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Clinical Neuroscience

SEPTEMBER 30, 2020

[Pompe disease treated with enzyme replacement therapy in pregnancy]

GROSZ Zoltán, VÁRDI Visy Katalin, MOLNÁR Mária Judit

[Pompe disease is a rare lysosomal storage disease inherited in a recessive manner resulting muscular dystrophy. Due to the lack of the enzyme alpha glucosidase, glycogen accumulates in the cells. In the infantile form of Pompe disease hypotonia and severe cardio-respiratory failure are common leading to death within 2 years if left untreated, while the late-onset form is characterized with limb-girdle and axial muscle weakness accompanied with respiratory dysfunction. Pompe disease has been treated with regular intake of the missing enzyme since 2006, which significantly improved the survival and severity of symptoms in patients of both subtypes. The enzyme replacement therapy (ERT) is safe and well tolerated. However, limited data are available on its use in pregnancy. Our goal is to share our experience and review the literature on the safety of enzyme replacement therapy for Pompe disease during pregnancy and post partum.]

Lege Artis Medicinae

SEPTEMBER 30, 2020

[The pain-trigger role of cytokines in the nervous system – the direct analgesic effect of anti-cytokine therapy ]


[Nociceptive, neuropathic and central me­chanisms are involved in the perception, transmission and processing of chronic pain and shaping of cerebral pain image. Alar­mins – molecules alarming defence and signing the presence of pathogens and tissue damage - trigger a series of pathogenic events resulting in inflammatory pain stimuli. Proinflammatory cytokines play a determining role in the pain perception at the level of the nervous system. Continuous inflammatory stimuli while sensitizing the periferic and central neurons activate the pain-related cerebral areas and develop the complex pain image, the pain matrix. Ce­reb­ral functional connections are operating in networks and can be visualized by functional MRI. Cytokines activate the neurons directly or indirectly by other neuromediators. Cytokine receptors are expressed on no­ciceptors and even on higher-level neurons and on various non-neural cells, such as microglia and astrocytes. The most ubiquitous cytokines are the Tumour Necrosis Factor and Interleukin 6 in the nervous sys­tem. The signaling pathways are the Nuclear Factor κB and the Janus-kinase enzyme system. The proinflammatory cytokines and the Janus-kinase are therefore primary therapeutic targets. Anti-cytokine biologicals and small molecular kinase inhibitors decrease the pain and improve functional activity in rheumatoid arthritis. Decrease of pain was more pronounced than expected only from the decrease of the clinical biomarkers of inflammation. The early and ra­pid painkiller effect of targeted biological and chemical-biological response modifiers is attributed to their direct analgesic effect on the brain.]

Clinical Neuroscience

MAY 30, 2020

[The long-term follow-up of enzyme replacement treatment in late onset Pompe disease]

MOLNÁR Mária Judit, BORSOS Beáta, VÁRDI Visy Katalin, GROSZ Zoltán, SEBÕK Ágnes, DÉZSI Lívia, ALMÁSSY Zsuzsanna, KERÉNYI Levente, JOBBÁGY Zita, JÁVOR László, BIDLÓ Judit

[Pompe disease (PD) is a rare lysosomal disease caused by the deficient activity of acid alpha-glucosidase (GAA) enzyme due to mutations in the GAA gene. The enzymatic deficiency leads to the accumulation of glycogen within the lysosomes. Clinically, the disease has been classically classified in infantile and childhood/adult forms. Presently cc. close to 600 mutations distributed throughout the whole gene have been reported. The c.-32-13T>G splice mutation that is very common in patients of Caucasian origin affected by the childhood/adult form of the disease, with an allelic frequency close to 70%. Enzyme replacement treatment (ERT) is available for the patients with Pompe disease (Myozyme). In this paper, we are presenting the long term follow up of 13 adult onset cases treated more than 5 years. The longest follow up was 15 years. To evaluate the treatment efficacy, the 6 minutes walking test (6MWT) and the respiratory functions were monitored annually. The analysis revealed that at the beginning of ERT for 3-4 years the 6MWT had been generally increasing, then it declined, and after 10 years it was lower in 77% of the cases than it had been at the start of the treatment. In 23% of the cases the 6MWT increased during the follow up time. Only one of the patients become wheelchair dependent during the follow-up period. The respiratory function showed similar results especially in supine position. A high degree of variability was observed among patients in their responses to the treatment, which only partially associated with the antibody titer against the therapeutic protein. The efficacy of the ERT was associated with the type of the disease causing mutation, the baseline status of the disease, the lifestyle and the diet of the patient. The long-term follow up of the patients with innovative orphan drugs is necessary to really understand the value of the treatment and the need of the patients.]

Lege Artis Medicinae

NOVEMBER 15, 2019

[Hypertension in the elderly ]

BARNA István

[Elevated isolated systolic pressure is the most common and greatest cardiovascular risk factor with age. The prevalence of hypertension increases with age and ex­ceeds 60% over 70 years. Proper treatment of hypertension in the elderly, even in very old age (> 80 years), increases life expectancy and reduces the risk of cardiovascular events. For patients over 65 years of age, the target blood pressure range is between 130-139 / 70-80 mmHg if the patient tolerates the treatment. In elderly patients with poorer conditions, systolic blood pressure may be <150 mmHg. White-coat hypertension is common, nondipper ratio is increased, autonomic nervous system dysregulation is more common, and orthostatic decrease of blood pressure. The renal function is decreased or already impaired, often resulting in poorer therapeutic cooperation due to impaired cognitive function. The blood pressure lowering effect of targeted lifestyle changes may be the same as medication monotherapy, with the main disadvantage of decreasing adherence over time, for which a proper physician-patient relationship is essential. First-line agents for the treatment of elderly hypertension include angiotensin converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs), long-acting calcium channel blockers, and thiazide, thiazide-like diuretics. Beta-blockers should be used in the treatment of elderly hypertension if they have other indications (coronary heart disease, heart failure, arrhythmias). More than 70% of hypertensive patients should use combination therapy to achieve target blood pressure. Take advantage of fixed dose combination to improve compliance to optimize treatment. ]

Hypertension and nephrology

MAY 10, 2019

[One-year persistence of fixed-dose combinations of angiotensin-converting enzyme inhibitor and calcium channel blocker in hypertensive patients]


[Introduction: The most recent European guidelines for the treatment of hypertension suggest the use of renin-angiotensin-aldosterone system antagonists (RAAS inhibitors) and calcium channel blockers (CCBs) or diuretics fixed-dose combinations (FDCs) as the first therapeutic option. In antihypertensive therapy, the patient’s adherence is one of the most important factors in reducing unwanted cardiovascular events. Aim: Our aim was to assess the one-year persistence of angiotensin-converting enzyme inhibitor (ACEI) and CCB FDCs in hypertensive patients. Method: Authors have analysed the prescription database of the National Health Insurance Fund in Hungary on pharmacy claims between October 1, 2012 and September 30, 2013. Those patients were identified who filled prescriptions for FDCs of ACEI and CCBs prescribed for the first time for hypertensive patients and who had not re ceived similar drugs during the year before. Apparatus of survival analysis was used, where ‘survival’ was the time to abandon the medication. Results: 124,388 patients met the inclusion criteria. One-year persistence rate and hazard ratio (HR) of discontinua tion in patients with ramipril/amlodipine FDC was 54% (HR = 1.00, reference), perindopril/amlodipine 47% (HR = 1.30, p<0.0001), lisinopril/amlodipine 36% (HR = 1.79, p<0.0001), ramipril/felodipine 26% (HR = 2.28, p<0.0001) and trandolapril/verapamil 12% (HR = 4.13, p<0.0001). The average survival time of drug limited to 360 days was 270.2 days for ramipril/amlodipine FDC, 242.7 days for perindopril/amlodipine FDC, 211.2 days for lisinopril/amlodipine FDC, 186.3 days for ramipril/felodipine FDC and 125.7 days for trandolapril/verapamil FDC. Conclusions: The authors demonstrated that the one-year persistence of ACEI/CCB FDCs was significantly different in hypertensive patients. Ramipril/amlodipine FDC was more advantageous for patient adherence.]

Hypertension and nephrology

FEBRUARY 20, 2019

[The importance of statin therapy in hypertension]

PARAGH György, PÁLL Dénes

[Hypertension and hypercholesterolaemia often co-occur and promote early cardiovascular disease. Previous studies have shown that antihypertensive treatment may be more effective if LDL cholesterol is also reduced. This may be due to the increased expression of angiotensin-1 receptor in hypercholesterolaemia, which increases peripheral vascular resistance through angiotensin-2, and adversely affects endothelial and smooth muscle cells. Other authors indicate that high cholesterol levels increase the production of angiotensin-2 through the activation of the chymase system. High cholesterol levels increase the amount of circulating oxidized LDL which binds to the transmembrane oxidized LDL receptor (LOX- 1) also activates the angiotensin-1 receptor. In addition, angiotensin-2 has an effect on intracellular cholesterol synthesis by enhancing the key enzyme of the synthesis of intracellular cholesterol, HMG-CoA reductase. The authors present the studies that support cholesterol lowering can contribute to lowering blood pressure and other major meta-analyses in which the beneficial effects of cholesterol lowering and lipid lowering on blood pressure reductions were not proven. In the background, it may well be that these studies are not designed to evaluate the effect of cholesterol-lowering drugs on hypertension in patients with hypercholesterolaemia, and non-statin-treated patients are not randomized.]

Clinical Neuroscience

JANUARY 30, 2019

Additional value of tau protein measurement in the diagnosis of Creutzfeldt-Jakob disease

CSEH Katalin Edina, VERES Gábor, DANICS Krisztina, SZALÁRDY Levente, NÁNÁSI Nikolett, KLIVÉNYI Péter, VÉCSEI László, ZÁDORI Dénes

Since the definite diagnosis of Creutzfeldt-Jakob disease (CJD) can currently only be provided by autopsy, there is a special need for fine diagnostic tools in live patients to achieve accurate diagnosis as early as possible. The aim of this study was to perform a preliminary retrospective analysis on the utility of the measurement of total Tau (tTau) and some other biomarkers from the cerebrospinal fluid (CSF) of patients with rapidly progressive dementia in the diagnostic work up of CJD. Beside the assessment of relevant clinical data and the findings of electroencephalography and brain magnetic resonance imaging, the presence of 14-3-3 protein and the levels of tTau were determined by Western blot technique and enzyme-linked immunosorbent assay from the CSF of 19 patients diagnosed with rapidly progressive dementia between the period of 2004-2017 at the Department of Neurology, University of Szeged. This preliminary study provided 100% sensitivity for 14-3-3, and interestingly, only 40% specificity to support the clinical diagnosis of CJD. Regarding tTau, the sensitivity values were calculated to be 100% or 83%, whereas the specificity values were 71% or 86%, depending on the applied cut-off levels. The poor specificity of 14-3-3 is not in line with literature data and may be the result of the small number of patients in the cohort with non-prion disease, predominantly consisting of disorders with considerable tissue damage, whereas tTau presented good sensitivity and specificity values. The combined application of these and novel chemical biomarkers may increase both sensitivity and specificity to a desired level.

Lege Artis Medicinae

AUGUST 30, 2018

[Vision or reality? Can Hungary become hepatitis C virus free by 2030?]


[According to the WHO, there are 71 million people worldwide and 3 million people in the EU who are infected with hepatitis C virus. Most of these infections, however, remain undiagnosed and only 6-7% of them received antiviral therapy. In Hun-gary, there are an estimated 50.000 infections, out of these 20.000 are identified, the remaining 30.000 infections are outside the reach of the health care sector. Early diagnosis and therapy are of utmost importance as late diagnosis leads to se-vere liver insufficiency, hepatocellular carcinoma and multiple other extrahepatic organ impacts. In Hungary, second generation direct acting enzyme inhibitor antiviral medications with a recovery rate of almost 100% are available since 2015. Since 2018, all patients are treated with this type of therapy. Nevertheless, there are several remaining professional, organisational and health policy issues to solve. Firstly, Hungary should join the EU’s HCV elimination programme which aims to eradicate hepatitis C virus from Europe by 2030. Secondly, the frequency and efficiency of national screening should be increased. Furthermore, better information of the general population, inclusion of general practitioners and civil organisations, and introduction of the compulsory screening of high risk groups and health care professionals would be necessary. This review summarises the evolution of hepatitis C virus diagnostics and therapy over the past three decades, current best practice and the still outstanding tasks. ]

Clinical Neuroscience

JULY 30, 2018

Isocitrate dehydrogenase mutations in defining the biology of and supporting clinical decision making in glioblastoma


Background and purpose - Oncogenesis is related to a sequential accumulation of somatic mutations. Comprehensive characterizations of the genomic landscapes have been completed recently for several tumors, glioblastoma being among the first ones. Our own translational research studies have been focused on defining molecular subtypes of glioblastoma in the clinical setting because of an expected prognostic and therapeutic utility of the information. Somatic mutations in genes of the isocitrate dehydrogenase (IDH) enzyme family appear to be among the best-defined biomarkers that also influence tumor behavior and confer clinical utility. Methods - We have reviewed the literature including our own results to summarize basic science and clinical correlates of IDH mutations. Results - The surveyed data reveal genomic, transcriptomic, epigenomic and biochemical consequences of IDH mutations in the context of glioblastoma biology and phenotype. In addition, a few studies highlight the therapeutic potential of targeting IDH, although thus far all tests have only been conducted in the preclinical setting. Conclusions - Somatic mutations in isoforms of IDH genes represent important biomarkers that correlate with biochemical, biological and phenotypic features of glioblastoma, and may also facilitate the development of new therapeutic strategies complementing the currently available approved protocols.