Patogeneza sindroma posteriorne reverzibilne encefalopatije uzrokovanog citotoksičnom terapijom

master's thesis

• Title (english): Pathogenesis of Posterior Reversible Encephalopathy Syndrome (PRES) caused by cytotoxic therapies
• Author: Antonio Pozaić
• Mentor: Natalija Dedić Plavetić (mentor)
• Committee member: Branko Malojčić (predsjednik povjerenstva)
• Committee member: Jasenka Markeljević (član povjerenstva)
• Committee member: Natalija Dedić Plavetić (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; (Department of Pathophysiology); Zagreb
• Defense date and country: 2018-07-13, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences; Pathophysiology

Abstract

Sindrom posteriorne reverzibilne encefalopatije (PRES) je kliničko-radiološki sindrom obilježen glavoboljom, epileptičnim napadima, promijenjenim stanjem svijesti i smetnjama vida. Nespecifičnu kliničku sliku tipično prate radiološki nalazi simetričnog edema hemisfera u posterio-okcipitalnim regijama najbolje uočljivog pretragom magnetskom rezonancom (MR-om). Iako naziv sindroma ukazuje na reverzibilnost simptoma, moguća su trajna neurološka oštećenja i smrtni, prilikom čega letalitet može biti 15%. Najčešća stanja koja se povezuju s PRES-om su preeklampsija/eklampsija, transplantacija solidnih organa i koštane srži, autoimunosne bolesti, hipertenzija te imunosupresivna terapija i citotoksični lijekovi. Cilj ovog rada je ponuditi moguće mehanizme kojima citotoksični lijekovi uzrokuju PRES. Nijedna grupa citotoksičnih lijekova se nije konstantno povezivala sa nastankom PRES-a. Smatra se kako je endotelna disfunkcija glavni mehanizam kojim citotoksični lijekovi dovode do disrupcije krvno-moždane barijere i posljedičnog moždanog edema, a endotelna disfunkcija nastaje kao posljedica izravnog ili neizravnog djelovanja lijekova. Neki citotoksični lijekovi uzrokuju endotelnu disfunkciju uglavnom preko oksidativnog stresa. Osim endotelne disfunkcije, opisat ćemo kako drugi čimbenici rizika inducirani citotoksičnom terapijom, poput hipertenzije, hipoalbuminemije, hipomagnezemije i hiponatremije, doprinose nastanku PRES-a. Iako se smatralo kako je hipertenzija najvažniji pojedinačni čimbenik za nastanak PRES-a, ona bi u slučaju PRES-a induciranog citotoksičnim lijekovima bila posljedica endotelne disfunkcije, a ne njen uzrok. Hipomagnezemija se povezuje s povećanom endotelnom permeabilnošću, moguće zbog povećane ekspresije akvaporina 4, vodopropusnog transmembranskog proteina, a liječenje magnezijevim sulfatom smanjuje propusnost krvnomoždane barijere za 41% na životinjskim modelima. Hiponatremija smanjuje osmolalnost plazme, a hipoalbuminemija onkotski tlak, uzrokujući prijelaz tekućine iz vaskularnog u ekstravaskularni prostor. Navedeni čimbenici rizika naglašavaju važnost regulacije elektrolitnog disbalansa pri liječenju PRES-a, kao i regulaciju tlaka i plazmatske razine albumina.

Abstract (english)

Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiological syndrome characterized by headache, seizures, altered consciousness, and visual disturbance. Nonspecific symptoms are typically coupled with symmetric hemispheric edema in the posterio-occipital regions, best seen on MR. Although the name of the syndrome indicates it is reversible, permanent neurologic injury or death are possible. Lethality by PRES is 15%. Most frequent conditions associated with PRES are preeclampsia/eclampsia, solid organ and bone marrow transplantation, autoimmune diseases, hypertension and immunosupressive and cytotoxic drugs. The aim of this study is to propose a mechanism by which cytotoxic drugs cause PRES. No single antineoplastic class or agent has been consistently associated with PRES. It is believed that endothelial dysfunction is the main mechanism by which cytotoxic drugs lead to disruption of the blood-brain barrier and consequently to brain edema. Some cytotoxic drugs cause endothelial dysfunction, mostly by oxidative stress. Here we will also discuss how other risk factors, induced by cytotoxic drugs, such as hypertension, hypoalbuminemia, hypomagnesemia and hyponatremia, contribute to the development of PRES. Althought hypertension is the single most important risk factor for developing PRES, she is a consequence of endothelial dysfunction and not it's cause. Hypomagnesemia is associated with increased endothelial permeability, possibly because of an increased expression of aquaporin 4, a water-permeabile transmembrane protein. Not only that, magnesium sulphate reduces the blood-brain permeabilityby 41% in animal models. Hyponatremia decerases plasma osmolality and hypoalbuminemia decreases oncotic pressure, allowing fluid to leak out from the intravascular to extravascular space. These risk factors point out the importance of the correction of electroyite imbalance, as well as the blood pressure and plasma albumin levels.

• Keywords: sindrom posteriorne reverzibilne encefalopatije; citotoksični lijekovi; endotelna disfunkcija
• Keywords (english): posterior reversible encephalopathy syndrome; cytotoxic drugs; endothelial dysfunction
• Language: croatian
• URN:NBN: urn:nbn:hr:105:437766
• Study programme: Title: Medicine; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: doktor/doktorica medicine (doktor/doktorica medicine)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2019-03-21 13:13:01