Morphological and clinical correlations in different forms of dystonia

Distonija predstavlja heterogeno oboljenje, kako po pitanju fenotipskog ispoljavanja, tako i po pitanju etiologije. Pored dobro poznatih motornih karakteristika (akciono pojačanje, fenomeni prelivanja i mirror pokreta, itd), nedavno su prepoznati i različiti nemotorni simptomi, uključujući psihijatrijske smetnje. Iako su rezultati neurovizuelizacionih studija kontradiktorni, u različitim formama distonije su pokazane promene u bazalnim ganglijama (BG), senzorimotornom korteksu i cerebelumu, kao i u cerebelotalamokortikalnim putevima. Najnoviji stavovi ukazuju na to da distonija predstavlja „bolest mreže“ i da može nastati usled disfunkcije ili poremećene komunikacije između bilo kojih tačaka u mreži. Ciljevi: Osnovni ciljevi studije su: 1) Ispitivanje obrasca fenotipskog ispoljavanja i karakteristika kliničkog toka u različitim formama distonije (fokalne-FokD, genetski definisane-GenD i funkcionalne distonije-FunkD); 2) Analiza psihijatrijske osnove, tj. psihijatrijskih komorbiditeta i procena profila ličnosti kod obolelih od funkcionalne distonije u poređenju sa obolelima od „organske distonije“; 3) Ispitivanje specifičnosti obrasca morfoloških i funkcionalnih promena u različitim formama fokalne distonije; 4) Ispitivanje strukturnih promena u genetskim formama distonije; 5) Ispitivanje morfoloških i funkcionalnih izmena u funkcionalnoj distoniji. Metode: U studiju je uključeno 205 bolesnika sa dijagnozom distonije, od toga 116 FokD, 41 GenD, 48 FunkD, koji su dalje uključeni u različite modalitete ispitivanja. Prvo se pristupilo analizi fenotipskog ispoljavanja, u okviru kojeg je u grupi FunkD korišćena klaster analiza, kao i prospektivno praćenje za definisanje dva različita fenotipa. Zatim je rađeno ispitivanje psihijatrijskih komorbiditeta i profila ličnosti u grupi FunkD u poređenju sa „organskom“ (primarnom) distonijom PrimD (FokD i GenD bolesnici upareni po polu, uzrastu i distribuciji distonije) korišćenjem široke palete neuropsihijatrijskih upitnika, uz psihijatrijski pregled. Drugi deo studije se odnosio na neurovizuelizacione metode. U sve 3 grupe bolesnika i u grupi zdravih kontrola (ZK) (83 ispitanika) rađeno je magnetno rezonatno (MR) snimanje mozga i pri tome su dobijeni trodimenzionalni T1 snimci, difuzioni tenzorski (DT) snimci, i funkcionalna MR u mirovanju. Procenjena je debljina korteksa pomoću morfometrije zasnovane na površini, supkortikalni volumeni sive mase (SM), DT MR merenja bele mase (BM). Ispitana je funkcionalna MR u mirovanju korišćenjem slobodnog pristupa. Zatim je u grupi FunkD ispitano funkcionalno povezivanje određenih regiona od interesa koji čine deo emocionalno-kognitivne mreže i učestvuju u definisanju motornog fenotipa. Rezultati: Analiza fenotipa: Bolesnici sa fokalnim distonijama su ispoljili očekivane fenotipske karakteristike, dok su nosioci genetskih mutacije prezentovali značajnu fenotipsku heterogenost, čak i unutar porodica. U grupi FunkD definisana sa dva različita fenotipa. Jedan fenotip – fiksne distonije (FiksFunkD) karakteriše početak simptoma u sredini tridesetih godina života, izražen bol, rani fiksni, abnormalni položaj koji uglavnom zahvata ekstremitete, često udružen sa sindromom kompleksnog regionalnog bola, sa progresivnom deterioracijom simptoma. Drugi fenotip – mobilne distonije (MobFunkD) karakterišu statičke ili akcione intermitentne mišićne kontrakcije koje uzrokuju abnormalne položaje i pokrete, uglavnom, ali ne isključivo, sa kranijalnom i cervikalnom distribucijom, uz relapsno-remitentan klinički tok. Psihijatrijska osnova: Gotovo polovina bolesnika sa FunkD je lečena psihijatrijski pre pojave distoničnih simptoma, a najčešći psihijatrijski komorbiditet je depresivni poremećaj, kako pre početka pojave distoničkih fenomena, tako i tokom trajanja FunkD. U poređenju sa PrimD, kod bolesnika sa FunkD značajno češće je zabeležen precipitirajući stres, viši skorovi na skalama za procenu apatije, disocijativnih i somatoformnih fenomena, kao i prisustvo znaka La Belle Indifférence. Kao nezavisni prediktori FunkD izdvojili su se znak La Belle Indifférence, stres pre početka distonije i prethodno psihijatrijsko oboljenje. Bolesnici sa FunkD su imali nižu ekstroverziju i otvorenost ka iskustvu nego pacijenti sa PrimD...Dystonia is a heterogeneous disorder, both in terms of phenotypic manifestation and etiology. In addition to well-known motor characteristics (action reinforcement, overflow phenomena, mirror movements, etc.), non-motor symptoms, including psychiatric disorders, have recently been recognized recently. Although the results of neuroimaging studies are conflicting, changes in basal ganglia (BG), sensorimotor cortex and cerebellum, as well as cerebello-thalamo-cortical pathways have been shown in various forms of dystonia. The new model indicates that dystonia is a "disorder of network" that can occur due to dysfunction of one node or more nodes, or disturbed communication between them. Objecitves: The main objectives of our study are: 1) to examine the pattern of phenotypic expression and clinical course in various forms of dystonia (focal dystonia-FocD, genetically defined dystonia- GenD and functional dystonia-FuncD); 2) to analyse the psychiatric background, i.e. psychiatric comorbidity and personality profile in patients with FuncD compared to those with "organic” dystonia; 3) to investigate the specificity of the pattern of morphological and functional brain changes in different forms of focal dystonia; 4) to investigate morphological changes in hereditary dystonia; 5) to investigate morphological and functional brain changes in functional dystonia Methods: The study included 205 patients diagnosed with dystonia (116 FocD, 41 GenD, 48 FuncD) who were further involved in different modalities of examination. First, the analysis of phenotypic expression was done. Cluster analysis and follow-up study were used for definition of two different phenotypes of FuncD. Then, psychiatric comorbidity and personality profile in FuncD group were compared with "organic" primary dystonia PrimD (FocD and GenD patients matched by sex, age and distribution of dystonia) using a number of neuropsychiatric questionnaires, and psychiatric interview. The second part of the study concerned neuroimaging methods. Three different groups of patients and the group of healthy controls (HC) underwent three-dimensional T1-weighed, diffusion tensor (DT) MRI, and resting-state functional MRI (RS-fMRI). We assessed cortical thickness with surface-based morphometry, subcortical volumes using region of interest, and DT MRI and RS fMRI using a free model approach. Further, in the FuncD group, the functional connectivity of certain regions of interest that form the emotional-cognitive network and are involved in the definition of motor phenotype were examined using “seed”-based approach. Results: Phenotype analysis: Patients with focal dystonia exhibited the expected phenotypic characteristics, while genetic mutation carriers presented significant phenotypic heterogeneity, even within families. Two different phenotypes were defined in the FuncD group. One phenotype –fixed dystonia (FixFuncD) was characterized by the onset of symptoms in the middle of the thirties, prominent pain, early fixed, abnormal posture that mainly involves extremities, often associated with a complex regional pain syndrome, with progressive deterioration of symptoms. Another phenotype – mobile dystonia (MobFuncD) was characterized by static or action intermittent muscular contractions that cause abnormal postures and movements, mainly but not exclusively, with cranial and cervical distribution, with relapse-remitting clinical course. Psychiatric background: Almost half of patients with FuncD had been treated psychiatrically prior to dystonia onset. The most common psychiatric comorbidity was a depressive disorder, both before the onset of dystonia and actually. Precipitating stress, higher scores on the apathy, dissociative and somatoform scales, and the presence of the La Belle Indifférence sign were significantly more frequent in patients with FuncD in comparison with PrimD. La Belle Indifférence sign, stress before the onset of dystonia and previous psychiatric disorder were independent predictors of FuncD. Patients with FuncD had lower extroversion and openness to experience than patients with PrimD Structural and functional characteristics of focal dystonia: Findings characteristic for task nonspecific dystonia (TNSD) were focal cortical changes (atrophy of the right inferior frontal gyrus) and reduced resting-state functional connectivity within the left frontoparietal network..