of the pa tient shows gen eral changes in bioelectrical ac tiv ity and re cur rent syn chro nized in termit tent theta-delta ac tiv ity the car dio vas cu lar and cerebrovascular sys tems [7].Another pos si ble mech a nism for SARS-CoV-2 en try into the CNS is through ol fac tory neu rons, given that one of the first signs of dam age to the CNS is anosmia [11].The unique an a tom i cal struc ture of the ol fac tory nerves and the ol fac tory bulb in the na sal cav ity and an te rior part of the brain be comes a chan nel be tween the na sal ep i the lium and the CNS [12] which may be a di rect path way for the spread of SARS-CoV-2 vi rus.Post-mor tem histological brain sam ples sug gest that there is cur rently more ev i dence that CNS dam age may be caused by the sys temic in flam ma tory re sponse, ischemic changes due to sys temic hypoxia, lo cal vas cu lar en do the lial dam age or throm bo sis and toxic effects of me tab o lites than by di rect ex po sure to the vi rus itself [13].

CLIN I CAL SYMP TOMS
Encephalopathy is more com mon in pa tients with se vere COVID-19 treated in the in ten sive care unit.In a study of 509 hos pi tal ized COVID-19 pa tients, 31.8% were di agnosed with COVID-19 encephalopathy [5].The study found that encephalopathy is more com mon in el derly patients.Risk fac tors for encephalopathy in cluded se vere COVID-19, shorter time to on set of symp toms, ad ja cent neu ro log i cal dis or ders, his tory of chronic dis ease, male gen der, smok ing, and obe sity [5].
Encephalopathy may also be a ma jor and one of the first symp toms of COVID-19.Of 817 pa tients di ag nosed with COVID-19 in fec tion, 28% had encephalopathy.Among these pa tients, 16% had a change in con scious ness as the main symp tom and 37% had no typ i cal symp toms of COVID-19 such as fe ver or dyspnoea [14].
COVID-19 encephalopathy is char ac ter ized by dif fuse brain dys func tion, usu ally man i fested by changes in the level of con scious ness, rang ing from con fu sion and de lusional symp toms to som no lence or deep coma [15].Patients with encephalopathy may also ex pe ri ence ad ja cent clin i cal symp toms such as con vul sions, head ache, extrapyramidal symp toms, or incoordination [7].
It is worth not ing that non-spe cific symp toms such as myalgia, diz zi ness, anosmia, and dysgeusia may be observed in the early stages of the dis ease [8].Based on the anal y sis by Liotta et al., encephalopathy was found to be the third most com monly ob served neu ro log i cal symp tom af ter myalgia and head ache, sig nif i cantly im pair ing overall func tional out comes and in creas ing pa tient mor tal ity [5].

DI AG NO SIS
Spe cific ab nor mal i ties are of ten not found in lab o ra tory or im ag ing tests in pa tients with COVID-19 encephalopathy, how ever, anal y sis of re cent stud ies helps to re veal some pat terns and mod els of changes in tests of pa tients with COVID-19 encephalopathy [7].Liotta et al. showed that blood tests in pa tients with COVID-19 encephalopathy showed higher white blood cell count, el e vated C-re ac tive pro tein, D-dimers, ferritin, and procalcitonin con cen tration than in pa tients with COVID-19 in fec tion with out encephalopathy.Nev er the less, some other stud ies do not re cord sta tis ti cally sig nif i cant changes be tween these groups of pa tients [16].
In case of sus pected encephalopathy, it is rec ommended to per form a lum bar punc ture and CSF ex am i nation as well as an EEG and head MRI to ex clude other pathol o gies that could worsen the state of con scious ness.Infor ma tion on dif fer en tial di ag nos tics is pre sented in the Ta ble.
CSF ex am i na tion find ings in pa tients with COVID-19 encephalopathy are of ten non-spe cific.CSF ex am i na tions in re cent stud ies have re vealed that the ma jor ity of pa tients tested had nor mal white blood cell count, nor mal glu cose and pro tein lev els and in most cases SARS-CoV-2 vi rus was not de tected by a PCR test.[4].Pa tients with el e vated white blood cell count in their CSF should be thor oughly in ves ti gated for en ceph a li tis and other pos si ble in fec tious causes [7].
In pa tients with COVID-19 encephalopathy, EEG abnor mal i ties are of ten found that cor re late with dis ease sever ity and pre-ex ist ing neu ro log i cal dis eases, in clud ing ep i lepsy.Changes in the ac tiv ity of the fron tal part of the brain are usu ally found and are con sid ered to be one of the biomarkers of COVID-19 encephalopathy [17].
In the study by An tony and Haneef, dif fuse de cel er ation of brain ac tiv ity was the most com mon EEG find ing in two-thirds (68.6%) of pa tients.It has been hy poth e sized that EEG al ter ations in the fron tal part of the brain are due 146 G. Baranauskienë, N. Tutlienë, G. Kaubrys Ta ble.Pos si ble eti ol o gies of encephalopathy for dif fer en tial di ag no sis ac cord ing to P. Atluri et al. [13] Toxic encephalopathy Med cines, nar cot ics, toxic chem i cals (lead, mer cury, ar senic) Met a bolic encephalopathy Hepatic or re nal in suf fi ciency, de hy dra tion, elec tro lyte im bal ance, thi a mine de fi ciency Trauma His tory of trau matic brain in jury, re cur rent trauma Encephalopathy of in fec tious or i gin Bac te rial, vi ral or i gin.Prion dis ease, Lyme dis ease encephalopathy, Sal mo nella infection encephalopathy He red i tary encephalopathy Mi to chon drial encephalopathy Au to im mune encephalopathy Hashimoto's encephalopathy Sys temic encephalopathy Caused by hy per ten sion or hypotension, hypoxia or ep i lepsy to di rect vi ral dam age, while dif fuse changes may be due to the in volve ment of a sys temic re sponse pro cess [17].Excess gen er al ized fron tal delta waves, three-phase waves, and smaller al pha and beta wave am pli tudes are also described [18].Sev eral stud ies have shown that for the confir ma tion of COVID-19 encephalopathy, EEG has dem onstrated greater sen si tiv ity com pared to head CT scan or MRI.Epileptiform changes were of ten ob served in patients with out ev i dence of changes in vi sual neu ro log i cal di ag nos tic tests [19].In one study, EEG changes were found in as many as 83% of pa tients with sus pected COVID-19 encephalopathy com pared to 59% de tected on head MRI [20].Data on head MRI fea tures as so ci ated with COVID-19 encephalopathy are cur rently lack ing.One study re viewed head MRI of 190 pa tients with se vere COVID-19 in fection, most of whom had symp toms of encephalopathy.Of these, only 37 pa tients showed changes that could be as soci ated with acute clin i cal symp toms of encephalopathy such as me dial-tem po ral sig nal changes, microhaemorrhages, and multifocal white mat ter dam age seen in dif fusion re stric tion and FLAIR se quences [21].An other study found that about half of vi sual neu ro log i cal di ag nos tic tests that are per formed in peo ple with encephalopathy show acute dis or ders.The most fre quently de tected changes are sym met ri cal multifocal foci of leukoencephalopathy, diffu sion re stric tion changes in volv ing the periventricular and deep white mat ter, as well as signs of microhaemorrhage and leptomeningitis [22].

TREAT MENT
There is no spe cific treat ment for COVID-19 encephalopathy, so treat ment con sists of treat ing the un der ly ing disease and symp tom atic treat ment.Due to the fact that patients di ag nosed with COVID-19 encephalopathy gen erally en coun ter a more acute course of the dis ease, they are more likely to re ceive sup ple men tal ox y gen ther apy and glucocorticoid ther apy [23].Pro phy lac tic antiepileptic ther apy should be con sid ered for pa tients in se vere con dition, who also ex pe ri ence sei zures and im paired conscious ness [24].The role of glucocorticoids or immunomodulatory drugs in the treat ment of pa tients with COVID-19 encephalopathy is not yet fully clear [7].In the case of a sys temic in flam ma tory re sponse, immunomodulatory ther apy with high-dose in tra ve nous corticosteroids (methylprednisolone 500 mg-1 g daily for 5 days) or in tra ve nous immunoglobulins (0.1-0.5 g/kg daily for 5-15 days) is rec om mended [25,26].Re placement plasmapheresis has also been shown to re sult in a faster im prove ment in con scious ness in some pa tients.How ever, glucocorticoids or other immunomodulatory ther a pies should not be con sid ered a stan dard treat ment op tion for pa tients with COVID-19 encephalopathy, as there is still a lack of re search to sup port the ef fi cacy of this treat ment [7].

PROG NO SIS
Encephalopathy is known to be a risk fac tor for poor outcome.Re cent stud ies have shown that pa tients di ag nosed with COVID-19 encephalopathy have a larger num ber of bed-days and worse func tional ca pac ity, with one-third of such pa tients re main ing with neu ro log i cal, mostly cog nitive, dis or ders at the time when the pa tient is dis charged from the hos pi tal [1,27].Pa tients with COVID-19 encephalopathy have a higher 30-day mor tal ity rate than those with COVID-19 with out encephalopathy [5].Although the long-term neu ro log i cal prog no sis of pa tients with COVID-19 encephalopathy is not yet fully un derstood, it has been shown that re sid ual symp toms tend to regress in the ma jor ity of pa tients mon i tored af ter dis charge from the hos pi tal [7].

CON CLU SIONS
Al though the most com monly re ported symp toms of COVID-19 are re spi ra tory symp toms and the dam age they cause, a large pro por tion of pa tients with COVID-19 may have a va ri ety of neu ro log i cal clin i cal symp toms.COVID-19 encephalopathy is com mon in pa tients with severe dis ease pro gres sion, but it can also oc cur as a pri mary symp tom in peo ple of all ages.COVID-19 encephalopathy is a di ag no sis of ex clu sion, there fore, to con firm this pathol ogy, a de tailed ex am i na tion of the pa tient and ex clusion of other dis eases are re quired.There is no spe cific treat ment for the dis ease, and treat ment with glucocorticoids or immunomodulatory ther apy is rec ommended to be in di vid u al ized de pend ing on the clin i cal sit ua tion.This ar ti cle de scribes a clin i cal case of the pa tient with COVID-19 encephalopathy.It is im por tant to note that the pa tient was of young age, had mild ini tial symptoms of the coronavirus in fec tion, and was be ing treated at home.The pa tient also did not have clear risk fac tors such as comorbidities, immunosuppression, or harm ful hab its that could have in creased the risk of de vel op ing COVID-19 encephalopathy.The aim of this ar ti cle is to reveal that even pa tients with a mild form of COVID-19 infec tion may ex pe ri ence symp toms of encephalopathy, there fore, a de tailed ex am i na tion of pa tients with acute neu ro log i cal symp toms in COVID-19 in fec tion is required.
nuo simp to mø at si ra di mo iki hos pi ta li za vi mo, lë ti nës li gos.Iðskir ti niais at ve jais en ce fa lo pa ti ja ga li bû ti anks ty vas ar net gi pagrin di nis COVID-19 simp to mas ir jau niems pa cien tams.Su COVID-19 su si ju sios en ce fa lo pa ti jos pa to ge ne zë në ra vi sið kai aið ki.Ta èiau la biau siai ti kë ti na etio lo gi ja yra dau gia fak to ri nësis te mi nës li gos at sa kas, uþ de gi mas, ko a gu lo pa ti ja, tie sio gi në viru so neu roin va zi ja, en do te li tas ir gal bût po in fek ci niai au to imu niniai me cha niz mai.Pa cien tams, ku riems áta ria mas sà mo nës ly gio po ky tis, nu lem tas ko ro na vi ru so in fek ci jos, re ko men duo ja ma atlik ti gal vos sme ge nø skys èio (GSS) ið ty ri mà, vaiz di nius gal vos ty ri mus, pir mu mà su tei kiant gal vos mag ne ti nio re zo nan so ty rimui (MRT), taip pat elek tro en ce fa log ra fi jà (EEG).Ver ta pa minë ti, kad, at lie kant la bo ra to ri nius ar vaiz di nius ty ri mus, en ce fa lopa ti ja ser gan tiems pa cien tams spe ci fi niø pa ki ti mø daþ nai ras ti ne pa vyks ta.At lik tuo se ty ri muo se lik vo ro ana li zë pa ro dë, kad cito zës daþ niau siai në ra ran da ma ar ba ji bû na la bai ne þy mi, bû dinga nor ma li bal ty mo kon cen tra ci ja.Svar bu tai, kad SARS-CoV-2 lik vo re ap tin ka ma tik pa vie niais at ve jais.Nors daþ nai EEG yra nor ma li, COVID-19 ser gan tiems pa cien tams nu sta to mi ir spe cifi niai en ce fa lo pa ti niai EEG pa ki ti mai -tai per tek li nës ge ne ra lizuo tos fron ta li nës del ta ban gos, tri fa zës ban gos ir ma þes nës al fa ir be ta ban gø am pli tu dës.MRT ap ra ðy tas neu ro vi zu a li niø anoma li jø spek tras, daþ niau siai ran da mi pa ki ti mai -leu ko en ce fa lopa ti jos þi di niai, di fu zi jos re strik ci jos po ky èiai bal to jo je, re tai ir pil ko jo je me dþia go je, mik ro he mo ra gi jos ir lep to me nin gi to po þymiai.COVID-19 en ce fa lo pa ti jos gy dy mas ap ima pa lai ko mà jà prie þiû rà ir simp to mi ná gy dy mà.Kai ku rie at lik ti ty ri mai at skleidþia, kad, ski riant imu ni nës mo du lia ci jos te ra pi jà, áskai tant di deliø do ziø kor ti kos te roi dus ir in tra ve ni nius imu nog lo bu li nus, kai ku riems sun kiai ser gan tiems pa cien tams pa sie kia mi ge ri re zul tatai.

Fig. 1 .
Fig. 1.Mag netic res o nance im ag ing of the head: slight dif fuse changes in the white mat ter are ob served in the FLAIR se quence Encephalopathy with Se vere Neu ro log i cal Symp toms: A Clin i cal Case Pre sen ta tion with Lit er a ture Re view