Intractable Seizures Research Articles

CSNK2B: A broad spectrum of neurodevelopmental disability and epilepsy severity.

CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.

Relationships among illness representations and depressive symptom severity in predominantly African-American and Caribbean-American people with epilepsy

Objective: Depression is the most common psychiatric comorbidity among people with epilepsy (PWE) and tends to be more prevalent among people of color (POC) and those with intractable seizures. However, the extent to which illness-related perceptions are associated with depressive symptom severity among POC with intractable seizures is unclear. Method: This cross-sectional study examined relationships among illness representations and self-rated depressive symptoms in 55 PWE (M Age = 41; 61.8% female) with intractable seizures (M seizures per month = 2) who identified as Black/African-American (52.7%), Black/Caribbean-American (27.3%), and/or Hispanic/Latino (21.8%). Epilepsy-related illness perceptions were assessed with the Illness Perception Questionnaire-Revised and depression was measured via the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). Results: Nearly half of the sample (41.8%) scored above the NDDI-E depression cut-off. PWE endorsing more severe depressive symptoms indicated that their epilepsy had more negative consequences, was hard to comprehend, was insufficiently controlled by treatment, and had a negative emotional impact (p’s ≤ 0.02). Controlling for sex, these four illness representations accounted for 48% of the variance in depression severity. Interestingly, participants with probable major depressive episodes were more likely to endorse several psychological causes of seizures compared to non-depressed PWE. Conclusions: Worse depression symptom severity was associated with negative illness perceptions and a tendency to attribute one’s epilepsy to psychological causes. Future research is needed to understand how the relationship between negative illness perceptions and depression symptoms unfold over time and whether interventions aimed at modifying illness representations reduce psychological distress in diverse PWE.

Effective treatments for FGF12-related early-onset epileptic encephalopathies patients

BackgroundFGF12 (FHF1) gene encodes voltage-gated sodium channel (Nav)-binding protein fibroblast growth factor homologous factor 1, which could cause seizures by regulating voltage dependence of Nav fast inactivation and neuron excitability. The most common pathogenic variant FGF12 c.341G > A related early-onset epileptic encephalopathies (EOEE) was characterized by intractable seizures and developmental disabilities. ResultsUsing whole exome sequencing, a de novo hotspot variant c.341G > A (NM_021032.4) of FGF12 was identified in three unrelated EOEE probands. All probands were seizure free after a combination treatment of valproic acid (VPA) and topiramate (TPM). The motor and cognitive skills in two probands were improved due to the early and effective treatment. In order to compare the effectiveness of different treatment strategies for the disease, a review of treatments for FGF12-related epilepsy was made. ConclusionWe reported three FGF12 c.341G > A related EOEE patients responded well to a combination antiepileptic therapy of VPA and TPM. The current study is the first to describe the combination therapy of VPA and TPM in FGF12 c.341G > A related EOEE patients. This study may contribute to future medication consultation for intractable epilepsy with FGF12 hotspot variants.

Migrating Focal Seizures and Myoclonic Status in ARV1-Related Encephalopathy.

ObjectiveTo report longitudinal clinical, EEG, and MRI findings in 2 sisters carrying compound heterozygous ARV1 mutations and exhibiting a peculiar form of developmental and epileptic encephalopathy (DEE). Neuropathologic features are also described in one of the sisters.MethodsClinical course description, video-EEG polygraphic recordings, brain MRI, skin and muscle biopsies, whole-exome sequencing (WES), and brain neuropathology.ResultsSince their first months of life, both girls exhibited severe axial hypotonia, visual inattention, dyskinetic movements, severe developmental delay, and slow background EEG activity. Intractable nonmotor seizures started in both at the eighth month of life, exhibiting the electroclinical characteristics of epilepsy of infancy with migrating focal seizures (EIMFS). In the second year of life, continuous epileptiform EEG activity of extremely high amplitude appeared in association with myoclonic status, leading to severely impaired alertness and responsiveness. Repeated brain MRI revealed progressive atrophic changes and severe hypomyelination. WES identified a compound heterozygous in the ARV1 gene [(p.Ser122Glnfs*7) and (p.Trp163*)] in one patient and was subsequently confirmed in the other. Both sisters died prematurely during respiratory infections. Postmortem neuropathologic examination of the brain, performed in one, revealed atrophic brain changes, mainly involving the cerebellum.ConclusionsThis report confirms that biallelic ARV1 mutations cause a severe form of DEE and adds epilepsy with migrating focal seizures and myoclonic status to the spectrum of epilepsy phenotypes. Considering the potential role of human ARV1 in glycosylphosphatidylinositol (GPI) anchor biosynthesis, this severe syndrome can be assigned to the group of inherited GPI deficiency disorders, with which it shares remarkably similar clinical and neuroimaging features. ARV1 should be considered in the genetic screening of individuals with EIMFS.

Teaching NeuroImage: CAR-T-Induced Nonconvulsive Status Epilepticus.

A 79-year-old woman receiving chimeric antigen receptor T-cell (CAR-T) therapy for high-grade lymphoplasmacytic lymphoma developed worsening confusion over 3 days. She became nonverbal and unable to follow commands. MRI of the brain demonstrated global atrophy. EEG showed 2.5- to 3-Hz generalized spike and slow complexes, indicative of nonconvulsive status epilepticus (NCSE), which resolved with the administration of lorazepam (figure). IV levetiracetam load was administered for maintenance therapy. The patient was able to answer simple questions the next morning and returned to baseline 3 days later with optimization of antiseizure medications. CAR-T–induced neurotoxicity can present with multiple neurologic manifestations including sometimes intractable seizures.1 It is imperative to consider CAR-T–induced NCSE as a complication that is potentially reversible.2

Endoscopic endonasal repair of a temporal lobe meningoencephalocele in the pterygoid fossa: A case report and literature review

IntroductionMeningoceles are defined as herniation of the meninges through a skull base defect. If brain tissue is herniated as well, then it is called meningoencephalocele. The most common locations of meningoceles are the cribriform plate and the lateral recess of the sphenoid sinus, with the most common presentation being CSF leakage. We present a case of temporal lobe meningocele that herniated through a defect in the greater wing of the sphenoid bone to the pterygoid fossa and that was diagnosed incidentally while evaluating the patient for seizures.MethodologyCase report and literature review.ConclusionThe endonasal endoscopic approach is a suitable minimally invasive approach for the management of pterygoid fossa lesions, including meningoceles. In this case, the patient had epilepsy with the surgery resulting in the resolution of the seizures.

Epilepsy in patients with focal cortical dysplasia may be associated with autism spectrum disorder

Introduction.Patients with epilepsy associated with focal cortical dysplasia (FCD) may be associated with autism spectrum disorder (ASD). Therefore, the purpose of this study was to compare surgically treated patients with epilepsy secondary to FCD and normal volunteers without epilepsy and to review the neuropathological findings of patients with FCD. MethodsThis study involved 38 patients with medically intractable focal onset epileptic seizures who underwent epilepsy surgery (Group 1). All patients had epilepsy associated with FCD. These patients and 38 normal volunteers without epilepsy (Group 2) were administered the autism spectrum quotient (AQ) test, and the groups were compared. ResultsThe 38 patients in Group 1 included 16 females and 22 males (age range 20–60, mean age, 33.0; standard deviation (SD), 11.8 years). The normal volunteers in Group 2 included 22 females and 16 males (age range 20–57, mean age, 30.6 years; SD, 8.8 years). Total AQ scores were significantly higher in Group 1 than Group 2 (p = 0.027). Patients with FCD I showed a higher AQ score than those with FCD II in the AQ test (p ≤ 0.001). ConclusionPatients with epilepsy secondary to FCD were associated with higher ASD score than normal volunteers. This tendency was seen more strongly in patients with FCD I than FCD II.

Stimulating Solutions for Intractable Epilepsy.

Implantable devices for controlling medically intractable seizures nondestructively are rapidly advancing. These offer reversible, potentially, restorative options beyond traditional, surgical procedures, which rely, largely on resection or ablation of selected brain sites. Several lines of, investigation aimed at improving efficacy of these devices are discussed, ranging from identifying novel subcortical, white matter, or cell-type specific targets to engineering advances for adaptive techniques based- on continuous, dynamic system analysis.

Clonally Focused Public and Private T Cells in Resected Brain Tissue From Surgeries to Treat Children With Intractable Seizures.

Using a targeted transcriptomics approach, we have analyzed resected brain tissue from a cohort of 53 pediatric epilepsy surgery cases, and have found that there is a spectrum of involvement of both the innate and adaptive immune systems as evidenced by the differential expression of immune-specific genes in the affected brain tissue. The specimens with the highest expression of immune-specific genes were from two Rasmussen encephalitis cases, which is known to be a neuro-immunological disease, but also from tuberous sclerosis complex (TSC), focal cortical dysplasia, and hemimegalencephaly surgery cases. We obtained T cell receptor (TCR) Vβ chain sequence data from brain tissue and blood from patients with the highest levels of T cell transcripts. The clonality indices and the frequency of the top 50 Vβ clonotypes indicated that T cells in the brain were clonally restricted. The top 50 Vβ clonotypes comprised both public and private (patient specific) clonotypes, and the TCR Vβ chain third complementarity region (CDR3) of the most abundant public Vβ clonotype in each brain sample was strikingly similar to a CDR3 that recognizes an immunodominant epitope in either human cytomegalovirus or Epstein Barr virus, or influenza virus A. We found that the frequency of 14 of the top 50 brain Vβ clonotypes from a TSC surgery case had significantly increased in brain tissue removed to control recurrent seizures 11 months after the first surgery. Conversely, we found that the frequency in the blood of 18 of the top 50 brain clonotypes from a second TSC patient, who was seizure free, had significantly decreased 5 months after surgery indicating that T cell clones found in the brain had contracted in the periphery after removal of the brain area associated with seizure activity and inflammation. However, the frequency of a public and a private clonotype significantly increased in the brain after seizures recurred and the patient underwent a second surgery. Combined single cell gene expression and TCR sequencing of brain-infiltrating leukocytes from the second surgery showed that the two clones were CD8 effector T cells, indicating that they are likely to be pathologically relevant.

Awake craniotomy for epilepsy surgery on eloquent speech areas: a single-centre experience.

In patients with intractable partial epilepsy who are eligible for epilepsy surgery, the best seizure control requires complete resection of the epileptogenic zone. When the epileptogenic zone is located very near to, or even with the eloquent cortex, this can be a challenge. In this study, we investigated the efficacy of awake craniotomy techniques to completely resect these epileptic zones while preserving the neural functions. We conducted a retrospective cohort study of 17 consecutive patients with intractable partial seizures of different aetiologies (non-lesional epilepsy [n=3], tuberous sclerosis [n=1], hypoxic ischaemic insult [n=1], dysembryoplastic neuroepithelial tumours [DNET] [n=2], focal cortical dysplasia type 2 [FCD] [n=4], and other malformations of cortical development [n=6]), located in eloquent language cortex (frontal [n=7], insular [n=5], and latero-temporal [n=5] regions). All patients were operated on between 2010 and 2019 for resective epilepsy surgery under awake conditions, with the aid of direct cortical stimulation. This report aimed to study the feasibility, efficacy and limitations of using the awake craniotomy technique for surgical resections of epileptogenic zones involving eloquent language cortex. Postoperative epilepsy control and neurological function were assessed and followed. The mean follow-up period was 5.7 years. In one patient, the surgery was aborted before resection. In the other patients, Engel Class I was achieved in seven patients (43.75%) and Engel Class II in four patients (25%), and worthwhile improvement (Engel Class I and II) was achieved in 11 patients (68.75%). Postoperative neurological deficits were encountered in four patients (23.5%). However, all these deficits were regressive and were absent at the last follow-up visit. Using the awake craniotomy technique, seizure freedom can be achieved in a high proportion of patients with epileptogenic zones located in language areas, who were previously considered only candidates for palliative measures.

EP109 - SETD1B mutation identified in 15-year-old male with neurodevelopmental issues including: intractable seizure disorder, intellectual impairment, and autistic features

eP109 - SETD1B mutation identified in 15-year-old male with neurodevelopmental issues including: intractable seizure disorder, intellectual impairment, and autistic features

Symptomatologic pathomechanism of N-methyl D-aspartate receptor encephalitis.

N-methyl D-aspartate receptor (NMDAR) encephalitis is a well-characterized clinical syndrome. The main molecular mechanism of NMDAR encephalitis is autoantibody-mediated NMDAR hypofunction in the neuronal synapse. Several pathomechanistic hypotheses might explain how NMDAR hypofunction causes the typical symptoms and prognosis of NMDAR encephalitis. Suppression of NMDAR-dependent gamma-aminobutyric acid interneurons provokes an accelerated activation of the positive feedback loops of the dorsolateral prefrontal cortex/subiculum-nucleus accumbens circuit in the striatum, the ventral tegmental area (VTA), and the nucleus reuniens in the thalamus-hippocampus-VTA loop. Dysregulated activation of the VTA and cortex via those positive feedback loops may explain the rapid clinical deterioration at acute stages of the disease and the well-characterized syndrome that includes limbic system dysfunction, intractable seizures, dyskinesia, coma, and the characteristic extreme delta brush. Progressive cerebellar atrophy is correlated with cumulative disease burden and is associated with worse long-term outcomes, which might be explained by the NMDAR-dependent pathways required to maintain neuronal survival. Those pathomechanistic hypotheses for NMDAR encephalitis support the rationale for the early introduction of combination immunotherapy and the use of adjuvant immunotherapy in patients with persisting symptoms in chronic disease phases.

Hemimegalencephaly and intractable seizures associated with the NPRL3 gene variant in a newborn: A case report

Hemimegalencephaly (HME) is a rare hamartomatous congenital malformation of the brain characterized by dysplastic overgrowth of either one of the cerebral hemispheres. HME is associated with early onset seizures, abnormal neurological findings, and with subsequent cognitive and behavioral disabilities. Seizures associated with HME are often refractory to antiepileptic medications. Hemispherectomy is usually necessary to provide effective seizure control. The exact etiology of HME is not fully understood, but involves a disturbance in early brain development and likely involves genes responsible for patterning and symmetry of the brain. We present a female newborn who had refractory seizures due to HME. Whole genome sequencing revealed a novel, likely pathogenic, maternally inherited, 3Kb deletion encompassing exon 5 of the NPRL3 gene (chr16:161898-164745x1). The NPRL3 gene encodes for a nitrogen permease regulator 3-like protein, a subunit of the GATOR complex, which regulates the mTOR signaling pathway. A trial of mTOR inhibitor drug, Sirolimus, did not improve her seizure control. Functional hemispherectomy at 3months of age resulted in total abatement of clinical seizures.

Mood and quality of life in patients treated with brain-responsive neurostimulation: The value of earlier intervention

ObjectiveTo establish whether earlier treatment using direct brain-responsive neurostimulation for medically intractable focal-onset seizures is associated with better mood and Quality of Life (QoL) compared to later treatment intervention. MethodsData were retrospectively analyzed from prospective clinical trials of a direct brain-responsive neurostimulator (RNS® System) for treatment of adults with medically intractable focal-onset epilepsy. Participants completed the Quality of Life in Epilepsy Inventory (QOLIE-31) yearly through 9 years of follow-up and the Beck Depression Inventory-II (BDI-II) through 2 years of follow-up. Changes in each assessment after treatment with responsive neurostimulation were calculated for patients who began treatment within 10 years of seizure onset (early) and those who began treatment 20 years or more after seizure onset (late). ResultsThe median duration of epilepsy was 18.3 years at enrollment. At 9 years, both the early (N = 51) and late (N = 109) treatment groups experienced similar and significant reductions in the frequency of disabling seizures (73.4% and 77.8%, respectively). The early treatment patients had significant improvements in QoL and mood. However, the late treatment patients not only failed to show these improvements but also declined in the emotional QoL subscale. ConclusionsPatients treated with brain-responsive neurostimulation earlier in the course of their epilepsy show significant improvements in multiple domains of QoL and mood that are not observed in patients treated later in the course of their epilepsy despite similar efficacy in seizure reduction. Even with similar and substantial reductions in seizure frequency, the comorbidities of uncontrolled epilepsy may be less responsive to treatment when too many years have passed. The results of this study suggest that, as with resective and ablative surgery, treatment with brain-responsive neurostimulation should be delivered as early as possible in the course of medically resistant epilepsy to maximize the opportunity for improvements in mood and QoL.

The unchanging face of Lennox-Gastaut syndrome in adulthood

PurposeLennox-Gastaut syndrome (LGS) is a severe childhood-onset epileptic encephalopathy characterized by the presence of multiple types of intractable seizures, cognitive impairment, and specific electroencephalogram (EEG) patterns. The aim of this study was to investigate the electroclinical features of patients with LGS during adulthood. MethodsWe retrospectively identified the medical records of 20 patients aged over 18 years with a diagnosis of LGS from 3896 patients with epilepsy. ResultsThirteen (65 %) patients were male. The mean age of the patients was 23.4 ± 7.1 (min-max; 18–43) years, and the mean follow-up period was 5.6 ± 4.5 (min-max; 1–14) years. The etiology was identified in 11 (55 %) patients. None of the patients achieved seizure freedom. The most prevalent seizure types were atypical absences in 14 (70 %) patients, tonic seizures in 13 (65 %) patients, and atonic seizures in 11 (55 %) patients. One (5 %) patient was diagnosed as having psychogenic non-epileptic seizures. Mental retardation was reported in all patients and only half of them could walk independently. All patients had drug-resistant seizures and 16 (80 %) patients were on polytherapy. A vagus nerve stimulator was implanted into ten (50 %) patients and five reported 50–80 % seizure reduction. Ketogenic diet was administered to two (10 %) patients and epilepsy surgery was performed in two (10 %) patients with no significant benefit. ConclusionsPaying attention to all factors of seizure outcomes, cognitive impairment, and ambulatory status, all patients were dependent on caregivers for daily living abilities. LGS has life-long persistence with poor outcomes, even during adulthood.

The effect of dietary protein restriction in a case of molybdenum cofactor deficiency with MOCS1 mutation

Molybdenum cofactor deficiency (MoCD) is an autosomal recessive inborn error of metabolism that results from mutations in genes involved in molybdenum cofactor (Moco) biosynthesis. MoCD is characterized clinically by intractable seizures and severe, rapidly progressing neurodegeneration leading to death in early childhood in the majority of known cases. We report on a patient with an unusual late disease onset and mild phenotype, characterized by delayed development and a decline triggered by a febrile illness and a subsequent dystonic movement disorder. Magnetic resonance imaging showed abnormal signal intensities of the bilateral basal ganglia. Blood and urine chemistry tests demonstrated remarkably low serum and urinary uric acid levels. A urine sulfite test was positive. Specific diagnostic workup showed elevated levels of xanthine and hypoxanthine in serum with increased urinary sulfocysteine (SSC) levels. Genetic analysis revealed a homozygous missense mutation at c.1510C > T (p.504R > W) in exon 10 of the MOCS1 in isoform 7 (rs1387934803). At age 1 year 4 months, the patient was placed on a low protein diet to reduce cysteine load and accumulation of sulfite and SCC in tissues. At 3 months after introduction of protein restriction, the urine sulfite test became negative and the urine SCC level was decreased. After starting the protein restriction diet, dystonic movement improved, and the patient's course progressed without regression and seizures. Electroencephalogram findings were remarkably improved. This finding demonstrates that the dietary protein restriction suppresses disease progression in mild cases of MoCD and suggests the effectiveness of dietary therapy in MoCD.

Voltage Activation Mechanisms of Epilepsy- and ASD-Associated Mutations in Neuronal KCNQ Chanels

The voltage-gated potassium KCNQ2/3 channel mediates the M-current (IKM) which contributes to set the resting membrane potential, shapes action potentials, and hinders repetitive neuronal firing. Inherited mutations in the KCNQ2/3 channel has been linked to the onset of epileptic encephalopathy, which is often co-morbid in patients with autism spectrum disorder (ASD). However, the molecular mechanisms by which these mutations disrupt KCNQ2/3 channel function remain elusive. Moreover, because one in three patients fails to respond to available medications, there is a need to develop alternative therapies. Small lipophilic molecules have been shown to alleviate the symptoms of some intractable epileptic seizures, although the mechanisms are unknown. Here, we use voltage-clamp fluorometry (VCF) to simultaneously measure voltage sensor movement and gate opening in a set of epilepsy- and ASD-associated mutations in the voltage sensor (S4) of KCNQ2/3 channels expressed in Xenopus oocytes. We also investigate the effects of small lipophilic molecules on KCNQ2/3 channel activity and study how these molecules improve mutated channel function. We find that, compared to the wild type channel, the ASD-linked mutations in the S4 of KCNQ3 (R227Q and R236C) shift the voltage dependence of current G(V) and fluorescence F(V) activation towards negative and positive voltages, respectively. VCF also shows that, compared to wild type, the time courses of the fluorescence and current in R227Q and R236C are faster and slower, respectively. This suggests that whereas the mutation R227Q destabilizes the resting conformation of the S4, R236C mainly act by destabilizing the S4 activated state. Finally, we find a set of small molecules that partially reverse the defects caused by the mutations, thereby laying the groundwork for the development of mutation-specific therapies.

Potential Efficacy of Multimodal Mixed Reality in Epilepsy Surgery.

Mixed reality (MR) technology, which can fuse things in real and virtual space in real time, has been used mainly for simulation in neurosurgical training. To develop MR technology into multimodal MR for intraoperative guidance during epilepsy surgery. A 33-yr-old male patient suffered from intractable general tonic seizures due to left temporal meningoencephalocele. Preoperative scalp electroencephalograms localized interictal epileptic activity on the left temporal lobe. Iomazenil single photon emission tomography revealed temporal lobe lateralization. Magnetic resonance imaging (MRI) demonstrated left basal temporal meningoencephalocele extending into the pterygopalatine fossa through a bone defect at the base of the greater sphenoid wing. A 3-dimensional model was created for MR based on multimodal data including computed tomography, MRI tractography, and digital subtraction angiography, which enabled 3-dimensional visualization of abnormal subcortical fiber connections between the meningoencephalocele and the epileptic focus. By using intraoperative multimodal MR, we were able to safely remove the meningoencephalocele and perform epileptic focus resection. The patient was seizure-free postoperatively, and no adverse effects were noted. Intraoperative multimodal MR was a feasible and effective technique, and it can be applied for a wide range of epilepsy surgeries.

Over 10-Year Outcomes of Infantile-Onset Epilepsies.

Seizures in infancy have highly variable courses and underlying etiologies. However, there are only a few long-term follow-up studies regarding infantile-onset epilepsy. Therefore, we aimed to describe the clinical courses, seizure outcomes, and risk factors of infantile-onset epilepsy followed up for more than 10 years in a tertiary center. Methods: Data of the patients with epilepsy, diagnosed under the age of 12 months and followed up for more than 10 years, were retrieved from the electronic medical records of Asan Medical Center Children’s Hospital. The patients’ medical records were retrospectively reviewed, and clinical outcomes were assessed based on the duration of seizure freedom at the last follow-up. Results: Of the 146 patients, 103 (70.5%) entered at least one remission, of whom epilepsy was resolved in 46 (31.5%). Forty-nine (33.6%) were found to be intractable at last contact. Delayed development, neurological deficits, and later onset (>3 months) were significantly associated with intractable epilepsies (p < 0.01). Conclusions: This study demonstrated that many patients with infantile-onset epilepsy can experience seizure remission. However, in some cases, early onset epilepsy was highly associated with various comorbidities and intractable seizures. Therefore, appropriate diagnosis and treatment are necessary to prevent further neuropsychiatric complications.

Identification of UBE3A Protein in CSF and Extracellular Space of the Hippocampus Suggest a Potential Novel Function in Synaptic Plasticity.

Disruptions to the maternally inherited allele UBE3A, encoding for an E3 ubiquitin ligase, leads to the manifestation of Angelman Syndrome (AS). While this disorder is rare, the symptoms are severe and lifelong including but not limited to: intractable seizures, abnormal EEG's, ataxic gait, lack of speech, and most notably an abnormally happy demeanor with easily provoked laughter. Currently, little is known about the neurophysiological underpinnings of UBE3A leading to such globally severe phenotypes. Utilizing the newest AS rat model, comprised of a full UBE3A deletion, we aimed to elucidate novel mechanistic actions and potential therapeutic targets. This report demonstrates for the first time that catalytically active UBE3A protein is detectable within cerebrospinal fluid (CSF) of wild type rats but distinctly absent in AS rat CSF. Microdialysis within the rat hippocampus also showed that UBE3A protein is located in the interstitial fluid of wild type rat brains but absent in AS animals. This protein maintains catalytic activity and appears to be regulated in a dynamic activity-dependent manner. LAY SUMMARY: Angelman syndrome (AS) is a rare genetic disorder caused by the loss of the UBE3A gene within the central nervous system. Although we have identified the gene responsible for AS, we still have a long way to go to fully understand its function in vivo. Here we report that UBE3A is present within normal cerebrospinal fluid (CSF) but distinctly absent in AS CSF. Furthermore, we demonstrate that UBE3A is secreted and that this may occur in a dynamic activity-dependent fashion. Extracellular UBE3A maintained its ubiquitinating activity, thus suggesting that UBE3A may have a novel role outside of neurons. Autism Res 2021, 14: 645-655. © 2021 International Society for Autism Research and Wiley Periodicals LLC.