Francesco Copello

Menstrual cycle and ovary alterations in women with epilepsy on antiepileptic therapy

Impaired reproductive function is thought to frequently affect women with epilepsy, mainly when seizures originate in the temporal lobe. In this study, we evaluated menstrual cycle features and assessed ovulation by determining luteal progesterone (Pg) levels in 101 consecutive women with epilepsy (36 with idiopathic generalized epilepsy -IGE; 65 with partial epilepsy -PE), aged between 16 and 50 years, treated with various antiepileptic drugs (AED). PE originated in the temporal lobe (TLE) in 40 subjects, in the frontal lobe in 13, in the parietal lobe in 2, while the origin of focal seizures remained undetermined in 10 patients. In all patients, menstrual and reproductive history, body mass index, hair distribution and hormonal pattern were assessed. Suprapubic ovary ultrasound (US) examination was carried out in 83 patients (28 with IGE, 55 with PE). Three patients with IGE and one with PE were amenorrheic. Oligomenorrhea occurred in 16 patients, polymenorrhea in 2. Changes in menstrual cyclicity were independent from epilepsy type (19.4% in IGE; 23.1% in PE) and from origin of focal discharges (22.5% of patients with TLE; 20.0% with origin in other brain areas). Luteal Pg levels remained below 2 ng/ml in 30 patients independently of epilepsy type. Corpus luteum dysfunction was combined with hyperandrogenism in 15 of these patients. In the other cases different alterations of hypothalamus-pituitary-ovary axis were observed. Valproic acid blunted luteal Pg surge more frequently than other AED. Polycystic ovaries (PCO) were observed in 14 (16.9%) patients (21.0% with IGE; 14.5% with PE). These prevalences are not higher than those reported in the general population. Among PE patients, PCO was found in 1 case with undertemined focal origin and in 7 TLE cases, who also had ovary volume significantly larger than patients with seizures originating from the frontal or parietal lobe. Epileptic women exhibited an increased occurrence of multifollicular ovaries (MFO) found in 12 cases (14.4% vs 5% in the general population). However, no defined hormonal or clinical pictures were associated with this US alteration in most patients. These findings reappraise the impact of ovary alterations in women mainly affected by mild to moderate epilepsy, on differing AED regimens, with the exception of more frequent ovulatory dysfunction and PCO occurrence in patients taking VPA.

Relationships between cortisol, dehydroepiandrosterone sulphate and insulin-like growth factor-I system in dementia

ABSTRACT. Changes in the hypothalamus-pituitary- adrenal axis (HPAA) function, entailing elevated cortisol circulating titres, occur in aging and in some neurological conditions, such as Alzheimer’s disease (AD). Excess cortisol has neurotoxic effects which affect hippocampal neurones. Dehydroepiandrosterone sulphate (DHEAS) has an antiglucocorticoid activity and neuroprotective effects, but its levels decrease with aging. Glucocorticoids influence the production of insulin-like growth factor-I (IGF-I) and modify its systemic and neurotrophic biological activity by inducing changes in IGF-binding proteins (IGFBPs). We looked for relationships between cortisol, DHEAS levels, and IGF-I - IGFBPs system in AD. Cortisol, DHEAS and GH levels at 02:00, 08:00, 14:00, 20:00 h, basal IGF-I, IGFBP-1 and IGFBP-3 levels were determined by RIAs or IRMA in 25 AD patients, aged 58-89 yr, and in 12 age-matched healthy controls. AD subjects had higher cortisol, lower DHEAS levels and increased cortisol/DHEAS ratio (C/Dr) than controls. In AD cases, total IGF-I, IGFBP-3, and IGF-I/IGFBP ratios were significantly lowered, while IGFBP-1 levels were significantly higher than in controls. We found a significant inverse correlation between IGF-I and IGFBP-3 levels vs C/Dr, and between both IGF-I/IGFBPs ratios vs mean cortisol levels. IGFBP-3 correlated directly with DHEAS. Cortisol was directly and IGF-I inversely correlated with cognitive impairment. In AD patients we found that alterations in HPAA function and elevated C/Dr are related to lowered total and free IGF-I levels. These findings and their relationship to cognitive impairment suggest that changes in hormonal set-up might influence the clinical presentation of the disease.

Resting SPECT-neuropsychology correlation in very mild Alzheimer's disease

OBJECTIVE To investigate the relationships between brain function and some of the most frequently impaired cognitive domains in the first stages of Alzheimers disease (AD), we searched for correlation between the scores on 3 neuropsychological tests and brain perfusion, assessed by single photon emission computed tomography (SPECT) in patients with very mild AD. METHODS Twenty-nine consecutive outpatients (mean age 78.2+/-5.5) affected by probable AD in the very mild phase (i.e. with a score > or =20 on the mini-mental state examination, MMSE) underwent brain SPECT with (99m)Tc-ethylcisteinate dimer. For correlative purposes, word list learning (by the selective reminding test, SRT), constructional praxis test (CPT) and visual search test (VST) were chosen a priori out of an extended battery employed to diagnose AD at first patient evaluation. Voxel-based correlation analysis was achieved by statistical parametric mapping (SPM99) with a height threshold of P=0.005. Age, years of education and the MMSE score were inserted in the correlative analysis as confounding variables. RESULTS The SRT score showed correlation with brain perfusion in 3 clusters of the left hemisphere, including the post-central gyrus, the parietal precuneus, the inferior parietal lobule and the middle temporal gyrus, and in one cluster in the right hemisphere including the middle temporal gyrus and the middle occipital gyrus. The CPT score was significantly correlated with brain perfusion in the parietal precuneus and the posterior cingulate gyrus in the left hemisphere, whereas the VST score gave a significant correlation with brain perfusion in a left cluster including the parietal precuneus and the superior temporal gyrus. CONCLUSIONS Cognitive impairment in very mild AD is reflected by brain dysfunction in posterior associative areas, with peculiar topographical differences proper of each domain. The parietal precuneus was a common site of correlation of all 3 neuropsychological tests. This region, together with the posterior cingulate and the superficial posterior temporal-parietal cortex, is thought to be affected by disconnection from the mesial temporal lobe, besides being directly affected by increased oxidative stress and by atrophy as well. The impairment of these areas is thought to contribute to cognitive decline in verbal memory, constructional praxis and visual sustained attention which are indeed among the earliest signs of cognitive impairment in AD. SIGNIFICANCE Assessing the relationships between neuropsychology and brain functional imaging is a key approach to clarify the pathophysiology of cognitive failure in AD; the specificity of these findings in AD remains to be proven through comparison with correlation achieved in matched controls.

Alterations in the autonomic control of heart rate variability in patients with anorexia or bulimia nervosa: Correlations between sympathovagal activity, clinical features, and leptin levels

Changes in body composition, hormone secretions, and heart function with increased risk of sudden death occur in eating disorders. In this observational clinical study, we evaluated sympathovagal modulation of heart rate variability (HRV) and cardiovascular changes in response to lying-to-standing in patients with anorexia (AN) or bulimia nervosa (BN) to analyze: a) differences in autonomic activity between AN, BN, and healthy subjects; b) relationships between autonomic and cardiovascular parameters, clinical data and leptin levels in patients with eating disorders. HRV, assessed by power spectral analysis of R-R intervals, blood pressure (BP) and heart rate (HR) were studied by tilt-table test in 34 patients with AN, 16 with BN and 30 healthy controls. Autonomic and cardiovascular findings were correlated with clinical data, and serum leptin levels. Leptin levels were lowered in AN vs BN and healthy subjects (p<0.0001), but both AN and BN patients showed unbalanced sympathovagal control of HRV due to relative sympathetic failure, prevalent vagal activity, impaired sympathetic activation after tilting, independently from their actual body weight and leptin levels. No significant correlations were obtained between HRV data vs clinical data, BP and HR findings, and leptin levels in eating disorders. Body mass indices (BMI) (p<0.02), and leptin levels (p<0.04) correlated directly with BP values. Our data showed alterations of sympathovagal control of HRV in eating disorders. These changes were unrelated to body weight and BMI, diagnosis of AN or BN, and leptin levels despite the reported effects of leptin on the sympathetic activity.

Seizure Frequency and Cortisol and Dehydroepiandrosterone Sulfate (DHEAS) Levels in Women with Epilepsy Receiving Antiepileptic Drug Treatment

Summary:  Purpose: Hormonal changes occur in epilepsy because of seizures themselves and of antiepileptic drug (AED) effects on steroid production, binding, and metabolism. Conversely, steroids may influence neuron activity and excitability by acting as neuroactive steroids. This cross‐sectional observational study aimed to evaluating cortisol and dehydroepiandrosterone sulfate (DHEAS) levels in female epilepsy patients with different disease severity, as assessed by a seizure frequency score (SFS).

Timing of disease progression by quantitative EEG in Alzheimer' s patients.

This prospective study was planned to assess whether quantitative EEG (qEEG) can give an estimate of the timing of achievement of three endpoints (loss of activities of daily living, incontinence, and death) in 72 consecutive patients (53 females, 19 males; mean age, 70.8) affected with probable Alzheimers disease, as defined according to the NINCDS-ADRDA criteria. Power-weighted, log-transformed relative values of the four conventional EEG bands were considered in a central-posterior temporal region for each hemisphere. The hypothesis was tested by the lifereg procedure of the Statistical Analysis System package (first significance level accepted, P < or = 0.01). Because patients were in different stages of the disease, the statistical analysis was performed in the entire group as well as in the subgroup of 41 patients (mean age, 69.6) with mild dementia (scoring 3 or 4 on the global deterioration scale). In the whole group, the loss of activities of daily living was predicted by delta power in either side (P = 0.01), incontinence was predicted by alpha power in the right side (P < 0.01), whereas the statistical significance was not reached for death (P < 0.05). In the subgroup of mild demented patients, the loss of activities of daily living was predicted by delta power in the left side (P = 0.01), incontinence by both delta (P < 0.01) and alpha (P < 0.001) power in the right side, and death was not significantly predicted (P = 0.08). Quantitative EEG is a low-cost, discomfort-free technique which may be used to obtain information on the timing of disease evolution. The results showed in mild Alzheimers disease appear especially interesting to attempt a prediction of the future time course of the disease from its beginning.

Hippocampal Perfusion and Pituitary-Adrenal Axis in Alzheimer’s Disease

The hippocampus is involved in Alzheimer’s disease (AD) and regulates the hypothalamus-pituitary-adrenal axis (HPAA). Enhanced cortisol secretion has been reported in AD. Increased cortisol levels affect hippocampal neuron survival and potentiate β-amyloid toxicity. Conversely, dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are believed to antagonize noxious glucocorticoid effects and exert a neuroprotective activity. The present study was aimed at investigating possible correlations between hippocampus perfusion – evaluated by SPECT – and HPAA function in AD. Fourteen patients with AD and 12 healthy age-matched controls were studied by 99mTc-HMPAO high-resolution brain SPECT. Plasma adrenocorticotropin, cortisol, and DHEAS levels were determined at 2.00, 8.00, 14.00, 20.00 h in all subjects and their mean values were computed. Cortisol/DHEAS ratios (C/Dr) were also calculated. Bilateral impairment of SPECT hippocampal perfusion was observed in AD patients as compared to controls. Mean cortisol levels were significantly increased and DHEAS titers were lowered in patients with AD, as compared with controls. C/Dr was also significantly higher in patients. Using a stepwise procedure for dependent SPECT variables, the variance of hippocampal perfusional data was accounted for by mean basal DHEAS levels. Moreover, hippocampal SPECT data correlated directly with mean DHEAS levels, and inversely with C/Dr. These data show a relationship between hippocampal perfusion and HPAA function in AD. Decreased DHEAS, rather than enhanced cortisol levels, appears to be correlated with changes of hippocampal perfusion in dementia.

Regional Cerebral Blood Flow and Prognostic Evaluation in Alzheimer’s Disease

The present investigation reports the application of regional cerebral blood flow (rCBF; 133Xe method) to prognostic purposes in a consecutive series of 76 patients (mean age 68.4 ± 8.7 years) with probable Alzheimer’s disease (AD; NINCDS-ADRDA criteria). The likelihood that rCBF from a posterior temporal-inferior parietal area in each hemisphere at the first visit may predict timing of achievement of three endpoints (i.e. loss of activity of daily living, ADL, incontinence and death due to end-stage AD) was tested by the ‘lifereg’ procedure of the Statistical Analysis System package. With respect to baseline evaluation, 32 patients lost ADL 20.6 ± 17.4 months later, 31 developed incontinence 27.1 ± 19.0 months later, and 16 patients died after 40.9 ± 23.8 months of follow-up. Baseline rCBF significantly predicted all end-points: the loss of ADL (left hemisphere: p = 0.04; righth hemisphere: p = 0.02), incontinence (p = 0.02 in both hemispheres) and death (p = 0.01 in both hemispheres). Statistical significance was maintained for the loss of ADL and incontinence both in a subgroup of mildly demented patients, in whom death was not considered due to the low number of patients who died, and in a multivariate analysis including patient age, age at onset, sex, duration of illness, Mini-Mental State Examination score and presence of extrapyramidal signs and psychotic symptoms at the first visit. This study shows that rCBF measurement in a posterior temporal-inferior parietal area may give prognostic information on timing of evolution of AD, whenever performed during the course of the disease, and may be utilized both in clinical practice and for social planning.

Dexamethasone effects on cortisol secretion in Alzheimer’s disease: Some clinical and hormonal features in suppressor and nonsuppressor patients

Alterations in the hypothalamic-pituitary-adrenal axis (HPAA) and failure of dexamethasone (DXT) to suppress cortisol secretion occur in Alzheimer’s disease (AD). This study was aimed to settle possible differences in some clinical (age, body weight, body mass index, dementia severity) and hormonal parameters in AD patients non-responders to overnight 1 mg-DXT suppression test compared with the responder subjects. ACTH, cortisol and dehydroepiandrosterone sulphate (DHEAS) day-time levels were assessed in 25 AD patients and in 12 age-matched healthy controls before DXT administration. In view of their neuroprotective effects, plasma levels of Insulin-like Growth Factor-I (IGF-I) and of IGF-Binding Proteins (IGFBPs) were also determined. After DXT, 8 AD subjects (32%) showed cortisol levels above the conventional cut-off of 140 nmol/L. No significant differences were found in clinical parameters in suppressor vs nonsuppressor patients. AD subjects showed higher cortisol, cortisol/DHEAS ratios, and lower DHEAS levels in comparison with controls. Both ACTH and cortisol levels were not different in suppressor and nonsuppressor patients, but DHEAS levels were significantly lower in nonsuppressor cases, who also exhibited ACTH and cortisol periodicities more altered than in suppressor and in control subjects. IGF-I and IGFBP-3 levels were lower and those of IGFBP-1 higher in nonsuppressor than in suppressor cases and in healthy controls. IGF-I/IGFBPs system data were correlated with cognitive impairment and adrenal steroid levels in AD patients.

Latent tuberculosis infection and associated risk factors among undergraduate healthcare students in Italy: a cross-sectional study

BackgroundThe screening of both healthcare workers and students attending teaching hospitals for latent tuberculosis infection (LTBI) is recommended in hospitals of many countries with a low-incidence of TB, including Italy, as a fundamental tool of tuberculosis (TB) control programs. The aim of the study was to estimate the prevalence of LTBI and evaluate the main risk-factors associated with this condition in a cohort of healthcare Italian students.MethodsIn a cross-sectional study, performed between January and May 2012, 881 undergraduate students attending the Medical, Nursing, Pediatric Nursing and Midwifery Schools of the University of Genoa, trained at the IRCCS San Martino-IST Teaching Hospital of Genoa, were actively called to undergo the Tuberculin Skin Test (TST). All the TST positive cases were also tested with an Interferon-Gamma Release Assay (IGRA) to confirm the diagnosis of LTBI. A standardized questionnaire was collected for risk-assessment analysis.ResultsSeven hundred and thirty-three (83.2%) subjects underwent TST testing. The prevalence of TST positives was 1.4%, and in 4 (0.5%) out of 10 TST positive cases LTBI diagnosis was confirmed by IGRA. No difference in the prevalence of subjects who tested positive to TST emerged between pre-clinical (n = 138) and clinical (n = 595) students. No statistically significant association between TST positivity and age, gender, and BCG vaccination was observed. The main independent variable associated with TST positivity was to be born in a country with a high TB incidence (i.e., ≥20 cases per 100,000 population) (adjusted OR 102.80, 95% CI 18.09-584.04, p < 0.001).ConclusionsThe prevalence of LTBI among healthcare students resulted very low. The only significant association between TST positivity and potential risk factors was to be born in high TB incidence areas. In countries with a low incidence of TB, the screening programs of healthcare students before clinical training can be useful for the early identification and treatment of the sporadic cases of LTBI.