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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.]

Clinical Neuroscience

NOVEMBER 20, 2015

[The diagnostic and management challenges for posterior reversible leucoencephalopathy syndrome]

KILIC COBAN Eda, GEZ Sedat, KARA Batuhan, SOYSAL Aysun

[Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiological entity characterized by epileptic seizures, headaches, altered mental status and focal neurological signs. Hypertension is the second most common condition associated with PRES. The 50-year-old-male patient with right-sided hemiparesis and speech disturbances admitted to our clinic. His blood pressure at the emergency service was 220/140 mmHg. A left putaminal hematoma was seen in his CT and MRI. In his brain MRI, FLAIR and T2 –weighted sequences showed bilateral symmetric diffuse hyperintensities in the brain stem, basal ganglia, and occipital, parietal, frontal, and temporal lobes. After the intense antihypertensive drug treatment, his blood pressure came to normal limits within a week. During his hospitalisation he had a recurrent speech disturbance lasting an hour. His electroencephalography was normal. In his repeated diffusion weighted MRI, an acute lacunary infarct was seen on right centrum semiovale. Two months later, the control MRI showed only the previous lacuner infarcts and the chronic putaminal hematoma. We presented a case developping either a cerebral hemorrhage or a lacunar infarction due to PRES. The main reason of the following complications of the disease was delayed diagnosis. Uncontrolled hypertension was guilted for the events. ]

Clinical Neuroscience

MARCH 30, 2016

[The importance of anticoagulant therapy in patients with artial fibrillation in stroke prevention – summary of international data and novel therapeutic modalities]


[The most common cardiogenic cause of ischaemic stroke is atrial fibrillation which increases the probability of stroke five-fold and doubles case fatality. Based on international data the incidence of atrial fibrillation is approx. 2% however this rapidly increases with age. The necessity of using oral anticoagulants in the prevention of non-valvular atrial fibrillation related stroke is decided based on estimated stroke risk. The CHADS2 and the more predictive CHA2DS2-VASc scales are used for this purpose while the bleeding risk of patients treated with anticoagulant may be estimated by the HAS-BLED scoring scale. For decades oral anticoagulation meant using vitamin-K antagonists. Based on international data we can see that rate of anticoagulation is unacceptably low, furthermore most of the anticoagulated patients aren’t within the therapeutic range of INR (INR: 2-3). A lot of disadvantages of vitamin-K antagonists are known (e.g. food-drug interaction, need for regular coagulation monitoring, increased risk of bleeding), therefore compounds with new therapeutic target have been developed. The novel oral anticoagulants (NOAC) can be divided in two major subgroups: direct thrombin inhibitors (dabigatran etexilate) and Xa-factor inhibitors (rivaroxaban, apixaban, edoxaban). These products are administered in fix doses, they less frequently interact with other medications or food, and regular coagulation monitoring is not needed when using these drugs. Moreover several studies have shown that they are at least as effective in the prevention of ischaemic stroke than the vitamin-K antagonists, with no more haemorrhagic complications.]

Clinical Neuroscience

JANUARY 30, 2016

[Financing of medicines for treatment of rare diseases of the nervous system. orphan drugs in rare neurological diseases]


[Objectives – Nervous system involvement is expected up to 60-70% in case of rare diseases. This article aims to present the financial methods and expenditures of rare neurological diseases’ orphan medicinal products being financed in the frame of Hungarian social insurance system in 2012. Methods – The subsidized orphan medicines were selected on the Orphanet portal 2012 while orphans financed by compessionate use were provided by the Hungarian National Insurance Fund Administration (OEP) database. Three products exist without orphan designation, however those are intended for the treatment of rare neurological ailments. The medicines were categorized by financial methods and determined by costs. Results – Numerically, out of 36 pieces of subsidized orphan or orphan criteria fulfilled medicines 17 were authorized for the treatments of rare neurological diseases in the year of 2012. Most of the drugs (14 pieces) were to be financed in the frame of compassionate use by the reimbursement system. The cost amount of social insurance for 387 rare neurological disease patients reached more than 4.5 billion HUF (1.4% of the total pharmaceutical budget in outpatient care). Conclusions – In Hungary half of the subsidized orphans are intended for the treatments of rare neurological ailments. 30% of the total amount of social insurance for rare diseases’ medicinal treatments were used to subsidizing rare neurological disease patients in 2012. Most of the orphan medicines were to be financed in the frame of compassionate use by the reimbursement system for outpatient care. Consequently, a great deal of crucial problems occurred in relation with the unconventional subsidizing method. At the end of 2012 new financial methods have been elaborated and introduced in a pilot phase from 1 January 2013. In spite of the high cost commitment, nearly the entire diagnosed rare disease subpopulation have been provided with subsidized treatments in Hungary. In order to facilitate the acces to orphan medicines, collaboration shall be achieved by financing authority and professionals for identificating the descently sustainable, affordable and viable financial method. ]

Clinical Neuroscience

MARCH 30, 2020

Effects of valproate, carbamazepine and levetiracetam on Tp-e interval, Tp-e/QT and Tp-e/QTc ratio


Aim - To evaluate P-wave dispersion before and after antiepileptic drug (AED) treatment as well as to investigate the risk of ventricular repolarization using the Tpeak-Tend (Tp-e) interval and Tp-e/QT ratio in patients with epileptic disorder. Methods - A total of 63 patients receiving AED therapy and 35 healthy adults were included. ECG recordings were obtained before and 3 months after anti-epileptic treatment among patients with epilepsy. For both groups, Tp-e and Tp-e/QT ratio were measured using a 12-lead ECG device. Results - Tp-e interval, Tpe/QT and Tp-e/QTc ratios were found to be higher in the patient group than in the control group (p<0.05, for all), while QTmax ratio was significantly lower in the patient group. After 3 months of AED therapy, significant increases in QT max, QTc max, QTcd, Tp-e, Tp-e/QT, and Tp-e/QTc were found among the patients (p<0.05). When the arrhythmic effects of the drugs before and after treatment were compared, especially in the valproic acid group, there were significant increases in Tp-e interval, Tp-e/QT and Tp-e/QTc values after three months of treatment (p<0.05). Carbamazepine and levetiracetam groups were not statistically significant in terms of pre- and post-treatment values. Conclusions - It was concluded that an arrhythmogenic environment may be associated with the disease, and patients who received AED monotherapy may need to be followed up more closely for arrhythmia.

Lege Artis Medicinae

MARCH 10, 2020

[Primary care strategy of antihypertensive treatment of very elderly and frail patients]

TORZSA Péter, KALABAY László, CSATLÓS Dalma, HARGITTAY Csenge, MÁRKUS Bernadett, MOHOS András, SZIGETI Mátyás, FERENCI Tamás, MARJOLEIN Verschoor, ROZSNYAI Zsofia, JACOBIJN Gussekloo, ROSALINDE K. E. Poortvliet, SVEN Streit

[BACKGROUND - When treating very el­der­ly and frail hypertensive patients, there have to be taken in account the general health condition and frailty of patients, the present cardiovascular diseases (CVD) and values of the systolic blood pressure (SBP). Goals - In a clinical study performed in 29 countries, we aimed to analyse differences in practical antihypertensive therapy of family doctors among patients older than 80 years; further we sought to answer how much was influenced their therapeutic choice by frailty of the old age. The other goal of our study was to compare Hungarian versus international outcomes. Methodology - As part of an online survey, family practitioners had to decide about necessity of starting antihypertensive treatment among very elderly patients according to different patterns of frailty, SBP and CVD. The ratio of specific cases with positive treatment decision of family practitioners was compared in all 29 countries. We used a logistic mixed model analysis to multivariately model the role of frailty. Results - 2543 family practitioners participated in the cross-national study; 52% were female; 51% practised in urban environment. In 61% of practices, there was the ratio higher than 10% of very elderly patients. Hungary participated with 247 family practitioners in the study; 52.3% were female; 63.1% practised in urban environment. In 48.8% of practices the ratio of very elderly patients was higher than 10%. In 24 out of the 29 countries (83%), frailty was associated with GPs’ negative decision about starting treatment even after adjustment for SBP, CVD, and GP characteristics (odds ratio [OR 0.53]), 95% CI: 0.48-0.59; ORs per country 0.11-1.78). The lowest treatment ratio was in the Netherlands (34.2%; 95% CI: 32.0-36.5%) and the highest one in Ukraine (88.3%; 95% CI: 85.3-90.9%). In Hungary’s treatment ratio ranged 50-59%. This country ranked on the 27th place since Hungarian family practitioners chose rather to start antihypertensive treatment despite the frailty of the patient (OR=1.16; 95% CI: 0.85-1.59). Hungarian family practitioners started pharmacotherapy of elderly patients more frequently if they were males (OR= 1.45; 95% CI: 0.81-2.61), were working in their practice for less than 5 years (OR=2.41; 94% CI: 0.51-11.38), and if they had many patients aged over 80 years in their practice (OR=2.18; 95% CI: 0.70-6.80), however these differences were sta­­tistically not significant. Among Hun­ga­rian family practitioners starting therapy was significantly influen­ced by cardiovascular disease (OR=3.71; 95% CI: 2.64-5.23) and a SBP over 160 mmHg (OR=190.39; 95% CI: 106.83-339.28). Conclusions - In our study, there was significant difference between countries in starting antihypertensive treatment for very elderly patients. However, Hungary was among the countries where family practitioners preferred to treat their frail patients. The patients’ frailty did not have any impact on starting the therapy; rather cardiovascular disease and a SBP over 160 mmHg decided. It is an important message of the study that there is continuous need to educate family practitioners and trainees about the treatment of frail, elderly hypertensive patients.]

Clinical Oncology

DECEMBER 10, 2018

[PI3K–AKT–mTOR pathway as a therapeutic target]


[The PI3K-AKT-mTOR is one of the most busy signalling pathway, accepting and sending the message to the effector compartment. The pathway is very complex with activators (see the name), and inhibitors, as PTEN. Depending of the cell type this pathway participates in almost all functions of a given cell. The members of the pathway may have genetic failures, as a consequence, the risk for the development of different diseases, including cancer is high. Therefore it is logical to produce drugs to inhibit the dysregulated function. Unfortunately, despite the promising preclinical effectivity, so far only 4 drugs can be used to treat cancer patients. There are some hypothesis for the in effectivity, e.g. no useful marker for patient selection, high toxicity, false drivers for targeting. What is sure, combination therapy is much better than monotherapy]

Hypertension and nephrology

DECEMBER 12, 2019

[Serotoninergic drugs for weight loss. A review of efficacy and cardiovascular safety of lorcaserin]


[Complex therapy of obesity consist the medical treatment. Several weight lowering drugs are available in the United States, one of which is 5-HT2c agonist lorcaserin. After failures with former non-selective serotoninergic agents (fenfluramine, dexfenfluramine), there was great anticipation and more questions about the release of lorcaserin, which proved its effectiveness and safety in several phase 3 studies. Lorcaserin is a selective agonist of 5-HT2c receptors, therefore free form adverse effects of former non-selective serotoninergic drugs on valvulopathy or pulmonary hypertension. The results of the recently published CAMELLIATIMI 61 study confirmed the cardiovascular safety of lorcaserin.]

Lege Artis Medicinae

NOVEMBER 15, 2019

[Hypertensive emergency conditions in Family practice]


[Family doctors play an important role in the treatment of high blood pressure emergencies. There are two forms of these: hypertensive, non-life-threatening states (urgency) and the hypertensive crisis (emergency) with life-threatening complications. The boundary between these two forms is not sharp, and a non-life-threatening urgency can turn into a hypertensive crisis. Hypertensive emergency is defined as an acute, marked increase of blood pressure with concomitant life-threatening target organ dysfunction. Treatment always requires hospitalization and parenteral administration of antihypertensive agents. In the case of hypertensive urgency, the acute increase of blood pressure is not complicated with organ damage. In these cases treatment can be performed in primary care with oral drugs. ]

Lege Artis Medicinae

OCTOBER 20, 2019

[Population-level QALY gain estimates with the use of cariprazine for patients with negative symptoms of schizophrenia in Hungary]

BENDES Rita, NÉMETH Bertalan, PITTER János György, KÓCZIÁN Kristóf, GÖTZE Árpád, KALÓ Zoltán

[INTRODUCTION - The loss in quality of life caused by mental illnesses has been growing in developed countries. This study aims to quantify the possible gains in quality of life by advantages of cariprazine therapy while treating patients with negative symptoms of schizophrenia in Hungary. Comparator therapy was defined as the currently available second-generation oral antipsychotic drugs. METHODS - In order to estimate the reachable gain in quality of life with cariprazine, an 8-state deterministic Markov cohort model was developed. Data was gathered from relevant scientific literature and public databases. The main assumptions regarding patient pathways have been validated by clinical experts, based on their real-life experience. The number of patients with negative symptoms of schizophrenia was estimated by the same methods as well. Sensitivity analyses were conducted on the input parameters. RESULTS - When compared with currently available second-generation oral antipsychotics, cariprazine generated an estimated increase of 0.05 quality-adjusted life years per patient in 2 years run. The deterministic sensitivity analysis confirmed the robustness of the results. Based on data of the National Health Insurance Fund and the scientific literature, a total gain of 450 quality-adjusted life years is expected at national level over a time horizon of 2 years. Even higher gains of QALY can be expected for longer time horizons. CONCLUSION - Based on conservative estimates significant health gain can be ge­ne­rated, if all patients with negative symp­toms of schizophrenia would receive the adequate cariprazine therapy in Hungary in­stead of the currently used se­cond-ge­ne­ration oral antipsychotic drugs. ]