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Objective:Although individual neonatal epilepsy syndromes are rare, as a group they represent a sizable subgroup of neonatal seizure etiologies. We evaluated the profile of neonatal epilepsies in a prospective cohort of newborns with seizures.Methods:Consecutive newborns with seizures were enrolled in the Neonatal Seizure Registry (an association of 7 US children's hospitals). Treatment and diagnostic testing were at the clinicians' discretion. Neonates with seizures related to epileptic encephalopathies (without structural brain abnormalities), brain malformations, or benign familial epilepsies were included in this analysis.Results:Among 611 consecutive newborns with seizures, 79 (13%) had epilepsy (35 epileptic encephalopathy, 32 congenital brain malformations, 11 benign familial neonatal epilepsy [BFNE], 1 benign neonatal seizures). Twenty-nine (83%) with epileptic encephalopathy had genetic testing and 24/29 (83%) had a genetic etiology. Pathogenic or likely pathogenic KCNQ2 variants (n = 10) were the most commonly identified etiology of epileptic encephalopathy. Among 23 neonates with brain malformations who had genetic testing, 7 had putative genetic etiologies. Six infants with BFNE had genetic testing; 3 had pathogenic KCNQ2 variants and 1 had a pathogenic KCNQ3 variant. Comorbid illnesses that predisposed to acute symptomatic seizures occurred in 3/35 neonates with epileptic encephalopathy vs 10/32 with brain malformations (p = 0.03). Death or discharge to hospice were more common among newborns with brain malformations (11/32) than those with epileptic encephalopathy (3/35, p = 0.01).Conclusions:Neonatal epilepsy is often due to identifiable genetic causes. Genetic testing is now warranted for newborns with epilepsy in order to guide management and inform discussions of prognosis.

Infants with West Syndrome and underlying structural pathology typically experience persistent symptomatic focal seizures and intellectual disability. We performed a retrospective case review of 84 patients with West Syndrome evaluated at one institution between 1990 and 2013. From this group we identified three patients with West syndrome and congenital hemiplegia who later developed genetic epilepsy features and had normal intellectual development. This outcome is highly unusual and raises important questions about the relationship and possible influence of genetic epilepsy in patients with pre-existent West Syndrome and brain injury.

Introduction: Mutations in the KCNQ2 gene lead to autosomal dominant benign neonatal seizures or early-onset epileptic encephalopathy. We describe here a female patient with focal epileptic seizures starting from four months of age, carrying a heterozygous duplication of exons 9 – 17 of the KCNQ2 gene. Case Presentation: It is the second child of German non-consanguineous parents without any family history for seizures or epilepsy. After uneventful pregnancy, delivery and neonatal period, the patient developed focal seizures with impairment of awareness several times per week. Cranial MRI, screening for inborn disorders of metabolism or prenatal infections (TORCH) did not show pathogenic results. A panel analysis for epileptic encephalopathies (CeGaT) revealed a heterozygous duplication of exons 9 to 17 of the KCNQ2 gene which was classified as variant of unknown significance. With application of Levetiraetam (at least 40 mg/kg daily, blood level of ~10 μg/mL) absence of seizures except for febrile situations was achieved. After the 7th month, no more seizures were observed, even during infections, and Levetiraetam therapy could be gradually reduced and finally stopped. Psychomotor development of the patient is almost normal. Due to muscular hypotonia, she received physiotherapy, but the developmental milestones were all reached age-appropriately. Conclusion: The clinical interpretation of variants of unknown significance revealed through a panel analysis is often difficult, even with incorporation of data from large databases. So far, a partial KCNQ2 duplication, of exons 3 to 12, has been described only once in the literature in a patient with benign neonatal epilepsy. The reported disease course in our patient carrying another partial duplication of KCNQ2 suggests a benign outcome in this family as well.

The molecular pathogenesis of benign childhood epilepsy with centrotemporal spikes (BECTS) remains unclear whereas mutations of the KCNQ2 and KCNQ3 genes have been identified as causes of benign familial neonatal convulsions. We report here a girl with benign neonatal convulsions followed by BECTS, for whom a mutation of KCNQ2 was identified. This case may provide the clue to the understanding of the molecular pathogenesis of BECTS.

A 2-day-old baby girl was transferred to our facility for evaluation and management of seizures. She was born to nonconsanguineous parents from Somalia at 41 5 7 weeks of gestation. The pregnancy was uneventful. The mother was group B streptococcus–positive and was appropriately treated with antibiotics during labor. Labor and vaginal delivery were uncomplicated (no history of prolonged rupture of membranes or birth trauma). The baby's Apgar scores were 9 at 1 and 5 minutes. The baby appeared to be well on the first day of life but began having seizures on the second day. On presentation to our facility, the patient exhibited rhythmic jerking movements of her extremities, consistent with myoclonic seizures. She also had multiple apneic episodes and was therefore intubated and mechanically ventilated. EEG recording showed an asynchronous burst suppression pattern with occasional generalized epileptiform discharges that were associated with body jerking, consistent with severe encephalopathy with seizures. On general physical examination, she was normocephalic and nondysmorphic. There were no abnormal skin findings and no hepatosplenomegaly. Neurologic examination revealed diffuse hypotonia with symmetrically hypoactive reflexes in all 4 extremities. Bedside funduscopic examination revealed normal Moro; suck and rooting reflexes were poor, but palmar grasp reflex was present bilaterally. There was no family history of neurologic or metabolic disorders (including seizures). ### Questions for consideration: 1. What is the differential diagnosis for neonatal seizures? 2. Does the burst suppression pattern on EEG limit the differential diagnosis? 3. Can this infant's presentation be classified as an epilepsy syndrome? The diagnostic possibilities for neonatal seizures are broad and include common causes such as electrolyte imbalance (hypocalcemia, hypomagnesemia, hyponatremia, or hypoglycemia), hypoxic ischemic encephalopathy, neonatal stroke (ischemic or hemorrhagic), maternal drug withdrawal, benign neonatal seizures, and infectious diseases (e.g., group B streptococcus sepsis or meningitis) and less common …

SUMMARY Three families suffering from benign neonatal seizures are described, and the value of recognizing the condition in order to offer realistic reassurance to the family is stressed. Although it is uncommon, the rarity of its description in the literature probably does not reflect the true incidence of this dominantly inherited condition, in which there is an increased risk of the later development of epilepsy. RESUME Crises neona tales benignes dominantes Dans trois families, les enfants souffrent de crises neonatales benignes et l'article etudie la necessite de reconnaitre le trouble pour rassurer la famille inquiete. Quoique la manifestation soit inhabituelle, la rarete de sa description dans la litterature ne traduit pas probablement la frequence veritable de cette condition heritee sur le mode dominant, dans lequel le risque du developpement ulterieur d'une epilepsie est accru. ZUSAMMENFASSUNG Dominant vererbte benigne Neugeborenenkrampfe Es werden drei Familien mit benignen Neugeborenenkrampfen beschrieben und es wird daraufhingewiesen, daB die Diagnose dieses Krankheitsbildes fur eine genaue Beratung der Familien von groBer Bedeutung ist. Obwohl es selten ist, sind die wenigen Literaturangaben daruber sicher kein Anhalt fur die wirkliche Haufigkeit dieses dominant vererbten Krankheitsbildes, das ein erhotes Risiko fur die spatere Entwicklung einer Epilepsie in sich tragt. RESUMEN Convulsiones neonatales benignas dominantes Se describen tres familias con convulsiones neonatales benignas y se insiste en el reconocimiento de esta patologia para poder ofrecer a los padres una confianza realista. Aunque no es infrecuente, la rareza de su description en la literatura probablemente no refleja la real incidencia de esta alteration heredada de forma dominante y en la que existe un riesgo aumentado de que posteriormente se desarrolle una epilepsia.

In recent years, several genes have been causally associated with epilepsy. However, making a genetic diagnosis in a patient can still be difficult, since extensive phenotypic and genetic heterogeneity has been observed in many monogenic epilepsies. This study aimed to analyze the genetic basis of a wide spectrum of epilepsies with age of onset spanning from the neonatal period to adulthood. A gene panel targeting 46 epilepsy genes was used on a cohort of 216 patients consecutively referred for panel testing. The patients had a range of different epilepsies from benign neonatal seizures to epileptic encephalopathies (EEs). Potentially causative variants were evaluated by literature and database searches, submitted to bioinformatic prediction algorithms, and validated by Sanger sequencing. If possible, parents were included for segregation analysis. We identified a presumed disease-causing variant in 49 (23%) of the 216 patients. The variants were found in 19 different genes including SCN1A, STXBP1, CDKL5, SCN2A, SCN8A, GABRA1, KCNA2, and STX1B. Patients with neonatal-onset epilepsies had the highest rate of positive findings (57%). The overall yield for patients with EEs was 32%, compared to 17% among patients with generalized epilepsies and 16% in patients with focal or multifocal epilepsies. By the use of a gene panel consisting of 46 epilepsy genes, we were able to find a disease-causing genetic variation in 23% of the analyzed patients. The highest yield was found among patients with neonatal-onset epilepsies and EEs.

Benign epilepsies during infancy are a wide topic, which needs both clinical and nosological clarifications. Already in 1963 Fukuyama reported patients with seizures during infancy with a benign outcome. In the late 80s and early 90s, Watanabe reported series of infants with complex partial seizures or partial seizures with secondary generalization, with a normal development before onset and a benign outcome. In the same years Vigevano focused on familial cases: he described several families with seizures with onset around the 6-month of age, and autosomal dominant mode of inheritance. To define this condition, he coined the term "benign familial infantile seizures" (BFIS). Afterwards, studying families with this phenotype, loci on chromosomes 19, 16 and 2 responsible for BFIS were detected. Similar loci were found in families affected by BFIS and subsequent choreoathetosis, and BFIS associated with familial hemiplegic migraine. In most recent years a new form of benign epilepsy has been proposed, with an intermediate onset between the neonatal and infantile age, which was defined with the term benign familial neonatal-infantile seizures (BFNIS). This condition could have some clinical and genetic features overlapping with BFIS. Seizures with a benign outcome have been reported also in infants during episode of mild gastroenteritis (BIS with MG) frequently with positive Rotavirus antigen. Lastly, sleep EEG abnormalities have been reported in children with a peculiar form of epilepsy by Capovilla, who defined this condition as benign infantile focal epilepsy with midline spikes and waves during sleep (BIMSE). Some of these entities have been included in the last classification proposed by the ILAE and have been differentiated in familial and non-familial forms. The aim of this review is to describe these entities, discuss their nosological aspects, pointing out the similarities and differences with benign neonatal seizures and benign focal epilepsies appearing later in life such as early-onset benign occipital seizure susceptibility syndrome (EBOSS), or benign epilepsy of childhood with centro-temporal spikes (BECTS).

Summary Purpose: To assess the advantages of the 2001 ILAE proposed diagnostic scheme for classification of newborns with epileptic seizures over the 1989 ILAE classification. Method: Clinical features, seizure semiology and duration, neurological evaluation, ictal and interictal EEG, brain imaging and outcome at the end of the neonatal period (44 weeks post-conceptional age) of 94 newborns with EEG confirmed seizures were analyzed. The 2001 ILAE classification was applied where possible. Results: Twenty patients died before the end of the neonatal period. In the remaining patients, applying axis 3, we classified 54 newborns as having epileptic seizures that do not require a diagnosis of epilepsy; 14 as symptomatic partial epilepsy; 5 within the neonatal epileptic syndromes and one as benign neonatal seizures (NS). Axis 4 in all newborns provided a valuable tool in order to better define the individual patient. Conclusions: Compared to the 1989 ILAE classification, which allowed a syndromic diagnosis in only 6/94 patients, the remaining being classified as Epilepsies and Syndromes undetermined whether focal or generalized, the 2001 ILAE diagnostic scheme, applied at the end of the neonatal period, offers a variety of approaches to classification, allowing an early distinction between epilepsy and single or isolated clusters of seizures, with therapeutic and prognostic implications.

At full term, both glutamate and gamma-amino-butyric acid (GABA) are excitatory; cortical synapses are beginning to appear, there is little myelin in the cerebral hemispheres, and long tracts hardly start to develop. Neonatal myoclonic encephalopathy can result from premature activation of N-methyl-D-aspartate (NMDA) transmission. Benign neonatal seizures and migrating partial seizures in infancy could involve excessive or premature excitability of deep cortical layers. Benign rolandic epilepsy and continuous spike waves in slow sleep are consistent with an excess of both excitatory and inhibitory cortical synapses. West and Lennox-Gastaut syndromes express age-related diffuse cortical hyperexcitability, the pattern depending on the age of occurrence; synchronization of spikes is becoming possible with maturation of the myelin. Idiopathic generalized epilepsy is itself modulated by maturation that causes frontal hyperexcitability generating myoclonic-astatic seizures, between the ages of infantile and juvenile myoclonic epilepsies. Physiological delay of hippocampo-neocortical pathways maturation could account for the delayed occurrence of mesial temporal epilepsy following infantile damage, whereas premature maturation could contribute to fronto-temporal damage characteristic of fever-induced epileptic encephalopathy in school-age children, a dramatic school-age epileptic encephalopathy.

Neuromyotonia is a disorder of peripheral nerve hyperexcitability characterized by myokymia, muscle cramps and stiffness, delayed muscle relaxation after contraction (pseudomyotonia), and hyperhidrosis, associated with well described spontaneous electromyographic features. It is usually an acquired disorder associated with autoantibodies against neuronal voltage-gated potassium channels. However, mutations of KCNA1, encoding the K(+) channel subunit hKv1.1, have been reported in rare families with neuromyotonia, and mutations in KCNQ2, encoding voltage-gated potassium M channel subunit, in families with benign neonatal seizures and myokymia. We report a three-generation family with inherited neuromyotonia without evidence of immunological involvement. Genetic study excluded mutations in KCNA1, KCNA2, KCNA6 and KCNQ2 genes. Our study does not completely exclude the involvement of other genes encoding ion channels subunits in the pathogenesis of this disorder. Further studies of familial cases will shed light on the molecular basis of inherited neuromyotonia.

Summary: Purpose: The electroencephalographic hallmark of benign childhood epilepsy with centrotemporal spikes (BECTS, or rolandic epilepsy) are characteristically shaped centrotemporal spikes and sharp waves (CTS). This EEG trait, but not BECTS itself, has been reported to follow an autosomal dominant mode of inheritance with incomplete penetrance and age dependence. CTS therefore represents a neurobiologic marker for the increased risk of developing BECTS. Benign neonatal familial convulsions (BNFC) like BECTS is an idiopathic age-dependent epilepsy with a benign course. Observations of benign neonatal seizures and BECTS in the same individual are well documented. Neonatal seizures with benign course were found in increased numbers in a series of CTS carriers. Two genetic loci, EBNl and EBN2, have been mapped in families with BNFC, making these two loci strong candidates for the CTS trait underlying BECTS. The aim of this study was to determine whether these two epilepsy syndromes are allelic disorders. Methods: Linkage analysis was performed in 12 families with probands with BECTS and one or more relatives with CTS in the EEG with or without BECTS by using polymorphic DNA markers. Results: Assuming an autosomal mode of inheritance with penetrances of 0.9 and 0.45, respectively, both loci were consistently excluded. Conclusions: The CTS trait and EBN1 and EBN2 segregate independently. BECTS and BNFC therefore appear to be genetically distinct entities. Benign neonatal seizures may be a underrecognized symptom of the CTS trait itself.

Benign neonatal seizures is a rare but increasingly recognized syndrome characterized by seizures in the neonatal or infantile period. Two forms are recognized: familial and nonfamilial. In both instances, the seizures may be quite severe, and status epilepticus is common. The nonfamilial form is characterized by idiopathic, self-limited seizures occurring in previously normal neonates. The seizures most commonly occur at day 5 and have been called "fifth-day fits" by some authors. Familial seizures most frequently have their onset during the first week of life, but onset may occur as late as early infancy. These seizures may recur for several months before resolving. No cause is found for the seizures, and the patient appears healthy during the interictal period. The family history reveals benign neonatal seizures in other family members. Although the prognosis is favorable in both syndromes, seizures may occasionally occur later in life in the familial form. The familial form of benign neonatal seizures is autosomal dominant, and the gene has been localized to chromosome 20.

Eight individuals in two generations of a family experienced seizures neonatally or in early infancy. Evaluation in two of these infants documented an EEG pattern suggestive of seizure activity without discernible pathogenesis of their seizures. Subsequently, affected individuals had a normal neurodevelopmental outcome, although one person had later epilepsy. The benign course of this disorder and its association with adult epilepsy agree with previously reported cases from the literature.

Objective: Benign familial infantile epilepsy (BFIE) is an autosomal dominant epilepsy syndrome characterized by afebrile seizures beginning at about 6 months of age. Mutations in PRRT2 , encoding the proline-rich transmembrane protein 2 gene, have recently been identified in the majority of families with BFIE and the associated syndrome of infantile convulsions and choreoathetosis (ICCA). We asked whether the phenotypic spectrum of PRRT2 was broader than initially recognized by studying patients with sporadic benign infantile seizures and non-BFIE familial infantile seizures for PRRT2 mutations. Methods: Forty-four probands with infantile-onset seizures, infantile convulsions with mild gastroenteritis, and benign neonatal seizures underwent detailed phenotyping and PRRT2 sequencing. The familial segregation of mutations identified in probands was studied. Results: The PRRT2 mutation c.649-650insC (p.R217fsX224) was identified in 11 probands. Nine probands had a family history of BFIE or ICCA. Two probands had no family history of infantile seizures or paroxysmal kinesigenic dyskinesia and had de novo PRRT2 mutations. Febrile seizures with or without afebrile seizures were observed in 2 families with PRRT2 mutations. Conclusions: PRRT2 mutations are present in >80% of BFIE and >90% ICCA families, but are not a common cause of other forms of infantile epilepsy. De novo mutations of PRRT2 can cause sporadic benign infantile seizures. Seizures with fever may occur in BFIE such that it may be difficult to distinguish BFIE from febrile seizures and febrile seizures plus in small families.