Angiotensin-converting enzyme insertion/deletion gene polymorphism and interferon-ß treatment response in multiple sclerosis patients: a preliminary report.

We investigated the effect of the functional insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene on the response to interferon-ß (IFN-ß) therapy in Croatian and Slovenian patients with multiple sclerosis (MS). A total of 275 IFN-ß treated MS patients [162 responders (Rs) and 113 nonresponders (NRs)] were genotyped by PCR. The ACE I/D genotype distribution and allele frequencies did not differ between female Rs and NRs. However, male NRs tended to have a greater prevalence of the DD genotype (P=0.073; odds ratio: 2.64; 95% confidence interval: 0.91-7.60) and a significantly higher frequency of the D allele (P=0.022; odds ratio: 2.43; 95% confidence interval: 1.13-5.20) than male Rs. Multiple forward stepwise regression analysis indicated that the negative response to IFN-ß therapy was associated with the ACE-DD genotype in men (ß=0.371; multiple R change: 0.132; P=0.009) and a higher pretreatment relapse rate in both men (ß=-0.438; multiple R change: 0.135; P=0.015) and women (ß=-0.208; multiple R change: 0.042; P=0.034). The ACE I/D polymorphism and pretreatment relapse rate accounted for ∼26.7% of the IFN-ß response variability among the men in the sample. Further studies of a larger number of MS patients from different populations are necessary to evaluate these preliminary findings.

Angiotensin-converting enzyme insertion/deletion gene polymorphism in multiple sclerosis: a meta-analysis.

The activity of angiotensin-converting enzyme (ACE) has been increased in the blood and cerebrospinal fluid of multiple sclerosis (MS) patients. In addition, there has been suppression of disease development in experimental autoimmune encephalomyelitis after blockade of ACE. These findings suggest that ACE may play a role in the MS pathogenesis. Since the previous studies investigating the association between the insertion/deletion (I/D) polymorphism in intron 16 of the ACE gene and MS reported contradictory results, we performed a meta-analysis of four studies conducted in European populations of Slavic origin (1062 patients and 1067 controls) using the Comprehensive Meta-analysis 3.0 software. The results demonstrated that the ACE I/D polymorphism had no statistically significant association with an increased MS risk (all p ≥ 0.05) under all genetic comparison models: (1) allelic (D vs. I), (2) recessive (DD vs. ID + II), (3) dominant (DD + ID vs. II), and (4) additive (DD vs. ID vs. II). This meta-analysis indicates that the ACE I/D polymorphism is not associated with susceptibility to MS in Europeans of Slavic origin. Further studies with larger sample sizes from genetically different populations are warranted.

Interleukin 7 receptor alpha polymorphism rs6897932 and susceptibility to multiple sclerosis in the Western Balkans.

The interleukin 7 receptor alpha single nucleotide polymorphism rs6897932 was identified as a multiple sclerosis susceptibility-modifying polymorphism in genome-wide and gene scan studies, mainly in populations in western countries. The aim of this study was to investigate the association of interleukin 7 receptor alpha rs6897932 with multiple sclerosis in populations from the Western Balkans: Serbia, Croatia, and Slovenia. A total of 678 unrelated white patients and 597 unrelated, ethnically matched healthy controls were included in the study. Genotyping was performed by real-time polymerase chain reaction. We found no significant difference in genotype or allele frequencies between controls and patients with multiple sclerosis either separately in Serbian, Croatian, and Slovenian populations or in the whole sample from the Western Balkans. The odds ratio for multiple sclerosis in this study was 1.04 (0.86-1.25) for the C allele. It is known that demographic as well as environmental factors have a substantial role in multiple sclerosis development, as well as population genetic background. The results of this study indicate that other types of genome variants should be required for the development and/or progression of multiple sclerosis, which may vary among populations.

Drug-induced aseptic meningitis, sensorineural hearing loss and vestibulopaty.

We report clinically rare and serious adverse reactions that occurred after the co-administration of ranitidine, ibuprofen and ciprofloxacin: completely reversible aseptic meningitis and irreversible bilateral sensorineural hearing loss, tinnitus, and vestibulopathy. Recurrent urinary inflammations treated with antibacterials, classic familial migraine, and allergy to trimethoprim-sulfamethoxazole and chromium were favourable predisposing factors for the adverse event in this patient. A close chronological relation between administration of drugs (especially ibuprofen) and adverse reactions was noted. No evidence of infection and/or autoimmune disease was found. The mechanism of these serious events may be explained as a hypersensitive reaction affecting the meninges and, partially, cochlea.

Multiple sclerosis and cancers in Croatia--a possible protective role of the "Mediterranean diet".

Multiple sclerosis (MS) is an autoimmune disease triggered by a combination of genetic and environmental risk factors which are however individually insufficient to provoke the disease. Previous investigations studied the coexistence of cancer in MS patients, and only a few relations between the geographic distribution of MS and that of cancer. The aim of this research was to find an environmental link between the aetiology of MS and cancers in Croatia. Incidence and prevalence of MS in Croatia were compared with the incidence of the most frequent cancer sites: stomach cancer, cancer of the colon and the rectum, pancreatic cancer, lung cancer, cancer of the kidneys and brain cancer. Data for MS were collected from seven population-based epidemiologic studies which used Poser's diagnostic criteria and reported the number of cases and the magnitude of the studied population. Data for cancers were drawn from the Croatian National Cancer Registry. The analysis was done for single municipalities, grouped in their belonging regions or counties, and separately for the continental and the coastal area. For each rate a 95% confidence interval was calculated. The differences between rates were tested with the chi-square test as well. In addition, MS incidence or prevalence were correlated with the corresponding cancer incidence data. Pearson's correlation coefficients were used to measure the correlation between both diseases. Calculations were done with the statistical package Statistica V 7.1. and the Smith's Statistical Package freeware In the continental area of Croatia the mean annual incidence (per 100,000 inhabitants) of MS was nearly two folds higher than in the coastal area: 2.1 vs. 1.3 (p = 0.0029). The difference was lower when expressed by prevalence: 46.5 vs. 36.7 (p = 0.0601). Among the malignant neoplasms, in the continental area significantly higher incidence rates were found for stomach (32.9 vs. 20.8; p = 3.14E-14) and lung cancer (55.8 vs. 46.4; p = 1.21E-05), whilst colon cancer alone (20.4 vs. 15.7; p = 9.44E-05) or colorectal cancer (38.3 vs. 31.6; p = 8.18E-05) had a significantly higher incidence in the coastal area. The geographic distribution of MS expressed by incidence was significantly correlated with pancreatic (r = 0.62024, df=23, p = 0.00094) and lung cancer (r = 0.46380, df=23, p = 0.01953). This research adds further malignant neoplasms, possibly exposure-related, to the list of diseases with geographic distribution like MS. The similarity of MS distribution with the named malignancies is unlikely to be incidental. MS in Gorski Kotar and Slavonia seems to be associated with a diet rich in meat and fat. A diet rich in fat and meat and poor in vegetables is a risk factor for stomach, colorectum, pancreatic as well as lung cancers. Some authors have documented a possible protective role of the "Mediterranean diet" for the named cancers. Olive oil is the main source of fat in the "Mediterranean diet". Oleocanthal, aphenolic compound of the extra-virgin olive oil was found to inhibit the cyclooxigenase enzymes which are involved in demyelination and tumorigenesis. We hypothesize that the "Mediterranean diet", olive oil and particularly oleocanthal, to have a protective role in MS too.

[Adverse effects and interactions of fluoroquinolones]. / Nuspojave i interakcije fluorokinolona.

Floroquinolones are derivatives of nalidixic acid that act as a large-spectrum antibiotics. Adverse effects and interactions of the particular fluoroquinolone depend on its chemical structure and, often, on predisposing factors in patients, including the age, hidden or previous neurological diseases, metabolic disturbances, and allergies. The adverse effects do not significantly differ among different fluoroquinolones. They can be considered as mild, moderate and severe, and their incidence is irrespective of the gender. They can occur even after the short-term administration of these antibiotics, and usually vanish after diminishing the dose or cessation of the therapy in 24-48 hours. The adverse effects can affect nervous, digestive, urinary, cutaneous, musculo-skeletal, cardiovascular, and immune system. Rarely, fluoroquinolones can harm the spermatogenesis. Their use is not advised during pregnancy due to their possible teratogenic effects. Fluoroquinolones can interact with a variety of drugs: antacides, non-steroid antirheumatics, xantines, warfarin, and others. These drug combinations often occur during the therapeutic process in the clinical practice. The incidence of adverse effects and interactions of fluoroquinolones are low; however they can result in serious complications. The post-marketing control of these antibacterial drugs is therefore highly recommended.

Multiple Sclerosis patients carry an increased burden of exceedingly rare genetic variants in the inflammasome regulatory genes.

The role of rare genetic variation and the innate immune system in the etiology of multiple sclerosis (MS) is being increasingly recognized. Recently, we described several rare variants in the NLRP1 gene, presumably conveying an increased risk for familial MS. In the present study we aimed to assess rare genetic variation in the inflammasome regulatory network. We performed whole exome sequencing of 319 probands, comprising patients with familial MS, sporadic MS and control subjects. 62 genes involved in the NLRP1/NLRP3 inflammasome regulation were screened for potentially pathogenic rare genetic variation. Aggregate mutational burden was analyzed, considering the variants' predicted pathogenicity and frequency in the general population. We demonstrate an increased (p = 0.00004) variant burden among MS patients which was most pronounced for the exceedingly rare variants with high predicted pathogenicity. These variants were found in inflammasome genes (NLRP1/3, CASP1), genes mediating inflammasome inactivation via auto and mitophagy (RIPK2, MEFV), and genes involved in response to infection with DNA viruses (POLR3A, DHX58, IFIH1) and to type-1 interferons (TYK2, PTPRC). In conclusion, we present new evidence supporting the importance of rare genetic variation in the inflammasome signaling pathway and its regulation via autophagy and interferon-ß to the etiology of MS.

[Zvonimir Susic--doyen of Croatian neuropsychiatry in the 20th century]. / Zvonimir Susic--velikan hrvatske neuropsihijatrije 20. stoljeca.

There are three distinct phases in the life of Zvonimir Susic--neurologist, psychiatrist, forensic expert, educator, teacher, translator, and erudite of general and professional knowledge--Zagreb, Rijeka and Zadar phase. In Zagreb (1926-1946) he was promoted to physician (1932), there he was a student tutor, then the assistant at the Physiology Institute of the Medical Faculty; volunteer, hospital doctor (he got the specialization in 1938), assistant and head doctor of the Hospital for Mental Diseases in Vrapce, and the assistant professor (1941) at the Neuropsychiatric Department of the Zagreb University. In Rijeka (1947-1959) he reorganized Psychiatric and established the Neurology Department of the General Hospital "Brothers Dr. Sobol" and, at first, he was the honorary professor, then assistant professor and associate professor of neurology and psychiatry at the Medical Faculty of Rijeka. In Zadar (1960-1968) he was the manager of the Ugljan Hospital. He published approximately 100 works in the field of clinical neurology, neuropathology, psychiatry, and forensic psychiatry, His works on cortical presentation of the body scheme, hallucinations, tuberous sclerosis, pregnancy and multiple sclerosis, pathohistology of demyelisation, toxic neuritis, epilepsies, nervous manifestations of Malta fever, herpetic infections, pathogenesis of convulsive syndromes, psychiatric terminology, therapies of Parkinson disease and schizophrenia, ability of making will, organization of the psychiatric service, were published in national and prestigious European journals, and often cited. He wrote chapters in psychiatric handbooks and special notes in encyclopedic editions. Together with Stanislav Zupic he was the author of the first and only psychodrama in Croatia. He was one of the pioneers of neuropathology in Croatia because he founded the Neuropathology Laboratory in Vrapce Hospital in 1936. He had a remarkable preciseness in examining the patient. He was frequent and imaginative lecturer in various sections in Croatian Medical Association and other public institutions. As a gifted polyglot he was occupied by the translation work when retired. In our, till then Middle-European culture-oriented medical area, he introduced values and patterns of French neurological and German neuropathological schools.

Association of circadian rhythm genes ARNTL/BMAL1 and CLOCK with multiple sclerosis.

Prevalence of multiple sclerosis varies with geographic latitude. We hypothesized that this fact might be partially associated with the influence of latitude on circadian rhythm and consequently that genetic variability of key circadian rhythm regulators, ARNTL and CLOCK genes, might contribute to the risk for multiple sclerosis. Our aim was to analyse selected polymorphisms of ARNTL and CLOCK, and their association with multiple sclerosis. A total of 900 Caucasian patients and 1024 healthy controls were compared for genetic signature at 8 SNPs, 4 for each of both genes. We found a statistically significant difference in genotype (ARNTL rs3789327, P = 7.5·10-5; CLOCK rs6811520 P = 0.02) distributions in patients and controls. The ARNTL rs3789327 CC genotype was associated with higher risk for multiple sclerosis at an OR of 1.67 (95% CI 1.35-2.07, P = 0.0001) and the CLOCK rs6811520 genotype CC at an OR of 1.40 (95% CI 1.13-1.73, P = 0.002). The results of this study suggest that genetic variability in the ARNTL and CLOCK genes might be associated with risk for multiple sclerosis.

Epidemiology of multiple sclerosis in western Herzegovina.

OBJECTIVES: To determine epidemiological rates of multiple sclerosis (MS) in western Herzegovina. PATIENTS AND METHODS: We analysed data from 81 MS patients (49 females, 32 males) on the prevalence day, 31 December 2003. Patient information was obtained from a search of all available medical records from the period 1994-2003 in the investigated area. RESULTS: Crude prevalence of MS was 27/100,000 (95% confidence interval (CI) 20-34). Prevalence was highest in the mountainous municipality of Posusje (56/100,000) and lowest in the coastal municipality of Neum (0 incidence). The annual incidence of MS was 1.6/100,000 (95% CI 0-3.3). The female/male ratio of MS was 1.5. The mean age of the patients on prevalence day was 40.0+/-11.6 years, and the mean age at disease onset was 31.0+/-7.1 years. Eight (10%) of the patients had a first-degree relative with MS. The primary progressive (PP) disease course was observed only in females. Visual symptoms were the initial symptom of MS in 6 (7%) of the patients. CONCLUSIONS: Western Herzegovina is an area of moderate risk for MS, and the distribution of MS in western Herzegovina is heterogeneous. PP-MS occurred only in females, and involvement of the visual pathways as the initial symptom of MS was low.

Tumor necrosis factor-alpha-308 gene polymorphism in Croatian and Slovenian multiple sclerosis patients.

Previous findings regarding the role of TNF-alpha-308 gene polymorphism in multiple sclerosis (MS) are contradictory. The aim of this study was to investigate the possible influence of TNF-alpha-308 polymorphism on MS susceptibility and the MS disease process in a Croatian and Slovenian population. Genotyping was performed in 338 patients and 460 healthy controls. The TNF2 allele was present in 123 (26.8%) healthy controls vs. 67 (19.9%) MS patients (p = 0.023, odds ratio = 0.68, 95% confidence interval = 0.48-0.95), suggesting that carriage of the TNF2 allele might decrease MS risk. The difference in TNF2 allele carrier frequency between patients and controls was identified in the relapsing-remitting MS group. There was no association between TNF2 allele carrier status and age at disease onset or disease progression. Our results suggest that, in the study populations, the TNF-alpha-308 polymorphism may play a role in MS susceptibility.

HLA class II polymorphism in autochthonous population of Gorski kotar, Croatia.

The aim of this study was to examine frequencies and haplotypic associations of HLA class II alleles in autochthonous population of Gorski kotar (Croatia). HLA-DRB1, -DQA1 and -DQB1 alleles were determined by DNA based PCR typing in 63 unrelated inhabitants from Gorski kotar whose parents and ancestors were born and lived in tested area for at least over four generations. A total of 13 HLA-DRB1, 12 DQA1 and 14 DQB1 alleles were identified. The most frequent HLA class II genes in Gorski kotar population are: HLA-DRB1*13 (af = 0.150), -DRB1*03 (af = 0.142), -DRB1*07 (af = 0.119), and -DRB1*11 (af = 0.119), HLA-DQA1*0501 (af = 0.278), -DQA1*0102 (af = 0.183), -DQA1*0201 (af = 0.127) and HLA-DQB1*0301 (af = 0.157), -DQB1*0201 (af = 0.139), -DQB1*0501 (af = 0.111). We have identified 24 HLA class II three-locus haplotypes. The most common haplotypes in Gorski kotar population are DRB1*03-DQA* 0501-DQB1*0201 (0.120), DRB1*11-DQA1*0501-DQB1*0301 (0.111) and DRB1*07-DQA1*0201-DQB1*0202 (0.094). The allelic frequencies and populations distance dendrogram revealed the closest relationships of Gorski kotar population with Slovenians, Germans, Hungarians and general Croatian population, which is the result of turbulent migrations within this microregion during history.

The lack of association between angiotensin-converting enzyme gene insertion/deletion polymorphism and nicotine dependence in multiple sclerosis.

OBJECTIVE: Blood-borne angiotensin II is generated from angiotensinogen via cleavage by renin and angiotensin-converting enzyme (ACE), an enzymatic cascade known as the renin-angiotensin system (RAS). Several lines of evidence indicate that ACE, beyond its classical role of mediating blood pressure regulation, might contribute to the etiology of substance addictions by influencing dopaminergic signaling. A functional insertion/deletion (I/D) polymorphism of the ACE gene was associated with risk for being a smoker among individuals with depression and with smoking severity in studies comprising patients with depression and healthy controls. Several reports have described significantly increased ACE activity in cerebrospinal fluid and serum among MS patients. Furthermore, in our previous work with MS patients from Croatian and Slovenian populations, we demonstrated that the ACE-I/D polymorphism contributes to an elevated MS risk among male patients. Here we investigated whether the ACE-I/D polymorphism might influence smoking behavior among patients with MS. PATIENTS AND METHODS: Genotyping was performed in 521 patients (males/females: 139/382) using polymerase chain reaction. RESULTS: We revealed no significant differences in ACE genotype and allele frequencies between smokers and nonsmokers and no significant association between the ACE-I/D polymorphism and either pack-year smoking history or number of cigarettes smoked daily (p > .05, respectively). CONCLUSION: The ACE-I/D polymorphism does not contribute either to risk for nicotine dependence or to smoking severity among MS patients. In the context of reports on the ACE-I/D polymorphism and nicotine dependence among healthy controls and patients with depression, we may speculate that the mechanism by which this polymorphism influences nicotine dependence risk differs in MS compared to depression, although not compared to a healthy population. In addition to angiotensin II, other potential ACE substrates, such as substance P and neurotensin, which also influence dopaminergic neurotransmission (and are proposed to be associated with MS), may deserve study in future.

Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis.

The genetic etiology and the contribution of rare genetic variation in multiple sclerosis (MS) has not yet been elucidated. Although familial forms of MS have been described, no convincing rare and penetrant variants have been reported to date. We aimed to characterize the contribution of rare genetic variation in familial and sporadic MS and have identified a family with two sibs affected by concomitant MS and malignant melanoma (MM). We performed whole exome sequencing in this primary family and 38 multiplex MS families and 44 sporadic MS cases and performed transcriptional and immunologic assessment of the identified variants. We identified a potentially causative homozygous missense variant in NLRP1 gene (Gly587Ser) in the primary family. Further possibly pathogenic NLRP1 variants were identified in the expanded cohort of patients. Stimulation of peripheral blood mononuclear cells from MS patients with putatively pathogenic NLRP1 variants showed an increase in IL-1B gene expression and active cytokine IL-1ß production, as well as global activation of NLRP1-driven immunologic pathways. We report a novel familial association of MS and MM, and propose a possible underlying genetic basis in NLRP1 gene. Furthermore, we provide initial evidence of the broader implications of NLRP1-related pathway dysfunction in MS.

Region with persistent high frequency of multiple sclerosis in Croatia and Slovenia.

OBJECTIVE: The aim of this study was to evaluate the prevalence of multiple sclerosis (MS), and to determine the clinical characteristics and the occurrence of familial MS in the Gorski kotar-Kocevje region, which was previously considered to be a region of high prevalence of MS. METHODS: All clinically and laboratory supported definite cases of MS according to Poser's criteria, living residents of the chosen area on June 1, 1999 were included in the study. The patients were ascertained through national case registers for MS at the University Medical Centers (Rijeka and Ljubljana), registries of the national associations of MS patients, as well as from the medical records of regional outpatient clinics. RESULTS: The crude annual prevalence per 100,000 population was 151.9 (95% CI 123.2-187.4). 28.7% of patients had a history of MS among first-, second-, or third-degree relatives. The frequency of primary progressive course of disease was 23.5%. The sex ratio (F/M) was 1.41. CONCLUSION: A stable high prevalence of MS as well as a high number of familial MS cases was identified in the neighbouring regions of Slovenia and Croatia.

[Use of magnetic resonance imaging in the diagnosis and prognosis of multiple sclerosis]. / Upotreba magnetske rezonancije u dijagnozi i prognozi multiple skleroze.

Multiple sclerosis is an autoimmune disease characterized by demyelination and axonal loss. Conventional magnetic resonance imaging allows the demonstration of spatial and temporal dissemination of multiple sclerosis lesions earlier than is possible from clinical assessments. A variety of conventional magnetic resonance imaging protocols, in conjunction with clinical assessment, are now routinely used to increase the accuracy of diagnosis and long-term prognosis of multiple sclerosis. T2-weighted hyperintense lesions are related primarily to increased water content and thus cannot distinguish between inflammation, edema, demyelination, Wallerian degeneration, and axonal loss, whereas the contrast gadolinium-enhanced lesions on T1-weighted images reflect increased blood-brain barrier permeability associated with active inflammatory activity. Conventional magnetic resonance imaging metrics are not sufficiently sensitive to detect invisible brain damage in the normal appearing brain tissue, and they do not show a reliable correlation with clinical measures of disability. However, numerous studies showed that they can improve accuracy in the diagnosis and prognosis of multiple sclerosis. Recently, non-conventional magnetic resonance imaging techniques have been introduced to increase the accuracy of diagnosis and prognosis of multiple sclerosis. Several studies have used brain atrophy, T1-hypointense lesion volume, magnetization transfer imaging, diffusion-weighted imaging and magnetic resonance spectroscopy to test whether the extent and severity of tissue loss in lesions and in normal appearing gray and white matter at the time of clinically isolated syndrome may have diagnostic and prognostic value. These magnetic resonance imaging techniques represent a powerful tool to non-invasively study different pathological substrates of lesions and microscopic tissue changes. Additional short- and long-term prospective studies are requested to establish their value in the diagnosis and prognosis of multiple sclerosis.

Mutations in the hemochromatosis gene (HFE) and multiple sclerosis.

In the present study we have investigated whether HFE gene polymorphism may play a role in the disease process of Croatian and Slovenian MS patients and their potential genetic susceptibility to MS. We genotyped 314 MS patients and 400 healthy controls for the C282Y and H63D mutations by polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP) analysis. Our results showed no significant differences in the distribution of the two mutations between MS patients and controls, suggesting that HFE polymorphisms do not contribute to the susceptibility to MS. Also, there was no significant correlation between HFE polymorphism and the disease progression index. However, we observed that MS patients carrying the mutant C282Y allele exhibited earlier onset of disease symptom relative to other genotypes, but it warrants further study in a larger series of MS patients.

MMP-2 -1575G/A polymorphism modifies the onset of optic neuritis as a first presenting symptom in MS?

Previous studies show altered activities of matrix metalloproteinase (MMP)-2 and MMP-9 in serum and cerebrospinal fluid of multiple sclerosis (MS) and neuromyelitis optica (NMO) patients. Optic neuritis (ON) is a common symptom of both disorders. Here we investigated the impacts of MMP-2 -1575G/A and MMP-9 -1562 C/T gene polymorphisms on disease phenotype in 100 MS patients with ON as a first symptom and 376 MS patients with other initial symptomatology. The MMP-2 -1575G/A polymorphism led to a 5-year-earlier age of disease onset in MS patients with ON as a first symptom (p=0.009).

Epidemiology of primary central nervous system tumors in the Coast and Gorski Kotar County, Croatia, 1977-2000.

AIM AND BACKGROUND: To establish the incidence of primary tumors of the central nervous system (CNS) in the resident population of the Coast and Gorski Kotar County, Croatia, in the period 1977-2000. METHODS: A retrospective descriptive epidemiological study. Tumors were classified according to the World Health Organization's scheme. A total of 911 cases was identified. Information about patient gender and age at diagnosis, tumor location and histologic type was obtained from case histories, autopsy protocols and pathology reports. Age- and sex-adjusted incidence were determined by a direct standardization method. RESULTS: Histologic confirmation was obtained in 84.5% of cases. The most frequent tumors were glioblastoma in men (30.2%) and meningioma in women (29.5%). The average annual crude and world-standardized incidence was 11.2 (95% CI, 10.1-12.3) and 8.2/100,000/year (95% CI, 7.4-9.0), respectively. The highest specific age incidence was detected in the seventh decade of life, 24.7/100,000/year (95% CI, 21.4-28.8). The tumors occurred equally in each sex. The lowest incidence was detected on the islands, 7.4/100,000/year (95% CI, 5.9-9.2) and the highest along the coast, 12.7/100,000/year (95% CI, 11.4-14.0). The survey showed the highest incidence of these neoplasms in the coastal municipality of Senj, 14.7/100,000/year (95% CI, 10.3-20.5). CONCLUSION: The descriptive epidemiological incidence of primary CNS tumors in the Coast and Gorski Kotar County, Croatia, especially those of neuroepithelial and meningeal origin, correspond to the data reported in similar studies elsewhere in the world. The incidence of these neoplasms in the area investigated is uneven. Limitations in study design preclude definitive conclusions about the causes of these differences.

[Cognitive impairment in multiple sclerosis patients]. / Spoznajni poremecaji u multiploj sklerozi.

In addition to neurological symptoms, multiple sclerosis is characterized by cognitive function impairment. Disturbances of memory, recall, information processing, visual-spacial perception, attention, and executive function, in less extent of speech, are present in about 60% of patients. They are similar to disorders in other subcortical dementias. Once they appear, they rarely recede. Conventional, and especially nonconventional magnetic resonance imaging evaluates more precisely the tissue substrate--diffuse neuroaxonal lesion of the entire brain parenchyma--than clinical findings, already in the early stage of the disease. Alterations in the brain imaging are manifested by T2 hyperintensive and T1 hypointensive lesions, decreased neuronal marker N-acetyl-aspartate in magnetic spectroscopy, decreased magnetization transfer ratio, and increased diffusivity with reduced anisotropy in diffusion-weighted imaging. Total volume of brain lesion, corpus callosum diameter, and relation of measures of brain chambers and the rest of the brain, are best indices of cognitive dysfunction in multiple sclerosis. Their diagnosis in the very beginning of the disease allows early application of therapeutic procedures. Symptomatic treatment of these disorders is not efficient, and immunomodulation, particularly the use of biologic versions of interferon-beta, shows disputable effects. Cognitive dysfunctions affect relationships and working ability of patients.