Slobodni laki lanci imunoglobulina u likvoru i serumu bolesnika s klinički izoliranim sindromom

doctoral thesis

• Title (english): Free light immunoglobulin chains in cerebrospinal fluid and serum in patients with clinically isolated syndrome
• Author: Marina Ćurlin
• Mentor: Nada Vrkić (mentor)
• Mentor: Vanja Bašić Kes (komentor)
• Committee member: Željka Vogrinc (predsjednik povjerenstva)
• Committee member: Lada Rumora (član povjerenstva)
• Committee member: Fran Borovečki (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of medical biochemistry and haematology); Zagreb
• Defense date and country: 2019-02-14, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Medical Biochemistry
• Universal decimal classification (UDC): 615 - Pharmacology. Therapeutics. Toxicology

Abstract

Uvod: Multipla skleroza (MS) je kronična upalna bolest središnjeg živčanog sustava (SŽS), a prvi napad bilježi se kao klinički izolirani sindrom (CIS). Dijagnostika uključuje u prvom redu nalaz magnetske rezonancije (MR) te dokazivanje intratekalne sinteze oligoklonskih IgG vrpci metodom izoelektričnog fokusiranja (IEF) s imunofiksacijom. Novija istraživanja pokazala su da likvor takvih bolesnika sadrži visoku koncentraciju slobodnih lakih lanaca, osobito kapa tipa (KFLC).
Svrha istraživanja bila je ispitati dijagnostičku i prediktivnu vrijednost određivanja slobodnih lakih kapa lanaca u cerebrospinalnoj tekućini (CSF) u usporedbi s kvalitativnim postupkom određivanja oligoklonskih vrpci (OB, u pacijenata s CIS-om koji su kroz dvije godine konvertirali u MS.
Metode i ispitanici: U 151 pacijenta primljenih na Klinici za neurologiju sa sumnjom na CIS mjereni su imunonefelometrijskom metodom KFLC, ukupni IgG i albumin u CSF-u i serumu, izračunati kvocijenti CSF/serum (QKFLC, QIgG i QAlb) i indeksi KFLCindeks (QKFLC/QAlb) te IgGindeks(QIgG/QAlb) u odnosu na albumin, te je izoelektričnim fokusiranjem s imunofiksacijom procijenjeno prisustvo OB-a. Na temelju kliničke slike, OB-a i magnetske rezonancije (MR) 50 pacijenata svrstano je u ostale neurološke bolesti (ONB), a 101 u CIS od kojih je 50 konvertiralo u MS (D-MS) unutar 2 godine.
Rezultati: Analizom i usporedbom ROC krivulja te usporedbom medijana KFLC parametara tražena je optimalna granična vrijednost u odnosu na dijagnozu CIS-a i konverziju u MS. ROC analiza za točnost detekcije intratekalne sinteze pokazala je najbolje rezultate za QKFLC s površinom ispod krivulje (AUC) od 0,891 uz graničnu osjetljivost od 0,027 s dijagnostičkom osjetljivošću od 73,2 % i specifičnošću od 96,0 %. Dijagnostička točnost KFLCindeksa za konverziju CIS-a u MS pokazala je AUC 0,840 i graničnu vrijednost 9,092. Vrijednosti QKFLC ispod 0,0148 i iznad 0,0270 upućuju da nije potrebno raditi metodu IEF-a s imunofiksacijom za dokazivanje OB-a. Vrijednost KFLCindeksa manja od 4,44 ne upućuje na konverziju u MS unutar dvije godine dok vrijednost KFLCindeksa iznad 104,54 upućuju na moguću dijagnozu MS.
Zaključak: Primjena KFLC parametara mogla bi poslužiti kao pretražna metoda, a OB bi se mogao koristiti samo u nerazjašnjenim kliničkim slučajevima. KFLC parametri u bolesnika koji su konvertirali u MS značajno su viši te svojom prediktivnom ulogom mogu pridonijeti ranoj dijagnozi i pravodobnoj terapiji.

Abstract (english)

Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) with the first relapse recorded as clinically isolated syndrome (CIS). The diagnostic primarily includes MRI findings and demonstration of intrathecal synthesis of oligoclonal IgG bands with a qualitative method of isoelectric focusing (IEF) with immunofixation. Recent studies have shown high concentrations of free light chains in CSF in these patients, especially kappa type (KFLC). The objective of the study was to evaluate diagnostic and predictive value of determination of KFLC in CSF compared to the qualitative procedure of determination of oligoclonal bands (OB) in patients with CIS who have converted to MS during a two-year period.
Methods and patients: For 151 patients with suspected CIS, who were admitted to Clinic of Neurology, concentrations of KFLC, total IgG and albumin in CSF and serum were measured by an immunonephelometric method. CSF/serum quotients (QKFLC, QIgG and QAlb) and indices KFLCindex (QKFLC/QAlb) and IgGindex(QIgG/QAlb) were also calculated with regards to albumin, and the presence of OB was assessed with isoelectric focusing. Based on the clinical picture, OB and MRI findings, 50 patients were classified as „other neurological diseases (OND)“ and 101 patients were classified as CIS, 50 of which converted to MS (D-MS) in a two-year period.
Results: An optimal cut-off was determined with analysis and comparison of ROC curve, and with median comparison of KFLC parameters, with regards to CIS diagnosis and conversion to MS. ROC analysis for accuracy of intrathecal synthesis showed the best results for QKFLC with AUC of 0.891 and cut-off of 0.027 with the diagnostic sensitivity of 73.2 % and specificity of 96.0 %. The diagnostic accuracy of KFLCindex for conversion of CIS to MS showed AUC of 0,840 and cut-off of 9.092. QKFLC values below 0.0148 and above 0.0270 indicate needlessness for a qualitative, technically demanding method of IEF with immunofixation for demonstration of OB. KFLCindex value below 4.44 in patients with CIS does not indicate conversion to MS inside a two-year period while value of KFLCindex above 104.54 is very indicative of this diagnosis.
Conclusion: The application of KFLC parameters could serve as a screening method, and OB could be used in undefined clinical cases only. KFLC parameters are significantly higher in patients who converted to MS, and can contribute to an early diagnosis and prompt therapy with their predictive role.

• Keywords: slobodni laki kapa lanci; multipla skleroza; klinički izolirani sindrom; oligoklonske IgG vrpce; izoelektrično fokusiranje; imunofiksacija
• Keywords (english): free light kappa chains; multiple sclerosis; clinically isolated syndrome; oligoclonal IgG bands; isoelectric focusing; immunofixation
• Language: croatian
• URN:NBN: urn:nbn:hr:163:709788
• Study programme: Title: Pharmacy and biochemistry; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor znanosti (doktor znanosti)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2019-10-14 11:24:45