Neonatal Seizures-Are We there Yet?

Neonatal seizures are the most prevalent and distinctive sign of neurologic dysfunction in early life and pose an immense challenge for clinicians. Improvements in neonatal care have increased the survival rate of extremely premature infants, considerably changing the spectrum of underlying etiologies, and instigating a gradual shift from mortality to morbidity. Recognizing neonatal seizures can be challenging due to variability in presentation but clinical features can often provide valuable clues about etiology. Yet, the majority of neonatal seizures are subclinical. Even though conventional electroencephalography (EEG) with simultaneous video detection of seizures still represents the diagnostic gold standard, continuous monitoring using a one- to two-channel amplitude-integrated EEG with concurrent unprocessed EEG can be crucial for early recognition and intervention. Furthermore, tremendous progress has been made in neuroimaging, and all infants with seizures should have a magnetic resonance imaging (MRI) to help identify the underlying etiology. While the majority of neonatal seizures are caused by hypoxic-ischemic events, stroke, hemorrhage, or infection, approximately 15% of patients will require more sophisticated algorithms for diagnostic workup, including metabolic and genetic screening. These recent developments have led to renew interest in the classification of neonatal seizures, which aim to help identify etiology and guide appropriate therapeutic and prognostic decisions. In this review, we outline recent progress made in the etiology, diagnosis, and treatment of neonatal seizures and highlight areas that deserve further research.

Focal cortical malformations in children with early infantile epilepsy and PCDH19 mutations: case report.

In this case report we assess the occurrence of cortical malformations in children with early infantile epilepsy associated with variants of the gene protocadherin 19 (PCDH19). We describe the clinical course, and electrographic, imaging, genetic, and neuropathological features in a cohort of female children with pharmacoresistant epilepsy. All five children (mean age 10y) had an early onset of epilepsy during infancy and a predominance of fever sensitive seizures occurring in clusters. Cognitive impairment was noted in four out of five patients. Radiological evidence of cortical malformations was present in all cases and, in two patients, validated by histology. Sanger sequencing and Multiplex Ligation-dependent Probe Amplification analysis of PCDH19 revealed pathogenic variants in four patients. In one patient, array comparative genomic hybridization showed a microdeletion encompassing PCDH19. We propose molecular testing and analysis of PCDH19 in patients with pharmacoresistant epilepsy, with onset in early infancy, seizures in clusters, and fever sensitivity. Structural lesions are to be searched in patients with PCDH19 pathogenic variants. Further, PCDH19 analysis should be considered in epilepsy surgery evaluation even in the presence of cerebral structural lesions. WHAT THIS PAPER ADDS: Focal cortical malformations and monogenic epilepsy syndromes may coexist. Structural lesions are to be searched for in patients with protocadherin 19 (PCDH19) pathogenic variants with refractory focal seizures.

Modified Atkins diet is an effective treatment for children with Doose syndrome.

OBJECTIVE: Children with myoclonic astatic epilepsy (MAE; Doose syndrome) whose seizures do not respond immediately to standard antiepileptic drugs (AEDs) are at high risk of developing an epileptic encephalopathy with cognitive decline. A classic ketogenic diet (KD) is a highly effective alternative to AEDs. To date, there are only limited data on the effectiveness of the modified Atkins diet (MAD), which is less restrictive and more compatible with daily life. We report findings from a retrospective study on 30 MAE patients treated with MAD. METHODS: Four participating centers retrospectively identified all patients with MAE in whom a MAD had been started before June 2015. Seven children were recruited from a cohort included in an open prospective controlled trial. A retrospective review of all available charts was performed in the other patients. RESULTS: Thirty patients (24 boys) were included. Mean age at epilepsy onset was 3.1 years (range 1.5-5.6). MAD was started at a mean age of 4.5 years (range 2.2-9.1) after the children had received an average of six different AEDs (range 2-15). Mean MAD observation time was 18.7 months (range 1.5-61.5). Twenty of 30 patients were still on MAD at the end of study (duration range 1.5-61.5, mean 18.5 months). MAD was stopped without relapse in three patients after sustained seizure freedom for >2 years. For the other seven cases, ineffectiveness (three patients), loss of efficacy (two), or noncompliance (two) led to termination. No severe adverse effects were noted. By the end of the observation period, 25 (83%) of 30 patients experienced a seizure reduction by ≥50% and 14 (47%) of 30 were seizure-free. None of the evaluated factors differed significantly between the groups of seizure-free and non-seizure-free children. SIGNIFICANCE: MAD is an effective treatment for MAE. It should be considered as an alternative to AEDs or the more restrictive classic ketogenic diet.

Postoperative Amplitude-Integrated Electroencephalography Predicts Four-Year Neurodevelopmental Outcome in Children with Complex Congenital Heart Disease.

OBJECTIVES: To evaluate the predictive value of pre- and postoperative amplitude-integrated electroencephalography (aEEG) on neurodevelopmental outcomes in children operated for congenital heart disease (CHD). STUDY DESIGN: Prospectively enrolled cohort of 60 infants with CHD who underwent cardiac surgery with cardiopulmonary bypass in the first 3 months of life. Infants with a genetic comorbidity were excluded. aEEG was assessed for 12 hours pre- and 48 hours postoperatively. Background pattern was classified by the use of standard categories, and the presence of seizures and sleep-wake cycles (SWCs) was noted. Outcome at 1 and 4 years of age was assessed with standardized developmental tests. RESULTS: Preoperatively, infants either showed continuous normal voltage (n = 56) or discontinuous normal voltage (n = 4). Postoperatively, abnormal background pattern (flat trace, burst suppression, or continuous low voltage) was detected in 7 (12%), discontinuous normal voltage in 37 (61%), and continuous normal voltage in 16 (27%) infants. Nineteen infants (32%) did not return to normal SWCs within the recording period. Seizures were detected in 4 infants preoperatively and in another 4 postoperatively. After we controlled for surgical and postoperative risk factors, abnormal postoperative background pattern and lack of return to SWCs independently predicted poorer intelligence quotient at 4 years (P = .03 and P = .04 respectively) but was not related to motor outcome. CONCLUSION: aEEG is a useful bedside tool that helps to predict outcome in infants undergoing open-heart surgery for CHD. Abnormal postoperative background pattern and lack of return to SWCs are markers for subsequent impaired cognitive development.

Treatment of Infantile Spasms: Report of the Interdisciplinary Guideline Committee Coordinated by the German-Speaking Society for Neuropediatrics.

Objectives This report aims to define treatment goals, to summarize the evidence level (EL) of different treatment options for infantile spasms (IS), both in terms of efficacy and adverse effect, and to give recommendations for the management of IS. Methods The Cochrane and Medline (1966-July 2014) databases were searched. Literature known to the guideline working group and identified through citations was also considered. The results of previously published guidelines were taken into account in our analysis. Rating the level of evidence followed the Scottish Intercollegiate Guidelines Network. Recommendations If IS are suspected, electroencephalogram (EEG) should be performed within a few days and, if confirmed, treatment should be initiated immediately. Response to first-line treatments should be evaluated clinically and electroencephalographically after 14 days.Adrenocorticotropic hormone, corticosteroids, and vigabatrin are the first-line drugs for the treatment of IS. In children with tuberous sclerosis complex, vigabatrin is the treatment of first choice. Ketogenic diet, sulthiame, topiramate, valproate, zonisamide, and benzodiazepines can be used when first-line drugs have proved ineffective. Children refractory to drug therapy should be evaluated for epilepsy surgery, especially if focal brain lesions are present.Regular follow-up controls, including EEG (preferably sleep EEG) and standardized developmental assessment are recommended.

Does vigabatrin treatment for infantile spasms cause visual field defects? An international multicentre study.

AIM: The aim of this study was to examine whether vigabatrin treatment had caused visual field defects (VFDs) in children of school age who had received the drug in infancy. METHOD: In total, 35 children (14 males, 21 females; median age 11y, SD 3.4y, range 8-23y) were examined by static Humphrey perimetry, Goldmann kinetic perimetry, or Octopus perimetry. The aetiologies of infantile spasms identified were tuberous sclerosis (n=10), other symptomatic causes (n=3), or cryptogenic (n=22). RESULTS: Typical vigabatrin-attributed VFDs were found in 11 out of 32 (34%) children: in one out of 11 children (9%) who received vigabatrin for <1 year (group 1), in three out of 10 children (30%) who received vigabatrin for 12 to 24 months (group 2), and in seven out of 11 children (63%) who received vigabatrin treatment for longer than 2 years (group 3). VFDs were mild in five and severe in six children. Patients with tuberous sclerosis were at higher risk of VFDs (six out of 10 children). The mean cumulative doses of vigabatrin were 140.5, 758.8, and 2712g in group 1, 2, and 3, respectively. INTERPRETATION: VFDs were found in 34% of the cohort of children in this study. The rate of VFD increased from 9% to 63% as duration of treatment increased. The results of this study showed that the risk-benefit ratio should always be considered when using vigabatrin.

Does amplitude-integrated electroencephalogram background pattern correlate with cerebral injury in neonates with hypoxic-ischaemic encephalopathy?

AIMS: To determine the correlation between amplitude-integrated electroencephalogram (aEEG) background pattern and cerebral magnetic resonance imaging (MRI) in infants with hypoxic-ischaemic encephalopathy (HIE) and to examine whether the correlation changes with therapeutic hypothermia. METHODS: We included 38 term-born infants with HIE of whom 17 were cooled. All were continuously monitored with aEEG. Background pattern was scored at the beginning and the end of the recording. Cerebral MRI was obtained on median day 5 (2-11 days). Abnormalities were classified using a predefined scoring system for basal ganglia, watershed and overall injury, and then grouped into mild-moderate and severe. RESULTS: Abnormal aEEG background pattern correlated with more severe cerebral injury on MRI in the non-cooled infants (P < 0.01). In addition, cooled infants had less severe cerebral injury than non-cooled infants, in particular on T2-weighted images (watershed P = 0.04 and total injury score = 0.07). CONCLUSIONS: Abnormal aEEG background pattern is predictive of abnormal MRI, but therapeutic hypothermia seems to reduce this association. Thus, when cooling is applied in a clinical setting, the predictive value of aEEG may be limited.

Hippocampal sclerosis and chronic epilepsy following posterior reversible encephalopathy syndrome.

Chronic epilepsy has rarely been reported after posterior reversible encephalopathy syndrome (PRES) and the association with hippocampal sclerosis has been suggested only once before. We report the case of a girl admitted at the age of 8 years with idiopathic nephrotic syndrome. On the second day of admission, she presented with focal complex seizures and cerebral MRI showed posterior encephalopathy and no hippocampal sclerosis. MRI after one month confirmed the diagnosis of PRES. The seizures recurred and the girl developed pharmacoresistant epilepsy and was admitted to our hospital for further investigation. Cerebral MRI three years after the diagnosis of PRES showed hippocampal sclerosis which was not present on the initial MRI. We conclude that there is a triggering role of PRES in the development of hippocampal sclerosis. Hippocampal sclerosis may have resulted from seizure-associated damage, alternatively, hypertensive encephalopathy may have led to hippocampal damage via a vascular mechanism.

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.

Effect of sedation and analgesia on postoperative amplitude-integrated EEG in newborn cardiac patients.

The aim of this study is to describe the effect of sedation and analgesia on postoperative amplitude-integrated EEG (aEEG) in newborns with congenital heart disease (CHD) undergoing heart surgery. This is a consecutive series of 26 newborns with CHD of which 16 patients underwent cardiopulmonary bypass (CPB) surgery and 10 patients did not. aEEG was monitored for at least 12 h preoperatively and started within the first 6 h postoperatively for 48 h. Outcome was assessed at 1 year of age. All 26 patients showed a normal preoperative continuous cerebral activity with sleep-wake cycles (SWC). The postoperative duration to return to normal background activity with SWC was similar for both groups. Independent of group assignment, patients requiring midazolam had a significantly later onset of a normal SWC than those without midazolam (p=0.03). Three patients in the CPB group and two in the non-CPB group showed continuous low voltage or flat trace after administration of fentanyl. These changes did not correlate with neurodevelopmental outcome. Sedation with midazolam has a transient effect on the background activity, whereas fentanyl can induce a severe pathologic background pattern. The significance of these changes on outcome is not yet clear. Thus, more attention should be paid to these effects when interpreting aEEG in this population.

Seizures and paroxysmal events: symptoms pointing to the diagnosis of pyridoxine-dependent epilepsy and pyridoxine phosphate oxidase deficiency.

AIM: We report on seizures, paroxysmal events, and electroencephalogram (EEG) findings in four female infants with pyridoxine-dependent epilepsy (PDE) and in one female with pyridoxine phosphate oxidase deficiency (PNPO). METHOD: Videos and EEGs were analysed and compared with videos of seizures and paroxysmal events archived from 140 neonates. PDE and PNPO were proven by complete control of seizures once pyridoxine or pyridoxal 5'-phosphate was administered and by recurrence when withdrawn. Mutations in the antiquitin gene were found in three patients and in the PNPO gene in one child. RESULTS: Seizures began within 48 hours after birth in four newborns and at age 3 weeks in one. Frequent multifocal and generalized myoclonic jerks, often intermixed with tonic symptoms, abnormal eye movement, grimacing, or irritability, were observed in all infants with PDE and PNPO, but rarely in the other archived videos of neonates. EEGs were inconstant and frequently no discernable ictal changes were recorded during the seizures and the paroxysmal events. In addition, interictal EEGs were inconclusive, with normal and abnormal recordings. In older children tonic-clonic seizures, abnormal behaviour, inconsolable crying, frightened facial expression, sleep disturbance, loss of consciousness, paraesthesia, or intermittent visual symptoms were described during controlled and uncontrolled withdrawal or insufficient dosage. INTERPRETATION: PDE or PNPO should be considered in infants with prolonged episodes of mixed multifocal myoclonic tonic symptoms, notably when associated with grimacing and abnormal eye movements.

Status epilepticus in children with Alpers' disease caused by POLG1 mutations: EEG and MRI features.

PURPOSE: Refractory convulsive status epilepticus in infancy and childhood is a rare emergency situation. Metabolic disorders frequently underlie this condition, in particular Alpers' disease caused by POLG1 mutations. Status epilepticus may be the first symptom. A pathognomonic electroencephalography (EEG) signature may facilitate diagnosis of Alpers' disease and allow timely avoidance of valproic acid, which is contraindicated in this disorder because it may trigger fatal liver failure. PATIENTS: We present five patients with Alpers' disease caused by mutations in POLG1. Age of onset ranged from 7 months to 10 years. Three of the five children died after 3 to 12 months after onset of status epilepticus. Two of these had liver failure associated with use of valproic acid; liver transplantation in one child did not prevent a fatal neurologic outcome. RESULTS: Convulsive status epilepticus was the first obvious sign of Alpers' disease in all children. All had focal clonic and complex-focal seizures; four of them developed epilepsia partialis continua. In four children, initial EEG showed unilateral occipital rhythmic high-amplitude delta with superimposed (poly)spikes (RHADS). Magnetic resonance imaging (MRI) revealed cortical and thalamic involvement in all, although there were only discrete abnormalities in one child. Metabolic investigations remained normal in three children. CONCLUSION: Alpers' disease is an important differential diagnosis in childhood refractory convulsive status epilepticus. Its EEG hallmark of RHADS is important for timely diagnosis, management, and counseling.

The role of recessive inheritance in early-onset epileptic encephalopathies: a combined whole-exome sequencing and copy number study.

Early-onset epileptic encephalopathy (EE) and combined developmental and epileptic encephalopathies (DEE) are clinically and genetically heterogeneous severely devastating conditions. Recent studies emphasized de novo variants as major underlying cause suggesting a generally low-recurrence risk. In order to better understand the full genetic landscape of EE and DEE, we performed high-resolution chromosomal microarray analysis in combination with whole-exome sequencing in 63 deeply phenotyped independent patients. After bioinformatic filtering for rare variants, diagnostic yield was improved for recessive disorders by manual data curation as well as molecular modeling of missense variants and untargeted plasma-metabolomics in selected patients. In total, we yielded a diagnosis in ∼42% of cases with causative copy number variants in 6 patients (∼10%) and causative sequence variants in 16 established disease genes in 20 patients (∼32%), including compound heterozygosity for causative sequence and copy number variants in one patient. In total, 38% of diagnosed cases were caused by recessive genes, of which two cases escaped automatic calling due to one allele occurring de novo. Notably, we found the recessive gene SPATA5 causative in as much as 3% of our cohort, indicating that it may have been underdiagnosed in previous studies. We further support candidacy for neurodevelopmental disorders of four previously described genes (PIK3AP1, GTF3C3, UFC1, and WRAP53), three of which also followed a recessive inheritance pattern. Our results therefore confirm the importance of de novo causative gene variants in EE/DEE, but additionally illustrate the major role of mostly compound heterozygous or hemizygous recessive inheritance and consequently high-recurrence risk.

Electroencephalographic evolution of hypsarrhythmia: toward an early treatment option.

PURPOSE: A retrospective study for a classification of prehypsarrhythmic elecroencephalographies (EEGs) was carried out to enable an early treatment option for West syndrome. METHODS: Out of 39 infants with symptomatic West syndrome, 18 infants (age 3-14 months) with 61 serial non-REM sleep EEG records of the prehypsarrhythmic phase were identified. The prehypsarrhythmic phase encompassed 2 to 13 months (mean 4.5 months) after an initial insult. A classification system of three EEG types corresponding to the clinical states prior to West syndrome occurrence was developed. In addition, follow-up of all patients presenting with type 2 EEGs (n = 22) was evaluated. RESULTS: Three clinical states and corresponding EEG types were classified. Clinical state 1 (weeks to months, silent phase) presented with (multi-)focal epileptic discharges <50% of the non-REM EEG recording time (type 1 EEG). Clinical state 2 (several weeks, beginning mental deterioration) was accompanied by type 2 EEG with bihemispheric epileptic discharges >50% of the non-REM EEG recording time within abnormal background activity (imminent hypsarrhythmia). Clinical state 3 (mental deterioration) was characterized by hypsarryhthmia. Interrater reliability of seven blinded raters was good (median weighted kappa 0.67). Out of 22 patients presenting with type 2 EEGs, two were lost for follow-up, and 16 developed West syndrome, whereas four were treated early with anti-epileptic drugs and remained stable. CONCLUSIONS: Infants with West syndrome could be reliably identified several weeks before the occurrence of hypsarrhythmia by a typical EEG pattern (type 2), thereby opening the way for early intervention studies.

famoses: a modular educational program for children with epilepsy and their parents.

BACKGROUND: It is known that most adult patients with epilepsy often have poor knowledge of their disorder, treatment options, and social and vocational consequences, despite the huge amount of information available. Being pressed for time, health care professionals often are not able to provide the repetitive counseling and instruction necessary to address epilepsy care adequately. Therefore educational programs are considered extremely important in filling the gap. METHOD: For German-speaking countries, two educational programs called famoses, modulares Schulungsprogramm Epilepsie fur Familien [modular service package epilepsy for families], were developed by a multidisciplinary group of neuropediatricians, psychologists, social workers, and educators. The aims of the famoses programs are to improve children's and parents' knowledge about epilepsy and to help patients of childhood age and their parents achieve a better understanding of their disease, gain more self-confidence, and reduce specific fears regarding epilepsy. famoses comprises two different educational programs: famoses for kids with epilepsy within the developmental period of ages 7 to 13, and famoses for parents or caretakers. The programs are designed for interactive small-group education. RESULTS: The child-centered educational program is based on a fictional story: The children are sailors on a virtual cruise, sailing from island to island, accompanied by educated trainers. On each island there is something new to discover about epilepsy. The parent (and caretaker)-centered educational program covers different topics-overview and content of the program, basic knowledge, diagnostics, therapy, prognosis and development, and living with epilepsy-within six modules. The program was implemented in Germany and Switzerland in the spring of 2005 and is now operating in different epilepsy centers. CONCLUSION: Within comprehensive therapeutic management of epilepsy, educational programs for patients, and for parents (caretakers) of children with epilepsy, are considered to be extremely important. Such educational programs have two main goals: to increase knowledge about the disorder, and to strengthen the patients' responsibility for themselves, with the consequence of living with as few limitations as possible. famoses is an effective component of this comprehensive care. The program has been operating successfully in different epilepsy centers in Germany and Switzerland since the spring of 2005.

Neonatal seizures with tonic clonic sequences and poor developmental outcome.

Seizures consisting of a tonic followed by a clonic phase have rarely been described in neonates and are not included in the current classifications of neonatal seizures. Our video archive of 105 neonates with seizures or suspected seizures revealed six neonates with such tonic clonic or tonic myoclonic sequences. Two of those neonates had pyridoxine dependent seizures. The other four neonates had drug refractory seizures and demonstrated similarities in electro-clinical pattern, clinical course and outcome. Their seizures started with tonic posturing and after 10-20s tonic posturing was superimposed by focal or multifocal cloni or myocloni. Ictal EEG started with voltage attenuation followed by bilateral or alternating focal epileptic discharges. The interictal EEG was abnormal. One child died, while the other three children became seizure free but had severe motor delay and mental retardation. In one of those three children, a de novo missense mutation was detected in the voltage gated potassium channel gene KCNQ2, indicating a genetic relationship between drug refractory neonatal seizures of unknown etiology with tonic clonic or myoclonic sequences and the well-known syndrome of benign familial neonatal convulsions (BFNC).

Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes.

Idiopathic focal epilepsy (IFE) with rolandic spikes is the most common childhood epilepsy, comprising a phenotypic spectrum from rolandic epilepsy (also benign epilepsy with centrotemporal spikes, BECTS) to atypical benign partial epilepsy (ABPE), Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike and waves during slow-wave sleep (CSWS). The genetic basis is largely unknown. We detected new heterozygous mutations in GRIN2A in 27 of 359 affected individuals from 2 independent cohorts with IFE (7.5%; P = 4.83 × 10(-18), Fisher's exact test). Mutations occurred significantly more frequently in the more severe phenotypes, with mutation detection rates ranging from 12/245 (4.9%) in individuals with BECTS to 9/51 (17.6%) in individuals with CSWS (P = 0.009, Cochran-Armitage test for trend). In addition, exon-disrupting microdeletions were found in 3 of 286 individuals (1.0%; P = 0.004, Fisher's exact test). These results establish alterations of the gene encoding the NMDA receptor NR2A subunit as a major genetic risk factor for IFE.

Neonatal seizures: eyes open or closed?

PURPOSE: It has been shown that persistent eye closure during paroxysmal events in infants makes seizures unlikely. Our study aims to assess whether this is also true in neonates. METHODS: We reviewed and classified all archived neonatal seizures in our video database, considering electroclinical seizures only and excluding electrographic seizures and clinical seizures without ictal change in EEG. We assessed whether eyes were open during the seizure. One hundred and thirty-one electroclinical seizures (clonic, focal and generalized tonic, tonic-clonic, generalized myoclonic, subtle and spasms) in 46 neonates were included. RESULTS: In 115 (88%) seizures, eyes were open; in 10 seizures, they were closed; and in six seizures, eye opening could not be evaluated. All 10 seizures with persistent eye closure were clonic seizures. CONCLUSIONS: Our data demonstrate that persistent eye closure during an event suggestive of a seizure in a newborn makes an electroclinical seizure unlikely.

Proven startle-provoked epileptic seizures in childhood: semiologic and electrophysiologic variability.

PURPOSE: To delineate further the clinical and electrophysiologic features of proven startle-provoked epileptic seizures (SPESs) in children. METHODS: Clinical, neuroradiologic, and neurophysiologic data of 22 consecutive patients with SPESs were analyzed. Eighty-nine SPESs were documented by video-EEG and evaluated with respect to semiology and ictal and interictal EEG findings. RESULTS: Mean age was 68 months (10-178 months). Most children had severe mental retardation (86%). Neuroimaging demonstrated diffuse cerebral abnormalities in 15 of 19. Somatosensory evoked potentials revealed cortical abnormalities in 10 of 13 children. The underlying causes were heterogeneous. Only two patients were normally developed. Seizure frequency was usually high (>10/day). Two children had less frequent SPESs (two per month; two per week). Seizures were easily precipitated by sudden sound (n=15), unexpected touch (n=3), or both (n=4). The most common semiologic findings (50%) were generalized tonic seizures or those characterized by a predominant tonic phase, followed in frequency by myoclonic seizures (36%), which were generalized in seven, and unilateral in one. Generalized clonic seizures were observed in one. A complex seizure spread was documented in two children. The most common ictal EEG finding (60%) was a diffuse electrodecremental pattern (DEP). Generalized spike/polyspike waves were found in five and focal discharges in four. CONCLUSIONS: Our results imply that startle epilepsy is not a uniform epileptic entity. We were able to demonstrate a number of distinct patterns of SPESs, characterized by clinical, semiologic, and electrophysiologic features. Considering the high diversity of SPES patients, a common underlying pathophysiologic mechanism seems unlikely.