Učinak toksina botulinuma tipa – A na nemotoričke simptome u bolesnika s fokalnom distonijom

Miletić, Vladimir (2018) Učinak toksina botulinuma tipa – A na nemotoričke simptome u bolesnika s fokalnom distonijom. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Background: Traditionally, isolated adult-onset cervical dystonia (IAOCD) is considered as a ‘pure’ motor disorder. However, non-motor symptoms (NMS) are increasingly recognized as a part of IOACD phenotype. Cognitive functions in IAOCD were rarely investigated and poorly understood making this issue still a matter of debate. The aim of this prospective study was to investigate, for the first time, the effect of acute and long-term therapeutic applications (more than one year) of botulinum toxin type-A (BoNT-A) on NMS and cognitive functions in IAOCD patients previously not treated with BoNT-A. Design/Methods: The study included 51 IAOCD patients (29 females and 22 males) and 90 (50 female i 40 males) age, gender and education matched healthy controls. Questionnaires used in this study included: Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). Beck Depression Inventory – Second Edition (BDI-II), Beck Anxiety Inventory (BAI), Starkstein Apathy Scale (AS), Pitsburgh Sleep Quality Index (PSQI), Fatigue Severity Scale (FSS), Short Form-36 Health Survey (SF-36). Cognitive functions were assessed using Cogtest®, a computerized neurocognitive battery set of 5 tests: Auditory Number Sequencing (ANS), Spatial Working Memory (SWM), Strategic Target Detection (STD), Continuous Performance Test – Flanker version (Flanker CPT) and Tower of London (ToL). All of the above mentioned investigations were performed prior to initial BoNT-A application (first test). The follow-up was performed after 4 month (second test) and 12 to 16 months after initial BoNT-A application (third test). During the follow-up period the patients received 3 BoNT-A applications. Results: On initial investigation 46 (90,2%) IAOCD patients had at least one psychiatric disorder in comparison to 36 (40%) healthy controls. Mean BDI-II score, BAI score and AS score were significantly higher in IAOCD patients than in healthy controls (12,59 ± 6,28 vs. 6,11 ± 4,26, p<0,001; 13,59 ± 6,78 vs. 7,76 ± 4.95, p<0,001; 10,27 ± 5,09 vs.7,68 ± 4,35, p=0,002, respectively). Mean PSQI and FSS score were higher in IAOCD patients (4,90 ± 1,7 vs. 4,08 ± 1.44, p=0,003; 4,17 ± 1,2 vs. 3,50 ± 0,95; p<0,001, respectively). There were no differences between IAOCD patients and controls in determined variables of ANS and SWM tests (p>0,05). However, IAOCD patients had worse performance in STD, ToL, and Flanker CPT test (p<0,05). IAOCD patients had significantly reduced quality of life (QoL) determined by SF-36 questionnaire. During follow-up period, we found no significant difference in total BDI-II, BAI, AS, PSQI and FSS score between all three tests. Still, no difference in total AS score on third test was observed between IAOCD and control group, and improvement in total PSQI score was observed in second and third test when compared to initial one. Significant pain amelioration, unrelated to improvement of motor symptoms, was observed during follow-up period. Long-term BoNT-A applications had no effect on cognitive performance as measured by ANS, SWM, Flanker CPT and ToL test. Significant improvement was detected in variables of strategic efficiency and total perseverative errors of STD test, designed for evaluation of complex attention and processing speed. Improvement of QoL was observed in two SF-36 domains: bodily pain and general health perception. Conclusion: Spectrum of IAOCD symptoms includes various NMS such as pain, psychiatric comorbidities, impaired sleep quality, pathological fatigue, and cognitive dysfunction, especially in the domains of attention and executive functioning, thus implicating shared neurobiology of motor symptoms, NMS and cognitive dysfunction. Except for major analgesic effect and mild positive effect on sleep quality and apathy, long-term BoNT-A treatment had no statistically significant impact on other NMS. In addition, long-term BoNT-A application showed modest improvement of attention without any negative implication on other cognitive domains. Finally, we can say that in the dosages applied in this study (150-200U per application), BoNT-A is significantly effective in reducing pain and motor symptoms, probably minimally effective in improvement of sleep quality and apathy, ineffective in reducing anxiety, depression and fatigue. We did not find any negative influence of BoNT-A on cognitive functions with the applied objectivization methods, moreover, a slight improvement in complex attention and processing speed was found.

Abstract in Croatian

Uvod: Tradicionalno, izolirana cervikalna distonija (CD) odrasle dobi se smatra isključivo motoričkim poremećajem. Međutim, nemotorički simptomi (NMS) se sve više prepoznaju kao sastavni dio njenog fenotipa. Kognitivne funkcije CD bolesnika su rijetko ispitivane i nedovoljno objašnjene te i danas predstavljaju predmet rasprave. Cilj ovog prospektivnog istraživanja bio je po prvi put istražiti učinak akutne i dugotrajne terapijske primjene (duže od jedne godine) botulinum toksina tip-A (BoNT-A) na NMS i kognitivne funkcije CD bolesnika koji prethodno nisu liječeni BoNT-A. Ispitanici i metode: Istraživanje je uključilo 51 CD bolesnika (29 žena i 22 muškarca) prethodno neliječenog BoNT-A i 90 zdravih ispitanika (50 žena i 40 muškaraca) koji se po dobi, spolu i obrazovanju nisu razlikovali od grupe bolesnika. U ispitivanju su korišteni sljedeći upitnici: Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), Beck Depression Inventory – Second Edition (BDI-II), Beck Anxiety Inventory (BAI), Starkstein Apathy Scale (AS), Pitsburgh Sleep Quality Index (PSQI), Fatigue Scale (FSS), Short Form-36 Health Survey (SF-36). Kognitivne funkcije su ispitane pomoću Cogtest®, računalnog neurokognitivnog seta od 5 testova: Auditory Number Sequencing (ANS), Spatial Working Memory (SWM), Strategic Target Detection (STD), Continuous Performance Test – Flanker version (Flanker CPT) and Tower of London (ToL). Sva gore navedena ispitivanja provedena su prije prve primjene BoNT-A (prvi test). Drugo testiranje je učinjeno nakon 4 mjeseca, a treće nakon 12 do 16 mjeseci od prve primjene BoNT-A. Tijekom praćenja bolesnicima je u 3 navrata apliciran BoNT-A. Rezultati: Na prvom testiranju, 46 (90,2%) CD bolesnika su imala najmanje jedan psihijatrijski poremećaj u usporedbi s 36 (40%) zdravih kontrola. Prosječne vrijednosti BDI-II, BAI i AS skora bile su znatno veće kod CD bolesnika nego u kontrolnoj skupini (12.59 ± 6,28 vs. 6,11 ± 4,26, p <0,001; 13,59 ± 6,78 vs. 7,76 ± 4,95, p <0,001; 10,27 ± 5,09 vs.7,68 ± 4,35, p=0,002). Prosječne vrijednosti PSQI i FSS skora, također su bile veće u CD bolesnika (4,90 ± 1,7 vs. 4,08 ± 1,44, p=0,003; 4,17 ± 1,2 vs. 3,50 ± 0,95, p <0,001). Između kontrolne skupine i CD bolesnika nije postojala razlika u mjerenim varijablama ANS i SWM testa (p> 0,05). Međutim, CD bolesnici imali su statistički značajno lošije rezultate u STD, ToL i Flanker CPT testu (p<0,05). Kvaliteta života mjerena SF-36 upitnikom je bila značajno snižena u CD bolesnika. Tijekom jednogodišnjeg praćenja, nije pronađena značajna razlika u prosječnim vrijednostima BDI-II, BAI, AS, PSQI i FSS skora između sva tri testiranja. Ipak, usporedba AS skora CD bolesnika u trećem testiranju nije pokazala razliku s kontrolnom skupinom, a poboljšanje prosječnog PSQI skora zabilježeno je u drugom i trećem ispitivanju. Značajna redukcija boli, koja nije bila povezana s poboljšanjem motoričkih simptoma, zabilježena je tijekom jednogodišnjeg praćenja. Dugotrajna primjena BoNT-A nije imala utjecaja na mjerene varijable ANS, SWM, Flanker CPT i ToL kognitivnih testova. Značajno poboljšanje je zabilježeno tek u varijablama strateške učinkovitosti i ukupnog broja perseverirajućih grešaka u STD testu, namijenjenog procjeni kompleksne pažnje i brzine procesiranja. Poboljšanje kvalitete života uočeno je u dvije domene SF-36 upitnika: tjelesna bol i percepcija općeg zdravlja. Zaključak: Spektar simptoma CD uključuje razne NMS poput boli, psihijatrijskih poremećaja, smanjene kvalitete spavanja, patološkog umora i kognitivne disfunkcije, osobito u domeni pažnje i egzekutivne funkcije, što implicira zajedničku neurobiološku podlogu motoričkih simptoma, NMS i kognitivne disfunkcije. Osim jakog analgetskog učinka i skromnog pozitivnog učinka na kvalitetu spavanja i apatiju, dugotrajna primjena BoNT-A nije pokazala statistički značajan utjecaj na druge NMS. Dodatno, dugotrajna aplikacija BoNT-A je pokazala blago poboljšanje pažnje bez negativnih implikacija na druge kognitivne domene. Konačno, možemo reći da je primjena BoNT-A u dozama primijenjenim u ovoj studiji (150-200U po aplikaciji) izrazito učinkovita u smislu redukcije boli i motoričkih simptoma, moguće minimalno učinkovita u poboljšanju kvalitete spavanja i apatije, te neučinkovita u vidu redukcije anksioznosti, depresije i umora. Uz primijenjene metode objektivizacije nismo našli negativan utjecaj BoNT-A na kognitivne funkcije, štoviše, nađeno je blago poboljšanje kompleksne pažnje i brzine procesiranje.

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