The burden of neurological diseases in Europe: an analysis for the Global Burden of Disease Study 2017.

BACKGROUND: Neurological disorders account for a large and increasing health burden worldwide, as shown in the Global Burden of Diseases (GBD) Study 2016. Unpacking how this burden varies regionally and nationally is important to inform public health policy and prevention strategies. The population in the EU is older than that of the WHO European region (western, central, and eastern Europe) and even older than the global population, suggesting that it might be particularly vulnerable to an increasing burden of age-related neurological disorders. We aimed to compare the burden of neurological disorders in the EU between 1990 and 2017 with those of the WHO European region and worldwide. METHODS: The burden of neurological disorders was calculated for the year 2017 as incidence, prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost, and years lived with disability for the countries in the EU and the WHO European region, totally and, separately. Diseases analysed were Alzheimer's disease and other dementias, epilepsy, headache (migraine and tension-type headache), multiple sclerosis, Parkinson's disease, brain cancer, motor neuron diseases, neuroinfectious diseases, and stroke. Data are presented as totals and by sex, age, year, location and socio-demographic context, and shown as counts and rates. FINDINGS: In 2017, the total number of DALYs attributable to neurological disorders was 21·0 million (95% uncertainty interval 18·5-23·9) in the EU and 41·1 million (36·7-45·9) in the WHO European region, and the total number of deaths was 1·1 million (1·09-1·14) in the EU and 1·97 million (1·95-2·01) in the WHO European region. In the EU, neurological disorders ranked third after cardiovascular diseases and cancers representing 13·3% (10·3-17·1) of total DALYs and 19·5% (18·0-21·3) of total deaths. Stroke, dementias, and headache were the three commonest causes of DALYs in the EU. Stroke was also the leading cause of DALYs in the WHO European region. During the study period we found a substantial increase in the all-age burden of neurodegenerative diseases, despite a substantial decrease in the rates of stroke and infections. The burden of neurological disorders in Europe was higher in men than in women, peaked in individuals aged 80-84 years, and varied substantially with WHO European region and country. All-age DALYs, deaths, and prevalence of neurological disorders increased in all-age measures, but decreased when using age-standardised measures in all but three countries (Azerbaijan, Turkmenistan, and Uzbekistan). The decrease was mostly attributed to the reduction of premature mortality despite an overall increase in the number of DALYs. INTERPRETATION: Neurological disorders are the third most common cause of disability and premature death in the EU and their prevalence and burden will likely increase with the progressive ageing of the European population. Greater attention to neurological diseases must be paid by health authorities for prevention and care. The data presented here suggest different priorities for health service development and resource allocation in different countries. FUNDING: European Academy of Neurology.

Altered immune regulation in type 1 diabetes.

Research in genetics and immunology was going on separate strands for a long time. Type 1 diabetes mellitus might not be characterized with a single pathogenetic factor. It develops when a susceptible individual is exposed to potential triggers in a given sequence and timeframe that eventually disarranges the fine-tuned immune mechanisms that keep autoimmunity under control in health. Genomewide association studies have helped to understand the congenital susceptibility, and hand-in-hand with the immunological research novel paths of immune dysregulation were described in central tolerance, apoptotic pathways, or peripheral tolerance mediated by regulatory T-cells. Epigenetic factors are contributing to the immune dysregulation. The interplay between genetic susceptibility and potential triggers is likely to play a role at a very early age and gradually results in the loss of balanced autotolerance and subsequently in the development of the clinical disease. Genetic susceptibility, the impaired elimination of apoptotic ß -cell remnants, altered immune regulatory functions, and environmental factors such as viral infections determine the outcome. Autoreactivity might exist under physiologic conditions and when the integrity of the complex regulatory process is damaged the disease might develop. We summarized the immune regulatory mechanisms that might have a crucial role in disease pathology and development.

[Prospective study of the clinical features of cluster headache]. / A cluster fejfájás klinikumának prospektív vizsgálata.

INTRODUCTION: Although cluster headache (CH) is one of the most severe human pain syndromes, its symptoms and therapeutic possibilities may be suboptimally recognised in current medical practice in Hungary. AIM: To present the clinical characteristics of CH based on a prospective study of patients attending the Headache Service of the Department of Neurology, Semmelweis University. METHODS: We collected information about the symptoms, diagnosis and previous treatment of CH patients by filling in a 108-item questionnaire during outpatient visits. RESULTS: In the 5-year period between 2004 and 2008 we obtained data from 78 CH patients (57 males and 21 females; mean age: 44.6 +/- 14.6 years). The male:female ratio did not change in subgroups based on disease onset (calendar years). Ninety-three percent considered CH the most severe pain state of their life. The pain was strictly unilateral, affecting the territory of the 1st trigeminal division in all patients. The attacks were accompanied by signs of ipsilateral cranial parasympathetic activation (lactimation 83%, conjunctival injection 67%, rhinorrhea 56%, nasal congestion 43%); less frequently, signs of sympathetic dysfunction (ptosis 48%, miosis 7%) were also present. Two patients had attacks showing the typical localisation, severity and time course of CH attacks, but not accompanied by autonomic phenomena. A considerable part of the patients also observed symptoms that are usually ascribed to migraine (nausea 41%, vomiting 18%, photophobia 68%, phonophobia 58%). This may have been instrumental in the fact that, regardless of the characteristic clinical symptoms, the diagnosis of CH took 10 years on average. At the time of their examination 63% of patients were not using adequate abortive medications and 59% did not have an adequate prophylactic measure. DISCUSSION: Cluster headache is characterised by attacks of devastating pain that warrant an early diagnosis and adequate treatment. Our study underlines that information about the diagnosis and therapy of CH should be emphasized on occasions of neurology specialty training and continuing medical education.

[Changes in cognitive function in patients with diabetes mellitus]. / A kognitív funkciók változásai cukorbetegségben.

Patients with diabetes are approximately 1.5 times more likely to experience cognitive decline than individuals without diabetes mellitus. Most of the data suggest that patients with diabetes have reduced performance in numerous domains of cognitive function. In patients with type 1 diabetes, specific and global deficits involving speed of psychomotor efficiency, information processing, mental flexibility, attention, and visual perception seem to be present, while in patients with type 2 diabetes an increase in memory deficits, a reduction in psychomotor speed, and reduced frontal lobe (executive) functions have been found. The complex pathophysiology of changes in the central nervous system in diabetes has not yet been fully elucidated. It is important to consider the patient's age at the onset of diabetes, the glycemic control status, and the presence of diabetic complications. Neurological consequences of diabetes appear parallel to those observed in the aging brain. Neuroimaging studies highlight several structural cerebral changes, cortical and subcortical atrophy, beside increased leukoaraiosis that occurs in association with diabetes. There is supporting evidence from many hypotheses to explain the pathophysiology of cognitive decline associated with diabetes. The main hypotheses pointing to the potential, implied mechanisms involve hyperglycemia, hypoglycemia, microvascular disease, insulin resistance, hyperinsulinism, hyperphosphorylation of tau protein, and amyloid-ß deposition.

Higher serum DPP-4 enzyme activity and decreased lymphocyte CD26 expression in type 1 diabetes.

Dipeptidyl peptidase-4 (DPP-4) is involved in the metabolism of peptide hormones, T-cell activation and proliferation. In type 1 diabetes mellitus (T1DM) ß-cell destruction involves a number of dysregulated T-cells. Our aim was to assess the serum DPP-4 activity and the lymphocyte membrane bound CD26 expression in patients with type 1 diabetes and healthy controls. Ninety-eight (T1DM: 48, F/M = 20/28, mean age: 34.4y; control: 50, F/M = 39/11 mean age: 32,4y) individuals were included. Fasting serum DPP-4 enzymatic activity, plasma glucose (FPG), CD26 expression on CD3+, CD4+ and CD8+ lymphocytes, HbA1c and body mass index (BMI) were assessed. ICA and GAD antibodies were assessed in the T1DM group. DPP-4 enzymatic activity was determined by kinetic enzyme assay, ICA and GAD were assessed by ELISA. Determination of the CD26 expression on CD3+, CD4+ and CD8+ lymphocytes was performed by flow-cytometric analysis. We found higher serum DPP-4 activity (Mean: T1DM: 30.069 U/L, control: 22.62 U/L, p < 0.0001) and decreased CD26 lymphocyte expression on all lymphocyte subpopulations in T1DM. Fasting serum DPP-4 activity was independent from the ICA or GAD status of patients with T1DM. Here we first present that the serum DPP-4 activity is increased and the lymphocyte membrane bound CD26 expression is decreased in type 1 diabetes. Decreased lymphocyte membrane bound CD26 expression in T1DM might be a novel part of the T-lymphocyte regulatory dysfunction observed in type 1 diabetes mellitus. These results might provide some basis for the clinical implication of DPP-4 inhibition in patients with T1DM.

[Verrucous carcinoma of the anal margin. The importance of adequate biopsy technique]. / Verrucosus analis carcinoma (Buschke-Löwenstein-tumor): a körültekinto biopsziás mintavétel jelentosége.

Buschke-Löwenstein tumor (verrucous carcinoma, giant condylomata) of the anal margin is a locally invasive, destructively growing carcinoma that does not metastasize. The lesions are rare despite the increased incidence of anal condylomata and anal carcinomas. Authors report a case of a 63-year-old woman suffering from verrucous carcinoma (Buschke-Löwenstein tumor) of the anal margin. The tumor invaded the rectal sphincter and extended beyond the muscle, infiltrating the lower abdomen. Infiltration of the perivesical soft tissue caused bilateral hydronephros. Because both under- and overdiagnosis of anal cancer and precancer may lead to inappropriate treatment, it is important to perform adequate sampling for histology. Non-representative superficial biopsies may result underdiagnosis of the disease.

Evolution and predictors of morphological and functional arterial changes in the course of type 1 diabetes mellitus.

BACKGROUND: Diabetes mellitus results in accelerated atherosclerosis. We evaluated preclinical, morphological and functional vascular changes in type 1 diabetes mellitus. METHODS: Diameter, intima-media thickness, intima-media cross-section area, and elasticity features (compliance, distensibility coefficient, circumferential strain, stiffness index, incremental elastic modulus) of the common carotid arteries and carotid-femoral pulse wave velocity were studied in 42 patients with type 1 diabetes mellitus without macroangiopathy, and 41 control subjects matched for sex, age and body mass index using an ultrasonographic vessel wall-movement tracking system and applanation tonometry. RESULTS: Significantly larger intima-media thickness (523 ± 55 versus 567 ± 89 µm, p < 0.01), intima-media cross-section area (11.60 ± 1.81 versus 13.08 ± 3.02 mm(2) , p < 0.01), SI (5.58 ± 1.24 versus 7.08 ± 2.69, p < 0.01) and pulse wave velocity (6.00 ± 0.82 versus 6.61 ± 1.56 m/s, p < 0.05) were found in type 1 diabetes mellitus patients compared to controls. When type 1 diabetes mellitus patients with short and long disease duration (≤ or > 10 years) were compared, diameter (6450 ± 433 versus 6847 ± 750 µm, p < 0.05), intima-media cross-section area (11.97 ± 1.98 versus 14.01 ± 3.43 mm, p < 0.05) and pulse wave velocity (5.90 ± 0.92 versus 7.20 ± 1.74 m/s, p < 0.01) differed significantly. When multivariate analyses were restricted to type 1 diabetes mellitus patients, age was an independent predictor of stiffness index and pulse wave velocity, the duration of diabetes mellitus of intima-media cross-section area and pulse wave velocity, systolic blood pressure of diameter and pulse wave velocity, and low-density lipoprotein-cholesterol of intima-media thickness, intima-media cross-section area and stiffness index. CONCLUSIONS: There are differences in the time course of evolution and in predictors of morphological and functional changes in arteries in type 1 diabetes mellitus.

Serum dipeptidyl peptidase-4 activity in insulin resistant patients with non-alcoholic fatty liver disease: a novel liver disease biomarker.

BACKGROUND: In a cross-sectional study we studied the fasting serum DPP-4 enzymatic activity (sDPP-4) and the insulin resistance index (HOMA2-IR) in gliptin naïve patients with type 2 diabetes and in non-alcoholic fatty liver disease (NAFLD) and in healthy controls (CNTRL). METHODS AND FINDINGS: sDPP-4 was measured by kinetic assay in 39 NAFLD (F/M:19/20, mean age: 47.42 yrs) and 82 type 2 diabetes (F/M:48/34, 62.8 yrs) patients and 26 (F/M:14/12, 35.3 yrs) controls. Definition of T2D group as patients with type 2 diabetes but without clinically obvious liver disease created non-overlapping study groups. Diagnosis of NAFLD was based on ultrasonography and the exclusion of other etiololgy. Patients in T2D and NAFLD groups were similarly obese. 75 g CH OGTT in 39 NAFLD patients: 24-NGT, 4-IGT or IFG ("prediabetes"), 11-type 2 diabetes. HOMA2-IR: CNTRL: 1.44; T2D-group: 2.62 (p = 0.046 vs CNTRL, parametric tests); NAFLD(NGTonly): 3.23 (p = 0.0013 vs CNTRL); NAFLD(IFG/IGT/type 2 diabetes): 3.82 (p<0.001 vs CNTRL, p = 0.049 vs 2TD group). sDPP-4 activity was higher in NAFLD both with NGT (mean:33.08U/L) and abnormal glucose metabolism (30.38U/L) than in CNTRL (25.89U/L, p<0.001 and p = 0.013) or in T2D groups (23.97U/L, p<0.001 and p = 0.004). Correlations in NAFLD among sDPP-4 and ALT: r = 0.4637,p = 0.0038 and gammaGT: r = 0.4991,p = 0.0017 and HOMA2-IR: r = 0.5295,p = 0.0026 and among HOMA2-IR and ALT: r = 0.4340,p = 0.0147 and gammaGT: r = 0.4128,p = 0.0210. CONCLUSIONS: The fasting serum DPP-4 activity was not increased in T2D provided that patients with liver disease were intentionally excluded. The high serum DPP-4 activities in NAFLD were correlated with liver tests but not with the fasting plasma glucose or HbA1C supporting that the excess is of hepatic origin and it might contribute to the speedup of metabolic deterioration. The correlation among gammaGT, ALT and serum DPP-4 activity and also between serum DPP-4 activity and HOMA2-IR in NAFLD strongly suggests that serum DPP-4 activity should be considered as a novel liver disease biomarker.

[Elevated serum dipeptidyl peptidase-4 activity in type 1 diabetes mellitus: a direct comparison]. / Emelkedett szérum-dipeptidil-peptidáz-4 enzimaktivitása 1-es típusú diabetesben: összehasonlító vizsgálat.

UNLABELLED: Dipeptidyl peptidase-4 (DPP-4) has an important role in the carbohydrate metabolism with the degradation of incretin hormones. AIM: We assessed the serum DPP-4 activity both in fasting and postprandial condition in patients with type 1-, type 2 diabetes and healthy controls. METHODS: Serum DPP-4 activities were determined at fasting sate and at 60 and 180 minutes after test meal. DPP-4 activity was measured by microplate-based kinetic assay in 41 type 1-, and in 87 type 2 diabetic patients and in 25 healthy volunteers. RESULTS: Serum DPP-4 activities were found significantly higher both in fasting and postprandial state in patients with type 1 diabetes than in type 2 and control subjects. No change in the enzyme activities was found after test meal. Correlation was neither detected between the fasting plasma glucose nor between the HbA(1C) and the DPP-4 values in any of the groups studied. CONCLUSIONS: RESULTS suggest that it is not the hyperglycemia, rather the type of diabetes which determinates the serum DPP-4 enzymatic activity. The exact background of this phenomenon is not yet clear, however, increased serum DPP-4 enzyme activity in type 1 diabetes mellitus may refer to pancreatic autoimmune process, concomitant autoimmune diseases, hormonal feed back mechanism, or even target organ damage.

P2RX7 Gln460Arg polymorphism is associated with depression among diabetic patients.

AIMS: Both diabetes mellitus and major depression are public health concerns, and the co-occurrence of these illnesses is highly frequent. Acting as a potential risk factor, hyperglycemia might facilitate the manifestation of depression in patients genetically predisposed to affective disorders. In the present study, candidate polymorphisms of the serotonin transporter, the tryptophan hydroxylase 2 (TPH2) genes, as well as of the brain-derived neurotrophic factor BDNF, and the P2RX7 purinergic receptor genes were analyzed in Hungarian diabetic population. We assumed that genetic influence would be stronger on depressive symptoms in the "poor glycemic control" group (PC: HbA1C>7%) compared to the "good glycemic control" group (GC: HbA1C

[Development of silent gastric carcinoid in a type 1 diabetic patient with primer hypothyreosis]. / Tünetmentes gyomorcarcinoid kialakulása 1-es típusú diabéteszben és primer hypothyreosisban szenvedo betegben.

Type 1 diabetes is usually associated with other autoimmune diseases. Parietal cell antibodies (PCA) are found in 20% of type 1 diabetic patients which might be an early sign of autoimmune gastritis and pernicious anemia. PCA destroy the gastric H+/K+ ATP-ase. The chronic auto-destruction of the proton pump leads to hypo/achlorhydria and hypergastrinemia which leads to the hyper/dysplasia of enterochromaffin-like cells (ECL). ECL hyper/dysplasia is known to increase the likelihood of gastric carcinoid tumor development in affected patients. Gastric carcinoid tumors forming from the hyperplasia of ECL cells are found in 4-9% of patients having autoimmune gastritis or pernicious anemia. The 29-years-old type 1 diabetic patient, having primer hyperthyroidism was admitted to our clinic because of gastric pain. Results of endoscopy and biopsy showed multiple small polyps in the fundus with non-antral hypergastrinemic (type A) atrophic gastritis. The parietal cell antibody test was positive, the serum chromogranin A level was 289,7 ng/ml (normal value $ 98 ng/ml), TSH level was 9,93 mIU/L. The histological examination indicated carcinoid tumor. Sandostatin therapy was started then partial gastrectomy was done. After the operation the plasma chromogranin level normalized. Non-antral, multiple polyps could cover silent neuroendocrine tumors, which are slowly growing benign endocrine tumors, however, they also might be high malignity endocrine carcinomas. These tumors could be easily recognized in the clinical practice by measuring the serum or tissue chromogranin A level and other markers of tumor growth. Thus screening of gastric endocrine tumors in type 1 diabetic patients with co-morbid autoimmune diseases is recommended.