Jozef Michalik

Visual Evoked Potential and Magnetic Resonance Imaging are More Effective Markers of Multiple Sclerosis Progression than Laser Polarimetry with Variable Corneal Compensation

Background: The aim of our study was to assess the role of laser polarimetry and visual evoked potentials (VEP) as potential biomarkers of disease progression in multiple sclerosis (MS). Participants: A total of 41 patients with MS (82 eyes) and 22 age-related healthy volunteers (44 eyes) completed the study. MS patients were divided into two groups, one (ON) with a history of optic neuritis (17 patients, 34 eyes) and another group (NON) without it (24 patients, 48 eyes). The MS patients and controls underwent laser polarimetry (GDx) examination of the retinal nerve fiber layer (RNFL). In the MS group, we also examined: Kurtzke “expanded disability status scale” (EDSS), the duration of the disorder, VEP – latency and amplitude, and conventional brain magnetic resonance imaging (MRI). Our results were statistically analyzed using ANOVA, Mann–Whitney, and Spearman correlation analyses. Results: In the MS group, brain atrophy and new T2 brain lesions in MRI correlated with both VEP latencies and amplitudes. Separate comparisons revealed VEP latency testing to be less sensitive in ON than in NON-patients. In ON patients, VEP amplitudes correlated mildly with brain atrophy (ru2009=u2009−0.15) and strongly with brain new MRI lesions (ru2009=u2009−0.8). In NON-patients, highly significant correlation of new MRI brain lesions with VEP latencies (ru2009=u20090.63, ru2009=u20090.6) and amplitudes (ru2009=u2009−0.3, ru2009=u2009−4.2) was found. EDSS also correlated with brain atrophy in this group (ru2009=u20090.5). Our study did not find a correlation of GDx measures with MRI tests. The GDx method was not able to detect whole brain demyelinization and the degeneration process, but was only able to reveal the involvement of optic nerves in ON and NON-patients. Conclusion: In our study, we found that both methods (VEP and GDx) can be used for the detection of optic nerve damage, but VEP was found to be superior in evaluating whole brain demyelinization and axonal degeneration. Both VEP and MRI, but not GDx, have an important role in monitoring disease progression in MS patients, independent of the ON history.

Early and delayed auditory oddball ERPs and brain MRI in patients with MTBI

Introduction: Mild traumatic brain injury (MTBI) is a common neurotraumatologic diagnosis. It is possible to confirm objective cognitive impairment in MTBI patients not only by complex neuropsychological testing but also by event-related potentials (ERPs). The most common ERPs used in clinical practice are based on an oddball paradigm. Magnetic resonance imaging (MRI) is not routinely used in MTBI despite its proven greater sensitivity and specificity in comparison with computer tomography (CT). Methods: This study investigated 31 MTBI patients and 31 sex and age-matched healthy controls. Both groups underwent clinical neurological examinations. Auditory oddball ERPs and brain MRI were done early after the injury and 3–7 months later. Results: There were no significant sex, age and education differences between the analysed groups. No significant differences were found in N2 and P3 wave parameters in both ERP examinations. Conclusion: Standard auditory oddball ERPs are not sensitive enough to detect and/or quantify subtle objective neuropsychological changes in selected MTBI patients, especially those with traumatic MRI brain lesions. More complex auditory or other oddball paradigms have to be tested in the future.

Genetic variants in interleukin 7 receptor α chain (IL-7Ra) are associated with multiple sclerosis risk and disability progression in Central European Slovak population

In this study, we determined the association between rs6897932 in interleukin 7 receptor α (IL7Ra) gene and the risk and disability progression of multiple sclerosis (MS) in 270 MS patients and 303 controls. We found allele C to be associated with the risk of MS and minor allele T to be protective against MS development. Moreover, we revealed for the first time that rs6897932 in IL7Ra gene is associated with the progression of MS, evaluated by MSSS scores. The minor allele T and genotype TT are protective against a rapid disability progression in MS in the Central European Slovak population.

FokI vitamin D receptor gene polymorphism in association with multiple sclerosis risk and disability progression in Slovaks

Abstract Objective: It is still unclear as to why multiple sclerosis (MS) is so devastating and rapidly progressive in one patient and less so in another. Recent data implicate vitamin D in modulation of the risk as well as the clinical course of disease. Since vitamin D acts through the vitamin D receptor (VDR), association of single nucleotide polymorphisms (SNPs) in the VDR gene might account for variations in the MS risk within populations. The aim of our study was to determine the association between FokI gene polymorphism (rs10735810) and the risk of MS in a cohort of Slovak population and to investigate possible correlations of this SNP with the rate of disease disability progression. Methods: FokI SNP was detected in 270 clinically diagnosed MS patients and 303 healthy control subjects. Genotyping was performed by polymerase chain reaction (PCR) and restriction analysis. We used multiple sclerosis severity score (MSSS) for patient’s stratification by the rate of disease disability progression. Results: We observed a significantly higher frequency of Ff genotype of FokI SNP (53·4 vs 43·7%, P u200a=u200a 0·042) in women with MS compared to women of the control group. There was no significant association between FokI SNP and the rate of disease disability progression. Discussion: Although our findings suggest a weak association between VDR SNP FokI and the MS risk in women, further studies are needed to explore the role of VDR polymorphic alterations in MS disease etiology and pathogenesis.

ApaI, BsmI and TaqI VDR gene polymorphisms in association with multiple sclerosis in Slovaks

Objective: Vitamin D acts through vitamin D receptor (VDR) and has promising beneficial effects in the development and progression of multiple sclerosis (MS). The purpose of our study was to investigate the possible association of the VDR gene polymorphisms ApaI, BsmI and TaqI with the MS susceptibility and with the rate of disease disability progression in the Central European Slovak population. Methods: The allele and genotype variants of ApaI, TaqI and BsmI VDR gene polymorphisms were analysed in 270 clinically diagnosed MS patients and 303 healthy controls. Genotyping was performed by polymerase chain reaction and restriction analysis. Patients were stratified by the rate of disease disability progression using MSSS scores. Results: By logistic regression analysis, we revealed that genotype BB (AA) of BsmI VDR gene polymorphism is decreasing the risk of MS (BB (AA) vs Bb (AG) + bb (GG); OR = 0.59, 95% CI = 0.39–0.90, plog = 0.014). We did not identify any association of ApaI and TaqI polymorphisms neither with MS development nor with the disease progression. Discussion: We showed for the first time that BsmI genotype BB (AA) is associated with the decreased susceptibility to MS in Slovak population. We propose the BsmI gene polymorphism to be one of the important genetic markers in evaluation of the risk of MS. However, our data suggest that VDR gene polymorphisms ApaI, BsmI and TaqI are not useful in the prediction of disease disability progression rate in MS in Slovaks.

The association of HLA-DRB1 and HLA-DQB1 alleles with genetic susceptibility to multiple sclerosis in the Slovak population

Objective: The aim of the present study was to assess the association between HLA-DRB1 and -DQB1 allele groups with the genetic predisposition to multiple sclerosis (MS) in the Caucasian Central European Slovak population. Methods: A total of 282 unrelated patients with sporadic MS were enrolled in this case-control study. HLA-DRB1 and HLA-DQB1 allele groups were genotyped using a polymerase chain reaction with sequence-specific primers. The DRB1 and DQB1 allele carrier frequencies, genotypes and haplotype frequencies were compared between MS cases and healthy controls. Results: Positive association with MS was found for alleles HLA-DRB1*15 (OR = 3.64; Pcor = 6.9x10–11), DRB1*03 (after elimination of carriers of DRB1*15, OR = 2.8; Pcor = 0.0029), DQB1*06 (OR = 1.99; Pcor = 7.0x10–4), genotypes HLA-DRB1*15/*15 (OR = 7.6; Pcor = 0.001) and DQB1*06/*06 (OR = 3.81; Pcor = 4.0x10–4) and for haplotype DRB1*15-DQB1*06 (OR = 3.03; Pcor = 0.001). Carriage of alleles DRB1*07 (OR = 0.53; Pcor = 0.04), DRB1*13 (OR = 0.39; Pcor = 4.0x10–4), DQB1*03 (OR = 0.46; Pcor = 1.0x10–4), genotypes HLA-DRB1*13/*11 (OR = 0.12; Pcor = 0.004), DQB1*05/*03 (OR = 0.39; Pcor = 0.035), DQB1*03/*03 (OR = 0.38; Pcor = 0.029) and haplotypes DRB1*13-DQB1*06 (OR = 0.47; Pcor = 0.0128) and DRB1*11-DQB1*03 (OR = 0.58; Pcor = 0.0352) was found to be protective against MS development. Discussion: This is the first study performed to analyse the association of HLA-DRB1/DQB1 with susceptibility to MS in Slovakia. The results of our study confirm that HLA class II alleles, genotypes and haplotypes are associated with MS risk.

Tumefactive demyelination of the spinal cord: a case report.

Study design:Case report.Objectives:We report on a 52-year-old male patient with tumefactive demyelination of the spinal cord.Setting:University Hospital and Jessenius Faculty of Medicine, Comenius University, Martin, Slovakia.Background:In contrast to relatively frequent tumefactive fulminant lesions in the brain, cases affecting the spinal cord in isolation have been reported less frequently.Methods:Description of the case report.Results:Clinical, neuroradiological and necropsy findings are described in a 52-year-old man with tumefactive fulminant demyelination of the spinal cord. Progression of the demyelination process produced paraplegia, mild paresis of the right upper limb, neurogenic bladder and sensitive loss over 2 weeks. MRI scans revealed several ovoid lesions in cervical segments and tumefactive T2-hyperintense signals with oedema and post-contrast enhancement located in thoracic segments Th3 to Th6. Cerebrospinal fluid (CSF) examination displayed lymphomonocytic pleocytosis with normal proteinorhachia, positive CSF oligoclonal IgG bands (OCB) and elevated IgG index (1.55). Serum anti-AQP4-Ab was not tested. Stored frozen CSF samples were later repeatedly examined with negative findings of anti-AQP4-Ab. Treatment with high-dose methylprednisolon and plasma exchange had limited effect. Immunosuppressive medication was interrupted because of an acute urinary infection. The patient died suddenly because of pulmonary embolism as a secondary complication. Histopathology of the spinal cord confirmed active demyelination. We considered that tumefactive demyelination could be a variant of neuromyelitis optica.Conclusion:Our case could be anti-AQP4-Ab-negative longitudinally extensive transverse myelitis, a variant of neuromyelitis optica.

The age at onset in Multiple Sclerosis is associated with patient’s prognosis

BACKGROUNDnThe causes of the individual differences in the rate of disability progression in multiple sclerosis (MS) are still not completely clear. According to the long-term prognosis of MS patients, the search for new valuable prognostic markers of benign or malign MS is necessary.nnnOBJECTIVESnOur aim was to assess the possible association of MS onset age with the disease disability progression rate in Slovak patients with MS.nnnMETHODSnBy the unique pattern of evaluation of disability progression rate using Multiple Sclerosis Severity Score (MSSS), each of 270 MS patients was defined as slow-progressing, mid-rate progressing or rapidly progressing.nnnRESULTSnWe found a significant differences in the age at onset between MS patients with different rate of disability progression (p(K-W)<0,00005). The faster was a disability progression assessed by MSSS score, the higher was the MS onset age.nnnCONCLUSIONnWe showed for the first time in Central European Slovak population that MS onset age is an early marker that is in the positive correlation with disease disability progression rate, evaluated by MSSS score. We conclude that relapsing-remitting MS patients older at clinical onset have a higher risk of unfavorable prognosis (Tab. 2, Fig. 1, Ref. 21).

The +190 G/A (rs1799864) polymorphism in the C-C chemokine receptor 2 (CCR2) gene is associated with susceptibility to multiple sclerosis in HLA-DRB1*15:01-negative individuals.

C-C chemokine receptor 2 (CCR2) is one of the key players involved in the transmigration of mononuclear cells into the central nervous system (CNS) and subsequent development of multiple sclerosis (MS). The aim of the current study was to analyse the association of CCR2 +190 G/A (rs1799864) polymorphism with susceptibility to MS and its influence on the age at onset, severity and neurological disability in MS. CCR2 genotyping was carried out by a polymerase chain reaction with restriction fragment length polymorphism (PCR-RFLP) in 301 MS patients and 342 healthy controls. Logistic regression analysis suggested a marginally significant association between MS and rs1799864 A allele (AA+GA vs. GG, P=0.047, OR=1.50, 95% CI=1.00-2.25), however, after stratification of study groups for the presence of HLA-DRB1*15:01 risk allele, this association could be found in HLA-DRB1*15:01-negative individuals only (AA+GA vs. GG, P=0.014, OR=1.84, 95% CI=1.13-2.98). Furthermore, there was no association between CCR2 polymorphism and clinical features of MS. In conclusion, our results suggest that CCR2 +190 G/A polymorphism may increase the susceptibility to MS, but its action seems to be restricted to individuals who do not possess the major risk allele HLA-DRB1*15:01.

The HLA-DRB1 and HLA-DQB1 alleles are associated with multiple sclerosis disability progression in Slovak population

Abstract Objective: The aim of our present study was to analyse the association of HLA-DRB1 and -DQB1 alleles and genotypes with Multiple Sclerosis (MS) disability progression in a cohort of Central European Slovak population. Methods: The allele and genotype variants were analyzed in 282 non-related MS patients. Rate of disease disability progression was evaluated using EDSS score in the 5th, 7th, 10th, and 15th year of disease duration, time to reach EDSS score 3 and 5, and MSSS score. Genotyping was performed by polymerase chain reaction with sequence-specific primers. Results: We found that carriers of homozygous genotype for alleles DRB1*15 and DQB1*03 reached EDSS score 3 significantly earlier than non-carriers of these alleles (p = 0.0172; p = 0.00183, respectively). Genotype DQB1*03/03 carriage was also associated with significantly reduced time to reach EDSS score 5 (p = 0.00316). Lower EDSS score in the 5th year of disease duration was found in carriers of DRB1*07 allele (p cor = 0.028). When MSSS score was used, genotype DRB1*15/15 was found to be less frequent in slow progressing MS patients, when compared to MS patients with mid-rate and rapid disease disability progression (p cor = 0.0305). Discussion: We showed for the first time that HLA-DRB1 and -DQB1 genotypes are genetic markers associated with disability progression in Slovak MS patients. Genotypes DRB1*15/15 and DQB1*03/*03 were identified as short-term clinical negative prognostic factors, while allele DRB1*07 carriage appeared to be a positive prognostic marker of better MS outcome.