Epilepsy Due to Mild TBI in Children: An Experience at a Tertiary Referral Center.

RATIONALE: Posttraumatic epilepsy (PTE) is a common cause of morbidity in children after a traumatic brain injury (TBI), occurring in 10-20% of children following severe TBI. PTE is diagnosed after two or more unprovoked seizures occurring 1-week post TBI. More often, studies have focused on children with epilepsy due to severe TBI. We aim to understand the utility of head computed tomography (HCT), EEG, and the risk of developing drug-resistant epilepsy in children after mild TBI. METHOD: We retrospectively studied 321 children with TBI at a tertiary pediatric referral center during a 10-year period. Mild TBI was defined as loss of consciousness (LOC) or amnesia < 30 min, moderate TBI as LOC or amnesia between 30 min and 1 day, and severe TBI as LOC or amnesia > 1 day, subdural hemorrhage, or contusion. Multiple clinical variables were reviewed, including past and present antiepileptic drug(s), seizure control, and mode of injury. First and subsequent post-TBI EEGs/prolonged video-EEGs were obtained acutely, subacutely, and/or chronically (range, day 1-3 years, median 1 month). Descriptive analyses were conducted using medians and ranges for continuous data. Categorical data were reported using frequencies and percentages, while comparisons between groups were made using Fisher's exact test for small sample sizes. RESULTS: Forty-seven children were diagnosed with posttraumatic epilepsy: eight children (17%) due to mild TBI, 39 children (83%) due to severe TBI. For the eight children with mild TBI whom all had an accidental trauma (non-inflicted), the median follow-up time was 25 months (range 1.5 months-84 months). The median age was 10 years (range 4-18 years), and the median age at the time of injury was seven years (range: 23 months-13 years). No relevant previous medical history was present for six patients (80%), and two patients' (20%) relevant previous medical histories were unknown. Seven patients (88%) had no history of seizures, and patient #6 (12%) had unknown seizure history. Six patients (75%) had normal routine EEG(s). Patient #6 (13%) had an abnormal VEEG 3 months after the initial normal routine EEG, while patient #1 (13%) had an initial prolonged EEG 8 months after TBI. Compared to the 39 patients with severe TBI, 31 (79%) of whom had abnormal EEGs (routine and/or prolonged with video), mild TBI patients were more likely to have normal EEGs, p = 0.005. Head CT scans were obtained acutely for seven patients (90%), all of which were normal. One patient only had brain magnetic resonance imaging (MRI) 8 months after the injury. Compared to the 39 patients with severe TBI, all of whom had abnormal HCTs, mild TBI patients were less likely to have abnormal HCTs, p < 0.0001. In patients with mild TBI, no patient had both abnormal EEG/VEEG and HCT, and no one was on more than one Antiepileptic drug (AED), p < 0.005. Six patients (75%) had MRIs, of which five (63%) were normal. Two patients (#1, 7) did not have MRIs, while one patient's (#4) MRI was unavailable. Five patients (63%) had a seizure <24 h post TBI, while the rest had seizures after the first week of injury. CONCLUSION: Children with epilepsy due to mild TBI, loss of consciousness, or amnesia < 30 min are more likely to have normal HCT and EEG and to be on 0-1 AED. Limitations of our study include the small sample size and retrospective design. The current findings add to the paucity of data in children who suffer from epilepsy due to mild TBI.

Management of Infantile Spasms During the COVID-19 Pandemic.

Circumstances of the COVID-19 pandemic have mandated a change to standard management of infantile spasms. On April 6, 2020, the Child Neurology Society issued an online statement of immediate recommendations to streamline diagnosis and treatment of infantile spasms with utilization of telemedicine, outpatient studies, and selection of first-line oral therapies as initial treatment. The rationale for the recommendations and specific guidance including follow-up assessment are provided in this manuscript. These recommendations are indicated as enduring if intended to outlast the pandemic, and limited if intended only for the pandemic health care crisis but may be applicable to future disruptions of health care delivery.

Stereo-EEG in Tuberous Sclerosis Complex.

A collaborative research team lead by an investigator from the Lyon Neuroscience Research Center and Lyon University Hospital and Lyon 1 University studied epileptogenicity of tuber and its surrounding cortex using stereoelectroencephalography (SEEG) in patients diagnosed with tuberous sclerosis complex (TSC) (genetic or clinical).

Focal EEG abnormalities and focal ictal semiology in generalized epilepsy.

In clinical practice, the diagnosis of focal vs generalized epilepsy dictates the management of the patient. The distinction between generalized and focal epilepsy is at times imperfect and some epilepsies have features that fall in between these two extremes. An example is the occurrence of focal interictal and focal ictal abnormalities in generalized epilepsies. As a part of the special issue on "The epileptogenic zone in pediatric epilepsy surgery", this focused narrative review will discuss different focal abnormalities seen in generalized epilepsy. An overlap of focal and generalized epileptiform abnormalities may support a continuum between focal and generalized epilepsy. When evaluating patients in the "gray zone", other factors such as ictal semiology, neuroimaging, genetic testing and functional deficits may need to be considered to reach an accurate diagnosis. Being aware of possible occurrence of focal clinical and EEG features in generalized epilepsy will help clinicians select more preferred AED (s), avoiding potential iatrogenic side effects and inappropriate consideration for epilepsy surgery.

Epileptic seizure semiology in infants and children.

Epileptic seizure semiology adds important information to the formulation of the hypothesis of the epileptogenic zone. Seizure semiology in infants and children are simple and elementary, becoming more complex with maturation of brain. Also in this age group, seizure semiology may be generalized in a setting of a focal lesion or may show focal signs with misleading localization values. We review seizure semiology of patients aged one month to ten years with respect to lateralization and localization of the epileptogenic zone.

Hippocampal transection for stereo-electroencephalography-proven dominant mesial temporal lobe epilepsy in a child: a detailed case report and critical review.

Resection of the hippocampus ipsilateral to the verbal memory-dominant hemisphere frequently results in severe memory deficits. In adults with epilepsy, multiple hippocampal transections (MHTs) have resulted in excellent seizure outcome with preservation of verbal memory. The authors report the first detailed case of a child undergoing MHTs for mesial temporal lobe epilepsy. A 13-year-old right-handed boy had intractable seizures characterized by epigastric discomfort evolving to unresponsiveness and chewing automatisms, lasting 1 minute and occurring 2-3 times weekly, sometimes ending in a generalized tonic-clonic seizure. He had no seizure risk factors and nonfocal examination results. Interictal electroencephalography (EEG) showed frequent left temporal epileptiform discharges (maximum FT9) and intermittent slowing. Video EEG, FDG-PET, and 1.5-T MRI were nonlocalizing. Neuropsychological evaluation suggested left temporal lobe dysfunction. A stereo-EEG investigation using 8 electrodes localized the seizure onset zone to the anterior mesial temporal region, immediately involving the hippocampus. The temporal pole and amygdala were resected en bloc with 3 MHTs. Comparison of neuropsychological tests 4 months before and 6 months after the surgery showed a significant decline only in confrontational naming and no significant change in verbal memory. Six and a half years later, the patient remains seizure free with no antiepileptic drugs. In children with established hemispheric dominance suffering from mesial temporal lobe epilepsy, MHTs may be an option.

Epileptic seizure semiology in different age groups.

Seizure semiology provides information about the eloquent cortex involved during a seizure and helps to generate a hypothesis regarding the localization of the epileptogenic zone (EZ), a prerequisite for surgical management of epilepsy. We aimed to study the seizure semiology among all different age groups to better characterize semiological changes that occur with age. We performed a retrospective review of video-EEG data in paediatric and adult patients admitted to the Epilepsy Monitoring Unit over a three-year period. Authors independently reviewed and classified the seizure semiology while blinded to clinical, EEG, and neuroimaging data. A total of 270 patients were included in the study. The most frequent EZ in patients who were one month to three years old was undetermined. Focal epilepsy became more frequent in patients older than 10 years. Among patients with focal epilepsy, a posterior quadrant EZ was most frequent in children younger than three years old, a temporal EZ between three and six years old, and a frontal EZ between six and 10 years old. The temporal lobe was the most frequent location for focal EZ in patients older than 18 years. Auras, automotor seizures, and generalized tonic-clonic seizures were extremely infrequent in patients younger than 10 years old. The youngest patient with auras was 5.7 years old. The youngest patient with automotor seizures was 3.7 years old. We identified only three patients with generalized tonic-clonic seizures who were younger than 10 years (aged six months, 6.6 years, and nine years, respectively). Patients younger than three years exhibited mostly generalized simple motor seizures and hypomotor seizures. Generalized epileptic spasms, generalized tonic seizures, and generalized clonic seizures were infrequent in patients older than 10 years. Seizure semiology and electroencephalographic changes most likely reflect the maturation of cortical functions.

Clinical and Electroencephalographic Correlates in Pediatric Cardiac Arrest: Experience at a Tertiary Care Center.

Pediatric cardiac arrest is a significant cause of death and neurologic disability; however, there is a paucity of literature specifically evaluating the utility of prognostic factors in the pediatric population. This retrospective chart review examines clinical, laboratory, and electroencephalographic (EEG) data in children following cardiopulmonary arrest to better characterize findings that may inform prognosis. Pre-arrest clinical characteristics, resuscitation details, and post-arrest hospital course variables were analyzed and neurologic outcome was determined using the Pediatric Cerebral Performance Category scale. Forty-one patients were identified who had cardiac arrest from March, 2011 to January, 2015. Duration of cardiopulmonary resuscitation (p = 0.013), out-of-hospital arrest (p = 0.005), arterial pH (0.014), arterial lactate (0.004), lack of pupil reactivity to light (p < 0.001), absent motor response to noxious stimuli (p < 0.001), and absent brainstem reflexes (p < 0.001) were all predictors of poor neurologic outcome. EEG background suppression (p = 0.005) was associated with poor outcome. Nine patients had electrographically recorded seizures, which began up to 1 week following cardiac arrest. Two patients (4.9%) experienced post-anoxic myoclonic status epilepticus and both had a poor outcome.

Noninvasive Presurgical Data for One-Stage Leucotomy in Catastrophic Epilepsy.

BACKGROUND: Catastrophic epilepsy results in severe neurodevelopmental delay in infants because of frequent and/or long seizures. Therefore, consideration of early epilepsy surgery is essential for neurodevelopmental outcome. Once an infant with catastrophic seizures is identified as a surgical candidate, it is important that the surgical plan be carefully defined based on detailed presurgical evidence to minimize surgical complications in this age group. CASE DESCRIPTION: We present 2 infants with catastrophic epilepsy, epileptic spasms, and bihemispheric electroencephalographic abnormalities who underwent one-stage disconnection surgery based on a sound hypothesis of the epileptogenic zone. Each patient underwent an extensive noninvasive presurgical investigation followed by stereotactic disconnection leucotomy in a single stage. After the 2 children were followed for 24-36 months. A seizure reduction by at least 90% (Engel class I) was achieved in both cases with subsequent improvement in neurodevelopmental progress. There were no perioperative complications. Both patients had widespread cortical dysplasia on pathologic evaluation. CONCLUSIONS: Careful consideration of the noninvasive presurgical workup can identify focal onset even in the presence of catastrophic epilepsy with widespread bilateral abnormalities. Single-stage lobar leucotomy for disconnection of the epileptogenic zone can lead to excellent outcome in these patients.

Utility of Stereoelectroencephalography in Children with Dysembryoplastic Neuroepithelial Tumor and Cortical Malformation.

BACKGROUND: Uncontrolled seizures in children can contribute to irreversible cognitive impairment and developmental delay, in addition to placing them at risk for sudden unexplained death in epileptic patients (SUDEP). Since its introduction at Saint Ann Hospital in Paris in the 1960s, stereoelectroencephalography (SEEG) is increasingly being utilized at epilepsy centers in the United States as an invasive tool to help localize the seizure focus in drug-resistant focal epilepsy. INDICATIONS: Children with symptomatic epilepsy, commonly due to cortical dysplasia and dysembryoplastic neuroepithelial tumor (DNET), may benefit from SEEG investigation. The arrangement of SEEG electrodes is individually tailored based on the suspected location of the epileptogenic zone (EZ). The implanted depth electrodes are used to electrically stimulate the corresponding cortices to obtain information about the topography of eloquent cortex and EZ. Morbidity: Surgical morbidity in these children undergoing SEEG investigation is low, but not negligible. The number of electrodes directly correlates with the risk of intraoperative complication. Thus a risk and benefit analysis needs to be carefully considered for each patient. Neurodiagnostic technology: Both during and after the SEEG electrode implantation, the intraoperative monitoring and EEG technologists play a vital role in the successful monitoring of the patient. CONCLUSION: SEEG is an important tool in the process of epilepsy surgery in children with symptomatic epilepsy, commonly due to cortical dysplasia and DNET.

Epileptic spasms in paediatric post-traumatic epilepsy at a tertiary referral centre.

To recognize epileptic spasms (ES) as a seizure type after traumatic brain injury (TBI), accidental or non-accidental, in infants and children. In the process, we aim to gain some insight into the mechanisms of epileptogenesis in ES. A retrospective electronic chart review was performed at the Children's Hospital of Michigan from 2002 to 2012. Electronic charts of 321 patients were reviewed for evidence of post-traumatic epilepsy. Various clinical variables were collected including age at TBI, mechanism of trauma, severity of brain injury, electroencephalography/neuroimaging data, and seizure semiology. Six (12.8%) of the 47 patients diagnosed with post-traumatic epilepsy (PTE) had ES. Epileptic spasms occurred between two months to two years after TBI. All patients with ES had multiple irritative zones, manifesting as multifocal epileptiform discharges, unilateral or bilateral. Cognitive delay and epileptic encephalopathy were seen in all six patients, five of whom were free of spasms after treatment with vigabatrin or adrenocorticotropic hormone. The risk of PTE is 47/321(14.6%) and the specific risk of ES after TBI is 6/321 (1.8%). The risk of ES appears to be high if the age at which severe TBI occurred was during infancy. Non-accidental head trauma is a risk factor of epileptic spasms. While posttraumatic epilepsy (not ES) may start 10 years after the head injury, ES starts within two years, according to our small cohort. The pathophysiology of ES is unknown, however, our data support a combination of previously proposed models in which the primary dysfunction is a focal or diffuse cortical abnormality, coupled with its abnormal interaction with the subcortical structures and brainstem at a critical maturation stage.

Tailored disconnection based on presurgical evidence in catastrophic epilepsy: report of 2 cases.

Catastrophic epilepsy in infants, often due to extensive cortical dysplasia, has devastating consequences with respect to brain development. Conventional lobar, multilobar, or hemispheric resection in these infants is challenging, carrying an increased operative risk compared with that in older children. Removing a larger tissue volume versus removing or disconnecting the epileptogenic region does not always guarantee better seizure outcome. The authors describe 2 infants with catastrophic epilepsy who benefited from individually tailored disconnections based on a hypothesized epileptogenic zone following intensive presurgical evaluation. Two infants with catastrophic epilepsy and epileptic spasms underwent leukotomies between 3 and 12 months of age. They were followed up postoperatively for 19-36 months. Both patients had 90%-100% seizure reduction and a significantly improved neurodevelopmental outcome without postoperative complication. Cortical malformation was seen in both patients. Modifications of established surgical disconnection techniques, tailored to each patient's specific epileptogenic zone, optimized seizure and neurodevelopmental outcomes while minimizing the risks associated with more extensive resections.

Common pediatric epilepsy syndromes.

Benign rolandic epilepsy (BRE), childhood idiopathic occipital epilepsy (CIOE), childhood absence epilepsy (CAE), and juvenile myoclonic epilepsy (JME) are some of the common epilepsy syndromes in the pediatric age group. Among the four, BRE is the most commonly encountered. BRE remits by age 16 years with many children requiring no treatment. Seizures in CAE also remit at the rate of approximately 80%; whereas, JME is considered a lifelong condition even with the use of antiepileptic drugs (AEDs). Neonates and infants may also present with seizures that are self-limited with no associated psychomotor disturbances. Benign familial neonatal convulsions caused by a channelopathy, and inherited in an autosomal dominant manner, have a favorable outcome with spontaneous resolution. Benign idiopathic neonatal seizures, also referred to as "fifth-day fits," are an example of another epilepsy syndrome in infants that carries a good prognosis. BRE, CIOE, benign familial neonatal convulsions, benign idiopathic neonatal seizures, and benign myoclonic epilepsy in infancy are characterized as "benign" idiopathic age-related epilepsies as they have favorable implications, no structural brain abnormality, are sensitive to AEDs, have a high remission rate, and have no associated psychomotor disturbances. However, sometimes selected patients may have associated comorbidities such as cognitive and language delay for which the term "benign" may not be appropriate.

Post-traumatic epilepsy in children-experience from a tertiary referral center.

BACKGROUND: Post-traumatic epilepsy after a traumatic brain injury occurs in 10%-20% of children. Unfortunately, a biomarker that could provide prognostic information about both post-traumatic epilepsy and cognitive development is lacking. In this first of a series of studies, we have reviewed and analyzed clinical variables in children following traumatic brain injury to understand the epidemiologic and clinical characteristics of post-traumatic epilepsy in our urban population. METHODS: We performed a retrospective electronic chart review of patients who had suffered traumatic brain injury and subsequently evaluated at Children's Hospital of Michigan from 2002 to 2012. Various epidemiologic and clinical variables were analyzed. RESULTS: Patients who had severe traumatic brain injury and post-traumatic epilepsy had an abnormal acute head computed tomography. These patients had increased number of different seizure types, increased risk of intractability of epilepsy, and were on multiple antiepileptic drugs. Hypomotor seizure was the most common seizure type in these patients. There was a high prevalence of patients who suffered nonaccidental trauma, all of whom had severe traumatic brain injury. CONCLUSIONS: This study demonstrates a need for biomarkers in children following traumatic brain injury to reliably evaluate the risk of post-traumatic epilepsy.

Treatment of Focal Status Epilepticus plus Epileptic Spasms with Leukotomy in an Infant with TSC 1 Mutation: A Case Study.

BACKGROUND: Focal status epilepticus and catastrophic epilepsy are not rare in infants. Epilepsy surgery can be safely done in selected infants to cure epilepsy. PATIENT DESCRIPTION: We report on an infant who began having drug-resistant status epilepticus at 2 weeks of age and developed epileptic spasms. We discuss in detail how the clinical and electroencephalographic data were used to reach a consensus for epilepsy surgery and why a particular surgical approach was preferred over other alternatives. METHOD: Presurgical evaluation consisted of 32-channel scalp video EEG using the standard 10-20 system of electrodes, 3-Tesla brain magnetic resonance imaging, and 18 F-fluorodeoxyglucose positron emission tomography. The surgery consisted of resection of the extensive epileptogenic lesion, in addition to disconnection of the left frontal lobe anterior to the motor strip. RESULT: The infant underwent epilepsy surgery at three months of age. At two-year follow up, she remained seizure free, with no focal motor deficit and the epileptic encephalopathy resolved. The disconnected left frontal lobe shows epileptiform discharges restricted to the disconnected tissue. CONCLUSION: We highlight the importance of epilepsy surgery in selected infants to achieve seizure freedom and to reverse epileptic encephalopathy. In the process, we demonstrate how epileptic spasms, although clinically and electrographically generalized, resolved after disconnecting the epileptogenic zone.

Industry and regulatory experience of the glycosylation of monoclonal antibodies.

We surveyed 23 antibody-related marketing applications for glycoform analytical and functional information. Our database analysis shows a clear trend of increasing sophistication of analytical methods used to identify and quantify glycans. These have revealed a high degree of complexity and heterogeneity of glycans attached to antibody products. The nature of the complexity is influenced by product type and expression system, and may be associated with functional consequences in some but not all cases.

Rapid optimization of antibotulinum toxin antibody fragment production by an integral approach utilizing RC-SELDI mass spectrometry and statistical design.

A process for the rapid development and optimization of the fermentation process for an antibotulinum neurotoxin antibody fragment (bt-Fab) production expressed in Escherichia coli was achieved via a high-throughput process proteomics and statistical experimental design. This process, using retentate chromatography-surface enhanced laser desorption/ionization mass spectrometry (RC-SELDI MS), was employed for identifying and quantifying bt-Fab antibody in complex biological samples for the optimization of microbial fermentation conditions. Five variables (type of culture media, glycerol concentration, post-induction temperature, IPTG concentration, and incubation time after induction) were statistically combined using an experimental 2(5)(-1) fractional factorial design and tested for their effects on maximal bt-Fab antibody production. When the effects of individual variables and their interactions were assessed, type of media and post-induction temperature showed statistically significant increase in yield of the fermentation process for the maximal bt-Fab antibody production. This study establishes an integral approach as a valuable tool for the rapid development of manufacturing processes for producing various biological materials. To verify the RC-SELDI MS method, a Fab-specific immuno-affinity HPLC assay developed here was also employed for the quantification of the bt-Fab antibody in crude lysate samples obtained during the fermentation optimization process. Similar results were obtained.