Clinical Neuroscience

[The role of MRI in measuring the effectivity of disease modifying treatments I]

TÓTH Eszter1, BENCSIK Krisztina1, VÖRÖS Erika2, FRICSKA-NAGY Zsanett1, FÜVESI Judit1, RAJDA Cecília1, CSOMOR Angéla2, PALKÓ András2, VÉCSEI László1,3, KINCSES Zsigmond Tamás1,2

MARCH 30, 2018

Clinical Neuroscience - 2018;71(03-04)

DOI: https://doi.org/10.18071/isz.71.0077

[MRI has a significant role in the diagnosis of multiple sclerosis. The newer and newer treatment options of the disease make it necessary to monitor the effectiveness of the therapy. Besides the clinical signs (clinical relapses and progression), the different MRI parameters can also reflect the disease activity. In our current article we summarize those MRI markers, which best predict the long-term disability, based on the international standards.]

AFFILIATIONS

  1. Szegedi Tudományegyetem, Neurológiai Klinika, Szeged
  2. Szegedi Tudományegyetem, Radiológiai Klinika, Szeged
  3. MTA-SZTE, Idegtudományi Kutatócsoport, Szeged

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Clinical Neuroscience

[The role of MRI in measuring the effectivity of disease modifying treatments II]

KINCSES Zsigmond Tamás, TÓTH Eszter, FRICSKA-NAGY Zsanett, FÜVESI Judit, RAJDA Cecília, BENCSIK Krisztina, VÖRÖS Erika, CSOMOR Angéla, PALKÓ András, VÉCSEI László

[The paraclinical examinations, principally the MRI have an increasing significance in the diagnosis of multiple sclerosis. However, MRI markers also have a prominent role in monitoring of the disease-course and activity, and also in the planning of possible therapeutic changes. In accordance with previously published international guidelines, in this article we propose a protocol for the monitoring the treatment efficacy in multiple sclerosis. This could be the basis of a consensus based guideline to be implemented in Hungary.]

Clinical Neuroscience

Long-term follow-up results of concomitant chemoradiotherapy followed by adjuvant temozolomide therapy for glioblastoma multiforme patients. The importance of MRI information in survival: Single-center experience

LUKÁCS Gábor, TÓTH Zoltán, SIPOS Dávid, CSIMA Melinda, HADJIEV Janaki, BAJZIK Gábor, CSELIK Zsolt, SEMJÉN Dávid, REPA Imre, KOVÁCS Árpád

Introduction - Glioblastoma multiforme (GBM) is the most common malignant primary anomaly of central nervous system. The GBM infiltrates the nearly sturctures from the initial tumor and its metastatic attribution is well known. The aim of our single-centered retrospective study was to introduce the importance of postoperative medical imaging confirmation of total tumor resection for patient with GBM combined concomitant and adjuvant chemoradiotherapy on a 10 year long patient follow up. Methods - From January 2006 to April 2015 we registered 59 patients with newly diagnosed GBM at the University of Kaposvár Health Center Institute of Diagnostic Imaging and Radiation Oncology. The histological diagnosis was confirmed by a proficient neuropathologist (World Health Organisation WHO; grade IV astrocytoma). According to histological status if the ECOG performance status of patients allowed it the mutidisciplinary oncoteam recommended adjuvant chemoradiotherapy all features strictly by Stupp protocol. (60 Gy dose on the gross tumor volume and 2-3 cm margin for the clinical target volume with parallel 75 mg/m2 TMZ. Four weeks after monotherapial phase patients had to recieve 6 cycles of TMZ first cycle with 150 mg/m2 up to 200 mg/m2). The irradiation was carried out by a conformal three dimensional planning system. Results - 59 patients with the median age of 63 (range 17-84) year. Our sample counted 34 male patients and 25 woman patients. 14 patients underwent gross total tumor resection while, 39 patients underwent partial resection and the rest from our sample 6 patients passed through biopsy. Statistical analysis showed a lengthier survival among males than females, with a median survival of 13 months for males and females, the OS of 26.209 for males, meanwhile 15.625 for females. However, the difference is not considerable (log-rank p=0.203). Our study found that the estimated survival of patients at least 50 years old is significantly shorter at a median survival of 12 months (log rank p=0.027) than that of patients below 50 years of age at a median survival of 23 months. The longest estimated median survival was calculated with patients of ECOG '0' condition (16 months). However, no significant difference was found in the estimated survival of patients of different ECOG conditions (log-rank p=0.146). Based on the extent of surgery, complete resection resulted in the longest average survival of 36.4 months, followed by 21.5 months among patients with biopsy, and 15.8 months among patients with partial resection. Different surgical procedures, however, did not result in significant differences in survival (log-rank p=0.059). The overal survival of patients who had complete resection confirmed by MRI compared with the overal survival of patients with residual tumor confirmed by MRI as well we can estimate that there is significant difference between these two groups (p=0,004). Conclusion - Despite complex and intense treatment, recurrence is inevitable and causes relatively rapid death. In our analysis complete resection, as defined from the neurosurgeon’s report and postoperative MRI, resulted in an independently significant improvement in OS. Our results are the evidences that the treatment of patients with glioblastoma multiforme in Hungary is at least on the same level as any other developed European countries.

Clinical Neuroscience

[Changes of cognitive functions in healthy aging]

JUHÁSZ Dóra, NÉMETH Dezsõ

[Introduction - Mental health has crucial role in our life. Cognitive changes or decline can lead to many difficulties in daily routine of older people (e.g. organization of daily activities), which can, consequently, influence their well-being. Therefore it is an important question, which cognitive abilities are affected by age-related decline. Methods - In our study we aimed to investigate the changes of cognitive abilities in healthy older adults between 61 and 85 years of age compared to the performance of younger adults. Digit span, counting span, listening span, letter fluency, semantic fluency and action fluency tests were used to assess cognitive abilities, namely working memory and executive functions. Results - The results showed that younger adults performed significantly better in all tests than older adults. Importantly, the performance of older adults was better on tests requiring less complex mental computations (e.g. digit span test) than on more complex tests where both storing and mani-pulating information was required (e.g., counting span test). We also showed that within the older age group, cognitive functions’ decline was linearly associated with increasing age. Conclusion - The present study used several, well-established neuropsychological tests to map the changes of working memory and executive functions in healthy older adults between 61 and 85 years of age compared to younger adults. Our findings can contribute to the development of prevention programs aimed at improving the quality of life of older adults and preventing age-related cognitive decline.]

Clinical Neuroscience

[Nusinersen in the treatment of spinal muscular atrophy]

SINKÓ Gabriella, KISS Zsuzsanna, BERNADETTE Kalman

[Until recently, the diagnosis of spinal muscular atrophy (SMA) has been associated with severe life-long motor disability in adults and with early death in infants. The new experimental therapeutic approaches of the last few years have become more and more promising, while nusinersen was approved for the treatment of SMA in December 2016 in the USA, and in May 2017 in Hungary. Our paper presents mechanisms and clinical benefits of this new medication, and highlights some of the other therapeutic strategies still in experimental stages.]

Clinical Neuroscience

[Schizotypal traits and verbal creativity]

FEJES Nikolett Éva, RÓZSA Sándor, MUST Anita

[Introduction - The relationship of schizophrenia and its milder, subclinical forms, with creativity has been in the centre of theoretical interest for decades, however, the systematic research of the topic only prevailed more recently. Purpose - Here we aimed to examine the connection between different schizotypal and non-schizotypal personality traits and verbal creativity in a nonclinical sample. We also investigated the correspondence of two schizotypy inventories, the Oxford-Liverpool Inventory of Feelings and Experiences and a special character configuration of the Temperament and Character Inventory associated with schizotypy. Method - 57 healthy adults (14/43 m/f, mean age 21.51±1.43 years) - took part in the experiment. All participants received a detailed information sheet and gave informed consent prior to participation. Participants completed the Oxford-Liverpool Inventory and the Temperament and Character Inventory to measure both schizotypal and non-schizotypal personality traits. Torrance Test of Creative Thinking was used to measure verbal creativity. Associations between reported measures were examined with correlational and regression analyses. Results and conclusion - Out of the specific Temperament and Character configuration associated with schizotypy (low self-directedness, cooperativeness and high self- transcendence), we only found low self-directedness to be correlated significantly with Oxford-Liverpool schizotypy rates (Self-directedness-schizotypy: r=-.730, p<.01). There was no significant connection between schizotypal traits and verbal creativity. In our sample, the Self-directedness and Reward-dependence character and temperament subscales predicted significantly the verbal creativity level (Self-directedness: b=.330, p=.015; Reward - dependence: b=-.260; p=.049). Based on our results, besides schizotypal traits, other personality measures might be considered in relation to verbal creativity, providing further details to the empirical investigation of creativity. We found low self-directedness to be correlated with Oxford-Liverpool schizotypy rates, however, the sample size was not large enough to test the concurrent validity of the two inventories. Future studies might consider to extend the study sample, preferably to both clinical and non-clinical populations.]

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Clinical Neuroscience

Matrix metalloproteinases and their tissue inhibitors in relapsing remitting multiple sclerosis: Possible markers and treatment agents

SANLI Arzu, OZTURK Musa, SOYSAL Aysun, DOVENTAS Yasemin, BASOGLU Fulya, GOZUBATIK-CELIK R. Gokcen, BAYBAS Sevim

Matrix metalloproteinases (MMPs), which are synthesized by many cell groups and responsible for the destruction of matrix proteins, and endogen tissue inhibitors of MMPs (TIMPs) have a role in the pathogenesis of Multiple Sclerosis (MS) by affecting the blood-brain barrier. We aimed to investigate the role of MMPs and TIMPs in the immunopathogenesis and in the course of multiple sclerosis (MS). We enrolled 25 relapsing remitting MS patients, who had a definite MS diagnosis according to McDonald criteria and 25 healthy subjects similar for age and gender as control group. MMP-9- and TIMP-1 levels were measured twice in patient group (one time during an attack and one in remission) and once in healthy subjects. MMP-9- and TIMP-levels of patients during attack and remission period and MMP-9/TIMP-1 ratio were found significantly higher than in the control subjects. In patient group MMP-9 and TIMP-1 levels and MMP-9/TIMP-1 ratio during attacks were not significantly different than during remission period. However, when subdivided according to their number of attacks, patients with 2 attacks had significantly higher levels during attack period comparing to remission period (p<0.05); in case of patients with more than 2 attacks did not have a statistically significant difference in attack and remission periods. Matrix metalloproteinases are important actors in MS immunopathogenesis, particularly in the early period and inhibitor agents for these enzymes can be used as a treatment option.

Clinical Neuroscience

[Family planning in multiple sclerosis: conception, pregnancy, breastfeeding]

RÓZSA Csilla

[Family planning is an exceptionally important question in multiple sclerosis, as women of childbearing age are the ones most often affected. Although it is proven that pregnancy does not worsen the long-term prognosis of relapsing-remitting multiple sclerosis, many patients are still doubtful about having children. This question is further complicated by the fact that patients – and often even doctors – are not sufficiently informed about how the ever-increasing number of available disease-modifying treatments affect pregnancies. Breastfeeding is an even less clear topic. Patients usually look to their neurologists first for answers concerning these matters. It falls to the neurologist to rationally evaluate the risks and benefits of contraception, pregnancy, assisted reproduction, childbirth, breastfeeding and disease modifying treatments, to inform patients about these, and then together come to a decision about the best possible therapeutic approach, taking the patients’ individual family plans into consideration. Here we present a review of relevant literature adhering to international guidelines on the topics of conception, pregnancy and breastfeeding, with a special focus on the applicability of approved disease modifying treatments during pregnancy and breastfeeding. The goal of this article is to provide clinicians involved in the care of MS patients with up-to-date information that they can utilize in their day-to-day clinical practice. ]

Clinical Neuroscience

[Controversies in neurology: Diagnosis, follow up and therapy of multiple sclerosis with pathomechanismal approach]

VÉCSEI László

[The clinical boundaries between the relapsing and progressive course of multiple sclerosis are often indistinct. Despite the variable patterns of evolution, there are no biological reasons for discerning different multiple sclerosis phenotypes. Indeed, both primary progressive and secondary forms of the disease share similar pathological features in respect of the extent of inflammatory infiltrates, axonal damage, and cortical demyelination. The data indicating that primary progressive multiple sclerosis is preceded by an asymptomatic relapsing remitting phase. The proposed definition of secondary progressive multiple slcerosis, the attainment of at least EDSS of 4 is required to mark the transition to the progressive phase. Therefore, the clinical progress can be uncovered in the early phase of the disease. Furthermore, a continuous progression independent of relapsing activity is commonly observed during the relapsing remitting phase. A continuous smouldering process underpins the subtle clinical deterioration, which stands out as an important unmet treatment target. Concerning cognitive dysfunction of the patients pro-inflammatory cytokines have been associated with worse cognition in active multiple sclerosis, and this inflammatory milieu could also contribute to altered mentation during relapses. Therefore, long before people with multiple sclerosis become physically disabled, they have usually acquired hidden disabilities related to cognitive impairment. Silent progression appears during the relapsing remitting phase and it associates with brain atrophy. This suggests that the same process that underlies secondary progressive multiple sclerosis likely begins far earlier than is generally recognized. This supports a unitary view of multiple sclerosis biology. ]

Clinical Neuroscience

[Current questions of multiple sclerosis: the secunder progressive form of the disease]

VÉCSEI László

[Recent data suggest that long-term worsening is common in relapsing-remitting multiple sclerosis patients and is largely independent of relapses or new lesion formation on brain MRI. The current definition of secunder progressive multiple sclerosis is worsening of disability independent of relapses over at least 6-month interval. Early focal inflammatory disease activity and spinal cord lesion are predictors of very-long term disease outcomes in relapse - onset multiple sclerosis. The potential of PET imaging to visualize hidden inflammation in MS brain in vivo is an important contribution for better understanding the progression of the disease. Therefore, PET imaging is a promising tool in detecting the conversion from relapsing remitting multiple sclerosis to secunder progressive form of multiple sclerosis. Furthermore, neuro-axonal damage is the pathological substrate of permanent disability in different neurological disorders including multiple sclerosis. The neurofilament proteins have promise in this context because their levels rise upon neuro-axonal damage not only in the cerebrospinal fluid but also in blood. Patients with increased serum levels of neurofilament at baseline, independent of other clinical and MRI variables, experience significantly more brain and spinal cord volume loss over 2 years and 5 years of follow-up. The kynurenine-pathway abnormalities may be associated with the swich from early-mild stage multiple sclerosis to debilitating progressive forms of the disease. Analysis of these metabolites in serum may have application as multiple sclerosis disease biomarkers. Free radical action has been suggested as a causal factor in the illness. Increased free radical production and consumption of the scavenger molecules were found during the active phase of the disease. Based on the clinical findings (EXPAND Study) and pathomechanism of the disease siponimod is approved by the US Food and Drug Administration for the treatment of relapsing remitting forms of multiple sclerosis, to include secunder progressive multiple sclerosis with active disease, relapsing-remitting multiple sclerosis and clinically isolated syndrome.]

Clinical Neuroscience

[Health status and costs of ambulatory patients with multiple sclerosis in Hungary]

PÉNTEK Márta, GULÁCSI László, RÓZSA Csilla, SIMÓ Magdolna, ILJICSOV Anna, KOMOLY Sámuel, BRODSZKY Valentin

[Background and purpose - Data on disease burden of multiple sclerosis from Eastern-Central Europe are very limited. Our aim was to explore the quality of life, resource utilisation and costs of ambulating patients with multiple sclerosis in Hungary. Methods - Cross-sectional questionnaire survey was performed in two outpatient neurology centres in 2009. Clinical history, health care utilisation in the past 12 months were surveyed, the Expanded Disability Status Scale and the EQ-5D questionnaires were applied. Cost calculation was conducted from the societal perspective. Results - Sixty-eight patients (female 70.6%) aged 38.0 (SD 9.1) with disease duration of 7.8 (SD 6.7) years were involved. Fifty-five (80.9%) had relapsing-remitting form and 52 (76.5%) were taking immunomodulatory drug. The average scores were: Expanded Disability Status Scale 1.9 (SD 1.7), EQ-5D 0.67 (SD 0.28). Mean total cost amounted to 10 902 Euros/patient/year (direct medical 67%, direct nonmedical 13%, indirect costs 20%). Drugs, disability pension and informal care were the highest cost items. Costs of mild (Expanded Disability Status Scale 0-3.5) and moderate (Expanded Disability Status Scale 4.0-6.5) disease were 9 218 and 17 634 Euros/patient/year respectively (p<0.01), that is lower than results from Western European countries. Conclusion - Our study provides current inputs for policy making and contributes to understanding variation of costof- illness of multiple sclerosis in Europe.]