A real-life pilot study of the clinical application of pharmacogenomics testing on saliva in epilepsy.

Response to antiseizure medications (ASMs) can be influenced by several gene polymorphisms, causing either lower efficacy or higher occurrence of adverse drug reactions (ADRs). We investigated the clinical utility of salivary pharmacogenomic testing on epilepsy patients. A commercialized pharmacogenomic salivary test was performed in a cohort of epileptic patients. Genetic variants on five genes (i.e., CYP1A2, CYP2C9, CYP2C19, EPHX1, and ABCB1) involved in common ASMs metabolism were selected. Twenty-one individuals (median age [Q1 -Q3 ]: 15 [6.5-28] years) were enrolled. Six patients harboring the homozygous *1F allele in CYP1A2 could have reduced chance of response to stiripentol due to fast metabolism. CYP2C9 had reduced activity in 10 patients (alleles *2 and *3), potentially affecting phenytoin (PHT), phenobarbital (PB), primidone, lacosamide (LCM), and valproic acid metabolism. Seven patients, carrying the *2 allele of CYP2C19, had an increased risk of ADRs with clobazam (CLB), PB, PHT, LCM, brivaracetam; while one individual with the *17 allele in heterozygosity reported a CLB fast metabolism. Six patients showed a CC polymorphism of EPHX1 associated with the impaired efficacy of carbamazepine. ABCB1 polymorphisms related to drug-resistance (3435 CC) or drug-sensitive phenotype (CT or TT) were found in 6 out of 7 patients. Pharmacogenomic testing on saliva proved easy and safe in clinical practice to convey information for the management of epileptic patients, especially those resistant to treatment or sensitive to severe ADRs.

Clinical, Sociodemographic, and Psychological Factors Associated with Transition Readiness in Patients with Epilepsy.

BACKGROUND: The transition to adult care for patients with epilepsy is a complicated clinical issue associated with adverse outcomes, including non-adherence to treatment, dropout of medical care, and worse prognosis. Moreover, youngsters with epilepsy are notably prone to emotional, psychological, and social difficulties during the transition to adulthood. Transition needs depend on the type of epilepsy and the epileptic syndrome, as well as on the presence of co-morbidities. Having a structured transition program in place is essential to reduce poor health consequences. A key strategy to optimize outcomes involves the use of transition readiness and associated factors assessment to implement the recognition of vulnerability and protective aspects, knowledge, and skills of these patients and their parents. Therefore, this study aims to provide a comprehensive framework of clinical and psychosocial aspects associated with the transition from pediatric to adult medical care of patients with epilepsy. METHODS: Measures examining different aspects of transition readiness and associated clinical, socio-demographic, psychological, and emotional factors were administered to 13 patients with epilepsy (Mage = 22.92, SD = 6.56) with (n = 6) or without (n = 7) rare diseases, and a respective parent (Mage = 56.63, SD = 7.36). RESULTS: patients showed fewer problems in tracking health issues, appointment keeping, and pharmacological adherence as well as low mood symptoms and moderate resiliency. Moreover, they referred to a low quality of sleep. Notably, parents of patients with rare diseases reported a lower quality of sleep as compared to the other group of parents. CONCLUSIONS: Increasing awareness around transition readiness is essential to promote self-management skills of patients with epilepsy and their parents. Anticipating the period of transition could be beneficial, especially to prevent problematic sleep patterns and promote independence in health care management. Parents of patients with epilepsy and rare diseases should be monitored for their mental status which can affect patients' well-being.

Occurrence of hyperventilation-induced high amplitude rhythmic slowing with altered awareness after successful treatment of typical absence seizures and a network hypothesis.

BACKGROUND: Typical absence seizures (AS) are epileptic phenomena typically appearing in children 4-15 years of age and can be elicited by hyperventilation (HV). Hyperventilation-induced high-amplitude rhythmic slowing (HIHARS) represents a paraphysiological response during HV and may manifest with alteration of awareness (HIHARSAA). To date, HIHARSAA has mostly been described in patients without epilepsy. AIM: To describe five patients with treatment-responsive typical AS who, after becoming seizure free, presented with HIHARSAA. METHODS: By using video-electroencephalographic recording (Video-EEG), we describe differential clinical characteristics and ictal electrophysiological patterns of both typical AS and HIHARSAA. RESULTS: We demonstrate that when HIHARSAA occurs in patients with typical AS there is a temporal window between the two phenomena. This suggests that the presence of typical AS precludes the appearance of HIHARSAA. CONCLUSIONS: We hypothesize that alkalosis and dysfunction of the same neural network are involved in both typical AS and HIHARSAA and that their distinct electroclinic manifestations are due to the involvement of different ion channels. SIGNIFICANCE: A better understanding of the characteristics of typical AS and HIHARSAA and of the role of alkalosis in both, can help avoiding misdiagnosis and identifying more suitable therapies for typical AS.

Clinical and Genetic Features in Patients With Reflex Bathing Epilepsy.

OBJECTIVE: To describe the clinical and genetic findings in a cohort of individuals with bathing epilepsy, a rare form of reflex epilepsy. METHODS: We investigated by Sanger and targeted resequencing the SYN1 gene in 12 individuals from 10 different families presenting with seizures triggered primarily by bathing or showering. An additional 12 individuals with hot-water epilepsy were also screened. RESULTS: In all families with bathing epilepsy, we identified 8 distinct pathogenic or likely pathogenic variants and 2 variants of unknown significance in SYN1, 9 of which are novel. Conversely, none of the individuals with hot-water epilepsy displayed SYN1 variants. In mutated individuals, seizures were typically triggered by showering or bathing regardless of the water temperature. Additional triggers included fingernail clipping, haircutting, or watching someone take a shower. Unprovoked seizures and a variable degree of developmental delay were also common. CONCLUSION: Bathing epilepsy is genetically distinct reflex epilepsy caused mainly by SYN1 mutations.

Cognitive phenotype and language skills in children with achondroplasia.

BACKGROUND: Although achondroplasia (ACH) may not be considered a condition that is strictly related to neuropsychiatric problems, many children referred to pediatric neurologists and psychiatrists to undergo motor and linguistic diagnostic-rehab procedures. The purpose of this study was to delineate a characterization of language difficulties in a sample of Italian children with achondroplasia and analyze how an untreated language disorder can develop into a learning disability. METHODS: Seventeen Italian children (average age: 5 years and 8 months) with a clinical diagnosis genetically confirmed of achondroplasia were enrolled. Each child underwent a neuropsychological evaluation depending on the age, which included the following areas: intelligence, language, visual-spatial skills, memory, academic achievements, behavior. RESULTS: Most of ACH patients showed delayed speech development milestones. Cognitive evaluation revealed average abilities. All the ACH children have received a diagnosis of language impairment (DSM-5 "The Diagnostic and Statistical Manual of Mental Disorders 5° edition"): "Speech sound disorder" in the pre-school-age group, "Language disorder" with impairment of both verbal expression and verbal comprehension in the school age children. CONCLUSIONS: Several studies on general population demonstrated that children with developmental speech and language problems are at considerable risk for learning disability. Considering that in our ACH sample the language disorder has been diagnosed in all children, we expect a higher prevalence of learning disabilities in ACH than in general population.

Refractory absence seizures: An Italian multicenter retrospective study.

BACKGROUND: To evaluate evidence and prognosis of refractory cases of absence seizures. METHODS: Subjects with refractory absence seizures were identified retrospectively in 17 Italian epilepsy pediatrics Centers. We analyzed age at onset, family history, presence of myoclonic components, seizure frequency, treatment with antiepileptic drugs (AEDs), interictal electroencephalography (EEG) and neuropsychological assessment. Two subgroups were identified: one with patients with current absence seizures and another with patients that had become seizure free with or without AED treatment. The chi-square test was applied. RESULTS: A total of 92 subjects with drug-resistant absence seizures were analyzed. 45 subjects still show absence seizures (49%) and the other 47 became seizure free (51%) after a period of drug-resistance. The statistical analysis between these two groups showed no correlation between age of onset, family history and abnormalities at interictal EEG. Statistically significant differences were observed with regard to the number of AEDs used and intellectual disability. CONCLUSION: Typical absence epilepsy classifiable as Childhood Absence Epilepsy could not be considered so "benign", as suggested in literature. A longer duration of disease and a higher frequency of seizure seem to be correlated with a higher presence of cognitive impairment. No significant risk factor was observed to allow the faster and better recognition of patients with worse prognosis.

Use of the DISCERN tool for evaluating web searches in childhood epilepsy.

Epilepsy is an important cause of neurological disability in children. Nowadays, an increasing number of parents or caregivers use the Internet as a source of health information concerning symptoms, therapy, and prognosis of epilepsy occurring during childhood. Therefore, high-quality websites are necessary to satisfy this request. Using the DISCERN tool, we evaluated online information on childhood epilepsy provided by the first 50 links displayed on the Google search engine. The same links were evaluated by a team of pediatric neurologists (PNs) and by a lay subject (LS). The evaluation performed by the PNs found out that only 9.6% of the websites showed good reliability, that only 7.2% of the websites had a good quality of information on treatment choices, and that only 21.5% of the websites showed good overall quality of the content. With regard to the evaluation performed by the neutral subject, it was found that 21.4% of the websites showed good reliability, that 59.5% of the websites showed poor quality of information on treatment choices, and that only 2% of the websites showed good overall quality of the content. Our conclusion is that online information about childhood epilepsy still lacks reliability, accuracy, and relevance as well as fails to provide a thorough review of treatment choices.

Current advances in childhood absence epilepsy.

BACKGROUND: Childhood absence epilepsy is an age-dependent, idiopathic, generalized epilepsy with a characteristic seizure appearance. The disorder is likely to be multifactorial, resulting from interactions between genetic and acquired factors, but the debate is still open. We review recent studies on different aspects of childhood absence epilepsy and also to describe new concepts. METHODS: Data for this review were identified using Medline and PubMed survey to locate studies dealing with childhood absence epilepsy. Searches included articles published between 1924 and 2013. RESULTS: The diagnosis comprises predominant and associated seizure types associated with other clinical and electroencephalographic characteristics. Many studies have challenged the prevailing concepts, particularly with respect to the pathophysiological mechanisms underlying the electroencephalographic seizure discharges. Childhood absence epilepsy fits the definition of system epilepsy as a condition resulting from the persisting susceptibility of the thalamocortical system as a whole to generate seizures. This syndrome, if properly defined using strict diagnostic criteria, has a good prognosis. In some cases, it may affect multiple cognitive functions determining risk for academic and functional difficulties; the detection of children at risk allows tailored interventions. Childhood absence epilepsy is usually treated with ethosuximide, valproate, lamotrigine, or levetiracetam, but the most efficacious and tolerable initial empirical treatment has not been well defined. CONCLUSIONS: We review recent studies and new concepts on the electroclinical features and pathophysiological findings of childhood absence epilepsy in order to highlight areas of consensus as well as areas of uncertainty that indicate directions for future research.

Focal epilepsy with ictal abdominal pain: a case report.

Focal epilepsy with ictal abdominal pain is an unusual partial epilepsy characterized by paroxysmal episodes of abdominal or visceral pain, disturbance of awareness and electroencephalographic abnormalities. We describe a new case of ictal abdominal pain in which gastrointestinal complaints were the only manifestation of seizures and review the previously described pediatric patients. In our patient clinical findings, ictal EEG abnormalities, and a good response to antiepileptic drugs allowed us to make a diagnosis of focal epilepsy with ictal abdominal pain. This is a rare epileptic phenomenon that should be suspected in patients with unexplained paroxysmal abdominal pain and migraine-like symptoms. We suggest that, after the exclusion of more common etiologies, focal epilepsy with ictal abdominal pain should be considered in patients with paroxysmal abdominal pain and ictal EEG abnormalities.

Electroclinical features and long-term outcome of cryptogenic epilepsy in children with Down syndrome.

OBJECTIVE: To describe the electroclinical features and the long-term outcomes of epilepsy in a large cohort of males and females with Down syndrome who developed epilepsy in childhood. STUDY DESIGN: Subjects with Down syndrome and cryptogenic epilepsy with onset in childhood were identified retrospectively from the databases of 16 Italian epilepsy centers over a 40-year period. For each subject, age at onset of seizures, seizure semiology and frequency, electroencephalography characteristics, treatment with antiepileptic drugs, and long-term clinical and electroencephalography outcomes were analyzed. RESULTS: A total of 104 subjects (64 males [61.5%], 40 females [38.5%]) were identified. Seizure onset occurred within 1 year of birth in 54 subjects (51.9%), between 1 and 12 years in 42 subjects (40.4%), and after 12 years in 8 subjects (7.7%). Males had a younger age of seizure onset than females. Of the 104 subjects, 51 (49.0%) had infantile spasms (IS), 35 (33.7%) had partial seizures (PS), and 18 (17.3%) had generalized seizures (GS). Febrile seizures were recorded in 5 (4.8%) subjects. Intractable seizures were observed in 23 (22.1%) subjects, including 5 (9.8%) with IS, 8 (44.4%) with PS, and 10 (31.3%) with GS. CONCLUSION: Cryptogenic epilepsy in Down syndrome may develop during the first year of life in the form of IS or, successively, as PS or GS. Electroclinical features of IS resemble those of idiopathic West syndrome, with a favorable response to treatment with adrenocorticotropic hormone seen. Patients experiencing PS and GS may be resistant to therapy with antiepileptic drugs.

Pancreatic neuroendocrine tumor in a child with a tuberous sclerosis complex 2 (TSC2) mutation.

OBJECTIVE: Pancreatic neuroendocrine tumors (PanNETs) are rare in children with tuberous sclerosis complex (TSC). The objective of this report is to describe a case of PanNET in a boy with TSC. METHODS: We describe the patient's clinical presentation, biochemical workup, and laboratory tests. RESULTS: A 10-year-old boy with a TSC2 mutation presented with a nonsecretory PanNET discovered during routine annual abdominal ultrasound. Surgical distal pancreatectomy with spleen preservation was undertaken. The excised tumor appeared nodular, whitish, and encapsulated. The tumor was composed of pancreatic endocrine monomorphic cells, and the solid appearance of the tumor was interrupted by areas of cystic degeneration. Mitoses were rare; the proliferation index was estimated around 4%. Local lymph nodes showed hyperplasia but were free of metastatic disease. Immunohistochemical examinations were positive for the neuroendocrine markers chromogranin, neurospecific enolase, synaptophysin, CAM52, and vimentin and were negative for CD10 and alpha-1 antitrypsin. The immunohistochemistry also showed a lack of hyperactivation of mammalian target of rapamycin (mTOR) mTOR pathway. All data supported the diagnosis of a grade II well-differentiated neuroendocrine neoplasm, according to the World Health Organization (WHO). CONCLUSIONS: Thirteen non-secretory PanNET cases associated with TSC have been reported, including our patient (9 men and 4 women; 7 with TSC2 mutation). These tumors are usually asymptomatic and can be associated with metastasis; therefore, early diagnosis is crucial for prompt treatment. It is still unclear whether PanNETs should be considered a feature of TSC; however due to this association, we suggest that pancreas investigation should be included in routine examinations in men with TSC2 mutation.

Seizures induced by desloratadine, a second-generation antihistamine: clinical observations.

Some clinical experiences indicate that H1-antihistamines, especially first-generation H1-antagonists, occasionally provoke convulsions in healthy children as well as epileptic patients. Desloratadine is a frequently used second-generation antihistamine considered to be effective and safe for the treatment of allergic diseases. We describe four children who experienced epilepsy associated with the nonsedating H(1)-antagonist desloratadine and discuss the neurophysiologic role of the central histaminergic system in seizure susceptibility. In conclusion, we recommend caution in treating epileptic patients with the histamine H(1)-antagonists, including second- and third-generation drugs that are frequently referred because they are considered to be nonsedating antihistamines.

Attention impairment in childhood absence epilepsy: an impulsivity problem?

Although attention problems have often been described in children with childhood absence epilepsy (CAE), the use of different methodological approaches, neuropsychological tests, and heterogeneous experimental groups has prevented identification of the selective areas of attention deficit in this population. In this study, we investigated several components of attention in children with CAE using a unique computerized test battery for attention performance. Participants included 24 patients with CAE and 24 controls matched for age and sex. They were tested with a computerized test battery, which included the following tasks: selective attention, impulsivity, focused attention, divided attention, alertness, and vigilance. Compared with healthy controls, patients with CAE made more commission errors in the Go/No-Go task and more omission errors in the divided attention task. Childhood absence epilepsy patients also showed decreased reaction times in measures of selective attention and a great variability of reaction times in alertness and Go/No-Go tasks. Our findings suggest that patients with CAE were impaired in tonic and phasic alertness, divided attention, selective attention, and impulsivity.

Attention and executive functions profile in childhood absence epilepsy.

Childhood absence epilepsy (CAE) has been associated with executive functions and attention deficits. To clarify the issue of neurocognitive impairments in CAE, we investigated whether specific executive functions and attention deficit patterns were present in a well-defined group of children with CAE who were taking valproic acid. Participants included 15 children with CAE and 15 healthy controls aged 8-15 years and matched for sex, age and IQ. We compared the performances of the two groups in the following neuropsychological domains: planning and problem solving (TOL), verbal fluency (FAS and CAT), verbal short-term memory (DSF), verbal working memory (DSB), visuospatial memory (Corsi Block Tapping Test) and sustained and divided attention (TMT-A and TMT-B). No differences were found between the two groups on measures of intellectual functioning, verbal short-term memory and visuospatial memory. By contrast, significant differences were found in total time of planning task, phonological and category fluency and sustained and divided attention. Future studies that systematically examine different aspects of attention and executive functions are needed to outline a clear and specific neuropsychological profile in CAE.

Two epileptic syndromes, one brain: childhood absence epilepsy and benign childhood epilepsy with centrotemporal spikes.

Childhood absence epilepsy (CAE) and benign childhood epilepsy with centrotemporal spikes (BCECTS), or benign rolandic epilepsy (BRE), are the most common forms of childhood epilepsy. CAE and BCECTS are well-known and clearly defined syndromes; although they are strongly dissimilar in terms of their pathophysiology, these functional epileptic disturbances share many features such as similar age at onset, overall good prognosis, and inheritance factors. Few reports are available on the concomitance of CAE and BCECTS in the same patients or the later occurrence of generalized epilepsy in patients with a history of partial epilepsy. In most cases described in the literature, absence seizures always started after the onset of benign focal epilepsy but the contrary has never occurred yet. We describe two patients affected by idiopathic generalized epileptic syndrome with typical absences, who experienced BCECTS after remission of seizures and normalization of EEG recordings. While the coexistence of different seizure types within an epileptic syndrome is not uncommon, the occurrence of childhood absence and BCECTS in the same child appears to be extremely rare, and this extraordinary event supports the hypothesis that CAE and BCECTS are two distinct epileptic conditions. However, recent interesting observations in animal models suggest that BCECTS and CAE could be pathophysiologically related and that genetic links could play a large role.

Hypnic headache in children.

BACKGROUND: Hypnic headache (HH) is a rare, short-lasting headache occurring exclusively during sleep and usually affecting the elderly population. According to the ICHD-II diagnostic criteria, HH is characterized exclusively by sleep-related dull headache attacks, either lateralized or bilateral, a recurrence of >15 times per month and a persistence of pain >15 minutes after waking. No autonomic symptoms and no more than nausea, photophobia, or phonophobia are present. CASES: We report three children between 7 and 11 years old with HH features. The characteristics of our patient's headache, with particular reference to the nocturnal pattern, the short duration and the absence of autonomic symptoms, lead us to consider the diagnosis of HH. CONCLUSIONS: Considering the very few cases of HH reported in paediatric age, our cases may expand the clinical spectrum of this disorder, suggesting a possible revision of the diagnostic criteria, with particular regard to the developmental age.

A clinical and genetic study of 33 new cases with early-onset absence epilepsy.

PURPOSE: To investigate the electroclinical features and the outcome of patients with typical absences starting before the 3 years of life. METHODS: We reviewed the clinical data of patients with absences started before 3 years observed over a 15-year period. Mutation analysis of SLC2A1 (GLUT-1) gene was performed when possible. Their clinical features were compared with those of subjects with a diagnosis of childhood absence epilepsy (CAE). RESULTS: Among 33 children with absence epilepsy starting before 3 years of life, there were 20 boys and 13 girls. Mean seizure onset was at 28.0 ± 8.3 (range: 8-36) months of life. Two children displayed borderline intellectual functioning at long-term follow-up. Twenty-eight (85%) patients showed excellent response to therapy. Three subjects evolved into a different form of idiopathic generalized epilepsy (IGE). No SLC2A1 mutation was identified in 20 (60.6%) patients tested. The main clinical features of patients with early-onset absences did not differ from those of CAE except for increased prevalence of males (p=0.002) and longer treatment duration (p=0.001) in the former. CONCLUSIONS: Strong similarities in the electroclinical features and outcome between children with early-onset absences and those with CAE support the view that these conditions are part of the wide spectrum of IGE.

A multicenter, randomized, placebo-controlled trial of levetiracetam in children and adolescents with newly diagnosed absence epilepsy.

PURPOSE: To evaluate the potential efficacy of levetiracetam as an antiabsence agent in children and adolescents with newly diagnosed childhood or juvenile absence epilepsy. METHODS: Patients were randomized in a 2:1 ratio to receive de novo monotherapy with levetiracetam (up to 30 mg/kg/day) or placebo for 2 weeks under double-blind conditions. Responder status (primary end point) was defined as freedom from clinical seizures on days 13 and 14 and from electroencephalographic (EEG) seizures during a standard EEG recording with hyperventilation and intermittent photic stimulation on day 14. The double-blind phase was followed by an open-label follow-up. KEY FINDINGS: Nine of 38 patients (23.7%) were responders in the levetiracetam group, compared with one of 21 (4.8%) in the placebo group (p = 0.08). Seven of 38 patients (18.4%) were free from clinical and EEG seizures during the last 4 days of the trial (including 24-h EEG monitoring on day 14) compared with none of the patients treated with placebo (p = 0.04). Seventeen patients remained seizure-free on levetiracetam after 1 year follow-up. Of the 41 patients who discontinued levetiracetam due to lack of efficacy (n = 39) or adverse events (n = 2), 34 became seizure-free on other treatments. SIGNIFICANCE: Although superiority to placebo just failed to reach statistical significance for the primary end point, the overall findings are consistent with levetiracetam having modest efficacy against absence seizures. Further controlled trials exploring larger doses and an active comparator are required to determine the role of levetiracetam in the treatment of absence epilepsy.