Reproductive endocrine health in pubertal females with epilepsy on antiepileptic drugs: time to screen?

OBJECTIVES: Although previous studies suggest that valproate (VPA) may induce reproductive endocrine disorders, the effects of newer antiepileptic drugs (AEDs) on reproductive endocrine health have not been widely investigated and compared with those of older AEDs. Therefore, this multicenter cross-sectional study aimed to evaluate the prevalence of reproductive endocrine dysfunctions in pubertal females with epilepsy receiving VPA, lamotrigine (LTG), or levetiracetam (LEV) monotherapy. PATIENTS AND METHODS: Pubertal girls on VPA (n = 11), LTG (n = 8), or LEV (n = 13) monotherapy for at least 6 months were recruited. Healthy sex-matched and age-matched subjects were enrolled as controls (n = 32). Each participant underwent a comprehensive physical examination concerning signs of hyperandrogenism. The Ferriman-Gallwey score of hirsutism was assessed. In addition, all patients completed a standardized questionnaire regarding epilepsy, menstrual cycle, and hirsutism features. Adiposity indices were measured and weight gain was documented for each subject. RESULTS: Hirsutism score, occurrence of hyperandrogenism features, and adiposity indices were significantly higher in the VPA group when compared with LEV and control groups. VPA therapy was more frequently associated with weight gain when compared with LTG and controls, whereas no significant differences with regard to signs of hyperandrogenism were found between VPA and LTG groups. Furthermore, no differences in menstrual disorders were observed between groups. CONCLUSIONS: Pubertal girls with epilepsy receiving VPA monotherapy were more likely to develop signs of hyperandrogenism, that is, hirsutism and acanthosis, than those on LEV or controls. However, no differences in occurrence of menstrual disorders and other reproductive dysfunctions were found between VPA, LTG, LEV, and control groups. These findings do not allow us to clearly determine whether or not VPA, LEV, and LTG monotherapies considerably affect reproductive endocrine health in pubertal girls with epilepsy. Therefore, further prospective studies of larger sample sizes are needed to establish if screening tests should be recommended.

Clinical dissection of early onset absence epilepsy in children and prognostic implications.

PURPOSE: To investigate whether patients with typical absence seizures (TAS) starting in the first 3 years of life, conformed to Panayiotopoulos's definition of childhood absence epilepsy (CAE), show different electroclinical course than those not fulfilling CAE criteria. METHODS: In this multicenter retrospective study, we choose a fixed duration follow-up of 36 months to examine the electroclinical course of epilepsy in all children with TAS starting before 3 years of age. The probands who fulfilled Panayiotopoulos's criteria for CAE were classified as having pure early onset absence epilepsy (P-EOAE), whereas those who did not as nonpure EOAE (NP-EOAE). In addition, these two groups of patients were further stratified according to the number of antiepileptic drugs taken to obtain initial seizure control (mono-, bi-, and tritherapy). KEY FINDINGS: Patients with P-EOAE (n = 111) showed earlier initial seizure control (p = 0.030) and better seizure-free survival curve (p = 0.004) than those with NP-EOAE (n = 77). No mutation in SLC2A1 gene or abnormal neuroimaging was observed in P-EOAE. Among patients with NP-EOAE, those receiving tritherapy showed increased risk of structural brain abnormalities (p = 0.001) or SLC2A1 mutations (p = 0.001) but fewer myoclonic features (p = 0.031) and worse seizure-free survival curve (p = 0.047) than those treated with mono- and bitherapy. Children with NP-EOAE had 2.134 the odds of having relapse during the follow-up compare to those with P-EOAE. SIGNIFICANCE: Children with early onset TAS who did meet Panayiotopoulos's criteria showed a favorable course of epilepsy, whereas patients not fulfilling Panayiotopoulos's criteria showed increased risk of relapse at long-term follow-up.

Motor coordination impairment and migraine in children: a new comorbidity?

Migraine without aura (MoA) could be considered the most frequent form of primary headache in children, associated with many known comorbidities, but only the recent literature has begun to consider the importance of motor impairment linked to the attacks. The developmental coordination disorder (DCD) is a very common problem among children, with a prevalence ranging up to 19 %. The aim of this study was to evaluate the presence of motor coordination impairment in a population of children affected by MoA, and its role as putative risk factor for motor skills impairment. This observational study was performed in the Clinic of Child and Adolescent Neuropsychiatry of the Second University of Naples. MoA was diagnosed according to the International Classification of Headache Disorders (IHS-2) criteria. The study population consisted of 27 patients affected by MoA (16 females, 11 males) (mean age: 8.7 ± 2.15 years) and 59 typically developing children (34 females, 25 males) (mean age: 8.0 ± 2.1 years). The whole population underwent a clinical evaluation in order to assess the total IQ level, the visual motor integration skills, and the presence of DCD. Our results showed that MoA children had more impairments in motor coordination (p < 0.001) and visual motor integration (p < 0.001) than control group. To our knowledge, this is the first study to assess the association of poor motor coordination and MoA in children using objective measurements. These findings suggest a new perspective in the management of migraine disease in children, pinpointing that the relationship between DCD and migraine could represent a not yet understood or identified comorbidity, even if further reports are necessary, and that migraine probably could be considered not only a painful syndrome in future.

Obese children suffer more often from migraine.

AIM: To determine a possible relationship between migraine and body mass index. METHODS: Migraine shows a wide spectrum of comorbidities, including cardiocerebral, vascular, psychiatric, metabolic, neurological as well as other pathologies. Recent researches suggest that obesity was significantly correlated with migraine frequency and disability in children, as well as in adult population studies. We reviewed data from the literature to clarify this possible relationship. RESULTS: Translational and basic science research shows multiple areas of overlap between migraine pathophysiology and the central and peripheral pathways regulating feeding. Specifically, neurotransmittors such as serotonin, peptides such as orexin, and adipocytokines such as adiponectin and leptin have been suggested to have roles in both feeding and migraine. A relationship between migraine and body mass index exists, and therefore, interventions to modify body mass index may provide a useful treatment model for investigating whether modest weight loss reduces headache frequency and severity in obese migraineurs. CONCLUSION: The effect of obesity and weight change on headache outcomes may have important implications for clinical care.

Nonalcoholic fatty liver disease in adolescents receiving valproic acid.

OBJECTIVE: The aim of this study was to investigate the association between the metabolic derangements induced by valproic acid (VPA) and ultrasound-diagnosed nonalcoholic fatty liver disease (NAFLD) in adolescents. METHODS: Using a cross-sectional design, we evaluated 86 adolescents with epilepsy who had received VPA monotherapy. Subjects for comparison were 67 normal-weight and 43 weight-matched adolescents. Participants underwent hepatic ultrasound, anthropometric evaluations, and biochemical tests. RESULTS: Although the occurrence of ultrasound-diagnosed NAFLD was higher in VPA-treated patients than in normal-weight controls (36.0% vs 7.5%, P<0.001), it was similar in VPA-treated patients and weight-matched controls (36.0% vs 34.9%, P>0.05). The identified predictors of NAFLD in VPA-treated patients were abdominal obesity (OR=3.2, 95% CI=2.1-6.8), insulin resistance (OR=2.8, 95% CI=1.7-5.2), metabolic syndrome (OR=2.6, 95% CI=1.4-4.8), and generalized obesity (OR=1.9, 95% CI=1.2-3.7). CONCLUSION: Valproic acid monotherapy is associated with NAFLD in a high percentage of adolescents with epilepsy who have typical VPA-related metabolic disturbances.

Long term outcome in children affected by absence epilepsy with onset before the age of three years.

OBJECTIVE: The goal of this study was to define the long-term outcome of absence epilepsy presenting before the age of 3 years. METHODS: We retrospectively studied the medical records of 40 children from eight neuropediatric centers in Italy with respect to the personal and family histories of epilepsy or febrile seizures, time of follow-up, cognitive functions, treatment, and outcome. RESULTS: Forty patients were enrolled in this study. They all fulfilled the criteria for absence epilepsy with 3-Hz spike-wave complexes on the EEG, normal neurological examination, and no other seizures types. Seizure onset occurred between 24.1 and 36.0 months. There was a family history of epilepsy in 28%, and of febrile seizures in 13%. Thirty-three patients were treated with valproic acid (VPA), mostly used in monotherapy (26 patients) or in association with ethosuximide. At final follow-up, 33 patients were seizure free and 29 had normal EEGs. Thirty-four patients had a normal intelligence quotient (IQ), whereas 6 had a decreased IQ, mainly associated with poor control of seizures. CONCLUSION: In our series, absence seizures presenting before the age of 3 appeared to have quite a good long-term clinical prognosis; the neuropsychological outcome was comparable to that of childhood epilepsy presenting after 3 years of age.

Early-onset pure absence epilepsy: a distinct epileptic syndrome.

UNLABELLED: Early-onset pure absence epilepsy has not yet considered in the International League Against Epilepsy classification, but several reports have supported its existence as a distinct epileptic syndrome primarily manifesting with typical absences in early childhood. This review summarizes the current understanding on this epilepsy. CONCLUSIONS: Early-onset pure absence epilepsy is a distinct epilepsy characterized by absences starting from a few months to 4 years of age, normal early psychomotor development, good antiepileptic drug seizure control and normal intellectual outcome.

The metabolic syndrome in overweight epileptic patients treated with valproic acid.

PURPOSE: To evaluate the presence of metabolic syndrome (MS) in children and adolescents treated with valproate (VPA). METHODS: One hundred fourteen patients (54 male and 60 female) were studied. These patients were followed from the beginning of therapy for at least 24 months; at the end of follow-up, 46 patients (40.4%) had a considerable increase in body weight, whereas the other patients (59.6%) remained with the same weight. The MS was defined as having at least three of the following: abdominal obesity, dyslipidemia, glucose intolerance, and hypertension. RESULTS: Forty-six patients developed obesity; 20 (43.5%) of 46 patients developed MS. Abnormal glucose homeostasis was identified in 45% of patients. High total serum cholesterol concentrations were noted in 10 (50%), high serum triglyceride concentrations in 7 (35%), and low high-density lipoprotein (HDL) in 15 (75%) of the 20 subjects with MS. However, there were no significant differences in the features of MS between boys and girls with MS. CONCLUSIONS: Patients who gain weight during VPA therapy can develop MS with a possible risk of cardiovascular disease.

Clinical features of psychogenic non-epileptic seizures in prepubertal and pubertal patients with idiopathic epilepsy.

A retrospective multicentre study was performed to analyse psychogenic non-epileptic seizures (PNES) in prepubertal and pubertal patients with idiopathic epilepsy and to determine whether have different clinical characteristics. In this study, we reviewed 36 patients from six neurological referral centres: Department of Pediatrics, Chieti (3 patients); Department of Child Neuropsychiatry, Naples (9 patients); Department of Child Neuropsychiatry, Bologna (8 patients); Department of Neuroscience, Tor Vergata University, Rome (3 patients); Department of Pediatrics, La Sapienza University, Rome (5 patients); and Department of Pediatrics, Siena (8 patients). The population was divided according to Tanner'stages into 14 prepubertal (group I) and 22 pubertal (group II) patients. The two groups were compared on several variables examining the differences between them. The most frequent clinical manifestations in group I were unresponsive events, whereas in group II, motor events were exhibited more significantly. Mood disorders, including major depression, appeared more frequently in pubertal group, but this did not reach a significant difference. Among the psychosocial stressors, fear of rejection and need for attention were the predominant types in the prepubertal patients. The findings of this study reveal some similarities and differences between prepubertal and pubertal patients, which might help to identify predictive factors in patients affected by idiopathic epilepsy who can develop PNES.

Weight regain after discontinuation of topiramate treatment in patients with migraine: a prospective observational study.

PURPOSE: To monitor weight regain after therapy discontinuation in patients with migraine experiencing weight loss during topiramate (TPM) treatment. METHODS: Patients with migraine without aura were enrolled in this observational prospective study. Weight, body mass index (BMI), waist circumference, systolic and diastolic blood pressure, plasma levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, leptin, and ghrelin, and homeostatic model assessment of insulin resistance (HOMA-IR) were evaluated before starting TPM (T1), at 3 (T2) and 6 (T3) months of treatment and 6 months after withdrawal of TPM (T4). Weight loss/regain was considered as a change of 5% of pre-TPM body weight. RESULTS: A total of 241 patients were analyzed. Of these, 87 (36%) patients experienced weight loss on TPM medication. During TPM therapy significant reductions in mean values of weight (p<0.001), BMI (p<0.001), waist circumference (p<0.01), HOMA-IR (p<0.01), and leptin (p<0.01) were observed. After TPM discontinuation, all of these parameters showed a clear trend to increase at T4, achieving pre-TPM values in 27 patients. Among potential predictors, only HOMA-IR before starting TPM (parameter estimate=1.36, effect size=0.75; p=0.006) was significantly associated with weight regain after therapy discontinuation. CONCLUSIONS: Loss of body weight is a reversible effect, which at 6 months after TPM discontinuation shows a clear trend to return to baseline values. HOMA-IR is the only predictive factor of weight regain.

Obesity and headache/migraine: the importance of weight reduction through lifestyle modifications.

The aim of this study is to determine a possible relationship between prevalence, frequency, and severity of migraine and obesity. All pertinent data from the literature have been critically examined and reviewed in order to assess the possible relationship between obesity and migraine, in particular migraine frequency and disability in children, as well as in adult population studies. Prevalence, frequency, and severity of migraine appear to increase in relation to the body mass index, although this evidence is not supported by all the studies examined. Data from literature suggest that obesity can be linked with migraine prevalence, frequency, and disability both in pediatric and adult subjects. These data have important clinical implications and suggest that clinicians should have a special interest for weight reduction of obese children suffering from migraine, prescribing and supporting intensive lifestyle modifications (dietary, physical activities, and behavioral) for the patient and the entire family.

Valproate in adolescents with photosensitive epilepsy with generalized tonic-clonic seizures only.

AIM: To assess the effects of valproate (VPA) on seizure response/control and photosensitivity (PS) in adolescents suffering from photosensitive epilepsy with generalized tonic-clonic seizures only (EGTCS). METHODS: We prospectively evaluated 55 adolescents with newly diagnosed EGTCS and PS at presentation, who received VPA monotherapy. Two phases of the study were defined and analysed separately. In the phase I, the electroclinical data of patients were compared over three time points: T1 (at 6 months of treatment); T2 (at 12 months of treatment); and T3 (at 36 months of treatment). In the phase II, only patients who stopped VPA were evaluated over a period of 12 months. RESULTS: At both T2 and T3 there was a significant great percentage of seizure-free patients compared with that at T1 (78.2% vs 69.1%, p < 0.01; and 85.5% vs 69.1%, p < 0.001) and a similar trend was also noted according to PS-free patients (70.9% vs 52.7%, p < 0.01; 80.0% vs 52.7% p < 0.001). At the end of the phase II, 46.5% and 32.6% out of 43 patients who stopped VPA had seizure relapses and reappearance of PS, respectively. In particular, 78.6% of the 14 patients with PS reappearance presented the same type of EEG response showed at study entry. CONCLUSIONS: VPA monotherapy is very effective for both seizure outcome control and PS reduction in adolescents with EGTCS. Treatment discontinuation induces relapse of seizures and PS in a certain number of patients. PS reappearance presented the same type of EEG response showed before VPA treatment.

Long-term follow-up in children with benign convulsions associated with gastroenteritis.

BACKGROUND: The outcome of benign convulsions associated with gastroenteritis (CwG) has generally been reported as being excellent. However, these data need to be confirmed in studies with longer follow-up evaluations. AIM: To assess the long-term neurological outcome of a large sample of children presenting with CwG. METHODS: We reviewed clinical features of 81 subjects presenting with CwG (1994-2010) from three different Italian centers with a follow-up period of at least 3 years. RESULTS: Follow-up period ranged from 39 months to 15 years (mean 9.8 years). Neurological examination and cognitive level at the last evaluation were normal in all the patients. A mild attention deficit was detected in three cases (3.7%). Fourteen children (17.3%) received chronic anti-epileptic therapy. Interictal EEG abnormalities detected at onset in 20 patients (24.7%) reverted to normal. Transient EEG epileptiform abnormalities were detected in other three cases (3.7%), and a transient photosensitivity in one (1.2%). No recurrence of CwG was observed. Three patients (3.7%) presented with a febrile seizure and two (2.5%) with an unprovoked seizure, but none developed epilepsy. CONCLUSIONS: The long-term evaluation of children with CwG confirms the excellent prognosis of this condition, with normal psychomotor development and low risk of relapse and of subsequent epilepsy.

Epilepsy in patients with Cornelia de Lange syndrome: a clinical series.

PURPOSE: Cornelia de Lange (CdLS) syndrome is characterized by multiple congenital anomalies and mental retardation. Epilepsy is a clinical feature found in about 20% of cases, but there are no data about its electroclinical features and long-term outcome. METHODS: we describe a clinical series of fourteen Caucasian CdLS paediatric patients who developed epilepsy, with special reference to the long term prognosis. RESULTS: Epilepsy manifested between age 0.6 and 16.3 years. The majority of patients (64.3%) presented with partial seizures and interictal EEGs mainly revealed focal epileptic paroxysms involving temporal and parietal areas. Thirteen of 14 children became seizure-free with treatment. Valproate monotherapy was used in eight patients (57.1%), controlling seizures in seven. Otherwise monotherapy with topiramate, levetiracetam, carbamazepine and oxcarbazepine appeared to be effective in controlling seizures in four cases. At the end of the follow-up (age range, 7.3-24.2 years; follow-up, 8.2±3.9 years), thirteen patients were seizure free (three still in therapy), while in one patient seizures were not controlled. CONCLUSIONS: Partial epilepsy is the most common type of epilepsy in CdLS patients. In the majority of cases the prognosis of this epilepsy is favourable and therapy can be withdrawn after few years of complete seizure control.

Diagnosis and management of catamenial seizures: a review.

Catamenial epilepsy is defined as a pattern of seizures that changes in severity during particular phases of the menstrual cycle, wherein estrogens are proconvulsant, increasing the neuronal excitability; and progesterone is anticonvulsant, enhancing GABA-mediated inhibition. Thus, changes in serum estradiol/progesterone ratio throughout a normal reproductive cycle bring about an increased or decreased risk of seizure occurrence. To date, there are no specific drug treatments for catamenial epilepsy however, non-hormonal and hormonal therapies have been proposed. The aim of this review is to report preclinical and clinical evidences about the relationship between female reproductive steroids and epileptic seizures, and to describe treatment approaches for catamenial epilepsy.

Topiramate-induced weight loss: a review.

BACKGROUND: Weight loss can occur during topiramate (TPM) treatment and it should be evaluated by clinicians, especially in children, whose growth could be compromised. In international literature, the reported body weight loss incidences linked to TPM therapy vary widely and, in some cases, are very conflicting. AIMS: The aims of this review are to quantify TPM-induced weight loss, analyze the pathogenetic mechanisms and evaluate its clinical implications in patients with epilepsy. RESULTS: The amount of weight loss appears to be related to some factors such as the duration of the treatment and a high baseline body mass index (BMI), while the role of daily dosage and gender of patients is controversial. The mechanism through which TPM may induce weight loss is still unclear. INTERPRETATION: TPM is able to induce weight loss, especially in high baseline BMI patients, not strictly depending on daily dosage and perhaps not influenced by gender. This makes TPM a good choice, especially in obese patients suffering from seizures. However, TPM can make nutritionally vulnerable children or adult patients, with epilepsy associated with other neuropsychiatric diseases, who cannot voluntarily increase their caloric intake.

Long-term outcome of epilepsy in Kabuki syndrome.

UNLABELLED: PURPOSES AND METHODS: Kabuki syndrome (KS) is a rare dysmorphic disorder characterized by multiple congenital anomalies and mental retardation. Although epilepsy is one of the most common clinical complications associated with KS, few studies have evaluated its electroclinical aspects and long-term outcome. Therefore, we describe here a clinical series of 10 Caucasian KS patients who developed epilepsy in childhood. We followed all children for at least 5 years. RESULTS: All patients presented partial seizures and interictal EEGs revealed focal epileptic paroxysms with prevalent involvement of temporo-occipital areas. Seven children had no central nervous system abnormalities, but enlargement of lateral ventricles, corpus callosum hypoplasia, and adenohypophysis hypoplasia were revealed in three. Although antiepileptic drug (AED) treatment was effective in controlling seizures and normalizing EEG abnormalities in 8 patients, the other 2 cases were resistant to multiple AEDs. In one of these two patients, withdrawal of AED resulted in status epilepticus and death. CONCLUSIONS: Partial seizures and temporo-occipital abnormalities on interictal EEG are common features of KS patients who suffer from epilepsy. Prognosis of this epilepsy is favourable in the majority of cases with complete disappearance of seizures and EEG abnormalities.

Benign convulsions associated with mild gastroenteritis: a multicenter clinical study.

PURPOSE: To assess the clinical characteristics and the outcome of benign convulsions associated with mild gastroenteritis (CwG) in Italian children. METHODS: We studied clinical and EEG features of 128 children with CwG who were hospitalized between January 2004 and February 2008 and then followed for at least 12 months in 14 Italian centers. RESULTS: Age at onset ranged from 6 to 60 months. The seizures were generalized in 73 cases (57%), only focal in 16 (12.5%), and secondarily generalized in 39 (30.5%). The duration of the seizures was under 5 min in 97 patients (75.8%), between 5 and 30 min in 26 (20.3%), and longer than 30 min in 5 (3.9%). Seventy-three participants (57%) had 2 or more seizures, which recurred within 24-48 h. In the acute phase, antiepileptic drugs were used in 72 patients (56.3%). Although interictal abnormalities were present in EEG of 28 children (21.9%), these reverted to normal. During the follow up period, only 6 patients (4.7%) suffered from recurrence of CwG, 7 (5.5%) suffered from simple febrile seizures, and 3 (2.3%) developed epilepsy. CONCLUSIONS: Recognition of CwG in children allows pediatricians to avoid extensive evaluations and continuous antiepileptic therapy and to reassure parents regarding the lack of long-term complications.