Suc cess ful Treat ment of Stiff-Per son Syn drome with Plasmapheresis: Case Re port and Lit er a ture Re view

comorbidities in clude tem po ral lobe ep i lepsy and type 1 di a be - tes mellitus. In this ar ti cle, we pres ent a clin i cal case of a pa tient il lus trat ing the course of the dis ease, di ag nos tic dif fi cul ties, and treat ment op tions, all of which are dis cussed in the lit er a - ture re view.

med i ca tions (NSAIDs), but she did not tol er ate these pharma co log i cal agents.Sub se quent re ha bil i ta tion and physiotherapeutic mea sures caused a par tial im prove ment of the pa tient's con di tion over time, but ep i sodic leg muscle stiff ness per sisted.The pa tient's symp toms ex ac erbated in the last 3 weeks be fore re fer ral to a neu rol o gist in Sep tem ber 2018.
The pa tient's anamnesis re vealed that in 2008 she was di ag nosed with ep i lepsy pre sent ing with fre quent (up to 10 times a day) Déjà vu phe nom e non and char ac ter is tic electroencephalographic (EEG) find ings.Treat ment with carbamazepine 200 mg three times a day helped to re duce the fre quency of these ep i sodes up to only 2-3 per month.Later, the dos age of carbamazepine was in creased to 900 mg per day.The pa tient was re ferred to a psy cho ther apist to man age walk ing dif fi cul ties.In 2011, the pa tient was di ag nosed with type 1 di a be tes mellitus (T1DM) and was treated with in su lin since then, but glycaemia con trol re mained un sat is fac tory (fast ing blood sugar lev els ranged from 8 to 16 mmol/L), es pe cially when ex posed to a stressful en vi ron ment.
Dur ing phys i cal ex am i na tion in Sep tem ber 2018, the pa tient was ag i tated, suf fered from an in tense pain, presented with im paired spas tic gait.Ob jec tive ex am i na tion re vealed hyperreflexia in the pa tient's legs, a patho log ical Babinski re flex in the right leg, and ep i sodic spon ta neous ac ti va tion of leg mus cles, more prom i nent in the right and pos te rior chain.Dur ing these ep i sodes the pa tient could hardly move her legs and re ported about an acute in crease of pain which even tu ally eased when ly ing down.The pa tient's mus cle strength was nor mal (scor ing 5/5 points in MRC scale), the re sults of co or di na tion tests were sat is fac tory, and no sen sory im pair ment was detected.The EEG showed an in creased ex cit abil ity of the bioelectric field of the ce re bral cor tex, more prom i nent in the right tem po ral lobe, but no ep i lep tic ac tiv ity was regis tered.
Tak ing into ac count the pa tient's symp toms (gait impair ment, pain ful mus cle spasms, and mus cle stiff ness) and pos si ble re la tion with T1DM and ep i lepsy, SPS was sus pected.The pa tient was ad mit ted to the in-pa tient depart ment of VUH SK Cen ter of Neu rol ogy.EMG showed con tin u ous fir ing of mo tor unit po ten tials in an tag o nist mus cle groups at rest and when per form ing move ments with both legs.Af ter in tra mus cu lar in jec tion of 10 mg of di az e pam, fir ing of mo tor ac tion po ten tials at rest ceased in the right leg.Stiff en ing of the an te rior tib ial mus cle was ob served dur ing plan tar ex ten sion.Based on EMG findings and pos i tive serological anti-GAD65 test ing in blood se rum (>500 IU/mL), the pa tient was di ag nosed with SPS.Treat ment with di az e pam up to 45 mg per day caused a notice able im prove ment in the pa tient's con di tion: func tional ity in ac tiv i ties of daily liv ing was re stored, though dif ficul ties per sisted when go ing to pub lic places.Within a few weeks, op ti mal ep i lep tic sei zure con trol was achieved, and treat ment with carbamazepine was dis con tin ued.Over time, the dose of di az e pam was main tained 30 mg per day with ex cel lent tolerability.
In Feb ru ary 2019, the pa tient was di ag nosed with hyperthyroidism, and treat ment with thiamazole 5 mg three times a day was started.SPS symp toms be gan to fluc tu ate.Be tween 2019 and 2022, the pa tient was treated at the inpa tient de part ment of VUH SK Cen ter of Neu rol ogy 3 more times.In Au gust 2019, the pa tient ex pe ri enced SPS ex ac er ba tion with fluc tu at ing lower spas tic pa re sis.She was con tin u ously treated with di az e pam 35 mg per day and un der went one cy cle of 5 ses sions of plasmapheresis.Since sat is fac tory con trol over the symp toms was re gained with an in creased dose of di az e pam and the ef fec tive ness of plasmapheresis ther apy was lim ited (grade I), the de cision to ad min is ter no fur ther immunomodulatory treatment for at least 6 months was made.
In Jan u ary 2020, the pa tient was ad mit ted to the in-patient de part ment of En do cri nol ogy of VUH SK due to bad con trol over T1DM and sig nif i cant daily fluc tu a tions of glycaemia (2.8-18 mmol/L) as so ci ated with emo tional stress.The pa tient was di ag nosed with T1DM in sub-compen sa tion phase, bad glycaemia con trol, di a betic nonproliferative retinopathy, dif fuse nod u lar goi ter (IB class, no signs of ma lig nancy), and hyperthyroidism.A suit able diet was rec om mended, cor rec tions in in su lin ther apy were made, thiamazole was pre scribed for the treat ment of hyperthyroidism.
In Feb ru ary 2020, the pa tient's blood se rum was tested to eval u ate changes in the lev els of anti-GAD65.The results showed per sis tently high lev els (>500 IU/mL).The pa tient was re-hos pi ta lised for treat ment of ex ac er ba tion of SPS.The bur den of dis ease con sisted of in tense noc tur nal pain in lum bar re gion, dis turb ing sleep, stiff ness in legs and waist, most prom i nent in the morn ing, and pro gres sive walk ing dif fi cul ties.The daily dose of di az e pam was increased to 40 mg and im mune-mod u lat ing treat ment with 5 plasmapheresis ses sions was ad min is tered.The pa tient tol er ated the treat ment well, how ever, im prove ment af ter plasmapheresis was lim ited (Grade II).
In Oc to ber 2020, the pa tient re ceived one more cy cle of plasmapheresis (5 ses sions) which ef fec tively im proved her con di tion (Grade III).
In March 2022, the pa tient ar rived for a rou tine mon itor ing visit to eval u ate the dis ease con trol and ef fect of treat ment.Ep i sodic stiff ness in lum bar, gluteal and leg mus cles per sisted, but was not as de bil i tat ing as be fore.Symp toms ex ac er bated af ter pro longed phys i cal ac tiv ity when walk ing in open spaces or with emo tional stress.The pa tient de vel oped a fear of fall ing, de spite the fact that no falls were re corded dur ing the last 2 years, she started to avoid large open ar eas in an tic i pa tion of stiff ness at tack.In ad di tion to these fears, the pa tient com plained of an increased level of anx i ety, but not as high as 4-5 years ago.The pa tient showed no signs of de pres sion or other mood dis or ders.She scored 10 points for anx i ety and 4-5 points for de pres sion on the Hos pi tal Anx i ety and De pres sion Scale (HADS).No sleep ing dis or ders, drows i ness, or instances of fall ing asleep dur ing day time were re corded, the pa tient scored 9 points on the Epworth sleep i ness scale.The con trol of di a be tes re mained un sat is fac tory, fast ing glycaemia ranged from 3 to 20 mmol/L.No ep i lep tic seizures were re corded in the past 3.5 years.As re gards the pa tient's mo bil ity, her con di tion im proved sig nif i cantly: she was able to walk in de pend ently and re ported no daily ac tiv ity dis tur bances.Neu ro logic ex am i na tion showed no pa re sis, mus cle at ro phy, fasciculations, or spasms.Hyperreflexia and patho log i cal Babinski re flex re mained pres ent in the legs bi lat er ally.EEG showed re pet i tive ep isodes of rhyth mic delta fre quency waves in the right frontotemporal lobe with out any typ i cal epileptiform poten tials.The pa tient is cur rently treated with di az e pam 40 mg per day and is un der the su per vi sion of a neu rol o gist.

DIS CUS SION AND LIT ER A TURE RE VIEW Clin i cal pre sen ta tion
Clas sic SPS is a con di tion with an in sid i ous on set and gradual pro gres sion over sev eral months.It usu ally pres ents with pro gres sive ax ial mus cle stiff ness and pain ful mus cle spasms [6], hyperreflexia, con tin u ous mo tor mus cle ac tivity, and height ened sen si tiv ity to both ex ter nal and in ter nal stim uli [7,8].All these symp toms were ob served in our case.Al though the symp toms more of ten man i fest in the ax ial mus cles, in al most one third of the cases they are first ob served in the prox i mal leg mus cles [5] and man i fest asym met ri cally, in ter mit tently, with out py ram i dal or extrapyramidal symp toms [8].Stiff ness is caused by simul ta neous co-ac ti va tion of an tag o nist mus cle groups which, in turn, is caused by in creased neuronal ex cit abil ity due to in suf fi cient GABA-ergic sig nal ing.GABA-ergic sig nal ing is re duced be cause GAD65, a vi tal en zyme respon si ble for GABA syn the sis, is in ac ti vated by anti-GAD65.Stiff ness in ter feres with the move ments of the limbs and trunk, dis turbs the gait; as dis ease pro gresses, it may cause joint de for ma tions, fre quent falls, and in abil ity to walk in de pend ently [3,5,[7][8][9].In our case, ir re vers ible com pli ca tions were avoided as a re sult of ad e quate and timely treat ment.
Pain ful mus cle spasms de velop in 88% of all clin i cal SPS cases [5].Spo radic and lo cal ized at the on set of the dis ease, they be come gen er al ized and de bil i tat ing as the con di tion pro gresses [8].SPS symp toms are of ten provoked by sud den un ex pected ex ter nal and in ter nal stim uli, such as loud, sud den noises, ex treme cold, emo tional stress, in fec tion, or sud den move ments in af fected mus cle groups [5,7,8].Symp toms of ten fluc tu ate di ur nally: increase in in ten sity dur ing the day time and de crease at night [3,5,8].In our case, pain ful mus cle spasms were trig gered by emo tional stress, they were de bil i tat ing, and de creased in in ten sity at night.
One of the key fea tures of SPS is the over lap with other anti-GAD65 spec trum dis or ders (GAD65-SD), and in our case SPS was ac com pa nied by au to im mune tem po ral lobe ep i lepsy (TLE).Anti-GAD65-as so ci ated TLE pres ent in 2 main clin i cal forms.The first form is a clin i cal syn drome over lap ping with acute limbic en ceph a li tis (LE) and charac ter ized by sei zures of tem po ral or i gin, acute anterograde am ne sia, be hav ior and per son al ity dis or ders, head ache, ver tigo, and blurred vi sion, signs of mesiotemporal inflam ma tion in brain MRI [10][11][12] The sec ond and more prev a lent form is in do lent chronic ep i lepsy with out clin ical or ra dio log i cal signs of ac tive CNS in flam ma tion, mani fested only by sei zures, which orig i nate in tem po ral lobe and gen er al ize in 50% of cases [10,11].Anti-GAD65 asso ci ated-TLE dif fers from other au to im mune epilepsies in its higher in ci dence among young peo ple, more fre quent pre sen ta tion with sei zures rather than cog ni tive or psy chiat ric dis or ders, and more prev a lent re sis tance to treat ment with antiepileptic drugs [10].Our pa tient's ep i lepsy pro file fits the anti-GAD65 as so ci ated TLE phe no type due to its tem po ral or i gin, in do lent course, poor re sponse to carbamazepine, and ex cel lent re sponse to treat ment with benzodiazepines.
Move ment and walk ing dis or ders caused by SPS are closely re lated to psy chi at ric symp toms.Most com mon of these are spe cific, task-re lated pho bias, such as fear of climb ing stairs, fall ing, or walk ing in open or crowded places in an tic i pa tion of stiff ness at tack [13].Dif fer ent authors dis agree whether these pho bias are caused pri mar ily by the dis ease it self due to the in hi bi tion of the GABAergic sys tem, or whether they are sim ply the re sult of progress ing dis abil ity.The main ar gu ment in fa vour of di rect or i gin is the oc cur rence of pho bias as the first symp tom [13], how ever, sec ond ary or i gin is sup ported by the fact that pho bias are rap idly re solved af ter ad e quate con trol of mo tor symp toms is achieved [14].Spe cific, task-re lated pho bias are of ten ac com pa nied by in creased lev els of anx iety, de pres sion, be hav iour and per son al ity dis or ders [13].Due to this comorbidity, walk ing dis or ders caused by SPS are of ten misdiagnosed to be of psy chi at ric or i gin.Un fortu nately, psy cho ther apy, which is usu ally rec om mended in these cases, is in ef fec tive, while treat ment of SPS and good symp tom con trol al low a rapid res o lu tion of psy chi at ric symp toms [3,13].In our case, the pa tient had spe cific task-re lated pho bias such as fear of walk ing in pub lic spaces and fall ing, in creased lev els of anx i ety, and de pressive mood.Psy cho ther apy, rec om mended for the treatment of walk ing dis or der, as the pa tient was di ag nosed with somatoform dys func tion of the au to nomic ner vous sys tem (F45.8),proved to be in ef fec tive.How ever, af ter SPS treat ment, at the last visit, the pa tient re ported a decrease in pho bias and anx i ety level and the ab sence of depres sive mood.
Apart from the CNS, GAD65 is also ex pressed in var ious sites through out the en do crine sys tem.For this rea son, SPS comorbidity with en do crine dis or ders, such as T1DM, Grave's dis ease, and hypopituitarism, is com mon.Since one of GAD65 ex pres sion sites is pan cre atic beta cells, anti-GAD65 is de tected in ap prox i mately 80% of pa tients with T1DM [1,4,5].Ac cord ingly, our pa tient was di agnosed with T1DM and de vel oped thy roid gland dys function.Al though up to 30% of pa tients with SPS are also diag nosed with T1DM, only 1/10 000 of pa tients with T1DM are di ag nosed with SPS.Some au thors be lieve it to be a con se quence of dif fer ent an ti bod ies bind ing to dif fer ent epitopes of GAD65 en zyme and thus hav ing heterogenous ef fect on its ac tiv ity through out dif fer ent sites in the or ganism [15].An other the ory claims CNS le sions to be as so ciated with higher lev els of an ti bod ies al low ing them to pass the blood-brain bar rier and ac cess the cerebrospinal fluid (CSF).This the ory is sup ported by the fact that pa tients with T1DM who de velop SPS and other GAD65-SD always have higher lev els of anti-GAD65 an ti bod ies than those who do not [7,15,16].

Di ag nos tics
To date, the di ag nos tic cri te ria de scribed by M. Dalakas in 2009 (pre sented in the Ta ble) re main the gold stan dard for di ag nos ing SPS.
Typ i cal SPS fea ture ob served in EMG is spi nal cord and brainstem hyperexcitability which man i fest by 3 types of find ings: con tin u ous mo tor unit (MU) fir ing, ex ag gerated acous tic star tle re flexes, and en hanced exteroceptive (cutaneo-mus cu lar) re sponses [2,4,8,17].Mus cle stiffness is caused by in vol un tary MU fir ing and co-ac ti va tion of mus cles in ag o nist and an tag o nist groups.Fail ure of recip ro cal in hi bi tion is ev i dent, as MU fir ing does not cease at rest or while per form ing var i ous move ments [2,3,5,8,17].Thus, EMG is cru cial in di ag nos ing SPS due to its avail abil ity and in for ma tive ness.EMG di ag nos tic ac curacy is de creased by GABA-ergic drugs (such as baclofen and benzodiazepines) since they in hibit MU fir ing.This is con sis tent with our case, as MU ceased fir ing at rest af ter the pa tient was ad min is tered di az e pam [2,4,5,18].The role of im ag ing in SPS di ag nos tics is only to ex clude other pa thol o gies, as anti-GAD65 as so ci ated SPS pres ents with no changes in brain or spi nal cord MRI [3,4,19].In the reported case, MRI was used to ex clude the pa thol ogy of sacral plexus and did not re veal any rel e vant ab nor mal i ties.Anti-GAD65 in blood se rum and CSF can be de tected by two main meth ods: radioimmunoassay (RIA) and enzyme-linked immunosorbent as say (ELISA).Lev els of anti-GAD65 play an im por tant di ag nos tic role in anti-GAD65-as so ci ated syn dromes though only high lev els of anti-GAD65 (>10 000 IU/mL) are de fin i tive for di ag nosing these nozologies.How ever, lev els be low 10 000 IU/mL are con sid ered to be of lim ited di ag nos tic sig nif i cance and should be sup ple mented by clin i cal data to reach a de fin i tive di ag no sis.In our case, lab o ra tory findings alone would have been in suf fi cient, how ever clin i cal find ings and good re sponse to treat ment with benzodiazepines con firmed the di ag no sis of SPS [3,7,19].

Man age ment
SPS treat ment con sists of two main lines of ther apy: symptom atic and immunomodulating.The first line of treat ment is symp tom atic and based on agents that en hance GABAergic trans mis sion.Ac cord ing to var i ous stud ies, this treatment re duces symp toms in 78-100% of all cases [4].One group of drugs used in this line of treat ment are benzodiazepines (BZD), of which di az e pam is the old est, most ef fec tive, and most well re garded first choice treat ment [3,4,17,20].Most pa tients re spond very well to treat ment with BZD: mus cle stiff ness and pain ful spasms, es pe cially caused by ex ter nal trig gers, are no tice ably de creased [7].In our case, treat ment with di az e pam yielded sim i lar results: af ter start ing di az e pam, the pa tient's con di tion improved rap idly and sig nif i cantly, al low ing dis con tinu a tion of anti-sei zure med i ca tion.Quite of ten, to reach a ther apeu tic ef fect in pa tients with SPS, large doses of BZD (up to 60 mg di az e pam daily) are re quired which in crease the risk of de pend ence, with drawal syn drome, or drows i ness and narcolepsy [4,7,17,19,20].This was not the case with our pa tient, who reached suf fi cient con trol of symp toms with 45 mg of di az e pam per day and scored 9 points on the Epworth sleep i ness scale which is con sid ered nor mal, at her last visit.Sec ond choice treat ment of GABA-ergic trans mis sion en hanc ing ther apy is baclofen which was admin is tered to the pa tient at one time, but she did not tol er ate the treat ment.
Sec ond line of ther apy is immunotherapy which is admin is tered when symp tom atic treat ment fails to im prove the pa tient's con di tion.Based on re search, immunotherapy is ef fec tive in 39-80% of cases, how ever, the con di tion of most pa tients re mains se vere and 30-57% of them require mo bil ity aid.In the re ported case, the symp toms exac er bated over time de spite con tin u ous symp tom atic treatment and re pet i tive plasmapheresis.Ac cord ing to the Amer i can So ci ety for Apheresis (ASFA), Guide lines on the Use of Ther a peu tic Apheresis in Clin i cal Prac tice, published 2019, SPS is con sid ered III cat e gory in di ca tion (opti mum role of apheresis ther apy is not es tab lished; de ci sion mak ing should be in di vid u al ized) with 2C grade of ev idence (weak rec om men da tion, low-qual ity or very lowqual ity ev i dence).The guide lines rec om mend that plasmapheresis should be ad min is tered only when response to con ven tional ther apy is in suf fi cient and in combi na tion with pharmacotherapy [21] which was pre cisely the strat egy cho sen in our case.Ac cord ing to dif fer ent stud ies, the ef fec tive ness of plasmapheresis in the treatment of SPS var ies, the im prove ment of symp toms can be di vided into 3 grades: Grade I -no clin i cal im prove ment, Grade II -min i mal or some im prove ments that do not result in sig nif i cant change in daily ac tiv i ties, and Grade IIIim prove ments are sig nif i cant to im pact daily ac tiv i ties [22].It is note wor thy that the re sponse of the same pa tient to plasmapheresis can dif fer dur ing the course of the disease [22][23][24][25] Ac cord ing to lit er a ture, in 50-80% of reported cases, pa tients show at least a short-term re gres sion of symp toms [22,23].Most au thors de scribe and rec ommend chronic plasmapheresis ther apy (1 ses sion ev ery 1-2 weeks) [23,24], but some de scribe cases of long-term re gres sion of symp toms af ter a sin gle cy cle of plasmapheresis [23].In our case, a dif fer ent strat egy was cho sen: plasmapheresis was ad min is tered only dur ing peri ods of symp tom ex ac er ba tion.The treat ment was success ful, as the pa tient's con di tion re mained sta ble over the past year, the symp toms have re gressed and are cur rently con trolled only by phar ma co log i cal treat ment.A sim i lar case was de scribed in 2014 by MB Pagano, when plasmapheresis ad min is tered ev ery few months dur ing peri ods of symp tom ex ac er ba tion re sulted in sta bi li za tion and im prove ment of the pa tient's con di tion [25].Dif ferences in treat ment ef fi ciency lead to the con clu sion that treat ment strat egy should be in di vid u al ized and cho sen in ac cor dance with the pa tient's tol er ance and re sponse to plasmapheresis [24].Most stud ies re port per sis tence of high lev els of se rum anti-GAD65 even with weekly plasmapheresis, but lev els of anti-GAD65 do not cor re late with the se ver ity of symp toms [22][23][24][25].One pos si ble expla na tion is the intrathecal syn the sis of anti-GAD65 and the lo cal ized ef fect on the CNS dur ing cir cu la tion in the CSF which is sep a rated from the blood se rum by blood-brain bar rier [15].An other ques tion arises: how and why does plasmapheresis im prove the con di tion of patients with out de creas ing anti-GAD65 blood se rum lev els?This can be ex plained by the elim i na tion of var i ous cytokines and other im mune re sponse com po nents from the blood se rum, thus mod u lat ing autoimmunity [24].
Other immunotherapy op tions in SPS in clude in tra venous im mu no glob u lin (IVIg) and rituximab, a monoclonal CD20 an ti body.How ever, in our case, good re sults were achieved with plasmapheresis, and other op tions were not ex plored.IVIg is widely used in clin i cal prac tice and is the only immunotherapy op tion that has been proven ef fec tive in clin i cal tri als.Rituximab is con sid ered by many au thors as the third choice of treat ment, as some stud ies re port occa sional ef fec tive ness of this agent.Rituximab is usu ally rec om mended when symp tom atic treat ment and immunotherapy with IVIg are in ef fec tive [4,7,20,26].

CON CLU SIONS
Clas si cal SPS is a rare dis ease of in sid i ous on set and progres sive course that is of ten misdiagnosed.Due to its frequent and sig nif i cant psy chi at ric symp toms such as anx iety, de pres sion, and pho bias com bined with ex ac er ba tion of symp toms re lated to emo tional stress, neu ro log i cal symp toms are of ten con sid ered to be sec ond ary and patients are of ten misdiagnosed with somatoform dys function of the au to nomic ner vous sys tem or anx i ety dis or der.In ev ery day clin i cal prac tice, the sus pi cion of this dis ease should be raised by spe cific comorbidities (TLE, late on set T1DM, and other en do crine dis or ders).The di ag no sis of SPS should be based on clin i cal and EMG find ings and detec tion of anti-GAD65 in blood se rum.First line of ther apy is symp tom atic, en hanc ing GABA-ergic trans mis sion: benzodiazepines (di az e pam) or baclofen (sec ond choice agent).Sec ond line of ther apy is immunotherapy that should be im ple mented when first line of treat ment is in effec tive.One of immunotherapy choices is plasmapheresis.In most cases, plasmapheresis yields lim ited re sults, namely a short-term clin i cal im prove ment, but in our case it was ef fec tive (grade III) and helped to im prove the patient's symp toms which re sulted in re stored func tion al ity in daily ac tiv i ties.