Juliet Klasing Knowles

All Publications

• Optimal stimulation of the thalamic centromedian nucleus in children with Lennox-Gastaut syndrome: patient series. Journal of neurosurgery. Case lessons Warren, A. E., Xu, A., Barros Guinle, M. I., Johnstone, T., Teeyagura, P., Solidum, R., Hyslop, A., Kim, H., Grant, G., Parker, J. J., Buch, V., Porter, B. E., Knowles, J. K. 2025; 10 (12)

  Abstract

  Lennox-Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy characterized by multiple seizure types, intellectual disability, and distinctive EEG findings. Deep brain stimulation of the centromedian nucleus (CM-DBS) is an emerging therapy for LGS, but pediatric experience remains limited.The authors report a single-center experience with CM-DBS in 6 children and adolescents (ages 12-18 years) with LGS. One patient experienced infection-related device removal after 2 months. The remaining 5 received sustained stimulation for 2.5-5 years. All 5 showed caregiver-reported improvements in seizure burden and alertness, with corroborating Clinical Global Impression-Improvement scores. Three patients exhibited marked seizure reduction following targeted reprogramming toward a previously identified optimal target of stimulation in the anterolateral CM. Pre- and post-DBS scalp EEG recordings were available in 1 patient and showed a reduced burden of interictal discharges.CM-DBS is a promising treatment for pediatric, medically refractory LGS when resective approaches are unsuitable. Benefits were sustained over years. Lead localization and direction of stimulation appear important to optimize clinical benefit. These findings support the feasibility and safety of pediatric CM-DBS and highlight the need for prospective trials incorporating EEG-based outcomes and patient-centered measures including comorbidities and quality of life. Early, network-targeted neuromodulation may improve long-term outcomes. https://thejns.org/doi/10.3171/CASE25478.

  View details for DOI 10.3171/CASE25478

  View details for PubMedID 40982986

  View details for PubMedCentralID PMC12455224

• Current practices and trends in surgical decision-making for children with Lennox-Gastaut syndrome: A cross-sectional survey by the Pediatric Epilepsy Research Consortium. Epilepsia open Chiu, M. Y., Keator, C. G., Warren, A. E., Knowles, J. K., Samanta, D., Dixon-Salazar, T., Koh, H. Y., Seinfeld, S. A., Paolicchi, J., Vidaurre, J., Patel, A. D., Loddenkemper, T., Shellhaas, R. A., Clarke, D. F., Fine, A. L., Bhalla, S., Depositario-Cabacar, D., Haridas, B., Stafstrom, C. E., Erdemir, G., Karakas, C. 2025

  Abstract

  OBJECTIVE: The objective of this study is to characterize contemporary surgical management practices and factors influencing surgical decision-making in the management of Lennox-Gastaut Syndrome (LGS) across pediatric epilepsy centers in the United States.METHODS: A 45-item cross-sectional survey was developed and distributed to Pediatric Epilepsy Research Consortium centers. Domains included institutional demographics, surgical evaluation timing and goals, presurgical workup, procedural utilization and outcomes, and barriers to surgery. Descriptive statistics and thematic analysis were performed.RESULTS: Thirty-two pediatric epilepsy centers participated (38% response), the majority comprising pediatric epileptologists at Level 4 National Association of Epilepsy Centers. Most centers (66%) considered surgery after failure of 3-4 antiseizure medications. Presurgical workup typically included brain magnetic resonance imaging (MRI), long-term electroencephalography (EEG) monitoring, and neuropsychological assessment, while use of functional imaging, magnetoencephalography, and intracranial EEG varied considerably. All centers offered vagus nerve stimulation and corpus callosotomy; 80%-90% offered resection, hemispherectomy, responsive neurostimulation (RNS); 60%-65% offered deep brain stimulation (DBS) and laser ablation. Among centers offering RNS, half targeted thalamic structures exclusively, and the remainder targeted cortical or combined cortical-thalamic structures; the centromedian nucleus was the preferred thalamic target for RNS and DBS. Surgical decision-making was influenced by patient characteristics, procedural considerations, and systemic factors. Seizure frequency, family preference, and multidisciplinary input were highly rated across all interventions. Etiology was critical for resection and hemispherectomy, while financial constraints, insurance barriers, and the need for future neuroimaging impacted neuromodulation selection. Scenario-specific trends included less frequent consideration of DBS and RNS in children under five years, less use of hemispherectomy in older children, preference for corpus callosotomy in children with predominantly drop seizures, and procedural selection based on MRI findings.SIGNIFICANCE: Substantial variability exists in the surgical management of LGS. These findings highlight critical opportunities to harmonize practices, reduce disparities, and guide comparative effectiveness research to optimize outcomes.PLAIN LANGUAGE SUMMARY: Lennox-Gastaut Syndrome (LGS) is a severe form of epilepsy that may require surgery when medications are not effective. This study found that surgical care for LGS varies widely across pediatric epilepsy centers in the United States, including when surgery is recommended, how patients are evaluated, and which procedures are available. Newer approaches such as brain stimulation are being used more often, although access remains inconsistent. These findings highlight the need for clearer treatment pathways to ensure that children with LGS have equitable access to the best possible care.

  View details for DOI 10.1002/epi4.70144

  View details for PubMedID 40965114

• Non-parametric prediction of brain MRI microstructure using transfer learning. Imaging neuroscience (Cambridge, Mass.) Chau Loo Kung, G., Weber, E. M., Batra, A., Ni, L., Zeineh, M., Chaudhari, A., Adeli, E., Knowles, J. K., McNab, J. A. 2025; 3

  Abstract

  Magnetic resonance imaging (MRI) can be sensitive to tissue microstructural features and infer parameterized features by performing a voxel-wise fit of the signal to a biophysical model. However, biophysical models rely on simplified representations of brain tissue. Machine learning (ML) techniques may serve as a data-driven approach to optimize for microstructural feature extraction. Unfortunately, training an ML model for these applications requires a large database of paired specimen MRI and histology datasets, which is costly, cumbersome, and challenging to acquire. In this work, we present a novel approach allowing a reliable estimation of brain tissue microstructure using MRI as inputs, with a minimal amount of paired MRI-histology data. Our method involves pretraining a conditional normalizing flow model to predict the distribution of microstructural features. The model is trained on synthetic MRI data generated from unpaired histology and MRI physics, reducing the data requirement in future steps. The synthetic MRI generation data combines segmentation of a publicly available EM slice, feature extraction and MRI simulators. Subsequently, the model is fine-tuned using experimental MRI/Electron Microscopy (EM) data of nine excised mouse brains through transfer learning. This approach enables the prediction of non-parameterized joint distributions of g-ratio and axon diameters for a given voxel based on MRI input. Results show a close agreement between the distributions predicted by the network and the EM ground-truth histograms (mean Jensen-Shannon Distances of 0.24 and 0.23 on the test set, for axon diameter and g-ratios respectively, compared to distances of 0.18 and 0.18 of a direct fitting of a Gamma distribution to the ground truth). The approach also shows up to 4% decreased mean percent errors of the distributions compared to biophysical model fitting and increased prediction capabilities that are consistent with electron microscopy validation and previous biological studies. For example, g-ratio values predicted along the corpus callosum anterior-posterior axis show a significant difference for mice after myelin remodeling seizures are well established (p < 0.001) but not before seizure onset (p = 0.562). The results suggest that pretraining on synthetic MRI and then using transfer learning is an effective approach for addressing the lack of paired MRI/histology data when training ML models for microstructure prediction. This approach is a step toward developing a versatile and widely used foundation model for predicting microstructural features using MRI.

  View details for DOI 10.1162/imag_a_00548

  View details for PubMedID 40800932

  View details for PubMedCentralID PMC12320010

• Non-parametric prediction of brain MRI microstructure using transfer learning IMAGING NEUROSCIENCE Kung, G., Weber, E. M. M., Batra, A., Ni, L., Zeineh, M., Chaudhari, A., Adeli, E., Knowles, J. K., McNab, J. A. 2025; 3

  View details for DOI 10.1162/imag_a_00548

  View details for Web of Science ID 001521331500001

• Intracranial neuromodulation for pediatric drug-resistant epilepsy: early institutional experience. Frontiers in surgery Uchitel, J., Lui, A., Knowles, J., Parker, J. J., Phillips, H. W., Halpern, C. H., Grant, G. A., Buch, V. P., Hyslop, A., Kumar, K. K. 2025; 12: 1569360

  Abstract

  Pediatric drug-resistant epilepsy (DRE) is defined as epilepsy that is not controlled by two or more appropriately chosen and dosed anti-seizure medications (ASMs). When alternative therapies or surgical intervention is not viable or efficacious, advanced options like deep brain stimulation (DBS) or responsive neurostimulation (RNS) may be considered.Describe the Stanford early institutional experience with DBS and RNS in pediatric DRE patients.Retrospective chart review of seizure characteristics, prior therapies, neurosurgical operative reports, and postoperative outcome data in pediatric DRE patients who underwent DBS or RNS placement.Nine patients had DBS at 16.0 ± 0.9 years and 8 had RNS at 15.3 ± 1.7 years (mean ± SE). DBS targets included the centromedian nucleus of the thalamus (78% of DBS patients), anterior nucleus of the thalamus (11%), and pulvinar (11%). RNS placement was guided by stereo-EEG and/or intracranial monitoring in all RNS patients (100%). RNS targets included specific seizure onset zones (63% of RNS patients), bilateral hippocampi (25%) and bilateral temporal lobes (12%). Only DBS patients had prior trials of ketogenic diet (56%) and VNS therapy (67%). Four DBS patients (44%) had prior neurosurgical interventions, including callosotomy (22%) and focal resection (11%). One RNS patient (13%) and one DBS patient (11%) required revision surgery. Two DBS patients (22%) developed postoperative complications. Three RNS patients (38%) underwent additional resections; one RNS patient had electrocorticography recordings for seizure mapping before surgery. For patients with a follow-up of at ≥1 year (n = 7 for DBS and n = 5 for RNS), all patients had reduced seizure burden. Clinical seizure freedom was achieved in 80% of RNS patients and 20% had a >90% reduction in seizure burden. The majority (71%) of DBS patients had a ≥50% reduction in seizures. No patients experienced no change or worsening of seizure frequency.In the early Stanford experience, DBS was used as a palliatively for generalized or mixed DRE refractory to other resective or modulatory approaches. RNS was used for multifocal DRE with a clear seizure focus on stereo-EEG and no prior surgical interventions. Both modalities reduced seizure burden across all patients. RNS offers the additional benefit of providing data to guide future surgical planning.

  View details for DOI 10.3389/fsurg.2025.1569360

  View details for PubMedID 40264742

  View details for PubMedCentralID PMC12011735

• Mobilizing a New Era in Lennox-Gastaut Syndrome Treatment and Prevention EPILEPSY CURRENTS Warren, A. E. L., Patel, A. D., Cross, J., Clarke, D. F., Dalic, L. J., Grinspan, Z. M., Conecker, G., Knowles, J. K. 2025

  View details for DOI 10.1177/15357597251321926

  View details for Web of Science ID 001451430800001

• Mobilizing a New Era in Lennox-Gastaut Syndrome Treatment and Prevention. Epilepsy currents Warren, A. E., Patel, A. D., Helen Cross, J., Clarke, D. F., Dalic, L. J., Grinspan, Z. M., Conecker, G., Knowles, J. K. 2025: 15357597251321926

  Abstract

  This review summarizes content presented at the Pediatric State of the Art Symposium held during the American Epilepsy Society's annual meeting in December 2024. The symposium focused on Lennox-Gastaut syndrome (LGS), a severe developmental and epileptic encephalopathy that emerges in childhood. Despite its diverse etiologies, LGS is defined by a convergent constellation of electroclinical features: multiple seizure types including tonic seizures, slow spike-wave and generalized paroxysmal fast activity on EEG, and intellectual disability. LGS is almost always refractory to available therapies and accounts for substantial costs-in healthcare spending and in quality of life for affected individuals, their families, and caregivers. The symposium highlighted recent breakthroughs in research, clinical care, and outcome measurement that have positioned the clinical, scientific, and patient advocacy communities to usher in a new, more hopeful era of treatment and prevention.

  View details for DOI 10.1177/15357597251321926

  View details for PubMedID 40161505

  View details for PubMedCentralID PMC11948257

• Neuromodulation Strategies in Lennox-Gastaut Syndrome: Practical Clinical Guidance from the Pediatric Epilepsy Research Consortium. Epilepsy research Samanta, D., Aungaroon, G., Fine, A. L., Karakas, C., Chiu, M. Y., Jain, P., Seinfeld, S., Knowles, J. K., Mohamed, I. S., Stafstrom, C. E., Dixon-Salazar, T., Patel, A. D., Bhalla, S., Keator, C. G., Vidaurre, J., Warren, A. E., Shellhaas, R. A., Perry, M. S. 2025; 210: 107499

  Abstract

  Lennox-Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, and distinctive electroencephalographic patterns. Neuromodulation techniques, including vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS), have emerged as important treatment options for patients with LGS who do not respond adequately to antiseizure medications. This review, developed with input from the Pediatric Epilepsy Research Consortium (PERC) LGS Special Interest Group, provides practical guidance for clinicians on the use of these neuromodulation approaches in patients with LGS. We discuss patient selection criteria, expected seizure and non-seizure outcomes, potential complications, and device management considerations for each technique. The review also covers initiation and titration strategies, ongoing care requirements, and emerging data on combining multiple neuromodulation modalities. While all three approaches can reduce seizure frequency in patients with LGS, with commonly reported responder rates ranging from 50 % to 60 %, their impacts on cognition, behavior and quality of life are more variable. Careful patient selection, individualized programming, and long-term follow-up are essential to optimize outcomes with neuromodulation in this challenging patient population. Further research is needed to identify optimal candidates, determine the ideal timing during patients' clinical course to consider neuromodulation, develop standardized outcome measures, and evaluate the comparative effectiveness and cost-effectiveness of different neuromodulation techniques for LGS.

  View details for DOI 10.1016/j.eplepsyres.2024.107499

  View details for PubMedID 39778379

• Zebrafish Provide Critical Insights in a Sea of Genes. Epilepsy currents Popson, P., Knowles, J. K. 2024: 15357597241301510

  View details for DOI 10.1177/15357597241301510

  View details for PubMedID 39703932

  View details for PubMedCentralID PMC11653375

• Clinical trials for Lennox-Gastaut syndrome: Challenges and priorities. Annals of clinical and translational neurology Knowles, J. K., Warren, A. E., Mohamed, I. S., Stafstrom, C. E., Koh, H. Y., Samanta, D., Shellhaas, R. A., Gupta, G., Dixon-Salazar, T., Tran, L., Bhatia, S., McCabe, J. M., Patel, A. D., Grinspan, Z. M. 2024

  Abstract

  OBJECTIVE: Lennox-Gastaut syndrome (LGS) is a severe, childhood-onset epilepsy that is typically refractory to treatment. We surveyed the current landscape of LGS treatment, aiming to identify challenges to the development of efficacious therapies, and to articulate corresponding priorities toward clinical trials that improve outcomes.METHODS: The LGS Special Interest Group of the Pediatric Epilepsy Research Consortium integrated evidence from the literature and expert opinion, into a narrative review.RESULTS: We provide an overview of approved and emerging medical, dietary, surgical and neuromodulation approaches for LGS. We note that quality of care could be improved by standardizing LGS treatment based on expert consensus and empirical data. Whereas LGS natural history is incompletely understood, prospective studies and use of large retrospective datasets to understand LGS across the lifespan would enable clinical trials that address these dynamics. Recent discoveries related to LGS pathophysiology should enable development of disease-modifying therapies, which are currently lacking. Finally, clinical trials have focused chiefly on seizures involving "drops," but should incorporate additional patient-centered outcomes, using emerging measures adapted to people with LGS.INTERPRETATION: Clinicians and researchers should enact these priorities, with the goal of patient-centered clinical trials that are tailored to LGS pathophysiology and natural history.

  View details for DOI 10.1002/acn3.52211

  View details for PubMedID 39440617

• Attentional Deficits and Absence Epilepsy: A Tale of 2 Interneuronopathies EPILEPSY CURRENTS Knowles, J. 2024

  View details for DOI 10.1177/15357597241251709

  View details for Web of Science ID 001222329000001

• Attentional Deficits and Absence Epilepsy: A Tale of 2 Interneuronopathies. Epilepsy currents Knowles, J. 2024; 24 (3): 188-190

  View details for DOI 10.1177/15357597241251709

  View details for PubMedID 38898911

  View details for PubMedCentralID PMC11185201

• Quantitative MRI reveals widespread, network-specific myelination change during generalized epilepsy progression. NeuroImage Kung, G. C., Knowles, J. K., Batra, A., Ni, L., Rosenberg, J., McNab, J. A. 2023: 120312

  Abstract

  Activity-dependent myelination is a fundamentally important mode of brain plasticity which significantly influences function. We recently discovered that absence seizures, which occur in multiple forms of generalized epilepsy, can induce activity-dependent myelination, which in turn promotes further progression of epilepsy. Structural alterations of myelin are likely to be widespread, given that absence seizures arise from an extensive thalamocortical network involving frontoparietal regions of the bilateral hemispheres. However, the temporal course and spatial extent of myelin plasticity is unknown, due to limitations of gold-standard histological methods such as electron microscopy (EM). In this study, we leveraged magnetization transfer and diffusion MRI for estimation of g-ratios across major white matter tracts in a mouse model of generalized epilepsy with progressive absence seizures. Electron microscopy was performed on the same brains after MRI. After seizure progression, we found increased myelination (decreased g-ratios) throughout the anterior portion (genu-to-body) of the corpus callosum but not in the posterior portion (body-splenium) nor in the fornix or the internal capsule. Curves obtained from averaging g-ratio values at every longitudinal point of the corpus callosum were statistically different with p<0.0001. Seizure-associated myelin differences found in the corpus callosum body with MRI were statistically significant (p = 0.0027) and were concordant with EM in the same region (p = 0.01). Notably, these differences were not detected by diffusion tensor imaging. This study reveals widespread myelin structural change that is specific to the absence seizure network.Furthermore, our findings demonstrate the potential utility and importance of MRI-based g-ratio estimation to non-invasively detect myelin plasticity.

  View details for DOI 10.1016/j.neuroimage.2023.120312

  View details for PubMedID 37574120

• Adaptive and maladaptive myelination in health and disease. Nature reviews. Neurology Knowles, J. K., Batra, A., Xu, H., Monje, M. 2022

  Abstract

  Within the past decade, multiple lines of evidence have converged to identify a critical role for activity-regulated myelination in tuning the function of neural networks. In this Review, we provide an overview of accumulating evidence that activity-regulated myelination is required for brain adaptation and learning across multiple domains. We then discuss dysregulation of activity-dependent myelination in the context of neurological disease, a novel frontier with the potential to uncover new mechanisms of disease pathogenesis and to develop new therapeutic strategies. Alterations in myelination and neural network function can result from deficient myelin plasticity that impairs neurological function or from maladaptive myelination, in which intact activity-dependent myelination contributes to the disease process by promoting pathological patterns of neuronal activity. These emerging mechanisms suggest new avenues for therapeutic intervention that could more fully address the complex interactions between neurons and oligodendroglia.

  View details for DOI 10.1038/s41582-022-00737-3

  View details for PubMedID 36376595

• Maturation and circuit integration of transplanted human cortical organoids. Nature Revah, O., Gore, F., Kelley, K. W., Andersen, J., Sakai, N., Chen, X., Li, M. Y., Birey, F., Yang, X., Saw, N. L., Baker, S. W., Amin, N. D., Kulkarni, S., Mudipalli, R., Cui, B., Nishino, S., Grant, G. A., Knowles, J. K., Shamloo, M., Huguenard, J. R., Deisseroth, K., Pașca, S. P. 2022; 610 (7931): 319-326

  Abstract

  Self-organizing neural organoids represent a promising in vitro platform with which to model human development and disease1-5. However, organoids lack the connectivity that exists in vivo, which limits maturation and makes integration with other circuits that control behaviour impossible. Here we show that human stem cell-derived cortical organoids transplanted into the somatosensory cortex of newborn athymic rats develop mature cell types that integrate into sensory and motivation-related circuits. MRI reveals post-transplantation organoid growth across multiple stem cell lines and animals, whereas single-nucleus profiling shows progression of corticogenesis and the emergence of activity-dependent transcriptional programs. Indeed, transplanted cortical neurons display more complex morphological, synaptic and intrinsic membrane properties than their in vitro counterparts, which enables the discovery of defects in neurons derived from individuals with Timothy syndrome. Anatomical and functional tracings show that transplanted organoids receive thalamocortical and corticocortical inputs, and in vivo recordings of neural activity demonstrate that these inputs can produce sensory responses in human cells. Finally, cortical organoids extend axons throughout the rat brain and their optogenetic activation can drive reward-seeking behaviour. Thus, transplanted human cortical neurons mature and engage host circuits that control behaviour. We anticipate that this approach will be useful for detecting circuit-level phenotypes in patient-derived cells that cannot otherwise be uncovered.

  View details for DOI 10.1038/s41586-022-05277-w

  View details for PubMedID 36224417

• Precision medicine for genetic epilepsy on the horizon: recent advances, present challenges and suggestions for continued progress. Epilepsia Knowles, J. K., Helbig, I., Metcalf, C. S., Lubbers, L. S., Isom, L. L., Demarest, S., Goldberg, E., George, A. L., Lerche, H., Weckhuysen, S., Whittemore, V., Berkovic, S. F., Lowenstein, D. H. 2022

  Abstract

  The genetic basis of many epilepsies is increasingly understood, giving rise to the possibility of precision treatments tailored to specific genetic etiologies. Despite this, current medical therapy for most epilepsies remains imprecise, aimed primarily at empirical seizure reduction rather than targeting specific disease processes. Intellectual and technological leaps in diagnosis over the last ten years have not yet translated to routine changes in clinical practice. However, the epilepsy community is poised to make impressive gains in precision therapy with continued innovation in gene discovery, diagnostic ability and bioinformatics; increased access to genetic testing and counseling; fuller understanding of natural histories; agility and rigor in preclinical research, including strategic use of emerging model systems; and engagement of an evolving group of stakeholders (including patient advocates, governmental resources, and clinicians and scientists in academia and industry). In each of these areas, we highlight notable examples of recent progress, new or persistent challenges and future directions. The future of precision medicine for genetic epilepsy looks bright if key opportunities on the horizon can be pursued with strategic and coordinated effort.

  View details for DOI 10.1111/epi.17332

  View details for PubMedID 35716052

• Maladaptive myelination promotes generalized epilepsy progression. Nature neuroscience Knowles, J. K., Xu, H., Soane, C., Batra, A., Saucedo, T., Frost, E., Tam, L. T., Fraga, D., Ni, L., Villar, K., Talmi, S., Huguenard, J. R., Monje, M. 2022

  Abstract

  Activity-dependent myelination can fine-tune neural network dynamics. Conversely, aberrant neuronal activity, as occurs in disorders of recurrent seizures (epilepsy), could promote maladaptive myelination, contributing to pathogenesis. In this study, we tested the hypothesis that activity-dependent myelination resulting from absence seizures, which manifest as frequent behavioral arrests with generalized electroencephalography (EEG) spike-wave discharges, promote thalamocortical network hypersynchrony and contribute to epilepsy progression. We found increased oligodendrogenesis and myelination specifically within the seizure network in two models of generalized epilepsy with absence seizures (Wag/Rij rats and Scn8a+/mut mice), evident only after epilepsy onset. Aberrant myelination was prevented by pharmacological seizure inhibition in Wag/Rij rats. Blocking activity-dependent myelination decreased seizure burden over time and reduced ictal synchrony as assessed by EEG coherence. These findings indicate that activity-dependent myelination driven by absence seizures contributes to epilepsy progression; maladaptive myelination may be pathogenic in some forms of epilepsy and other neurological diseases.

  View details for DOI 10.1038/s41593-022-01052-2

  View details for PubMedID 35501379

• Practical Advice on Surviving and Thriving as an Academic Physician-Neuroscientist. JAMA neurology Knowles, J. K., Porter, B. E. 2021

  View details for DOI 10.1001/jamaneurol.2021.3889

  View details for PubMedID 34694341

• A Standardized Protocol to Improve Acute Seizure Management in Hospitalized Pediatric Patients. Hospital pediatrics Pavitt, S., Carley, A., Porter, B., Knowles, J. K. 2021

  Abstract

  BACKGROUND: Studies of seizure management in the pediatric inpatient setting are needed. Seizures recorded by video EEG provide an opportunity to quantitatively evaluate acute management. We observed variation in delivery of standardized seizure safety measures (seizure first aid) during epilepsy monitoring unit admissions at our hospital. Our goals were to increase consistency and speed of seizure first aid and neurologic assessment in acutely seizing patients.METHODS: Using a root cause analysis, we identified major factors contributing to variation in seizure management and key drivers for improvement. Targeted interventions, centered around a protocol for acute seizure management, were implemented through quality improvement methodology. The primary outcome was correct performance of standardized seizure first aid and neurologic assessment. Secondary outcomes were time intervals to each assessment. Run charts were used to analyze primary outcomes, and statistical control charts were used for secondary outcomes. Nursing confidence in seizure management was determined through pre- and postsurveys and analyzed with the chi2 test.RESULTS: Thirteen seizures were evaluated in the preintervention phase and 10 in the postintervention phase. Completed components of seizure first aid increased from a median of 3 of 4 to 4 of 4; completed components of neurologic assessment increased from a median of 2 of 4 to 4 of 4. Responses to acute seizures were faster, and nursing confidence increased.CONCLUSIONS: A collaborative quality improvement effort between physicians and nurses led to prompt and correct delivery of seizure first aid by first responders. These relatively simple interventions could be adapted broadly to improve acute seizure management in the pediatric inpatient setting.

  View details for DOI 10.1542/hpeds.2020-000968

  View details for PubMedID 33685859

• Improving Bedside Seizure Care of Pediatric Epilepsy Monitoring Unit (EMU) Patients: Creation and Implementation of a Standardized Protocol Pavitt, S., Carley, A., Porter, B., Knowles, J. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000536058005062

• Neonatal genetic epilepsies display convergent white matter microstructural abnormalities. Epilepsia Sandoval Karamian, A. G., Wusthoff, C. J., Boothroyd, D. n., Yeom, K. W., Knowles, J. K. 2020

  Abstract

  White matter undergoes rapid development in the neonatal period. Its structure during and after development is influenced by neuronal activity. Pathological neuronal activity, as in seizures, might alter white matter, which in turn may contribute to network dysfunction. Neonatal epilepsy presents an opportunity to investigate seizures and early white matter development. Our objective was to determine whether neonatal seizures in the absence of brain injury or congenital anomalies are associated with altered white matter microstructure. In this retrospective case-control study of term neonates, cases had confirmed or suspected genetic epilepsy and normal brain magnetic resonance imaging (MRI) and no other conditions independently impacting white matter. Controls were healthy neonates with normal MRI results. White matter microstructure was assessed via quantitative mean diffusivity (MD). In 22 cases, MD was significantly lower in the genu of the corpus callosum, compared to 22 controls, controlling for gestational age and postmenstrual age at MRI. This finding suggests convergent abnormal corpus callosum microstructure in neonatal epilepsies with diverse suspected genetic causes. Further study is needed to determine the specific nature, causes, and functional impact of seizure-associated abnormal white matter in neonates, a potential pathogenic mechanism.

  View details for DOI 10.1111/epi.16735

  View details for PubMedID 33098118

• Refractory focal epilepsy in a paediatric patient with primary familial brain calcification. Seizure Knowles, J. K., Santoro, J. D., Porter, B. E., Baumer, F. M. 2018; 56: 50–52

  Abstract

  Primary familial brain calcification (PFBC), otherwise known as Fahr's disease, is a rare autosomal dominant condition with manifestations of movement disorders, neuropsychiatric symptoms, and epilepsy in a minority of PFBC patients. The clinical presentation of epilepsy in PFBC has not been described in detail. We present a paediatric patient with PFBC and refractory focal epilepsy based on seizure semiology and ictal EEG, but with generalized interictal EEG abnormalities. The patient was found to have a SLC20A2 mutation known to be pathogenic in PFBC, as well as a variant of unknown significance in SCN2A. This case demonstrates that the ictal EEG is important for accurately classifying epilepsy in affected subjects with PFBC. Further, epilepsy in PFBC may be a polygenic disorder.

  View details for PubMedID 29448117

• A Small Molecule p75NTR Ligand, LM11A-31, Reverses Cholinergic Neurite Dystrophy in Alzheimer's Disease Mouse Models with Mid- to Late-Stage Disease Progression. PloS one Simmons, D. A., Knowles, J. K., Belichenko, N. P., Banerjee, G., Finkle, C., Massa, S. M., Longo, F. M. 2014; 9 (8): e102136

  Abstract

  Degeneration of basal forebrain cholinergic neurons contributes significantly to the cognitive deficits associated with Alzheimer's disease (AD) and has been attributed to aberrant signaling through the neurotrophin receptor p75 (p75NTR). Thus, modulating p75NTR signaling is considered a promising therapeutic strategy for AD. Accordingly, our laboratory has developed small molecule p75NTR ligands that increase survival signaling and inhibit amyloid-β-induced degenerative signaling in in vitro studies. Previous work found that a lead p75NTR ligand, LM11A-31, prevents degeneration of cholinergic neurites when given to an AD mouse model in the early stages of disease pathology. To extend its potential clinical applications, we sought to determine whether LM11A-31 could reverse cholinergic neurite atrophy when treatment begins in AD mouse models having mid- to late stages of pathology. Reversing pathology may have particular clinical relevance as most AD studies involve patients that are at an advanced pathological stage. In this study, LM11A-31 (50 or 75 mg/kg) was administered orally to two AD mouse models, Thy-1 hAPPLond/Swe (APPL/S) and Tg2576, at age ranges during which marked AD-like pathology manifests. In mid-stage male APPL/S mice, LM11A-31 administered for 3 months starting at 6-8 months of age prevented and/or reversed atrophy of basal forebrain cholinergic neurites and cortical dystrophic neurites. Importantly, a 1 month LM11A-31 treatment given to male APPL/S mice (12-13 months old) with late-stage pathology reversed the degeneration of cholinergic neurites in basal forebrain, ameliorated cortical dystrophic neurites, and normalized increased basal forebrain levels of p75NTR. Similar results were seen in female Tg2576 mice. These findings suggest that LM11A-31 can reduce and/or reverse fundamental AD pathologies in late-stage AD mice. Thus, targeting p75NTR is a promising approach to reducing AD-related degenerative processes that have progressed beyond early stages.

  View details for DOI 10.1371/journal.pone.0102136

  View details for PubMedID 25153701

  View details for PubMedCentralID PMC4143160

• A small molecule p75NTR ligand, LM11A-31, reverses cholinergic neurite dystrophy in Alzheimer's disease mouse models with mid- to late-stage disease progression. PloS one Simmons, D. A., Knowles, J. K., Belichenko, N. P., Banerjee, G., Finkle, C., Massa, S. M., Longo, F. M. 2014; 9 (8)

  Abstract

  Degeneration of basal forebrain cholinergic neurons contributes significantly to the cognitive deficits associated with Alzheimer's disease (AD) and has been attributed to aberrant signaling through the neurotrophin receptor p75 (p75NTR). Thus, modulating p75NTR signaling is considered a promising therapeutic strategy for AD. Accordingly, our laboratory has developed small molecule p75NTR ligands that increase survival signaling and inhibit amyloid-β-induced degenerative signaling in in vitro studies. Previous work found that a lead p75NTR ligand, LM11A-31, prevents degeneration of cholinergic neurites when given to an AD mouse model in the early stages of disease pathology. To extend its potential clinical applications, we sought to determine whether LM11A-31 could reverse cholinergic neurite atrophy when treatment begins in AD mouse models having mid- to late stages of pathology. Reversing pathology may have particular clinical relevance as most AD studies involve patients that are at an advanced pathological stage. In this study, LM11A-31 (50 or 75 mg/kg) was administered orally to two AD mouse models, Thy-1 hAPPLond/Swe (APPL/S) and Tg2576, at age ranges during which marked AD-like pathology manifests. In mid-stage male APPL/S mice, LM11A-31 administered for 3 months starting at 6-8 months of age prevented and/or reversed atrophy of basal forebrain cholinergic neurites and cortical dystrophic neurites. Importantly, a 1 month LM11A-31 treatment given to male APPL/S mice (12-13 months old) with late-stage pathology reversed the degeneration of cholinergic neurites in basal forebrain, ameliorated cortical dystrophic neurites, and normalized increased basal forebrain levels of p75NTR. Similar results were seen in female Tg2576 mice. These findings suggest that LM11A-31 can reduce and/or reverse fundamental AD pathologies in late-stage AD mice. Thus, targeting p75NTR is a promising approach to reducing AD-related degenerative processes that have progressed beyond early stages.

  View details for DOI 10.1371/journal.pone.0102136

  View details for PubMedID 25153701

  View details for PubMedCentralID PMC4143160

• A small molecule p75(NTR) ligand prevents cognitive deficits and neurite degeneration in an Alzheimer's mouse model. Neurobiology of aging Knowles, J. K., Simmons, D. A., Nguyen, T. V., Vander Griend, L., Xie, Y., Zhang, H., Yang, T., Pollak, J., Chang, T., Arancio, O., Buckwalter, M. S., Wyss-Coray, T., Massa, S. M., Longo, F. M. 2013; 34 (8): 2052-2063

  Abstract

  The p75 neurotrophin receptor (p75(NTR)) is associated with multiple mechanisms linked to Alzheimer's disease (AD); hence, modulating its function might confer therapeutic effects. In previous in vitro work, we developed small molecule p75(NTR) ligands that inhibited amyloid-β-induced degenerative signaling and prevented neurite degeneration. In the present study, a prototype p75(NTR) ligand, LM11A-31, was administered orally to the Thy-1 hAPP(Lond/Swe) (APP(L/S)) AD mouse model. LM11A-31 reached brain concentrations known to inhibit degenerative signaling without toxicity or induction of hyperalgesia. It prevented deficits in novel object recognition after 2.5 months and, in a separate cohort, deficits in Y-maze performance after 3 months of treatment. Stereology studies found that the number and size of basal forebrain cholinergic neurons, which are normal in APP(L/S) mice, were unaffected. Neuritic dystrophy, however, was readily apparent in the basal forebrain, hippocampus and cortex, and was significantly reduced by LM11A-31, with no effect on amyloid levels. These studies reveal that p75(NTR) is an important and tractable in vivo drug target for AD, with LM11A-31 representing a novel class of therapeutic candidates.

  View details for DOI 10.1016/j.neurobiolaging.2013.02.015

  View details for PubMedID 23545424

• The p75 Neurotrophin Receptor Promotes Amyloid-beta(1-42)-Induced Neuritic Dystrophy In Vitro and In Vivo JOURNAL OF NEUROSCIENCE Knowles, J. K., Rajadas, J., Nguyen, T. V., Yang, T., LeMieux, M. C., Griend, L. V., Ishikawa, C., Massa, S. M., Wyss-Coray, T., Longo, F. M. 2009; 29 (34): 10627-10637

  Abstract

  Oligomeric forms of amyloid-beta (Abeta) are thought to play a causal role in Alzheimer's disease (AD), and the p75 neurotrophin receptor (p75(NTR)) has been implicated in Abeta-induced neurodegeneration. To further define the functions of p75(NTR) in AD, we examined the interaction of oligomeric Abeta(1-42) with p75(NTR), and the effects of that interaction on neurite integrity in neuron cultures and in a chronic AD mouse model. Atomic force microscopy was used to ascertain the aggregated state of Abeta, and fluorescence resonance energy transfer analysis revealed that Abeta oligomers interact with the extracellular domain of p75(NTR). In vitro studies of Abeta-induced death in neuron cultures isolated from wild-type and p75(NTR-/-) mice, in which the p75(NTR) extracellular domain is deleted, showed reduced sensitivity of mutant cells to Abeta-induced cell death. Interestingly, Abeta-induced neuritic dystrophy and activation of c-Jun, a known mediator of Abeta-induced deleterious signaling, were completely prevented in p75(NTR-/-) neuron cultures. Thy1-hAPP(Lond/Swe) x p75(NTR-/-) mice exhibited significantly diminished hippocampal neuritic dystrophy and complete reversal of basal forebrain cholinergic neurite degeneration relative to those expressing wild-type p75(NTR). Abeta levels were not affected, suggesting that removal of p75(NTR) extracellular domain reduced the ability of excess Abeta to promote neuritic degeneration. These findings indicate that although p75(NTR) likely does not mediate all Abeta effects, it does play a significant role in enabling Abeta-induced neurodegeneration in vitro and in vivo, establishing p75(NTR) as an important therapeutic target for AD.

  View details for DOI 10.1523/JNEUROSCI.0620-09.2009

  View details for PubMedID 19710315

• Small Molecule, Non-Peptide p75(NTR) Ligands Inhibit A beta-Induced Neurodegeneration and Synaptic Impairment PLOS ONE Yang, T., Knowles, J. K., Lu, Q., Zhang, H., Arancio, O., Moore, L. A., Chang, T., Wang, Q., Andreasson, K., Rajadas, J., Fuller, G. G., Xie, Y., Massa, S. M., Longo, F. M. 2008; 3 (11)

  Abstract

  The p75 neurotrophin receptor (p75(NTR)) is expressed by neurons particularly vulnerable in Alzheimer's disease (AD). We tested the hypothesis that non-peptide, small molecule p75(NTR) ligands found to promote survival signaling might prevent Abeta-induced degeneration and synaptic dysfunction. These ligands inhibited Abeta-induced neuritic dystrophy, death of cultured neurons and Abeta-induced death of pyramidal neurons in hippocampal slice cultures. Moreover, ligands inhibited Abeta-induced activation of molecules involved in AD pathology including calpain/cdk5, GSK3beta and c-Jun, and tau phosphorylation, and prevented Abeta-induced inactivation of AKT and CREB. Finally, a p75(NTR) ligand blocked Abeta-induced hippocampal LTP impairment. These studies support an extensive intersection between p75(NTR) signaling and Abeta pathogenic mechanisms, and introduce a class of specific small molecule ligands with the unique ability to block multiple fundamental AD-related signaling pathways, reverse synaptic impairment and inhibit Abeta-induced neuronal dystrophy and death.

  View details for DOI 10.1371/journal.pone.0003604

  View details for Web of Science ID 000265134200003

  View details for PubMedID 18978948

  View details for PubMedCentralID PMC2575383

• Small molecule neurotrophin receptor ligands: Novel strategies for targeting Alzheimer's disease mechanisms 7th International Conference on Alzheimers Disease Drug Discovery Longo, F. M., Yang, T., Knowles, J. K., Xie, Y., Moore, L. A., Massa, S. M. BENTHAM SCIENCE PUBL LTD. 2007: 503–6

  Abstract

  A number of factors limit the therapeutic application of neurotrophin proteins, such as nerve growth factor (NGF) and brain-derived growth factor (BDNF), for Alzheimer's and other neurodegenerative diseases. These factors include unfavorable pharmacological properties typical of proteins and the pleiotropic effects mediated by protein-ligand interactions with p75(NTR), Trk, and sortilin neurotrophin receptors. Targeted modulation of p75(NTR) provides a strategy for preventing degeneration without promoting TrkA-mediated deleterious effects, and targeted activation of TrkB might achieve more favorable neurotrophic effects than those achieved by concomitant activation of p75(NTR) and TrkB. The discovery of small molecules functioning as ligands at specific neurotrophin receptors has made possible for the first time approaches for modulating selected components of neurotrophin signaling processes for the purpose of modulating underlying Alzheimer's disease mechanisms.

  View details for Web of Science ID 000253592000002

  View details for PubMedID 18220511