Is Apolipoprotein E ε2 Associated with Delayed Onset of Non-Lesional Temporal Lobe Epilepsy?

The aim of the study was to evaluate the possible association between Apo E polymorphisms and age at seizure onset in patients with non-lesional temporal lobe epilepsy. Eighty patients with non-lesional temporal lobe epilepsy with or without bilateral tonic-clonic propagation were analyzed. Age at seizure onset was defined as age at the first unequivocal seizure (excluding febrile convulsions). ApoE alleles were determined by a procedure where genome DNA was amplified by chain reaction along with polymerase, using the LightCycler kit (Roche) for ApoE mutations on codons 112 and 158. There was a statistically significant difference between the groups of patients with ApoE ε2/3 and ε3/4 genotypes (p=0.03), but not between patients with ApoE, ε2/3 and ε3/3, and those with ApoE ε3/4 and ε3/3. In conclusion, the results of our study suggested positive association of a specific ApoE genotype and onset of non-lesional temporal lobe epilepsy.

Lack of association between polymorphism in ABCC2 gene and response to antiepileptic drug treatment in Croatian patients with epilepsy.

Despite advances in antiepileptic drug (AED) therapy, about one-third of patients with epilepsy are resistant to drug treatment. Functional impact of polymorphisms in drug-efflux transporter genes may contribute to multidrug resistance theory. Studies on ABCB1 gene gave contradictory results and available data suggest that this polymorphism may not directly cause altered P-glycoprotein (Pgp) transport activity but may be associated with one or more causal variants in the stretch of linkage disequilibrium or is caused by multiple gene polymorphisms. Genetic polymorphisms also occur frequently in other transmembrane transport systems including the multidrug resistance proteins (MRPs, ABCC2). The aim of this research was to investigate the possible association of ABCC2 gene polymorphisms G1249A in exon 10 and C24T in exon 1 with the development of drug resistance. This cross-sectional study is a part of ongoing pharmacogenomic study of epilepsy in Croatian population. All patients enrolled in the study had an established diagnosis of partial complex epilepsy with or without secondary generalization with non lesional brain MRI with epilepsy protocol and have been suffering for more than two years. They were divided into two groups. The first group comprised 52 patients refractory to the current therapy, while the second group consisted of 45 patients with well-controlled seizures. Our data did not identify any significant association between genetic polymorphisms of exon 1 (24C > T) and exon 10 (1249G < A) of ABCC2 gene or any combined effect in response to AED treatment and development of drug resistance in patients with partial complex epilepsy. Statistical significant difference was not found in genotype based analysis, allele frequency, haplotype and combined genotype analysis.

Direct medical cost of children and adolescents epilepsy at a university setting in Croatia.

The aim was to study the direct medical cost of epilepsy in children and adolescents and to determine the impact of epilepsy type and child's age on total costs of treatment. One-year prospective, prevalence based, "bottom up" analyses of sixty-nine (69) children with epilepsy (International League Against Epilepsy criteria was used). Direct medical costs were calculated by summing annual costs of hospital care, outpatient visits and antiepileptic drug (AED) treatment. The average annual cost per patient was 1293.0 Euro. The costs of hospital admissions were 942.9 Euro (72%), followed by drug treatment 240.0 Euro (19%) and outpatient medical services 121.2 Euro (9%). The costs of epilepsy were significantly higher for children under 5 years of age. AED costs were statistically significantly lower for children who received traditional AED (Euro 122.0) than modern AED (571.2 Euro). The costs of epilepsy in children and adolescents in Croatia are congruent to those of developed countries. Costs significantly varied regarding the child's age. The cost of illness studies are an important first step towards the rational use of available resources.

Parkinson's disease--challenges in new drug development.

Idiopathic Parkinson's disease (IPD) is the second most common neurodegenerative disorder after Alzheimer's disease. Treatment aims in IPD include the provision of symptomatic relief reduction of functional disability, halting or slowing of the neurodegenerative process, and the prevention of long-term complications by proper initiation of therapy. At present, pharmacotherapeutic strategies allow the amelioration of motor symptoms of IPD only, whereas non-motor manifestations are not helped by dopamine replacement strategies. In addition, levodopa-induced fluctuation and dyskinesia are still challenging, particularly in long-term treatment. Despite advances in pharmacotherapy that have improved quality of life for these patients, the mortality rate remains largely unchanged. Sustained interest in IPD will hopefully allow increased funding of research to develop new and better treatments.

Epilepsy due to malformations of cortical development--correlation of clinical, MRI and Tc-99mECD SPECT findings.

Malformations of cortical development (MCD) have been increasingly recognized as an important cause of intractable epilepsy. The aim of our study was to define epileptogenicity of MCDs by correlating MRI, EEG and semiology of epileptic attacks, and to determine the effect of MCD on drug resistant epilepsy. We also intended to reveal the utility of interictal single photo emission computed tomography (SPECT) in verification of MCD lesions and relative prevalence of different MCDs. Based on interictal EEG finding, semiology of the epileptic attacks and brain magnetic resonance imaging (MRI) "electroclinical epileptogenicity" of MCD was defined. Brain MRI revealed cortical dysplasia (CD) in nine patients, polymicrogyria in four patients, lissencephaly and schizencephaly in one patient each. Three patients had a combination of malformations. The localization of SPECT hypoperfusion corresponded to MCD lesion in ten (66.67%) patients. Electroclinically confirmed epileptogenicity of MCD overlapped with MR and interictal SPECT findings in fourteen (93.3%) and nine (60.0%) patients, respectively. Our study results demonstrated the MCD lesions to be highly epileptogenic and a frequent cause of intractability.

Rotigotine transdermal patch enables rapid titration to effective doses in advanced-stage idiopathic Parkinson disease: subanalysis of a parallel group, open-label, dose-escalation study.

OBJECTIVE: Rotigotine (Neupro) is formulated as a transdermal delivery system designed to provide a selective, non-ergot D3/D2/D1 agonist to the systemic blood flow over a 24-hour period. In clinical trials, patches were applied once daily and uptitrated to the individual effective dose in increments of 2 mg/24 h every week. The aim of this analysis was to determine the safety of a more rapid titration of rotigotine by assessing the tolerability of escalating transdermal doses of rotigotine given in 2 different titration schemes. METHODS: We analyzed the safety of rotigotine in 2 groups of patients with advanced stage Parkinson Disease. The starting dose of 4 mg/24 h was increased every week by 2 mg/24 h in the slow-titration group and 4 mg/24 h in the fast-titration group. The primary focus of this subanalysis was the separate tolerability of rotigotine in each randomized treatment arm, during the dose-escalation period. However, the 2 titration schemes were also compared with each other. RESULTS: The dose of first reported nausea and/or vomiting was 8 mg/24 h for the fast-titration group and 4 mg/ 24 h for the slow-titration group. There were no remarkable differences concerning the side-effect profile between the 2 different titration schemes. CONCLUSIONS: The fast-titration regimen had a similar adverse event profile to slower titration, and allowed rotigotine to be introduced quickly. This subanalysis suggests that rotigotine may be uptitrated more rapidly.

Gradual recovery of impaired cardiac autonomic balance within first six months after ischemic cerebral stroke.

BACKGROUND: The level of autonomic dysbalance in the first months after acute ischemic cerebral stroke has not been thoroughly investigated, and the available data are uncomplete. The aim of this research is to establish the degree and dynamics of impaired cardiac autonomic balance recovery within the first six months following the acute ischemic cerebral stroke. METHODS: This prospective study included 78 patients who had suffered the first ischemic cerebral stroke and 78 sex and age-matched healthy subjects. We have analyzed heart rate variability (HRV) from a 24-hour Holter ECG. In the group of patients with ischemic cerebral stroke, HRV was measured after two and six months following the acute phase, respectively. RESULTS: Two and six months after the acute ischemic cerebral stroke, all HRV variables, except low to high frequency ratio (LF/HF), were significantly lower in the group of stroke patients when compared to the control group. Furthermore, we found a significant increase in the overall HRV between months 2 and 6 after the acute phase of cerebral stroke; p = 0.03 for Standard deviation of all normal R-R intervals (SDNN) and p = 0.01 for Total power. CONCLUSIONS: The results point to the gradual recovery of impaired cardiac autonomic balance in the patients with ischemic cerebral stroke within the first months following the acute phase. Nevertheless, HRV remains significantly lower even six months after the acute phase in comparison to healthy subjects.

[Current concept of diagnostic procedure in Alzheimer's disease: an evidence based approach]. / Alzheimerova bolest: suvremeni dijagnosticki pristup temeljen na dokazima.

The aim of this article is to provide evidence-based recommendations for early diagnosis of Alzheimer's disease (AD) and hereby to give clinician the guidelines for optimal detection of patients with AD. Our intention is also to unify diagnostic schemes in accordance with our objective and specific possibilities. Basic diagnostic procedures primaruly are anamnesis and clinical examination with rational usage of neuroimaging, electrophysiological and laboratory procedures. Using these guidelines in medical practice in Croatia would be a solid basis for future epidemiological and clinical multicenter studies.

ApoE genotyping and response to galanthamine in Alzheimer's disease--a real life retrospective study.

This study was undertaken to evaluate the effect of galanthamine, a new cholinesterase inhibitor on cognitive performances in 84 patients with various apoE genotype and Alzheimer's disease (AD) during the six-month treatment. The diagnosis of AD was made on the basis of NINCDS/ADRDN criteria. ApoE4 genotype was determined by PCR procedure. The cognitive performance was assessed MMSE at baseline and six months later. The difference among the groups was statistically analyzed by ANOVA model and Pearson's chi2-test. The MMSE at baseline in all completes was 18.0 +/- 3.73, whereas the mean value of MMSE after 6 months was 16.4 +/- 5.61 indicating significant deterioration (p < 0.01). Of the 84 patients, 14 (169%) were apoE4 homozygous, 41 (49%) were heterozygous, whereas 29 (35%) were apoE4 negative. The significant number of responders was observed among apoE4 homozygous patients (71%; chi2 = 6.89; p = 0.032). The subgroup of apoE4 homozygous patients with AD in its mild to moderate stage may be considered as responders to galanthamine.

The effect of 3-weeks stationary cardiac rehabilitation on plasma lipids level in 444 patients with coronary heart disease.

The aim of this study was to investigate the effect of 3-weeks stationary cardiac rehabilitation on plasma lipids level in patients with CHD. The study included 444 consecutive patients (364 male and 80 female, mean age 58 +/- 9 year) with CHD who underwent 3-weeks stationary cardiac rehabilitation. Patients were divided into groups depending on their baseline levels of cholesterol and medication therapy: patients with normal (< 5 mmol/L, group I, 129 patients) and elevate plasma level of Total cholesterol (> 5 mmol/L, group II, 315 patients) and subgroups Ia and IIa (with statin in therapy), Ib and IIb (without statin in therapy). After 3-weeks cardiac rehabilitation, the levels of Total cholesterol 5.75 +/- 1.34 vs. 5.17 +/- 1.08 mmol/l; p < 0.001, triglycerides 2.04 +/- 1.33 vs. 1.81 +/- 1.06 mmol/L; p = 0.004, LDL-cholesterol 3.77 +/- 1.14 vs. 3.21 +/- 0.96 mmol/L; p < 0.001 were significantly lower while the level of HDL-cholesterol 0.94 +/- 0.28 vs. 0.99 +/- 0.27 mmol/L; p = 0.008 were significantly higher in comparison with the baseline values. Furthermore, we found significant changes in lipid profile at the end of rehabilitation in each group of patients compared with the baseline values. There were no significant differences in plasma lipids level between group of patients with or without statin in therapy at the end of rehabilitation. The results of this study suggest that moderate regular physical activity and diet alone or in combination with hypolipidemic drugs already after 3 weeks have a favourable effect on plasma lipids level and should be propagate in the prevention of CHD.

[Changes in autonomic control of heart rate after ischemic cerebral stroke]. / Promjene autonomne kontrole srcanog rada u bolesnika s preboljelim ishemijskim mozdanim udarom.

BACKGROUND AND PURPOSE: Heart rate variability (HRV) is a physiological phenomenon which reflects the influence of the autonomic nervous system on the heart work. The research in HRV has not been limited to the domain of basic and clinical cardiology, mostly with the aim of stratifying the risks of sudden death from malignant arrhythmias among patients with myocardial infarction (MI), but over the past few years the research has been done and studies have been published also in the area of neurology. Likewise acute MI, acute ischemic stroke leads to autonomic dysbalance and lowered HRV. However, literature lacks relevant data on autonomic dysbalance after the acute phase of ischemic stroke. The aim of this study was to assess the level of autonomic dysbalance in patients after the acute phase of ischemic stroke. PATIENTS AND METHODS: This prospective study included 86 consecutive patients who had suffered ischemic stroke (59 men and 27 women, mean age 56 +/- 13 years) and 86 age-matched healthy control subjects (62 men and 24 women, mean age 53 +/- 9 year). In the acute phase of the disease, along with clinically manifest neurologic deficit, there is ischemic hemispheric lesion verified by computed tomography (CT) scan. Lesion of the left and right cerebral hemisphere was detected in 56% and 44% of patients, respectively. After the acute phase of the disease, patients were hospitalized at one of the neurologic departments of the Hospital for Medical Rehabilitation in Krapinske Toplice, Croatia, where rehabilitation was carried out (mean duration 20 +/- 9 days) in the 1999-2002 period. Inclusion criteria were: age under 70 years, first ischemic stroke verified by CT scan within 2-12 weeks of the acute phase of the disease, Barthel index 30-50, and stable sinus rhythm in ECG. Exclusion criteria were: a history of previous ischemic stroke, intracerebral hemorrhage, MI, percutaneous coronary intervention or surgical revascularization of the myocardium, clinical signs of coronary artery disease, acute heart failure, diabetes mellitus, chronic atrial fibrillation, sinus node disease, AV block grade II or III, and the use of beta adrenergic blockers or antiarrhythmic agents class Ic or III in medication. Twenty-four hour Holter ECG was performed 58 +/- 23 days after the stroke (14 +/- 5 days from the beginning of rehabilitation). HRV was analyzed from the Holter ECG data. The values of the HRV parameters in stroke patients were compared with those recorded in the control group. Most of the variables proposed by the Task Force on HRV were analyzed. Time domain analysis included: mean RR, mean of R-R intervals for normal beats; SDNN, standard deviation of all normal R-R intervals; SDNN-i, mean of 5-minute standard deviations of RR intervals; SDANN-I, standard deviation of the 5-minute means of R-R intervals; rMSSD, square root of the mean of the squared successive differences in R-R intervals; and pNN50, percentage of R-R intervals that are by at least 50 ms different from the previous interval. Frequency domain analysis included: TP, total power (0.0-0.5 Hz); VLF, very low (0.0033-0.04 Hz); LF, low (0.04-0.15 Hz); HF, high (0.15-0.40 Hz) frequency components; and LF/HF, low to high frequency ratio. Statistical analysis was performed using the commercial software package, Microsoft SPSS for Windows, Version 8.0. RESULTS: Patients who had suffered an ischemic stroke had a significantly lower overall HRV and shorter mean RR interval than healthy subjects from the control group: SDNN 96 +/- 27 vs. 136 +/- 31 ms, p < 0.001; TP 1962 +/- 1338 vs. 3968 +/- 2857 ms2, p < 0.001; and mean RR 869 +/- 104 vs. 892 +/- 117 ms, p = 0.02. CONCLUSION: As in MI, the values of HRV stay significantly lower after the acute phase of the disease in patients who have suffered ischemic stroke compared to healthy persons of the same age.

[Pharmacotherapy of Alzheimer's disease--an evidence based approach]. / Farmakoterapija Alzheimerove bolesti--pristup temeljen na dokazima.

The aim of this article is to provide evidence-based recommendations for early diagnosis of Alzheimer's disease (AD) and hereby to give clinican guidelines for optimal detection of patients with AD. Our intention is also to unify diagnostic schemes in accordance with our objective and specific possibilities. Basic diagnostic procedures primarily are anamnesis and clinical examination with rational usage of neuroimaging, electrophysiological and laboratory procedures. Using these guidelines in medical practice in Croatia would be a good basis for future epidemiological and clinical multicentric studies.

High doses of rotigotine transdermal patch: results of an open-label, dose-escalation trial in patients with advanced-stage, idiopathic Parkinson disease.

OBJECTIVE: The objective of the study was to determine the maximal achievable dose of rotigotine by assessing the tolerability of escalating doses of rotigotine transdermal patch in patients with advanced-stage Parkinson disease. METHODS: Thirty-four patients aged 30 years or older on a stable dose of l-dopa with an off time of at least 2.5 h/d were randomized to 2-titration schemes. The patients started on a dosage of 4 mg/24 h and received an incremental dosage of 4 mg/24 h per week in the fast-titration group and 2 mg/24 h per week in the slow-titration group to the maximal target dosage of 24 mg/24 h (patch size of 120 cm(2)). Thereafter, both groups entered a maintenance period of 42 days or longer for the rapid-titration group and 7 days or longer for the slow titration group followed by a 2-week safety follow-up period with stepwise dosage de-escalation of 4 mg/24 h for 4 days. RESULTS: Twenty-seven patients completed the trial, of whom 24 completed without dose reduction. Twenty-six patients (76%) were titrated to the maximum target dose and thus had a maximal achievable dosage of at least 24 mg/24 h. Adverse events, generally mild or moderate, included application site reaction (12%), nausea, dyskinesia, and visual hallucinations (9% each). The mean time spent off decreased by 2 to 3 h/d. Duration of on without dyskinesia periods increased (2 h/d). The mean total (SD) Unified Parkinson's Disease Rating Score decreased by 18.9 (14.2) in the fast-titration group and 17.8 (14.0) in the slow titration group. A shift from off to on without dyskinesias in status after waking up was observed. CONCLUSIONS: Rotigotine transdermal patch, up to 24 mg/24 h, was effective and well tolerated by patients with advanced-stage Parkinson disease.

Association of refractory complex partial seizures with a polymorphism of ApoE genotype.

Apolipoprotein E (ApoE) is a constituent of many types of lipoproteins that play a role in metabolism of cholesterol and lipids in the body as well as in the brain. ApoE is synthesised in astrocytes and microglia and enter to neurons through LDL, LRP and VLDL receptors. Recently it was shown that ApoE is also produced in neurons. ApoE has a role in modulating learning and memory, structural plasticity, mobilization of cholesterol in repair, growth and maintenance of myelin and neuronal membranes during development and aging, and cell death after ischemic, convulsive, or other type of brain injury. The aim of this research was to investigate the possible association of ApoE gene polymorphism with the development of resistance to pharmacological therapy in patients with partial complex seizures with or without secondary generalization. In this prospective matched-pair controlled study, 60 patients with cryptogenic epilepsy with complex partial seizures, with or without secondary generalization, who have been suffering for five or more years, were studied. The first group comprised 30 patients refractory to the current therapy, while the second group consisted of patients with well-controlled seizures. The refractory and non-refractory groups of patients differed significantly in their phenotypes. Phenotype E3/4 was six times more frequent in refractory group than among non-refractory group. The lack of response was shown to be significantly associated with the presence of epsilon4 allele. This study provided evidence that the presence of epsilon4 allele is more often associated with a lack of response to current antiepileptic drugs as compared to epsilon2 and epsilon3 alleles.

Cognition in Parkinson's disease.

AIM: Studies of accentuated drop in cognitive functioning of Parkinson's disease patients mostly use global intelligence measures that have a masking effect on differential drop in specific cognitive abilities. The goal of this study was to investigate the possible differential drop in different types of cognitive tasks. Applied tests tapped fluid and crystallized intelligence, memory, and metacognition. METHOD: A sample of 116 participants participated in the study. Half of the participants were diagnosed with Parkinson's disease (average duration of disease 6.5 years) and control group participants equaled them in age, sex, and education level. All participants were tested using Raven's Colored Progressive Matrices (CPM), Crichton Vocabulary Scale (CVS), memory subtests from Wechsler Adult Intelligence Scale (WAIS DS-F, WAIS DS-B), and Mini-mental Status Examination (MMSE). Participants, and in the case of clinical group their caregivers as well, were asked questions concerning their metamemory and metacognition. RESULTS: Parkinson's disease patients scored lower than control group on all instruments used but the difference was significant only on CPM (F[1,114]=19.14, p=0.001) and MMSE (F[1,110]=4.04, p=0.047). CONCLUSION: Patients with Parkisons' disease have greater cognitive damage in fluid intelligence than in crystallized intelligence. They seem to have relatively accurate metamemory and metacognition.