Clinical Neuroscience

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

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

MARCH 30, 2018

Clinical Neuroscience - 2018;71(03-04)

DOI: https://doi.org/10.18071/isz.71.0081

[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.]

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

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

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

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

[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.]

Clinical Neuroscience

[Perinatal stroke - from symptoms to follow-up]

VOJCEK Eszter, CSÉCSEI Márta, FLACH Edina, RUDAS Gábor, GRÁF Rózsa, PRINCZKEL Erzsébet

[Background and purpose - We aimed to analyze patient characteristics of term neonates with the diagnosis of stroke between 2006 and 2017 at the 3rd level Neonatal Intensive Care Unit of the Szent János Hospital. Method - We conducted a retrospective and prospective analysis including 18 newborns with stroke. Presentation, imaging methods, etiology and clinical context were discussed. All patients had a follow-up at 2 years of age or later. Subject of the study - In the past 10 years 17 term born and one premature neonate born at 36 weeks of age were diagnosed with stroke in our unit. All patients were born at good condition generally with high Apgar scores (9±1). Cesarean section was performed in 4 cases. Results - With an estimated incidence of one in 1600-4000 births, the incidence of perinatal stroke in our unit was found to be the same as mentioned in the international databeses. Regarding imaging method, cranial ultrasound scan do not visualise arterial ischaemic stroke therefore head MRI is recommended. Neurological symptoms of the patients presented in the first two days of life. Etiology included thrombophilia (4/18), infection (4/18), vascular malformation (2/18), moderate asphyxia (2/18) and pre-eclampsia (2/18). Middle cerebral artery was involved in 50% while the anterior cerebral artery was affected in 33%. The stroke occured in the left hemisphaerium in 44%, in the right side in 39% and was bilateral in 17%. In two cases the stroke was diagnosed in utero. Early childhood developmental support resulted in average or above average gross and fine motor development and cognitive outcome. Conclusion - Presenting neurological symptoms tipically occur in the first few days after birth when perinatal stroke need to be considered among the broad spectrum of neonatal illnesses. Normal developmental outcome can be achieved even in cases of extensive brain damage with early childhood developmental support. Severely impaired development was observed in the cases of in utero stroke. Inherited prothrombotic disorders may have implications for subsequent pregnancies of the mother. ]

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

[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.]

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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

[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

Lymphopenia and tuberculous lymphadenitis under immunomodulatory agents in a multiple sclerosis patient: Follow-up of a challenging case

KOSEAHMET Basoglu Fulya, OZTURK Musa , CELIK R. Gokcen Gozubatik

Interferon-beta (IFN-β) 1a and glatiramer acetate (GA) are first-line therapies for multiple sclerosis (MS) with immunomodulatory effects. We present a patient who developed lymphopenia and tuberculous lymphadenitis under treatment with these agents. The female patient who at present 65 year old is followed at our MS outpatient clinics had received GA (20 mg/day, subcutaneous injection) and later IFN-β 1a (44 µg, thrice weekly, subcutaneous injection). During the course of her treatment, she developed mild to severe lymphopenia. A follow up thoracic spinal MRI (when lymphocyte count was 800/µl) showed multiple enlarged lymph nodes in the posterior mediastinum incidentally. Further investigation revealed tuberculous lymphadenitis. She received anti-tuberculosis (TB) treatment for nine months and her condition resolved. Although immunomodulatory treatments are considered safe with regard to opportunistic infections, and lymphopenia under these treatments are generally accepted as mild and asymptomatic, our experience was different with this patient. Further studies on the management of patients with lymphopenia and assessment of the risk of TB under immunomodulatory agents are needed.

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

[Diagnosis of multiple sclerosis: A review of the 2017 revisions of the McDonald criteria]

CSÉPÁNY Tünde

[The revolutionary progress of research in neuroimmu­nology has led to the introduction of disease modifying therapies in multiple sclerosis at the end of the last century. The International Panel on Diagnosis of Multiple Sclerosis originally proposed the 2001 McDonald criteria to facilitate the diagnosis of MS in patients with the first objective neurological symptom(s) suggesting demyelinating event, when magnetic resonance imaging is integrated with clinical and other paraclinical diagnostic methods. New terms have been introduced to substitute clinical information by MRI: dissemination in space - indicating a multifocal central demyelinating process and dissemination in time - indicating the development of new CNS lesions over time. The criteria for diagnosis of Multiple Sclerosis have continuously evolved, they were modified in 2005 and 2010 allowing for an earlier and more accurate diagnosis of MS over time, and they provided the most up-to-date guidance for clinicians and researchers. The last recommended revisions relied entirely on available evidence, and not on expert opinion thereby reducing the risk of the misdiagnosis. The 2017 McDonald criteria continue to apply primarily to patients experiencing a typical, clinically isolated syndrome. In this review, we provide an overview of the recent 2017 revisions to the criteria of dissemination in space and time with the importance of the presence of CSF-specific oligoclonal bands; keeping fully in mind that there is no better explanation for symptoms than diagnosis of MS. In the future, validation of the 2017 McDonald criteria will be needed in diverse populations. Further investigations are required on the value of new MRI approaches, on optic nerve involvement, on evoked potential and optical coherence tomography, in order to assess their possible contribution to diagnostic criteria.]