Giovanni Murialdo

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.

Relationship between Cognitive Function, Growth Hormone and Insulin-Like Growth Factor I Plasma Levels in Aged Subjects

Basal growth hormone (GH) and insulin-like growth factor I (IGF-I) as well as GH responses to GH-releasing hormone (GHRH) were studied in 22 subjects (7 females, 15 males), aged between 65 and 86 years. The study was aimed at investigating the possible correlations between the age-dependent GH-IGF-I axis decline and the cognitive function – assessed by the Mini Mental State Examination (MMSE). The relationship between hormonal data, cognition and age, body weight, body mass index (BMI), some nutritional indices (triceps skinfolds, TSF, mid-arm circumference, MAC), and physical activity – quantified by the physical functioning index (PFI) – were also analyzed. GH basal levels were within the normal range, while GH responses to GHRH were blunted in most cases. GH peaks after GHRH were directly correlated with GH basal values. IGF-I serum levels were found to be in the lower part of the reference range for adult subjects or below it. GH responses to GHRH, but not GH and IGF-I basal levels, were inversely correlated with subject age. GH secretion areas after GHRH were inversely correlated with BMI, but no further correlations between GH data and clinical or nutritional parameters were found. MMSE values directly correlated with MAC and PFI values. IGF-I levels were directly correlated with MMSE scores, being lowered in patients with more advanced cognitive deterioration, and with MAC values – the decrease of which is thought to reflect protein caloric malnutrition – but not with body weight, BMI, TSF and PFI. MMSE-related protein caloric malnutrition and decreased physical activity possibly take part in affecting IGF- I function in subjects with mild cognitive impairment and, reciprocally, IGF-I decrement might affect neuronal function.

Sex Hormones and Pituitary Function in Male Epileptic Patients with Altered or Normal Sexuality

Summary Male epileptic patients frequently complain of sexual dysfunction, particularly impotence and loss of libido. Epilepsy itself, antiepileptic drugs (AEDs), and psychosocial factors are believed to contribute to impaired sexuality. We studied luteinizing hormone (LH) ulsatile secretion, gonadotropin, and prolactin (PRL) esponses to LH‐releasing hormone (LHRH) and thyrotropin‐releasing hormone (TRH) in 37 adult male epileptic patients receiving AED monotherapy who were seizure‐free and had normal EEGs. Sexuality was assessed by psychological interview. Impotence was diagnosed in 8 patients (in 2 combined with loss of sexual desire). The occurrence of hyposexuality (‐20%) was independent of epilepsy syndrome or AED. No change in total testosterone (T) level was observed. Free T (ft)and dihydrotestosterone (DHT) levels were lower and sex hormone binding globulin (SHBG) levels were higher in epileptic subjects than in healthy controls, but a statistically significant difference was not observed between hypo‐ and normosexual patients. In impotent epileptic patients, estradiol (E2) levels were significantly increased as compared with those of patients with preserved sexuality and of healthy controls. The unbalanced relation between androgen and E2 levels was emphasized by decreased fT/E2, fT/E2, and DHT/E2 ratios obtained in hyposexual epileptic patients. In this group, LHRH induced blunted LH peaks. No changes were noted in LH pulsatility features. These findings of higher E2 levels and of decreased LH response to LHRH administration in some epileptic patients with impaired sexuality, may suggest they have subclinical hypogonadotropic hypogonadism.

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.

High prevalence of vitamin D deficiency and its association with left ventricular dilation: An echocardiography study in elderly patients with chronic heart failure

BACKGROUND AND AIMS Vitamin D deficiency has been associated with chronic heart failure (CHF). We evaluated vitamin D levels in relationship with New York Heart Association (NYHA) classes, N-terminal pro-brain natriuretic peptide (NT-proBNP) values and left ventricular (LV) measures in ≥60 year old patients with stable CHF. Differently from previous investigations, LV function was assessed by transthoracic echocardiography, to provide easily reproducible results. METHODS AND RESULTS The study was performed at geographic latitude 44° N, from March to May and from September to November 2008. Acute HF and diseases or drugs altering vitamin D status were exclusion criteria. NYHA scores and 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D and NT-proBNP concentrations were assessed in 90 (45 F, 45 M) Caucasian patients with CHF secondary to hypertension and/or coronary artery disease. Vitamin D levels were also measured in 31 subjects without heart disease (controls). LV echocardiography was performed in 52 (26 F, 26 M) representative patients. Vitamin D concentrations were significantly lower in CHF cases than in controls. Among subject with CHF, 97.8% presented vitamin D deficiency (25(OH)D<75 nmol/L), being severe (<25 nmol/L) in 66.7%. LV end-diastolic and end-systolic diameters were significantly longer, LV end-diastolic and end-systolic volumes bigger and fractional shortening lower in CHF patients with 25(OH)D<25 nmol/L than with 25(OH)D≥25 nmol/L (p<0.05). Log-values of 25(OH)D were negatively correlated with LV end-systolic diameter and volume (r=-0.28; p<0.05). On subgroup analysis, these results persisted only in male patients. CONCLUSIONS In elderly CHF patients, vitamin D deficiency was highly prevalent and often severe. This first addressed echocardiography study showed a sex-specific association between vitamin D deficiency and LV dilation. Since further echocardiography data are easily obtainable, larger investigations are demanded.

Clinical and diagnostic aspects of encephalopathy associated with autoimmune thyroid disease (or Hashimoto’s encephalopathy)

Encephalopathy associated with autoimmune thyroid disease, currently known as Hashimoto’s encephalopathy, but also defined as corticosteroid-responsive encephalopathy associated with autoimmune thyroiditis, is a relatively rare condition observed in a small percentage of patients presenting with autoimmune thyroid disease. It consists of a subacute, relapsing-remitting, steroid-responsive encephalopathy characterised by protean neurologic and neuropsychiatric symptoms, diffuse electroencephalographic abnormalities and increased titres of antithyroid antibodies in serum and/or in cerebrospinal fluid. Most of the cases presenting this neurologic complication are affected by Hashimoto’s thyroiditis or, less frequently, by other autoimmune thyroid diseases, chiefly Graves’ disease.The pathogenesis of this encephalopathy is still unknown and largely debated, because of extremely varied clinical presentation, possibly referable to different aetiologic and pathophysiologic mechanisms, as confirmed by the two clinical cases we report in this paper. Autoimmune aetiology is, however, very likely in view of the well established favourable response to corticosteroid administration. Both vasculitis and autoimmunity directed against common brainthyroid antigens represent the most probable aetiologic pathways.Clinical manifestations include consciousness changes, neurologic diffuse or focal signs, headache, and altered cognitive function. Although unspecific, cerebral oedema has also been described. Cerebrospinal fluid examination often discloses an inflammatory process, with a mild increase in protein content and occasionally in lymphocyte count. In this review, clinical criteria for the diagnosis of defined, probable, or possible encephalopathy associated with autoimmune thyroid disease are suggested. Corticosteroid therapy currently allows us to obtain rapid remission of disease symptoms, but adverse outcomes as well as spontaneous remissions have also been reported.

Lowered circannual urinary melatonin concentrations in episodic cluster headache

The circannual secretion of melatonin in 14 Swedish and 15 Italian patients suffering from episodic cluster headache was compared with 14 Swedish and 15 Italian healthy controls matched for sex and age. Overnight samples of urine were collected once a month from 8 to 14 months and kept at -20° C until analysed with RIA. The melatonin concentrations in nocturnal urine were permanently low in cluster headache and there was no consistent change of the melatonin concentration in relation to cluster periods occurring during the study. There was no definitive circannual or infraannual rhythmicity of melatonin in patients or controls. Multiple analysis of variance with repeated measurements showed a significant effect of disease (p < 0.05), but not of time. Sex, geographical location, age, and smoking also had significant effects (p < 0.001) on the melatonin concentrations. Lower melatonin levels in cluster headache patients than in controls may in part be related to a larger number of smokers in the patient group. The relation between tobacco use and melatonin should be further studied.

Urinary melatonin excretion throughout the ovarian cycle in menstrually related migraine

Nocturnal urinary melatonin excretion was significantly decreased throughout an ovarian cycle in 12 migraine without aura patients compared to 8 healthy controls. Normal increases in urinary melatonin excretion during the luteal phase was less pronounced in the migraine patients. Melatonin excretion was further decreased during headache. The data indicate impaired pineal function in migraine.

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).