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Introducere
Pandemiile anterioare de gripa, precum si cele determinate de coronavirusurile SARS-1 si
MERS s-au asociat cu consecinte neuropsihiatrice pe termen lung in populatiile afectate.
Studii recente sustin ipoteza ca si infectia COVID-19, determinata de SARS-CoV2, poate
asocia manifestari neurologice si psihiatrice, chiar de la debut, cu frecventa de 36.4%,
prezentate cu tulburari de gust si miros, cefalee, ameteli, alterarea starii de constienta, ataxie,
convulsii sau accidente vasculare ischemice sau hemoragice.
Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, Chang J, Hong C et al (2020) Neurologic
manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.
JAMA Neurol 77:683. https://doi.org/10.1001/jamaneurol.2020.1127 ,
Manifestarile persistente sau aparute in cursul evolutiei COVID-19 au fost partial grupate in
cadrul sindromului post-COVID, dar influenta asupra sanatatii mintale este inca insuficient
cunoscuta.
Mecanismele fiziopatologice care sa explice leziunile de la nivelul sistemului nervos central
(SNC) in cursul infectiei COVID-19 sunt hipoxia secundara disfunctiei respiratorii,
microtrombozele cerebro-vasculare in contextual leziunilor endoteliale si hipercoagulabilitatii
sistemice, leziunile virale indirecte, de natura imunologica. Ipoteza leziunilor virale directe
este insuficient explicate, dar virusul a fost evidentiat in lichidul cefalorahidian la pacientii
infectati. Virusul poate patrunde in creier pe cale hematogena sau de la nivelul epiteliului
respirator nazal, direct la nivelul SNC, urmand traseul axonal al nervilor olfactivi. Receptorii
ACE2 sunt exprimati la nivelul creierului, mai ales la nivelul trunchiului cerebral (brainstem),
cortexului striat si hipotalamusului, atat de neuroni cat si de celulele gliale, facandu-le
vulnerabile la atasarea SARS-COV-2. Rezultatele unor studii in vitro demonstreaza
capacitatea SARS-COV-2 de a se replica in celulele neuronale.
Baig AM, Khaleeq A, Ali U, Syeda H (2020) Evidence of the COVID-19 virus targeting the
CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS
Chem Neurosci 11:995–998.
Matschke, J., Lütgehetmann, M.,Hagel, C., Sperhake, J. P., Schröder, A. S., Edler, C.,
et al. (2020). Neuropathology of patients with COVID-19 in Germany: a postmortem
case series. Lancet Neurol. 19, 919–929. doi: 10.1016/S1474-4422(20) 30308-2
Leziunile asociate SARS-CoV-2 pot afecta direct substanta cenusie, prin edem si degenerare
neuronala partiala, dar si maduva alba, prin demielinizare.
Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, Liu S, Zhao P et al (2020) Pathological
findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir
Med 8:420–422. https://doi.org/10.1016/S2213-2600(20)30076-X
Zanin L, Saraceno G, Panciani PP, Renisi G, Signorini L, Migliorati K, Fontanella MM
(2020) SARS-CoV-2 can induce brain and spine demyelinating lesions. Acta Neurochir 162:
1491–1494. https://doi.org/10.1007/s00701-020-04374-x
Studiile imagistice au evidentiat modificari RMN la 44% dintre examenele effectuate la
pacienti cu COVID-19, cu semnale FLAIR anormale localizate mai ales cortical, interesand
lobul frontal, parietal, occipital, temporal, cortexul insular si girusul cingulat.
Kandemirli SG, Dogan L, Sarikaya ZT, Kara S,Akinci C,Kaya D, Kaya Y, Yildirim D et al
(2020) BrainMRI findings in patients in the intensive care unit with COVID-19 infection.
Radiology. 297: E232–E235. https://doi.org/10.1148/radiol.2020201697
Tipul evenimentelor neurocognitive in cursul infectiei COVID-19 variaza cu varsta,
predominand tulburarile neuropsihiatrice sub varsta de 60 de ani si tulburarile
cerebrovasculare peste aceasta varsta.
CoroNerve Study Group.Neurological and neuropsychiatric complications of COVID-
19 in 153 patients: a UK-wide surveillance study. Lancet. Published online June 25,
2020 https://doi.org/10.1016/S2215-0366(20)30287-X
Vasile MC, Arbune AA, Lupasteanu G, Vlase CM, Popovici GC, Arbune M. Epidemiologic and
Clinic Characteristics of the First Wave of the COVID-19 Pandemic in Hospitalized Patients
from Galați County. J Clin Med. 2021 Sep 17;10(18):4210. doi: 10.3390/jcm10184210.
Global COVID-19 Clinical Platform Case Report Form (CRF) for Post COVID condition
(Post COVID-19 CRF) [Internet]. 2021 Feb [cited 2023 Dec 6]. Available
from: https://www.who.int/publications/i/item/global-covid-19-clinical-platform-case-report-
form-(crf)-for-post-covid-conditions-(post-covid-19-crf-)
Atat pacientii din grupul COVID-19, cat si cei din grupul de control au fost evaluati prin
metoda chestionarului, utilizand scalele psihometrice MMSE, MoCA si timpul necesar
completarii acestor scale. Evaluarea neurocognitiva s-a facut in trei etape: la baseline (in
timpul spitalizarii pentru pacientii cu COVID-19 sau la data solicitarii primei consultatii non-
COVID-19 in serviciul ambulator), dupa 6 luni si dupa 12 luni.
Primul instrument aplicat pentru măsurarea deficitului cognitiv si monitorizarea schimbărilor
cognitive post-COVID-19 a fost testul MMSE.
Am utilizat versiunea scurta (breve version) a testului “MINI-MENTAL STATE
Examination” (MMSE) constituit din 11 intrebari cu rol de screening a disfunctiilor
cognitive, testand 6 domenii functionale mentale: orientarea in timp si spatiu, atentia si
concentrarea, memoria de scurta durata (recall), abilitatile visuospatiale si abilitatea de a
intelege si de a indeplini instructiunile. Cerintele testului sunt memorarea denumirilor unor
obiecte si repetarea acestora mai tarziu, copyng and drawing, scrierea unei propozitii corecte
gramatical, identificarea corecta a datei, lunii, sezonului, anului si locului in care se afla
pacientul.
Valoarea maxima a scorului este 30, considerand anormale valorile mai mici decat 24
(tulburari cognitive initiale 24-27, cod 1; faza usoara 21-23, cod 2, faza moderata 18-20, cod
3; faza marcata 15-17, cod 4; faza severa 12-16, cod 5; faza grava 0-11, cod 6). Am
cronometrat durata testului, care normal dureaza 5-10 minute.
nterpretare
Scor
MMSE
Stadiul Caracteristici
30
Tulburari
cognitive initiale
Simptome mnezice
21-23
Faza usoara Deficite mnezice si de
gandire conturate
18-20
Faza moderata
0-11
30
Tulburari
cognitive initiale
Simptome mnezice
21-23
Faza moderata
0-11
Figure 1: The frequency of the main clinical symptoms of COVID-19 in hospitalized patients
Durata medie a simptomelor de la debut-internare a fost 5.03±1.24 zile, iar durata medie a
spitalizarii a fost 10.75± 4.08 zile.
Dupa severitate, 71% au avut forme medii de boala si 29% forme severe, cu detresa
respiratorie si/sau sepsis, dar nu au fost cazuri critice. Saturatia oxigenului in aerul expirat
fost sub 91% la 28.5% dintre pacienti, cu valoarea minima de 76%, necesitand administrarea
suplimentara de oxygen minima a pe sonda nazala sau pe masca, dar nici un pacient nu a avut
ventilatie invaziva.
Alte complicatii aparute in timpul spitalizarii pentru COVID-19 au fost hepatitele secundare
(21.2%), diabetul zaharat de novo (10.2%), aritmiile cardiace (1.5%). Rata infectiilor asociate
asistentei medicale cu Clostridioides difficile a fost 4.4%.
Modificarile biologice predominante au fost cresterea raportului neutrofile/limfocite,
cresterea proteinei C reactive, a lactic dehidrogenazei si creatin-kinazei (Table A1).
Table A1: Biological blood characteristics of the hospitalized patients with COVID-19
VN Medie DS Mediana Max Min % val
anormale
Hb 13.91 1.14 13.9 16.9 9.8 14.5%
NL 12026 3854.8 11900 3900 25000 46.7%
N/Ly ≤3 7.36 3.00 6.72 3.11 18.58 100%
PLT 303036 65.01 314000 145000 431000 7.2%
CRP 57.33 49.99 36.42 3.21 164.28 100%
Ac lactic 14.06 6.11 13.86 4.98 35.19 75.2%
ALAT 109.94 198.65 34.19 10.5 1268.38 37.9%
ASAT 100.86 187.06 30.6 10.8 1149.62 36.5%
uree 46.15 10.36 48.53 12.1 78.21 76.6%
creatinina 1.10 0.25 1.07b 0.8 3.1 3%
CK 204.93 138.88 184.22 28.97 847.39 86.9%
LDH 365.98 138.67 347.91 119.49 1381.87 99.3%
feritina 309.61 239.30 264.85 31.67 1200 31.3%
D-Dimeri 1836.124 2556.152 683.29 118.62 10000 55.5%
100
72.26%
90
80
70
55.5%
60
Number of patients
31%
50
40 24.8%
26.2%
30
20 6.5%
10 4%
3.6%
0
A ntib A ntic Corti Immu A ntiv
iotics oagu coste nomo irals
lants roids dulat
ors
Remdesivirum Favipiravirum Lopinavirum Hydroxichlorochine
Table 2: Risk factors of the study group COVID-19 and control group non-COVID-19
In timpul primelor 3 valuri pandemice, frecventa afectarii neurocognitive evaluate prin testele
MMSE si MoCA a avut tendinta de usoara scadere, dar fara diferente semnificative statistic
(Figure 2 a,b).
29
28 a
27
MMSE 0
26
25
24
23
1 2 3
Pandemic wave
30
b
25
MoCA 0
20
15
10
5
0
1 2 3
Pandemic wave
Average±DS 1stWave 2nd Wave 3rd Wave
MMSE 27.17±0.90 26.77±1.36 26.75±1.52
MoCA 25.79±1.62 25.06±2.31 24.53±2.49
Figure 2: The tendency of MMSE (a) and MoCA (b) scores values in the baseline, along the
first three COVID-19 pandemic waves
Scorurile neurocognitive au fost mai sever afectate la barbati decat la femei, cu valori medii
de 24.33±2.65 versus 25.70±1.64 (p<0.001) la MoCA si 26.52±1.46 versus 27.16±1.12
(p=0.004) la MMSE.
Valorile scorurilor MMSE si MoCA la baseline s-au corelat cu nivelul nadirului saturatiei de
oxigen notificate in timpul spitalizarii si necesitatea administrarii de oxigen pe masca sau pe
canula nazala (Figure 3 a, b). Aceasta relatie confirma substratul hypoxic al disfunctiilor
neurocognitive semnalate in cursul infectiei COVID-19.
30 MoCA 0 = 0.359 SpO₂% min - 8.514
25
a
20
MoCA 0
15
10 Correlation Coeff=0.778
5
0
70 75 80 85 90 95 100
SpO₂% min
35
30 b MMSE 0 = 0.174 SpO₂% min + 10.567
25
MMSE 0
20 Correlation
15
10
5
0
70 75 80 85 90 95 100
SpO₂% min
Frecventa anosmiei si a cefaleei au fost mai crescute la pacientii cu scoruri MoCA si MMSE
scazute sub valorile considerate normale, sugerand ca invazia virala a tesutului nervos,
produsa pe calea nervilor olfactivi, influenteaza disfunctia neurocognitiva asociata infectiei
COVID-19 la baseline. Totusi, nu a fost gasita o corelatie semnificativa intre acesti parametri,
dar este posibil ca notificarea acestor simptome sa fie subestimata.
Formele severe de COVID-19 s-au asociat cu semnificativ scoruri mai scazute la baseline
fata de formele medii de boala: 22.36±2.35 versus 26.19±0.79(p<0.001) la testele MoCA;
25.61±1.61 versus 27.39±0.70 (p<0.001) la MMSE.
Discutii
Numarul solicitarilor pentru consultatii neuropsihiatrice a crescut incontestabil in contextual
pandemic, mai ales la persoane care au avut COVID si au fost sanatoase inaintea infectiei.
COVID-19. Totusi, majoritatea acestor cazuri au prezentat simptome usoare sau moderate,
asociate cu deficite in domeniile working memory (WM), set-shifting, divided attention, and
processing speed.
Varatharaj, A., Thomas, N., Ellul, M. A., Davies, N. W. S., Pollak, T. A., Tenorio, E. L., et
al. (2020). Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a
UK-wide surveillance study. Lancet Psychiatry 7, 875–882.
doi: 10.1016/S2215-0366(20)30287-X
O serie de tulburari neurocognitive prelungite sau chiar permanente pot fi Sechele ale
hipoxiei, encefalitei sau accidentelor vasculare aparute in timpul infectiei acute
Conditions such as hypoxia, encephalitis, and stroke (CVA), necesitand monitorizarea pe
termen indelungat.
Solomon IH, Normandin E, Bhattacharyya S, Mukerji SS, Keller K, Ali AS, Adams G,
Hornick JL et al (2020) Neuropathological features of Covid-19. N Engl J Med 383:989–992.
https://doi.org/10.1056/nejmc2019373
Sechelele cronice dupa encefalopatia hipoxica pot evolua de la deficite de atentie si tulburari
de memorie discrete pana la dementa si alterarea psihica grava. Alterarea cerebrala difuza se
poate insoti de alterarea mentala cu delir, tulburari de atentie, concentrare, orientare,
tulburarea ritmului somn/veghe, somnolenta, dar si tulburari de personalitate, de tipul
paranoia, iluzii, halucinatii, agitatie, bizarerii comportamentale. Tulburarile cognitive pot fi
asociate cu sechele localizate in anumite arii corticale, de exemplu in hipocamp – amnezie,
cerebel- alterarea comportamentelor motorii, lobul temporal- tulburari de limbaj si memorie,
lobul parietal – functionalitatea/perceptia vizuo-spatiala, occipital- perceptia vizuala, lobul
frontal – tulburari executive, de personalitate, apraxia, afazie expresiva, tulburari motorii.
Leziunile subcorticale din ganglionii bazali, thalamus. Hipotalamus, amigdala cerebeloasa,
altereaza proiectia corticala, emotiile si functiile autonome, iar tulburarile din trunchiul
cerebral scad atentia si vigilenta. Tulburarile difuze la nivelul substantei able contribuie la
scaderea volumului si conectivitatii retelelor neuronale, contribuind la disfunctii senzoriale
sau motorii si scaderea vitezei proceselor cognitive.
Paniz-Mondolfi A, Bryce C, Grimes Z, Gordon RE, Reidy J, Lednicky J, Sordillo EM,
Fowkes M (2020) Central nervous system involvement by severe acute respiratory syndrome
coronavirus-2 (SARS-CoV-2). J Med Virol 92:699–702
Li J, Long X, Zhang Q, Fang X, Fang F, Lv X, Zhang D, Sun Y et al (2020) Emerging
evidence for neuropsycho-consequences of COVID-19. Curr Neuropharmacol 18.
https://doi.org/10.2174/e1570159x18666200507085335
Bougakov D, Podell K, Goldberg E. Multiple Neuroinvasive Pathways in COVID-19. Mol
Neurobiol. 2021 Feb;58(2):564-575. doi: 10.1007/s12035-020-02152-5.
Aiello, E. N., Fiabane, E., Manera, M. R., Radici, A., Grossi, F., Ottonello, M.,
et al. (2022). Screening for cognitive sequelae of SARS-CoV-2 infection: a
comparison between the Mini-Mental state examination (MMSE) and the
Montreal cognitive assessment (MoCA). Neurol. Sci. 43, 81–84. doi: 10.1007/
s10072-021-05630-3
Patel, R., Savrides, I., Cahalan, C., Doulatani, G., O’Dell, M. W., Toglia, J., et al.
(2021). Cognitive impairment and functional change in COVID-19 patients
undergoing inpatient rehabilitation. Int. J. Rehabil. Res. 44, 285–288. doi: 10.
1097/MRR.0000000000000483
Pilotto, A., Cristillo, V., Cotti Piccinelli, S., Zoppi, N., Bonzi, G., Sattin, D.,
et al. (2021). Long-term neurological manifestations of COVID-19: prevalence
and predictive factors. Neurol. Sci. 42, 4903–4907. doi: 10.1007/s10072-021-05
586-4
In formele moderate, frecventa scorurilor MoCA scazute a variat de la 36% la 60%, dar in
formele cu support respirator BIPAP poate fi char de 94%. Cele mai afectate domenii au fost
viteza de procesare, memoria recenta si pe termen lung, limbajul.
Heyns, A., Dupont, J., Gielen, E., Flamaing, J., Peers, K., Gosselink, R., et al. (2021).
Impact of COVID-19: urging a need for multi-domain assessment of COVID-
19 inpatients. Eur. Geriatr. Med. 12, 741–748. doi: 10.1007/s41999-021-
00486-4
Solaro, C., Gamberini, G., and Masuccio, F. G. (2021). Cognitive impairment in
young COVID-19 patients: the tip of the iceberg? Neurol. Sci. 42, 4865–4866.
doi: 10.1007/s10072-021-05534-2
Alemanno, F., Houdayer, E., Parma, A., Spina, A., Del Forno, A., Scatolini, A., et al.
(2021). COVID-19 cognitive deficits after respiratory assistance in the subacute
phase: a COVID rehabilitation unit experience. PLoS One 16:e0246590. doi:
10.1371/journal.pone.0246590
Aceste date sunt concordante cu rezultatele studiului nostru privind afectarea MoCA la
baseline, a pacientilor sub 60 de ani, cu forme moderate si severe de COVID-19.
Intr-un studiu prospective timp de 12 luni, frecventa valorilor anormale la scorul MoCA a
scazut de la 25% la baseline la 13% dupa 12 luni, comparative cu studiul nostrum, la care
frecventa a scazut de la 34,3% la baseline la 15,3% la 12 luni.
Concluzii
Infectia COVID-19 cu forme medii si severe de boala se insoteste de disfunctie
neurocognitive evidentiate la 25.5% dintre pacienti la testul MMSE si 34.3% la scorul
MoCA. Disfunctiei cognitiva la pacientii cu COVID-19 a fost influentata de sexul masculin,
severitatea infectiei COVID-19, gradul hipoxiei si asocierea anosmiei. Disfunctia cognitiva
globala la pacientii COVID-19 este semnificativa in raport cu grupul martor, si se mentine la
12 luni de la episodul acut. Domeniile cognitive cu cea mai mare si persistenta afectare la
pacientii care au avut COVID-19 sunt viteza de executie, atentia, concentrarea, memoria
recenta, in timp ce alterarea abilitatilor de orientare si functionalitate vizuospatiala s-au
ameliorat in urmatoarele 12 luni post-COVID-19. Corespondenta disfunctiilor cognitive cu
regiunile cerebrale functionale sustine ipoteza afectarii principale a trunchiului cerebral si
ariilor temporale, parieto-occipitale, probabil prin mechanism hypoxic, dar si a substantei
albe, probabil prin demielinzare. Pacientii cu disfunctii neurocognitive persistente post-
COVID-19 necesita evaluare neurologica complexa, pentru diagnosticul precoce al
patologiilor neurologice progressive. Monitorizarea neurocognitiva post-COVID necesita
dezvoltarea unor programe accesibile pentru investigatii, diagnostic complex, reabilitare si
cercetare.
References;
https://www.mdpi.com/journal/biomedicines/special_issues/Immunology_COVID_2
Aiello, E. N., Fiabane, E., Manera, M. R., Radici, A., Grossi, F., Ottonello, M., Pain, D., &
Pistarini, C. (2022). Screening for cognitive sequelae of SARS-CoV-2 infection: a
comparison between the Mini-Mental State Examination (MMSE) and the Montreal
Cognitive Assessment (MoCA). Neurological Sciences, 43(1), 81–84.
https://doi.org/10.1007/S10072-021-05630-3/TABLES/2
Garrigues, E., Janvier, P., Kherabi, Y., le Bot, A., Hamon, A., Gouze, H., Doucet, L.,
Berkani, S., Oliosi, E., Mallart, E., Corre, F., Zarrouk, V., Moyer, J. D., Galy, A., Honsel, V.,
Fantin, B., & Nguyen, Y. (2020). Post-discharge persistent symptoms and health-related
quality of life after hospitalization for COVID-19. Journal of Infection, 81(6), e4–e6.
https://doi.org/10.1016/J.JINF.2020.08.029
Sarah H. Gulick, PsyD; Steven Mandel, MD; Edward A. Maitz, PhD, ABN; and Christopher
R. Brigham, MD, MMS. Special Report: Cognitive Screening After COVID-19 - Practical
Neurology. (n.d.). Retrieved February 11, 2023, from
https://practicalneurology.com/articles/2021-may/special-report-cognitive-screening-after-
covid-19/pdf
The MoCA classified 41% as cognitively impaired who were not detected with the MMSE.27 In a
study comparing the MoCA and the MMSE 1 week and 3 months after stroke in a group of 60 people
(mean age 72), the MoCA scores were lower and the MMSE skewed more towards test ceiling (the
point at which items become too difficult to answer). In this study, the MoCA was more sensitive
than the MMSE, but the MoCA had poorer specificity. The MMSE was also found to be valid in this
population.28
Cameron J, Worrall-Carter L, Page K, Stewart S, Ski CF. Screening for mild cognitive impairment in
patients with heart failure: Montreal cognitive assessment versus mini mental state exam. Eur J
Cardiovasc Nurs. 2013;12(3):252-260. 28. Cumming TB, Churilov L, Linden T, Bernhardt J. Montreal
Cognitive Assessment and Mini-Mental State Examination are both valid cognitive tools in stroke.
Acta Neurol Scand. 2013;128(2):122-129
Tsiakiri, A., Vlotinou, P., Terzoudi, A., Heliopoulos, I., & Vadikolias, K. (2022). Cognitive,
Functional, and Emotional Changes During the COVID-19 Pandemic in Greek Patients with
Neurocognitive Disorders. Journal of Alzheimer’s Disease, 88, 537–547.
https://doi.org/10.3233/JAD-220118
Houben, S., & Bonnechère, B. (2022). The Impact of COVID-19 Infection on Cognitive
Function and the Implication for Rehabilitation: A Systematic Review and Meta-Analysis.
International Journal of Environmental Research and Public Health, 19(13).
https://doi.org/10.3390/IJERPH19137748
Khanna SK, Khanna N, Malav MK, Bayad HC, Sood A, Abraham L. Profiling cognitive
impairment in mild COVID-19 patients: A case-control study at a secondary healthcare
centre in the hilly region of North India. Ann Indian Acad Neurol 2022;25:1099-103
A case-control study was conducted at a secondary care hospital in the hilly terrain of North
India from April 2020 to March 2022. The hospital is located at an altitude of 2202 meters
(7224 ft). All the consenting RT-PCR positive mild COVID-19 patients, irrespective of
gender, between 18 and 60 years of age were included as cases (Group A). Since this study
was conducted at a moderate-high altitude, the low environmental oxygen concentration
could have been a confounding factor. Therefore, we selected a control group (Group B) of
healthy non-COVID (who never contracted COVID-19 infection) individuals from the same
locality.[18] To avoid sample bias, the controls were matched for age, gender, and education.
Exclusion criteria for both cohorts were a history of neurological or psychiatric disorders
before the COVID-19 pandemic, drug abuse or drug dependence, and hearing or visual
impairments. Clinical records of all mild COVID-19 patients, containing detailed clinical
history, examination, and lab workup were analyzed.
Cognitive assessment
Initially, the cognitive assessment of Group A participants was done using the Montreal
Cognitive Assessment (MoCA)[19] and Mini-Mental State Examination (MMSE).[20] The
MoCA mainly includes extensive neuropsychological assessment of visuospatial
skills/executive functions, attention, memory, and language. MoCA and MMSE for Group A
were conducted at least 6 months after recovery from COVID-19 infection. The results of
both tests were compared to find a better screening tool. Depending on this comparison, we
chose the test which was found to be superior in the assessment of Group B [Figure 1].