Misdiagnosis and pitfalls in Panayiotopoulos syndrome.

Panayiotopoulos syndrome (PS) is a frequent (6% among children of 1-15 years) and benign epileptic syndrome, characterized by predominantly autonomic symptoms (emesis, pallor, flushing, cyanosis, mydriasis/miosis, cardiorespiratory and thermoregulatory alterations, incontinence of urine and/or feces, hypersalivation, and modifications of intestinal motility) associated with simple motor focal seizures, which can be followed by secondary generalization. Panayiotopoulos syndrome can be extremely insidious, because it can mimic several condition, such as gastroenteritis, gastroesophageal reflux disease, encephalitis, syncope, migraine, sleep disorders, or even metabolic diseases. This peculiar pleiotropism should be kept in mind by child neurologists and pediatricians and general practitioners, because a wrong diagnosis may lead to inappropriate interventions. The consequences are high morbidity, costly mismanagement, and stress for children and their parents. The availability of electroencephalography (EEG) recording in pediatric Emergency Departments might be useful for a prompt and not-cost-consuming diagnosis. On the other hand, it is important to be aware of the possible, multifaceted, clinical presentations of PS and its clinical, radiological, and neurophysiological features in order to improve both recognition and management.

Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care.

PURPOSE: Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS. METHODS: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations. RESULTS: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations. CONCLUSION: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.

Psychological disorders, adverse childhood experiences and parental psychiatric disorders in children affected by headache: A systematic review.

BACKGROUND: Pediatric headaches have been linked to adverse life events or psychological factors in children and their families, with a complex and bidirectional association. Moreover, it is well-known that psychological stress can trigger headaches. METHODS: We searched three databases for studies focusing on headaches and adverse events or psychological factors in children up to 12 years old or in their caregivers. RESULTS: We included 28 studies. Child psychological factors, including internal and external symptoms, were commonly associated with all types of headaches. Sleep disturbances showed a positive association with headaches in 3 out of 5 studies. Family conflict and unhappiness were frequently found in children suffering with headaches, while single-parent families and divorce were not associated. Stressful environments and adverse life events, particularly bullying, were also found to be linked with headaches. CONCLUSIONS: Childhood headaches represent an alarm bell for clinicians to investigate and treat psychological or psychiatric disorders in children and their family. Further studies are needed to elucidate the role of early-life adverse events in children and their families.

The relationship between sleep and epilepsy: the effect on cognitive functioning in children.

AIM: The purpose of this review was to examine the possible pathophysiological links between epilepsy, cognition, sleep macro- and microstructure, and sleep disorders to highlight the contributions and interactions of sleep and epilepsy on cognitive functioning in children with epilepsy. METHOD: PubMed was used as the medical database source. No language restriction was placed on the literature searches, and citations of relevant studies in the paediatric age range (0-18 y) were checked. Studies including a mixed population but with a high percentage of children were also considered. RESULTS: The searches identified 223 studies. One reviewer scanned these to eliminate obviously irrelevant studies. Three reviewers scanned the remaining 128 studies and their relevant citations. The review showed that several factors could account for the learning impairment in children with epilepsy: aetiology, electroencephalographic (EEG) discharges, and persistence and circadian distribution of seizures, etc. EEG discharges may affect cognition and sleep, even in the absence of clinical or subclinical seizures. The sleep deprivation and/or sleep disruption affect the neurophysiological and neurochemical mechanisms important for the memory-learning process, but also influence the expression of EEG discharges and seizures. Learning and memory consolidation can take place over extended periods, and sleep has been demonstrated to play a fundamental role in these processes through neuroplastic remodelling of neural networks. Epilepsy and EEG paroxysms may affect sleep structure, interfering with these physiological functions. INTERPRETATION: Improvement in the long-term cognitive-behavioural prognosis of children with epilepsy requires both good sleep quality and good seizure control. The antiepileptic drug of choice should be the one that interferes least with sleep structure and has the best effect on sleep architecture--thus normalizing sleep instability, especially during non-rapid eye movement sleep.

Targeted re-sequencing in malformations of cortical development: genotype-phenotype correlations.

PURPOSE: Malformations of cortical development (MCD) are a phenotypically and genetically heterogeneous group of disorders, for which the diagnostic rate of genetic testing in a clinical setting remains to be clarified. In this study we aimed to assess the diagnostic rate of germline and pathogenic variants using a custom panel in a heterogeneous group of subjects with MCD and explore genotype-phenotype correlations. METHODS: A total of 84 subjects with different MCD were enrolled. Genomic DNA was isolated from peripheral blood. Fifty-nine tartget genes were assessed using a custom next-generation sequencing (NGS) panel. RESULTS: Genetic causes were identified in one-fourth of our cohort (21.4 %). Overall, we identified 19 pathogenic or likely pathogenic single-nucleotide variants in 11 genes among 18 subjects, including PAFAH1B1 (LIS1) (n = 3), TUBA1A (n = 3), DYNC1H1 (n = 3), ACTG1 (n = 2), TUBB2B (n = 1), TUBB3 (n = 1), DCX (n = 1), FLNA (n = 1), LAMA2 (n = 1), POMGNT2 (n = 1) and VLDLR (n = 1). The diagnostic yield was higher in patients with lissencephaly/pachygyria (60 %) (p = 0.001), cobblestone malformation (50 %), and subcortical band heterotopia (SBH) (40 %). Furthermore, five out of six subjects with suspect tubulinopathies on imaging harboured pathogenic variants in tubulin genes. Overall, germline pathogenic variants were more likely to be identified if MCD were diffuse (p = 0.002) and associated with other central nervous system malformations (p = 0.029). Moderate to severe intellectual disability was also more commonly associated with pathogenic variants (p = 0.044). CONCLUSION: Customized gene panels may support the diagnostic work-up for some specific MCD, especially when these are diffuse, bilateral and associated with other brain malformations.

Epilepsy, electroencephalographic abnormalities, and regression in children with autism.

The association of epilepsy and autism is recognized, and it has been reported at a percentage that varies between 8 and 42%, depending on age and diagnostic criteria. One third of autistic children undergo a regression of language and behavior between 2 and 3 years, and epileptiform abnormalities and epilepsy can be concomitant in an undetermined percentage of them. The aim of this study was to investigate the prevalence of epilepsy and paroxysmal abnormalities in a group of children with autism and to determine the percentage of regression course in this group. Forty-six patients with autism (mean age 7.8 +/- 2.7 years; 34 boys and 12 girls) were consecutively examined, and clinical evaluation, assessment, and electroencephalographic (EEG) recordings were performed in all of them. Thirty-five percent showed paroxysmal abnormalities and epilepsy, 22% had only paroxysmal abnormalities without seizures, and 13% of the children suffered from epilepsy. Sixty-five percent had a normal EEG. No difference in regression rate was observed between patients with paroxysmal abnormalities and epilepsy and those with a normal EEG and without seizures. In the study group, the prevalence of epilepsy was in the low range of individuals with autism, and different types of epilepsy were observed. Autism with regression was not influenced by paroxysmal abnormalities and epilepsy.

Lacosamide in pediatric and adult patients: comparison of efficacy and safety.

PURPOSE: This multicenter, prospective study investigates the efficacy and safety of lacosamide adjunctive therapy in pediatric and adult patients with uncontrolled epilepsy. METHOD: This study was carried out between September 2010 and December 2011 at 16 Italian and 1 German neurologic centers. Lacosamide was added to the baseline therapy at a starting dose of 1 mg/kg/day in patients aged <16 years (group A) and 100 mg daily in subjects aged 16 and older (group B), and titrated to the target dose, ranging from 3 to 12 mg/kg/day or from 100 to 600 mg daily, respectively. After completing the titration period, patients entered a 12-month maintenance period and they were followed up at 3, 6 and 12 months. The primary assessment of efficacy was based on the change from baseline in seizure frequency per 28 days and was evaluated at 3, 6 and 12 months as follows: number and proportion of 100% responders, 50% responders, non-responders and worsening patients. Safety evaluation was also performed at 3, 6 and 12 months. RESULTS: A total of 118 patients (59 group A, 59 group B) with uncontrolled generalized and focal epilepsy were enrolled. Patient mean±SD age was 15.9±6.80 years and the age range was 4-38 years. At 3-month evaluation, of 118 treated patients 56 subjects (47.4% group A; 47.4% group B; p=0.8537) experienced at least a 50% reduction in seizure frequency. At 6 and 12-month follow-up, the 50% responders were 57 (52.5% group A; 44.1% group B; p=0.4612) and 51 (47.4% group A; 39% group B; p=0.4573), respectively. Thirty-five subjects (30.5% group A; 28.8% group B; p=1) experienced side effects during the treatment period. The most common adverse events were dyspepsia for group A and dizziness for group B. CONCLUSION: Lacosamide may be a useful and safe pharmacological treatment option for both pediatric and adult patients with uncontrolled seizures.

Reduced NREM sleep instability in benign childhood epilepsy with centro-temporal spikes.

OBJECTIVE: To analyze sleep architecture and NREM sleep instability by means of the cyclic alternating pattern (CAP) in children with benign epilepsy with rolandic spikes (BERS). METHODS: Ten children with BERS, drug free at the time of the study and 10 age-matched normal controls were included in this study. Sleep was visually scored for sleep architecture and CAP using standard criteria. RESULTS: Sleep architecture in BERS showed only few significant differences vs. controls with a reduction of total sleep time, sleep efficiency, and REM sleep percentage. CAP analysis revealed several significant differences: reduced total CAP rate, mainly in sleep stage 2, and reduced EEG slow oscillations and arousals during stages N1 and N2. CONCLUSIONS: Sleep architecture is not importantly affected in BERS but CAP analysis reveals a decrease of NREM instability, mainly in sleep stage 2. Since there is a spindle-related spike activation in BERS, we speculate that the decrease of CAP and of EEG slow oscillations and arousals might be linked with the inhibitory action of spindling activity and spikes on arousals. SIGNIFICANCE: CAP analysis discloses sleep structure abnormalities in children with BERS not shown by the classical sleep scoring. Spike activity and CAP A1 subtypes seem to be mutually exclusive probably because centro-temporal spikes disturb the physiological synchronization mechanisms needed for the generation of slow-wave components of CAP.

Natalizumab treatment in pediatric multiple sclerosis: a case report.

Pediatric multiple sclerosis (MS) with manifestations before 16 years of age occurs in 0.4-10.5% of whole MS population. The initial course of the disease is relapsing-remitting with a relapse rate generally higher than that of adults, less than 3% have a primary progressive form. Some recent reports have shown that Interferon beta (IFNbeta) has a strong effect in reducing the relapse rate in children with MS and is well tolerated. We report a 12-year-old girl with MS and a high relapse rate from the onset. Frequent magnetic resonance imaging (MRI) detected persisting inflammatory activity and increase of lesion burden. She continued to present acute relapses and progression of disability in spite of a treatment with IFNbeta-1a at different dosages and the addition of pulse IV steroid treatment. Then, we opted for Natalizumab treatment, recently approved as a monotherapy for patients with MS who experienced inadequate response to other disease modifying therapies and never used till now in pediatric MS. Our patient showed a complete response to Natalizumab with clinical and MRI suppression of disease activity.

All-night EEG power spectral analysis of the cyclic alternating pattern at different ages.

OBJECTIVE: To analyze in detail the frequency content of the different EEG components of the Cyclic Alternating Pattern (CAP) in the whole sleep of pre-school and school age children compared to normal young adults. METHODS: Fourteen pre-school age and 18 school age children and 16 adults were included in this study. Each participant underwent a polysomnographic overnight recording, after an adaptation night; sleep stages and CAP were scored following standard criteria. Average spectra were obtained for each CAP condition from the signal recorded from C3/A2 or C4/A1, separately in sleep stage 2 and slow-wave sleep (SWS), for each subject. RESULTS: The analysis of the relative power density in the three groups showed that in sleep stage 2 and in SWS, CAP A1, A2, A3 subtypes had a significantly higher power in all frequency ranges in pre-school children than in adults, while school children differed mainly for the lower frequencies (<7 Hz). For non-CAP, pre-school and school children differed from adults at almost all frequencies analyzed. Generally, A1, A2 and A3 showed clear spectral differences in the three different groups of subjects with pre-school age children showing slightly less evident differences. CONCLUSIONS: CAP subtypes are characterized by clearly different spectra at different ages and also the same subtype shows a different power spectrum, during sleep stage 2 or SWS. This study shows that pre-school children have a different structure of sleep, especially from the microstructural (CAP) point of view: the differences are evident for all the CAP components and for non-CAP in almost all the frequency bands. This finding might be associated to the age-related delta decline in the 0-3 Hz frequency reported in children of the same age. SIGNIFICANCE: Our data seem to provide information not available before and useful for the understanding of the impact of CAP on the sleep EEG neurophysiological dynamics at different ages. This type of information is crucial for a more adequate interpretation of data provided by a growing number of studies analyzing CAP in groups of pediatric patients.

Zonisamide in children and young adults with refractory epilepsy: an open label, multicenter Italian study.

PURPOSE: To report on the first multicenter Italian experience with zonisamide as an add-on drug for refractory generalised or partial epilepsy in children, adolescents and young adults. METHODS: The patients were enrolled in a prospective, add-on, open-label treatment study from eight Italian centres for children and adolescent epilepsy care. Eighty-two young patients (45 males, 37 females), aged between 3 and 34 years (mean 13.1 years), all affected by partial (47) or generalised (35) refractory epilepsy, were enrolled in the study. ZNS was added to the baseline therapy at a starting dose of 1 mg/kg/day twice daily. This dose was increased by 2 mg/kg every 1-2 weeks over a period of up 3 months, according to the patient's response and tolerability, up to a maximum dose of 12 mg/kg. ZNS was given at the mean daily dose of 5.7/mg/kg/24 h (range 1-12 mg/kg). RESULTS: After a mean follow-up period of 11.9 months (range 2-64 months), 9 patients (10.9%) were seizure-free. The number of seizures decreased by 50-99% in 31 cases (37.8%), by 25-49% in 5 cases (6.1%), remained the same in 29 cases (35.4%) and increased in 8 cases (9.7%). After 15 months of follow-up, 61 patients (74.4%) were still taking ZNS, while the remaining 21 (25.6%) had stopped. Twenty-two patients (26.8%) reported adverse effects while taking ZNS. They generally appeared during the first weeks of treatment, and were mild to moderate. The most frequent adverse effects were irritability and a reduced appetite. CONCLUSION: ZNS effectively reduced seizure frequency in this pediatric population with both partial and generalised crypto/symptomatic refractory epilepsy. Its overall tolerability was good.

Melatonin to prevent migraine or tension-type headache in children.

We designed a 3-month open label trial of melatonin prophylaxis in children with primary headache. After a one month baseline period without receiving preventive drugs, all children received a 3-month course of melatonin, 3 mg, administered orally, at bedtime. A total of 22 children were enrolled (10 boys, mean age 12.2+/-2.6 years, age range 6-16 years), 13 had recurrent migraine without aura, 1 with aura and 8 had chronic tension-type headache. When the trial ended, 14 of the 21 subjects reported that the headache attacks had decreased by more than 50% in respect to baseline and 4 of them reported having no headache attacks. After receiving melatonin for one month one subject dropped out because of excessive daytime sleepiness. Our promising results warrant randomized placebo-controlled trials in children to assess the real effectiveness of melatonin in preventing primary headache.

A case with atypical childhood occipital epilepsy "Gastaut type": an ictal migraine manifestation with a good response to intravenous diazepam.

We report the history of a 14-year-old girl with atypical childhood occipital epilepsy "Gastaut type" whose first generalized tonic-clonic seizure was preceded by migraine without aura and followed by a status migrainosus. This status lasted for 3 days despite standard analgesic therapy. An EEG recording revealed an occipital status epilepticus during her migraine complaints. Seven minutes after intravenous administration of 10 mg diazepam under continuous EEG recording, a suppression of the epileptiform discharges over the right occipital was seen, while the headache subsided 3 min later. After precise questioning about the circumstances that possibly could have led to these events, it appeared that she had played for hours with a play station on the new color TV and she had visited an exhibition of Matisse and Bonnard with bright colors and contrast-rich text. Standardized extensive intermittent photic stimulation (IPS), 2 days after the status migrainosus, evoked besides asymmetrical right-sided driving, green spots in her left visual field, while in the EEG sharp waves were recorded over the right parietotemporal region. After further IPS with 20 Hz (eye closure), she started complaining of a light pulsating headache right occipitally and in the EEG right parietotemporal sharp-waves were seen. This lasted for about 10 min. Later, an interictal routine EEG was normal except for some theta over the right temporooccipital area. The most likely diagnosis is an atypical form of occipital epilepsy "Gastaut type." We would therefore advocate recording EEGs with photic stimulation in patients with atypical migraneous features.

Attention-deficit/hyperactivity disorder (ADHD) and variable clinical expression of Aarskog-Scott syndrome due to a novel FGD1 gene mutation (R408Q).

Mutations of the FGD1 gene are responsible for a significant proportion of patients with Aarskog-Scott syndrome (AAS), an X-linked disorder characterized by short stature, brachydactyly, urogenital abnormalities, and a typical dysmorphic facial appearance. Although mental retardation does not occur significantly in AAS, this condition has been described associated with various degrees of mental impairment and/or behavioral disorders in some patients. In particular, attention deficit hyperactivity disorder (ADHD) is reported as a common characteristic of AAS. However, AAS/ADHD reported patients have been only clinically described, and diagnosis never has been confirmed on molecular basis. We present here a unique case of a 16-years-old patient presenting with ADHD, lower intelligence quotient, and dysmorphic features. Although the clinical features were not completely typical of AAS, genetic analysis demonstrated a novel FGD1 missense mutation (R408Q). The case we report confirms the highly variable expressivity of AAS and first documents that the FGD1 gene may play a role in ADHD susceptibility. We suggest that FGD1 analysis may be adequate in ADHD patients who exhibit dysmorphic features suggestive of AAS, also in the absence of the full phenotypical spectrum.

Intermittent vagal nerve stimulation in paediatric patients: 1-year follow-up.

OBJECT: Vagal nerve stimulation (VNS) has recently been proposed as a valid treatment for adult patients with drug-resistant partial epilepsy. Little experience in children has been reported. In order to evaluate the clinical efficacy and tolerance of VNS, we studied 13 paediatric patients with drug-resistant partial epilepsy. METHODS: Improvement in seizure frequency was estimated by calculating the percentage of change in seizure frequency during each 3-month period following initiation of VNS, compared with the 3-month period prior to the implantation of the VNS device. The improvement in quality of life (QOL) was evaluated with the Vineland Behavior Adaptive Scale (VBAS). RESULTS: In all patients, the surgical procedure was well tolerated. A recent modification of the implantation technique needing only a single cervical incision, has further reduced the aesthetic damage, particularly in small children who have a reduced muscular mass. Three months after the surgical procedure, 10 of the 13 patients demonstrated a seizure reduction rate greater than 50%. At the 1-year follow-up these positive results were maintained: 6 out of 8 patients continued to demonstrate a seizure reduction rate greater than 50%. Comparison with the pre-implantation period also showed a significant improvement in QOL in 4 out of 8 patients. We conclude that VNS is a valid treatment modality in children with drug-resistant partial epilepsy.