Vilho V. Myllylä

Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy

Background Reproductive endocrine disorders are more common among women with epilepsy than among normal women. These disorders have been attributed to epilepsy itself, but could be related to antiepileptic-drug therapy. Methods We studied 238 women with epilepsy who were seen regularly at the Outpatient Department of the University Hospital, Oulu, Finland. Their mean age was 33 years (range, 18 to 45), and the mean duration of therapy was 9 years (range, 0 to 31). Twenty-nine (12 percent) were treated with valproate, 120 (50 percent) with carbamazepine, 12 (5 percent) with valproate and carbamazepine, and 62 (26 percent) with other medications; 15 (6 percent) were untreated. Vaginal ultrasonography was performed to determine ovarian size, and serum sex-hormone concentrations were measured in 41 women with epilepsy and menstrual disturbances, 57 women with epilepsy and regular menstrual cycles, and 51 normal women. Results Menstrual disturbances were present in 13 of the women receiving valproate alone (45...

Poststroke Depression Correlates With Cognitive Impairment and Neurological Deficits

BACKGROUND AND PURPOSE The prevalence of poststroke depression is known to be high, but the knowledge of its neuropsychological correlates is limited. This 12-month prospective study was designed to evaluate the natural history of poststroke depression and to study its neuropsychological, clinical, and functional associates. METHODS We studied a series of 106 consecutive patients (46 women and 60 men, mean age 65.8 years) with acute first-ever ischemic stroke. The patients underwent a neurological, psychiatric, and neuropsychological examination at 3 and 12 months after the stroke. The psychiatric diagnosis of depression was based on DSM-III-R-criteria. RESULTS Depression was diagnosed in 53% of the patients at 3 months and in 42% of the patients at 12 months after the stroke. The prevalence of major depression was 9% at 3 months and 16% at 12 months. There was an association between poststroke depression and cognitive impairment; the domains most likely to be defective in stroke-related depression were memory (P=0.022), nonverbal problem solving (P=0.039), and attention and psychomotor speed (P=0.020). The presence of dysphasia increased the risk of major depression. The depressive patients were more dependent in ADL and had more severe impairment and handicap than the nondepressive patients. CONCLUSIONS More than half of the patients suffer from depression after stroke, and the frequency of major depression seems to increase during the first year. In addition to dysphasia, poststroke depression is correlated with other cognitive deficits. We emphasize the importance of psychiatric evaluation of stroke patients.

Rotigotine Effects on Early Morning Motor Function and Sleep in Parkinson's Disease: A Double-Blind, Randomized, pLacebo-Controlled Study (RECOVER)

In a multinational, double‐blind, placebo‐controlled trial (NCT00474058), 287 subjects with Parkinsons disease (PD) and unsatisfactory early‐morning motor symptom control were randomized 2:1 to receive rotigotine (2–16 mg/24 hr [n = 190]) or placebo (n = 97). Treatment was titrated to optimal dose over 1–8 weeks with subsequent dose maintenance for 4 weeks. Early‐morning motor function and nocturnal sleep disturbance were assessed as coprimary efficacy endpoints using the Unified Parkinsons Disease Rating Scale (UPDRS) Part III (Motor Examination) measured in the early morning prior to any medication intake and the modified Parkinsons Disease Sleep Scale (PDSS‐2) (mean change from baseline to end of maintenance [EOM], last observation carried forward). At EOM, mean UPDRS Part III score had decreased by −7.0 points with rotigotine (from a baseline of 29.6 [standard deviation (SD) 12.3] and by −3.9 points with placebo (baseline 32.0 [13.3]). Mean PDSS‐2 total score had decreased by −5.9 points with rotigotine (from a baseline of 19.3 [SD 9.3]) and by −1.9 points with placebo (baseline 20.5 [10.4]). This represented a significantly greater improvement with rotigotine compared with placebo on both the UPDRS Part III (treatment difference: −3.55 [95% confidence interval (CI) −5.37, −1.73]; P = 0.0002) and PDSS‐2 (treatment difference: −4.26 [95% CI −6.08, −2.45]; P < 0.0001). The most frequently reported adverse events were nausea (placebo, 9%; rotigotine, 21%), application site reactions (placebo, 4%; rotigotine, 15%), and dizziness (placebo, 6%; rotigotine 10%). Twenty‐four‐hour transdermal delivery of rotigotine to PD patients with early‐morning motor dysfunction resulted in significant benefits in control of both motor function and nocturnal sleep disturbances.

Sexual Functioning Among Stroke Patients and Their Spouses

BACKGROUND AND PURPOSE The aim of this study was to assess effects of stroke on sexual functioning of stroke patients and their spouses and to study the associations of clinical and psychosocial factors with poststroke changes in sexual functions. METHODS One hundred ninety-two stroke patients and 94 spouses participating in stroke adjustment courses sponsored by the Finnish Stroke and Aphasia Federation completed a self-administered questionnaire concerning their prestroke and poststroke sexual functions and habits. The main outcome measures were (1) libido, (2) coital frequency, (3) sexual arousal, including erectile and orgastic ability and vaginal lubrication, and (4) sexual satisfaction. RESULTS A majority of the stroke patients reported a marked decline in all the measured sexual functions, ie, libido, coital frequency, erectile and orgastic ability, and vaginal lubrication, as well as in their sexual satisfaction. The most important explanatory factors for these changes were the general attitude toward sexuality (odds ratio [OR] range, 7.4 to 21.9; logistic regression analysis), fear of impotence (OR, 6.1), inability to discuss sexuality (OR range, 6.8 to 18.5), unwillingness to participate in sexual activity (OR range, 3.1 to 5. 4), and the degree of functional disability (OR range, 3.2 to 5.0). The spouses also reported a significant decline in their libido, sexual activity, and sexual satisfaction as a consequence of stroke. CONCLUSIONS Sexual dysfunction and dissatisfaction with sexual life are common in both male and female stroke patients and in their spouses. Psychological and social factors seem to exert a strong impact on sexual functioning and the quality of sexual life after stroke.

Abnormal Heart Rate Variability as a Manifestation of Autonomic Dysfunction in Hemispheric Brain Infarction

BACKGROUND AND PURPOSE Abnormal heart rate variability is related to prognostically unfavorable ventricular arrhythmias and sudden arrhythmic death in coronary artery disease. Short-term electrocardiographic (ECG) recordings have shown similar abnormalities of heart rate variability in patients with acute stroke. However, there is no information regarding the clinical significance of these abnormalities and of heart rate variability in long-term ECG recordings in stroke. METHODS In this prospective study, we analyzed the time domain and frequency domain measures of heart rate variability from 24-hour ECG recordings in 31 consecutive patients with hemispheric brain infarction in the acute phase and at 1 and 6 months after the infarction and in 31 age- and sex-matched healthy control subjects. RESULTS All the measured components of heart rate variability, ie, standard deviation of RR intervals (P < .001), total power (P < .0001), very-low-frequency power (P < .0001), low-frequency power (P < .001), and high-frequency power (P < .05), were significantly lower than those of the control subjects in both the acute phase and 1 and 6 months later. Impaired heart rate variability correlated with the severity of neurological deficits and disability. In five patients with increased intracranial pressure due to large brain infarction, no relevant spectral components were found. CONCLUSIONS Hemispheric brain infarction seems to cause significant long-lasting damage to the cardiovascular autonomic regulatory system manifested as abnormalities of heart rate variability. Distorted heart rate variability in the acute phase of stroke may be prognostically unfavorable.

Reproductive effects of valproate, carbamazepine, and oxcarbazepine in men with epilepsy

Background: Recent observations have indicated that reproductive endocrine disorders are common among women taking valproate (VPA) for epilepsy, but it is not known whether respective abnormalities develop in men taking VPA for epilepsy. Carbamazepine (CBZ) may induce endocrine disorders in men with epilepsy, but the endocrine effects of oxcarbazepine (OXC) are not known. Methods: Reproductive endocrine function was evaluated in 90 men taking VPA (n = 21), CBZ (n = 40), or OXC (n = 29) as monotherapy for epilepsy and in 25 healthy control men. Results: Twelve men (57%) taking VPA had increased serum androgen levels. The mean serum level of androstenedione was high in patients taking VPA. Serum levels of dehydroepiandrosterone sulfate were low, and serum concentrations of sex hormone–binding globulin (SHBG) were high in men taking CBZ. The endocrine effects of OXC seemed to be dose-dependent, because serum hormone levels were normal in patients with low OXC doses (<900 mg/day), but serum concentrations of testosterone, gonadotropins, and SHBG were high in patients with a daily OXC dose ≥900 mg. Conclusions: VPA increases serum androgen concentrations in men with epilepsy. The endocrine effects of CBZ and OXC were different, because CBZ appears to decrease the bioactivity of androgens, whereas OXC does not.

Heart rate dynamics in refractory and well controlled temporal lobe epilepsy

Objectives: Disorders of cardiovascular and other autonomic nervous system functions are often found in patients with temporal lobe epilepsy (TLE). Cardiovascular dysregulation in TLE has previously been quantified assessing traditional time and frequency domain measures of heart rate (HR) variability from short term ECG recordings. However, new complexity and fractal measures of HR variability based on non-linear dynamics and fractals (“chaos theory”) may disclose certain patterns of HR dynamics that cannot be detected using only conventional measures. Methods: In addition to the traditional spectral and non-spectral components of HR variability, fractal correlation properties, approximate entropy (ApEn) of RR interval dynamics, and the slope of the power law relation were measured from 24 hour ambulatory ECG recordings to evaluate interictal autonomic cardiovascular regulatory function in 19 patients with refractory TLE, 25 patients with well controlled TLE, and in 34 healthy age and sex matched control subjects. Results: The traditional time and frequency domain measures were lower in patients with TLE than in controls (p<0.05). In addition, the power law slope (p<0.005) and ApEn (p<0.05) were also reduced in TLE patients. Furthermore, ApEn was smaller in patients with refractory TLE than in patients with well-controlled TLE ( p<0.01), whereas the long term fractal correlation value α2 was lower in patients with well controlled TLE (p<0.05). An altered HR variation was not associated with any particular AED regimen. Conclusions: In addition to reduced overall HR variability, the long term fractal organisation and complexity of HR dynamics seem to be altered in TLE. These abnormalities in HR behaviour may partly contribute to the occurrence of adverse cardiovascular events, such as life threatening arrhythmias in patients with TLE.

Valproate-induced hyperandrogenism during pubertal maturation in girls with epilepsy.

Valproate is effective for treatment of a variety of seizure types both in adults and in children with epilepsy, but it induces obesity and polycystic ovaries in a considerable proportion of adult women, particularly when the medication is started before the age of 20. In the present study we evaluated reproductive endocrine function in 41 girls, 8 to 18 years old, taking valproate for epilepsy and in 54 healthy control girls. Among the girls taking valproate, 16 were prepubertal, 11 were pubertal, and 14 were postpubertal, and the corresponding numbers were 20, 13, and 21 in the control group. The mean serum testosterone concentrations of prepubertal, pubertal, and postpubertal girls taking valproate were significantly higher than those of the control girls at the same pubertal stage. Hyperandrogenism, defined as serum testosterone levels higher than the mean + 2SD in the control girls at the same pubertal stage, was seen in 38% of prepubertal, 36% of pubertal, and 57% of postpubertal girls taking valproate. In addition, postpubertal girls taking valproate were more obese than the controls and the mean serum insulin‐like growth factor binding protein‐1 concentration of pubertal and postpubertal hyperandrogenic girls taking valproate was lower than in valproate‐treated girls without hyperandrogenism. Valproate may induce hyperandrogenism in girls with epilepsy during the sensitive period of pubertal maturation, and the frequency of hyperandrogenism increases with pubertal development. This emphasizes the importance of careful endocrine observation of girls taking valproate for epilepsy. Ann Neurol 1999;45:444–450

Natriuretic Peptides and Mortality After Stroke

Background and Purpose— Measurement of natriuretic peptides provides prognostic information in various patient populations. The prognostic value of natriuretic peptides among patients with acute stroke is not known, although elevated peptide levels have been observed. Methods— A series of 51 patients (mean age, 68±11years) with first-ever ischemic stroke underwent a comprehensive clinical examination and measurements of plasma atrial natriuretic peptides (N-ANP) and brain natriuretic peptides (N-BNP) in the acute phase of stroke. The patients were followed-up for 44±21 months. Risk factors for all-cause mortality were assessed. Control populations, matched for gender and age, consisted of 51 patients with acute myocardial infarction (AMI) and 25 healthy subjects. Results— Plasma concentrations of N-ANP (mean±SD, 988±993 pmol/L) and N-BNP (751±1608 pmol/L) in the stroke patients were at the same level as those in the AMI patients (NS for both), but significantly higher than those of the healthy subjects (358±103 pmol/L, P<0.001 and 54±26 pmol/L, P<0.01, respectively). Elevated levels of N-ANP and N-BNP predicted mortality after stroke (risk ratio [RR] 4.3, P<0.01 and RR 3.9, P<0.01, respectively) and after AMI (P<0.05), and remained independent predictors of death after stroke even after adjustment for age, diabetes, coronary artery disease, and medication (RR 3.9, P<0.05 and RR 3.7, P<0.05, respectively). Conclusion— Plasma levels of natriuretic peptides are elevated in the acute phase of stroke and predict poststroke mortality.

Exclusion of mutations in the gene for type III collagen (COL3A1) as a common cause of intracranial aneurysms or cervical artery dissections: Results from sequence analysis of the coding sequences of type III collagen from 55 unrelated patients

We performed detailed DNA sequencing analysis on type III collagen cDNA from 58 patients with either intracranial artery aneurysms or cervical artery dissections. The 58 patients were of seven different nationalities; among the patients were three pairs of relatives, so that 55 were unrelated, and of these, 29 had at least one blood relative with either an intracranial artery aneurysm or a cervical artery dissection. The age of the patients at the time of diagnosis ranged from 15 to 68 years (mean ± SD = 40.3 ± 11.0). The study group consisted of 25 males and 33 females. The analysis covered 3,232 nucleotides of significant (nonredundant) sequences per allele; therefore, we analyzed as many as 355,520 nucleotides. Mutations in the coding sequences for the triple-helical domain of type III collagen were excluded in 40 individuals with intracranial aneurysms and 18 individuals with cervical artery dissections. Direct sequencing of polymerase chain reaction products allowed mutations to be excluded with a high degree of confidence. Mutations that markedly decreased expression from one allele were also excluded in 42 of the 58 individuals, since the presence of both bases at one or more polymorphic sites in the 42 patients showed that two alleles were transcribed. The results indicated that mutations in the gene for type III procollagen (COL3A1) are not a common cause of either intracranial artery aneurysms or cervical artery dissections.