Psy cho sis as an Iso lated Man i fes ta tion of COVID-19 in Non-De mented Pa tients with Par kin son’s Dis ease: Clin i cal Cases and Lit er a ture Re view

se quence of COVID-19 with out any other clin i cal signs of in fec tion; no re cur rent psy chotic dis or ders were reg is tered dur ing the one-year fol low-up. The dis cus sion on di ag nos tic dif fi cul ties and treat ment op tions in cludes a re view of the lit er a ture. We rec om mend to per form re verse tran - scrip tion poly mer ase chain re ac tion (RT-PCR) swab test ing for SARS-CoV-2 in pa tients with Par kin son’s dis ease who de velop acute psychosis.

Un doubt edly, pa tients with COVID-19 may ex pe rience psy chi at ric symp toms, in clud ing psy cho sis [1][2][3], but to date there is a lack of spe cific ev i dence from clin i cal trials.Chaudhary AMD et al. re cently pub lished a sys tem atic re view to eval u ate the oc cur rence of new-on set psy cho sis or ex ac er ba tion of clin i cally sta ble psy cho sis dur ing COVID-19; as the au thors could not find any spe cific clin ical tri als, they in cluded 57 unique case re ports and case series [3].The mean age of the pa tients at on set of psy chotic symp toms was 43.4 years for men and 40.3 years for women; it is im por tant to note that 69% of these pa tients had no prior his tory of psy chi at ric dis or ders [3].The clinical pic ture was typ i cal: most pa tients had mild COVID-19-re lated symp toms and the most com monly reported psy chotic symp toms were de lu sions and hal lu ci nations; the course of psy cho sis in COVID-19 was con sis tent with the clin i cal se ver ity of COVID-19 and mostly fa vorable as psy chotic symp toms im proved sig nif i cantly or resolved com pletely in 72% of pa tients [3].
Pa tients with neurodegenerative dis or ders such as Parkin son's dis ease (PD) ap pear to be more vul ner a ble to men tal health dis or ders such as stress, de pres sion, anx i ety, or wors en ing qual ity of life dur ing COVID-19 lockdown.Nabizadeh F et al. pub lished a sys tem atic re view of 21 studies with a to tal of 5236 PD cases on psy cho log i cal out comes of COVID-19 [2]: most of the stud ies dem onstrated the in crease of the se ver ity or the prev a lence of psychi at ric dis tur bance due to the COVID-19 pan demic in PD pa tients (the prev a lence of anx i ety was 14.0-66.5%,depres sion 0-50%, ap a thy 0-50%, im pulse con trol dis or ders 44%, sleep prob lems 35.4-68.9%),but they did not cover psy chotic events.There is still a lack of stud ies on the preva lence of psy chotic events in PD pa tients with COVID-19.Psy chotic dis or ders in pa tients with PD are usu ally as so ciated with poor cog ni tive per for mance, comorbidities, and changes in treat ment re gime.De spite the ac knowl edgement of cog ni tive def i cit as a main risk fac tor for psy cho sis in PD, it has been re ported that mi nor (il lu sions) and even ma jor (hal lu ci na tions and de lu sions) psy chotic events can be ex pe ri enced by non-de mented PD pa tients.Each case of psy chotic dis or der in PD pa tients is al ways a di ag nos tic and ther a peu tic chal lenge for cli ni cians as it re quires specific man age ment de ci sions to stop the psy cho sis, to prevent its re cur rence and at the same time to avoid de te ri o ration of the pa tient's mo tor and non-mo tor func tion ing.
In this ar ti cle, we pres ent two clin i cal cases of non-demented pa tients with PD who de vel oped psy cho sis as a con se quence of COVID-19 with out any other clin i cal signs of in fec tion.The pa tients were on sta ble antiparkinso nian med i ca tion, had no sig nif i cant pre vi ous psychi at ric dis tur bances, and were fully vac ci nated against SARS-CoV-2.No re cur rent psy chotic dis or ders were regis tered in the pa tients dur ing the avail able one-year follow-up pe riod.

RE PORT ON CLIN I CAL CASES
Both pa tients were treated in the out pa tient de part ment of Vilnius Uni ver sity Hos pi tal Santaros Klinikos (VUHSK).Signed con sent for the use of med i cal data for the clin i cal re port was ob tained from the pa tients.

CASE 1
A 70-year-old man was di ag nosed with PD 10 years ago when he re ported ki netic tremor and mild slow ness of the right hand.At the ini tial ex am i na tion in 2012, there were no com plaints of smell, taste, bowel move ments, REM behav ior or im pulse con trol.Fam ily his tory was neg a tive.Brain mag netic res o nance im ag ing (MRI) was nor mal.The di ag no sis of PD, stage 1 ac cord ing to the Hoehn-Yahr scale, was con firmed by a pos i tive sin gle-pho ton emis sion com puted to mog ra phy (SPECT) scan with ioflupane [I-123], which re vealed re duced radiotracer up take in the putaminal ar eas, with the left side more af fected; the putamen/nu cleus caudatus ra tio was 0.74.The pa tient was pre scribed ropinirole, which was grad u ally ti trated up to 16 mg/day for symp tom atic ef fect and was well tol er ated.Propranolol 80 mg/day was added to con trol ki netic tremor.The con com i tant dis eases were pri mary ar te rial hy per ten sion (treated with ramipril 10 mg/day) and chronic lum bar radiculopathy in the right (treated with phys io ther apy and non-ste roid anti-in flam ma tory med i cations dur ing ex ac er ba tions).The pa tient was con sulted at the VUH SK reg u larly, not less than twice a year.As mo tor symp toms gen er al ized over two years, rasagiline 1 mg/day was added, fol lowed by amantadine 200 mg/day.Over the next 2 years, the dose of amantadine was in creased to 400 mg/day.The pa tient was mon i tored for im pulse control, sleep qual ity and day time alert ness, cog ni tive, mo tor and psy chi at ric symp toms.He re ported no im pulse con trol dis or der (ICD), sud den sleep at tacks or day time som nolence, no psy chotic events or mood dis or ders.The pa tient worked full-time job as a tech ni cal su per vi sor and re ported ep i sodic in som nia and anx i ety at sev eral con sul ta tions, which were re lieved by low doses of bromasepam.Amantadine was dis con tin ued and re in tro duced sev eral times be cause of pro gres sion of mo tor symp toms.As tremor, ri gid ity and bradykinesia pro gressed, levodopa/carbidopa 100/25 mg×3 times/day was in troduced in 2017 and in creased to 400 mg/day in 2020 (levodopa equiv a lent daily dose, LEDD=1170 mg/day).The pa tient was vac ci nated against SARS-Cov-2 in May 2021, June 2021 and No vem ber 2021.Dur ing a rou tine con tact con sul ta tion at the VUHSK on 20 July 2021, the pa tient re ported that tremor and stiff ness of the right extrem i ties in creased only dur ing stress and slightly in terfered with ac tiv ity, some times it was dif fi cult to fall asleep in the eve ning, but there were no sud den sleep at tacks and som no lence dur ing the day, no ICD ac cord ing to sub jective re port, no his tory of COVID-19; ep i sodic ex ac er ba -tion of lum bar pain re quired oral an al ge sia (lornoxicam 8 mg×1-2 times/day).Ob jec tive sta tus was with out neg ative dy nam ics: nor mal con scious ness and cog ni tion, slight hypomimia, mild bradykinesia and ri gid ity in the right arm and leg (1 point on the Uni fied Par kin son's Dis ease Rat ing Scale, UPDRS), mild pos tural tremor of the hands (2 UPDRS points in the left and 1 UPDRS point in the right), min i mal pos tural in sta bil ity (cor rec tion in one step dur ing the pos tural test), hypestesia in right S1 dermatome, Lasegue's sign neg a tive, blood pres sure 140/90 mmHg, heart rate 75 beats/min.The di ag no sis was Par kin son's dis ease, stage 2.5 ac cord ing to the Hoehn-Yahr scale; ep isodic in som nia; chronic right S1 radiculopathy; osteochondrosis.The dose of propranolol was in creased from 80 mg/day to 120 mg/day; there were no other cor rec tions in the treat ment scheme (rasagiline 1 mg/day, ropinirol 16 mg/day, amantadine 200 mg × 2 times/day, levodopa/ benserazide 100/25 mg × 4 times/day).The next con sul tation was sched uled for Jan u ary 2022.In De cem ber 2021, the pa tient sud denly be came ag i tated, re ported de lu sions and hal lu ci na tions (un known peo ple at home, do ing harm) and started to be have in ad e quately (fought with un real invad ers), so he was ur gently ad mit ted to a psy chi at ric hos pital.The pa tient had no fe ver, cough or gas tro in tes ti nal distress.There were no ab nor mal i ties in lab o ra tory anal y ses, chest X-ray and brain CT; the test for COVID-19 on addmission was neg a tive.The next day, the real-time PCR test for SARS-Cov-2 RNA was pos i tive.The pa tient was treated in the psy chi at ric de part ment of an other hos pi tal with olanzapine 15 mg/day, lorazepam 2.5 mg/day; rasagiline and ropinirol were dis con tin ued, but amantadine, propranolol and levodopa re mained un changed.The psy chotic con di tion re solved in 4 weeks and the pa tient was dis charged with olanzapine 10 mg/day, which was changed to quetiapine 100 mg/day and zopiclone 7.5 mg/day in March 2022 by the con sul tant psy chi a trist.Dur ing the neu ro log i cal ex am i na tion at the VUHSK in April 2022, the pa tient and his wife re ported about the disap pear ance of hal lu ci na tions, de lu sions and sleep dis turbances, but com plained of sig nif i cantly wors ened mo tor con di tion (se vere re tar da tion, ri gid ity and rest tremor) and of a wear ing-off phe nom e non.On ob jec tive ex am i na tion, the pa tient's gen eral and lo cal bradykinesia and hypokinesia were rated 3 points, rest tremor 2 points in the right and 1 point in the left ex trem i ties on the UPDRS, pos tural in sta bil ity was pres ent, able to change po si tions in de pendently with dif fi culty; cog ni tive con di tion was nor mal (29 points on the Mini-Men tal State Ex am i na tion, MMSE).PD was stage 3 ac cord ing to the Hoehn-Yahr scale.The med i ca tion scheme was ad justed: amantadine was dis con tin ued, the dose of stan dard-re lease levodopa/ benserazide in creased to 200/50 mg×4 times/day and controlled-release levodopa 200 mg was added at night, rasagiline 1 mg/day was re in tro duced (LEDD=1050 mg/day); quetiapinum 25 mg-25 mg-50 mg and propranolol 40 mg×3 times/day were con tin ued.In July 2022, the mo tor con di tion im proved and no ma jor or mi nor psy chotic events were re ported by the pa tient and fam ily.The last visit of the pa tient to the VUHSK was in March 2023.There was a de te ri o ra tion of the mo tor con dition dur ing the last 8 months, but no signs of psy cho sis during the last year.On ob jec tive ex am i na tion, his gen eral and lo cal bradykinesia and hypokinesia were rated 2-3 UPDRS points, rest tremor was 1 UPDRS point in the right side, pos tural in sta bil ity was pres ent, able to change the po sitions in de pend ently with dif fi culty; cog ni tive con di tion was nor mal (30 points on the Mini-Men tal State Ex am i nation, MMSE).The dose of stan dard-re lease levodopa was grad u ally in creased from 800 mg/day to 1200 mg/day, quetiapine was re duced to 25 mg at night, rasagiline, propranolol and con trolled-re lease levodopa re mained unchanged (LEDD=1550 mg/day).At fol low-up in April 2023, the pa tient and his wife re ported his con di tion to be sta ble, with mo tor im prove ment and with out psychiatric abnormalities.

CASE 2
A 61-year-old man be gan to feel loss of smell 20 years ago, con sti pa tion and in som nia 15 years ago, ep i sodic vo cali sations and mo tor re ac tions dur ing night mares, slow ness of the left leg and gait dis tur bance 10 years ago.He was di agnosed with PD at a re gional hos pi tal 9 years ago and prescribed levodopa.Fam ily his tory was pos i tive: the patient's fa ther was di ag nosed with PD.The ini tial brain MRI showed microangiopatic foci.Con com i tant dis eases were ar te rial hy per ten sion (nebivolol 5 mg/day) and hy per choles ter ol emia (rosuvastatin 10 mg/day).The pa tient had a full-time shift job.In Feb ru ary 2017, dur ing the pa tient's first con sul ta tion at the VUHSK, he re ported us ing prolonged levodopa 200 mg×4 times/day (LEDD=600 mg/day).Ob jec tive ex am i na tion re vealed hypophonia, bradilalia, frag mented smooth pur suit, moder ate gen eral and lo cal bradykinesia (2 UPDRS points), con tin u ous rest tremor in the right (leg 3 UPDRS points, arm 2 UPDRS points), tendence to pro pul sion, sta ble on pos tural test, no synkinesia in the left, short steps, no signs of de men tia.PD was stage 2.5 ac cord ing to the Hoehn-Yahr scale, and the treat ment scheme was changed: levodopa re gime was ad justed (stan dard re lease 200 mg×3 times/day and con trolled re lease 200 mg at bedtime), rasagiline 1 mg/day was in tro duced and grad u ally amantadine 100 mg×2 times/day was added (LEDD=1050 mg/day), melatonin 3 mg in the eve ning for REM parasomnias.The ef fect was pos i tive but par tial, and in March 2017, ropinirol 2 mg/day was added and ti trated to 12 mg/day (LEDD=1250 mg/day) in 6 months.No side ef fects were re ported dur ing fol low-ups, and ques tionnaires on ICD and day time som no lence were neg a tive.In 2018, the pa tient re ported a wear ing-off phe nom e non and was pre scribed entacapone 200 mg×3 times/day with standard-re lease levodopa (1400 mg/day).Af ter re lief of fluctu a tions in 2019, the pa tient re ported fa tigue and ep i sodic som no lence in the sec ond half of the day, with out sud den sleep at tacks.His score on the Epworth Sleep i ness Scale (ESS) was 8 points.Ropinirol was di vided into 8 mg in the morn ing and 4 mg in the eve ning and the dose of amantadine was in creased to 400 mg/day (LEDD=1600 mg/day), and the ESS score be came 4 points, there were no sud den sleep at tacks.Grad u ally, the pa tient be gan to ex pe ri ence choreatic dyskinesia which he did not con sid ered trou ble some.He missed his visit in 2020 dur ing the lockdown and ar rived at the VUHSK PD consultiation room in Sep tem ber 2021.He was vac ci nated against SARS-Cov-2 three times (Jan u ary, Jan u ary, Septem ber 2021).The pa tient com plained of grad ual wors ening of his con di tion in the last years: in creased dyskinesia, slurred speech, in som nia, night mares and arousal dur ing night sleep; he de nied ICD and sud den sleep at tacks, his ESS score was 10 points, he was driv ing and work ing.He re ported that a re gional neu rol o gist had in creased combined levodopa to 4 in takes per day and ropinirol to 16 mg/day (LEDD=1916.8 mg/day).Ob jec tive ex am i nation dur ing ON pe riod with trou ble some dyskinesia revealed nor mal cog ni tion (MMSE score 30), gen er al ized mod er ate cho rea, hyperkinetic dysarthria with im provement on fix a tion of at ten tion, ri gid ity 1 UPDRS point, more prom i nent in the left, no tremor, able to stand up with arms crossed on chest with out as sis tance, gait un sta ble but in de pend ent, blood pres sure 140/90 mmHg, heart rate 78 beats/min.The pa tient's PD was stage 3, and he was recom mended to stop entacapone and to de crease ropinirol to 12 mg/day (LEDD=1675 mg/day).At the fol low-up visit in De cem ber 2021, his con di tion re mained com pli cated with the same com plaints; he re in tro duced entacapone because his mo tor symp toms wors ened af ter ex cluding entacapone and de creas ing ropinirol (LEDD=1875 mg/day).The pa tient was sched uled for hospi tal iza tion at the VUHSK De part ment of Neu rol ogy for fur ther ex am i na tion (polysomnography, multi-team evalu a tion for deep brain stim u la tion).The pa tient was ad mitted to the De part ment of Neu rol ogy in Jan u ary 2021.His PCR for SARS-Cov-2 RNA 24 hours be fore ad mis sion was neg a tive.Blood and urine anal y sis showed no ab normal i ties, ther a peu tic con di tion and ECG were nor mal, videofluoroscopy for dysphagia re vealed no ab nor mal ities.Neu ro log i cal con di tion was sim i lar to pre vi ously described, MMSE score was 30.The pa tient started fill ing the PD di ary, but was not thor ough.The pa tient was con sulted by a rehabilitologist and started to at tend kinesitherapy and speech ther apy.He re fused a planned con sul ta tion with a psy chi a trist for re veal ing un der ly ing psy chi at ric pa thol -ogy and in som nia.On the fourth day of hos pi tal iza tion, in the morn ing, the pa tient be came con fused and re ported some vi sual hal lu ci na tions (rel a tives in the ward, un known ob jects) with in sight pre served; there were no changes in gen eral con di tion, no fe ver, no signs of trauma, no ab normal i ties of uri na tion and bowel move ments; the day be fore re pet i tive PCR for SARS-Cov-2 RNA was neg a tive.The pa tient re peat edly re fused to con sult a psy chi a trist, so he was un der con stant ob ser va tion af ter treat ment ad justments were made (amantadine and entacapone was dis contin ued and quetiapine 25 mg at bed time was pre scribed).Within a few hours the pa tient be came ag i tated, ag gres sive to wards cli ni cians and was trans ferred to the de part ment of psy chi a try.Treat ment rec om men da tions for PD at trans fer were: to dis con tinue amantadine, taper ropinirole to 4 mg/day (and dis con tinue in case of per sist ing psy cho sis), con tinue stan dard re lease levodopa 200 mg×4 times/day (or in crease to 5 times/day), con trolled re lease levodopa 200 mg at bed time, rasagiline 1 mg in the morn ing.PCR for SARS-Cov-2 RNA on ad mis sion to the emer gency room of the psy chi at ric de part ment was pos i tive.The patient was treated in the de part ment of psy chi a try for 10 days un til com plete res o lu tion of symp toms; chest X-ray and brain CT scan re vealed no ab nor mal i ties.He was dis charged to out-pa tient re gime in a sta ble con di tion with out psy chotic ac tiv ity with the rec om men da tion to con tinue quetiapine 50 mg at bed time.There are no data on the pa tient's ob jec tive neu ro log i cal sta tus and fur ther psychi at ric con di tion dur ing the last year as he did not at tend a con tact con sul ta tion af ter the psy cho sis.

DIS CUS SION AND LIT ER A TURE RE VIEW
The man age ment of psy cho sis in PD is a chal lenge for clini cians, care givers and/or fam ily mem bers of pa tients.It be gins with rec og ni tion of the psy chotic event, in cludes caus ative di ag no sis, ad just ment of PD treat ment and antipsychotic treat ment if needed, and leads to pre ven tive mea sures.
In 2007, the joint Na tional In sti tute of Neu ro log i cal Dis or ders and Stroke (NINDS) and Na tional In sti tute of Men tal Health (NIMH) work group de fined the land scape of psy cho sis in PD and, de spite fur ther deeper in sights into pathogenesis over the past 16 years, these cri te ria are presented in the Ta ble 1 and re main the gold stan dard for di agnos ing psy cho sis in PD (PPD) to date [4].

63
Psy cho sis as an Iso lated Man i fes ta tion of COVID-19 in Non-De mented Pa tients with Par kin son's Dis ease: Clin i cal Cases and... Ta ble 1. Di ag nos tic cri te ria for psy cho sis in Par kin son's dis ease ac cord ing to NINDS and NIMH work group, 2007 [4] 1. Char ac ter is tic symp toms At least one symp tom of il lu sions, false sense of pres ence, hal lu ci na tions, or de lu sions 2. Pri mary di ag no sis Per United King dom Brain Bank Cri te ria for PD 3. Chro nol ogy of symp toms Psy cho sis symp toms oc cur af ter PD on set 4. As so ci ated fea tures Note symp toms as oc cur ring with or with out in sight, de men tia, or PD treat ment 5. Ex clu sion of other causes Symp toms are not better ac counted for by an other cause of parkinsonism 6.Du ra tion of symp toms Symp toms re cur or are con tin u ous for 1 month In the typ i cal clin i cal case-sce nar ios, the mi nor phenom ena grad u ally evolve to formed vi sual hal lu ci na tions with in sight ini tially pre served but lost in later stages; de lusions and non-vi sual (au di tory, tac tile, ol fac tory) hal lu cina tions may also de velop over time.This spec trum of pos itive symp toms oc curs af ter the on set of Par kin son's disease, with or with out in sight, de men tia, or PD treat ment, other causes of parkinsonism have been ex cluded [4].PPD is di ag nosed when symp toms re cur or are con tin u ous for at least one month.Our pa tients did not have such pro gressive his tory of evo lu tion of psy chotic symp toms and this fact fa vors for sec ond ary cause of psy cho sis.Ob vi ously, the re port ing of il lu sions, false sense of pres ence, hal lu cina tions, or de lu sions in out pa tients may be not com pre hensive or even ab sent in rou tine clin i cal prac tice, es pe cially in case of cog ni tive de cline, loss of in sight, lack of sup port, caregivering or com pre hen sion [5].
Screen ing for psy cho sis in PD should be ac tive, es pecially af ter the in tro duc tion of new med i ca tions, in all cases of ad vanced dis ease, or in pa tients with pre-ex ist ing cog ni tive def i cits.Up to 70% of PD pa tients ex pe ri ence hal lu ci na tions and/or de lu sions at some point dur ing the course of the dis ease, but they (and/or their care givers) often do not re port these de bil i tat ing non-mo tor symp toms to phy si cians un less spe cif i cally ques tioned.
The most com mon move ment dis or der-fo cused screen ing tools used in clin i cal re search are the MDS-Unified Par kin son's Dis ease Rat ing Scale (MDS-UPDRS) [6], the MDS-Non-Mo tor Rat ing Scale [7], MDS Non-Mo tor Symp toms Scale (NMSS) [8], the Non-Mo tor Symp toms Ques tion naire (NMSQ) [9], and the Scale for As sess ment of Pos i tive Symp toms Adapted for Par kin son's Dis ease (SAPS-PD) [10,11].Such screen ing tools and rat ing scales for PPD that were de vel oped for clin i cal tri als are too com pli cated for rou tine clin i cal use or do not de fine psy chotic symp toms clearly enough to in form treat ment de ci sions, as de scribed in a re cently pub lished re view ar ti -cle by Sabbagh M et al. [12].The lack of sim pli fied and stan dard ized screen ing lim its the iden ti fi ca tion of pa tients suf fer ing from PPD and re duces the early prob a bil ity and ef fec tive ness of spe cific in ter ven tion.There fore, in 2022, a US ex pert panel re viewed the lit er a ture for ex ist ing guidelines on the di ag no sis and man age ment of psy cho sis in PD and de vel oped an el e gant screen ing tool and treat ment guid ance for prac ti cal clin i cal ap proach to PPD [13].This al go rithm con sists of two parts: (1) a brief pre-visit screening part to be com pleted by the pa tient and care giver, and (2) a cli ni cian part to be com pleted via clin i cal in ter view with the pa tient and care giver [13], as shown in Ta ble 2.
We looked at the pos si ble causes of psy cho sis in both pre vi ously de scribed clin i cal cases.Pa tient-re lated risk fac tors usu ally in clude de men tia, sen sory de pri va tion, sleep dis tur bances, se vere or even end-stage comor bidities.In pa tients with PD, un der ly ing cog ni tive im pair ment or pre ced ing psy chi at ric dis or ders in crease the risk of psychotic events dur ing acute con com i tant dis eases.Nei ther of our pa tients had been di ag nosed with any se ri ous in ternal in suf fi cien cies, cog ni tive def i cits, sig nif i cant anx i ety or de pres sion, im pulse con trol dis or ders, mi nor or ma jor psy chotic events prior to the man i fes ta tion this psy chotic ep i sode.Both of them had a his tory of ep i sodic in som nia due to job-re lated pe cu liar i ties (stress, shifts), but there was no re port of any change in the bur den of dis tress prior to the on set of the psy chotic event.
Ex clud ing any cause other than pos i tive SARS-CoV-2 an ti gen, we searched for ex pla na tions for the ab sence of typ i cal symp toms of in fec tion, such as fe ver, pain, rhi ni tis, cough, pul mo nary com pli ca tions, or gas tro in tes ti nal distur bances.In a sys tem atic re view of COVID-19-re lated new-on set psy cho sis by Chaudhary AMD et al., 25% of pa tients pre sented with clas sic COVID-19 symp toms (fever, cough, mal aise, head ache, loss of taste and smell, myalgia, short ness of breath, di ar rhea), and oth ers had clin i cal vari a tions; most pa tients had mild COVID-19-re -64 G. Lokominaitë, R. Kaladytë Lokominienë Ta ble 2. Screen ing tool and treat ment al go rithm for the di ag no sis and man age ment of psy cho sis in Par kin son's dis ease, 2022 [13] I. Pre-visit screener 1.Does the pa tient see, hear or oth er wise sense the things that oth ers do not?(e.g., see ing peo ple or an i mals that are not, hear ing mu sic, mis iden ti fy ing ob jects) 2. Does the pa tient be lieve things that oth ers do not be lieve to be true?(e.g., that other peo ple are cheat ing, con ceiv ing, harm ing, con spir ing against them)

II. Cli ni cian's assessment
Does the pa tient have hal lu ci na tions or de lu sions that af fect or dis rupt any of his/her be hav iors or activities or cause dis tress in clud ing care giver?IF YES -IF NO -Psy cho sis in Par kin son's dis ease with or with out de men tia Re as sess at the next visit

III. Treat ment guidance
1.As sess and treat sec ond ary med i cal and comorbid psy chi at ric con di tions, ad just med i ca tions (anticholinergics, opioids, miorelaxants, tricyclic an ti de pres sants) and ini ti ate be hav ioral in ter ven tion 2. Op ti mize med i ca tions for Par kin son's dis ease (e.g., amantadine, do pa mine agonists) 3. Ini ti ate treat ment: Clozapine and pimavanserine -clin i cally use ful; Quetiapine -pos si bly use ful; Avoid other atypicals if pos si ble. 4. Re-eval u ate in 4-6 weeks 5.If symp toms per sist, ad just and add other med i ca tions lated symp toms and 26.3% of pa tients had mod er ate to severe COVID-19-re lated dis ease; 8.8% of pa tients had a com pli cated course, with the death of one pa tient due to COVID-19 com pli ca tions [3].Anosmia and ageusia are ad mit ted to be spe cific to the clin i cal pre sen ta tion of COVID-19, but in PD pa tients this rule is not re li able as decreased sense of smell (and some times taste) is one of the most fre quent and ear li est non-mo tor symp toms of PD.
Vac ci na tion against SARS-Cov-2 helps pre vent or alle vi ate clin i cal symp toms of the in fec tion, and both of our pa tients were fully vac ci nated in ac cor dance with leg is lative re quire ments.Break through in fec tion is as so ci ated with a lower num ber of symp toms, a shorter du ra tion of symp toms, a lower like li hood of per sis tent symp toms for >28 days (i.e., a lower rate of "long COVID-19"), and a higher like li hood of asymp tom atic in fec tion com pared with in fec tion in un vac ci nated in di vid u als [14][15][16].Although the pre ven tive ef fect wanes over time, vac ci na tion may ex plain (to some ex tent) the lack of other clin i cal symp toms of coronavirus in fec tion in the cases de scribed.
We eval u ated the list of pre scribed med i ca tions in the cases pre sented ac cord ing to the na tional elec tronic health reg is try.The treat ment re gime has not changed in the last 6 months: there have been no dose es ca la tions or new prescrip tions.There were no signs of over dose or ab er rant behav ior in our cases.Both our pa tients were treated with amantadine 200 mg × 2 times/day.Since the be gin ning of the pan demic, there have been sug ges tions that amantadine may have some pro tec tive ef fect against COVID-19.How ever, the lat est ev i dence from clin i cal stud ies have not dem on strated any pre ven tive ben e fits of this med i ca tion.F. Przytuùa et al. re cently pub lished the results of an ob ser va tional, ret ro spec tive, multicenter co hort study of five hun dred and fifty-two (n=552) id io pathic PD pa tients and con cluded that amantadine does not af fect either the se ver ity or the risk of de vel op ing COVID-19 [17].
It is im por tant to dif fer en ti ate psy chotic events from focal neu ro log i cal symp toms, such as hemianopsia and other vi sual dis tur bances, apha sia, apraxia, and REM-be hav ior dis or der.Al though the search for causes in PPD in cludes a va ri ety of ther a peu tic con di tions and a de tailed phar ma colog i cal his tory, it is im por tant to re mem ber that some under ly ing dis eases may be oligosymptomatic like COVID-19 in vac ci nated pa tients.In a sys tem atic re view of COVID-19-re lated new-on set psy cho sis in the gen eral pop u la tion by Chaudhary AMD et al., re verse tran scription-poly mer ase chain re ac tion (RT-PCR) for COVID-19 was pos i tive in 66.7% of pa tients, re ac tive COVID-19 IgM/IgG an ti bod ies were re ported in 8.7% of pa tients, and the di ag nos tic test used was not re ported in the rest of cases [3].These data con firm that SARS-Cov-2 is a po tent provoc a tive fac tor for psy chotic events.There fore, when facing PPD, cli ni cians should not be mis led by the fact that Par kin son's dis ease is a main cause or a sin gle un der ly ing con di tion of psy chotic symp toms.Thor ough eti o log i cal in ves ti ga tions in PPD should in clude RT-PCR for COVID-19 even in the ab sence of other clin i cal signs of infec tion.

Prac ti cal rec om men da tions
Un treated symp toms of PPD are as so ci ated with worse out comes, poor qual ity of life, and sig nif i cant dis tress to the care giver and pa tient.The man age ment of psy cho sis in PD is a chal lenge for cli ni cians, care givers and/or the patient's im me di ate en vi ron ment.An ap pro pri ate treat ment plan for PPD is de vel oped ac cord ing to the re sults of assess ment (Ta ble 2).As sess ment and man age ment of second ary causes (ther a peu tic, med i cal) should be car ried out with out de lay, e.g., di ag no sis and man age ment of ane mia, pain, sleep dis tur bances, uri nary tract in fec tion, sen sory de pri va tion, hyponatremia, hypothyrosis, ab er rant drug be hav ior, over use of over-the-coun ter (OTC) med i ca tions.When op ti miz ing antiparkinsonian med i ca tions, the rule should be to stop first the one which was in tro duced the last; if the treat ment re gime has been sta ble, it is rec ommended to stop first those with the stron gest propsychotic ac tiv ity and then con tinue with the oth ers if psy cho sis persists: STEP 1 -anticholinergics; STEP 2 -amantadine; STEP 3 -do pa mine agonists; STEP 4 -COMT in hib i tors; STEP 5 -MAOB in hib i tors.Levodopa is con sid ered the saf est med i ca tion in terms of psy chotic ac tiv ity in PD.As the de crease in LEDD leads to a wors en ing of the PD condi tion, the LEDD should be com pen sated with levodopa and main tained at a safe ra tio nal level.Antipsychotic treatment is in tro duced when nec es sary.Only a few med i cations are con sid ered to have suf fi cient safety pro file: clozapine and pimavanserine are con sid ered to be clin ically use ful ac cord ing to MDS and NICE guide lines; quetiapine -pos si bly use ful; it is rec om mended to avoid other atypicals (all other antipsychotics) if pos si ble [5,12,13].
We did not find any spe cific rec om men da tions for the treat ment of PPD in COVID-19.Fu ture stud ies will provide a more pre cise anal y sis of the prev a lence, se ver ity, asso ci ated pa thol ogy of psy cho log i cal man i fes ta tions and out comes of COVID-19 in PD pa tients, and pos si bly will lead to some spe cific treat ment guide lines for PPD.

CON CLU SIONS
Psy chotic dis or ders in pa tients with PD are usu ally as so ciated with poor cog ni tive per for mance, comorbidities and changes in treat ment re gime.De spite the ac knowl edgement of cog ni tive def i cit as a ma jor risk fac tor for psy chosis in PD, psy chotic events have been re ported to oc cur in pa tients with out de men tia.SARS-CoV-2 so far is rec ognized as a harm ful in vader of the ner vous sys tem, and defin ing its con se quences still re quires mul ti di rec tional research.Pa tients with PD may de velop psy cho sis dur ing COVID-19 in fec tion.Ac cord ing to our ob ser va tion, psychotic dis or der may be an iso lated man i fes ta tion of SARS-CoV-2 in fec tion in PD, as in the pre sented two clini cal cases of non-de mented pa tients who were on sta ble antiparkinsonian med i ca tion, did not pre vi ously ex press any psy chi at ric dis tur bance and who de vel oped psy cho sis as a con se quence of COVID-19, with out any other clin i cal signs of in fec tion; they had been fully vac ci nated against SARS-CoV-2; no re cur rent psy chotic dis or ders were regis tered dur ing avail able one-year fol low-up.We rec ommend that pa tients with PD who de velop acute psy cho sis should have a re verse tran scrip tion poly mer ase chain re action (RT-PCR) swab test for SARS-CoV-2.