June 23, 2022

CURE Epilepsy Discovery: Investigating Mechanism of the Progression of Epilepsy

Key Points:

  • The development of seizures is associated with many changes in the brain; one of these changes is alterations in the white matter (the deep part of the brain) composed of axons covered in myelin. Myelin is a substance that acts as a nerve insulator and is critical for communication between neurons.
  • Dr. Juliet Knowles at Stanford University was granted both a CURE Epilepsy Taking Flight and a CURE Epilepsy Research Continuity Fund award to investigate whether changes in myelin might play a role in the development of epilepsy. Through her research, the team discovered that abnormal neuronal activity during absence seizures may lead to changes in myelination. The changes in myelin, in turn, lead to seizure progression.
  • This research paves the way for future studies that may identify ways to prevent harmful changes in myelination to treat some forms of epilepsy.

Deep Dive:

Some types of epilepsy are progressive, and the disease progression may manifest in the form of more frequent seizures, worsened control of seizures, or decline of cognition.[1] Progression of seizures has a direct correlation to the severity of epilepsy as time progresses.[2] Multiple factors may contribute to how seizures progress, but one factor that had not been investigated is a change, (known as plasticity), in the white matter or myelin of the brain. Myelin is a substance that acts as a form of insulation around the nerve cells of the brain and is essential for the conduction of electrical impulses between neurons and for the proper functioning of the brain. In fact, this white coating of myelin is what gives the collection of axons deep inside the brain the name “white matter”. Plasticity or changes in myelination can occur in response to neuronal activity and are important in the non-epileptic brain for functions such as learning, memory, and attention.[3,4] The team found that seizures in newborn infants with genetic forms of epilepsy may be associated with abnormalities in myelination.[5] These findings suggested that myelin plasticity might also occur in response to seizures. 

With her CURE Epilepsy Taking Flight Award, generously funded by the Ravichandran Foundation, Dr. Knowles and her colleagues sought to determine whether changes in myelination caused by a type of seizure called an absence seizure (formerly known as a petit mal seizure) contribute to the progression of epilepsy.[6] And when COVID-19 forced this study to be put on a temporary hold, the CURE Epilepsy Research Continuity Fund award, generously funded by the Cotton Family in memory of Vivian Cotton, helped Dr. Knowles’ team to finish these experiments when laboratories reopened. For her study, Dr. Knowles hypothesized that changes in myelin might influence seizure severity in absence seizure spreading.

Absence seizures are characterized by the abrupt stopping of behavior (“behavioral arrest”) and a specific pattern of brain activity. Even though absence seizures are typically brief, an individual can have an extremely high number of seizures in a day.[7, 8] Absence seizures originate in connections between two parts of the brain called the thalamus and cortex, after which seizure activity is transmitted through a large brain network by myelin-coated axons in white matter.[9, 10] 

The team used rodent models which had specific genetic mutations in their neurons that produce absence seizures. The pattern of seizure progression in these animals is similar to what is found in children with progressive forms of epilepsy.[2, 8] Electroencephalogram (EEG) was used to study electrical activity in the brain and the structure of neurons was examined using sophisticated microscopy techniques.[6] Additional techniques used to investigate the role of seizures in myelination included genetic interventions to block myelination (the process by which layers of myelin are produced) and drugs that decreased seizures.[6]

By using these methods, Dr. Knowles’ team first observed that there was an increase in myelination within the seizure network in seizure-prone animals, but this was seen only once seizures had started. This suggests that there is something unique and specific about the seizure activity that impacts myelination. Additionally, when Dr. Knowles’ team blocked seizures either genetically or using drugs, the increase in myelination was prevented. When the team blocked this abnormal myelination, the number of seizures decreased, and neuronal hypersynchrony decreased as well.[6] Neuronal hypersynchrony is the process by which networks of neurons fire together in an extremely organized and coordinated but abnormal way and is thought to underlie some aspects of seizure onset and spreading.[11]

The current study by Dr. Knowles’ group is the first that clearly shows that abnormal neuronal activity (in this case, due to absence seizures) can lead to harmful changes in myelination, which contribute to the continued progression of epilepsy.[6] Future work in the field will look at the exact molecules and neurotransmitters involved to better characterize this change in myelination. Although more studies are necessary, the current work suggests that developing treatments that address both abnormal neuronal activity and the associated abnormal myelination could more effectively prevent seizures and cognitive difficulties.[12] 


Literature Cited:

  1. Coan AC, Cendes F. Epilepsy as progressive disorders: what is the evidence that can guide our clinical decisions and how can neuroimaging help? Epilepsy Behav. 2013 Mar;26:313-321.
  2. Brigo F, Trinka E, Lattanzi S, Bragazzi NL, Nardone R, Martini M. A brief history of typical absence seizures – Petit mal revisited Epilepsy Behav. 2018 Mar;80:346-353.
  3. McKenzie IA, Ohayon D, Li H, de Faria JP, Emery B, Tohyama K, et al. Motor skill learning requires active central myelination Science. 2014 Oct 17;346:318-322.
  4. Pan S, Mayoral SR, Choi HS, Chan JR, Kheirbek MA. Preservation of a remote fear memory requires new myelin formation Nature Neuroscience. 2020 2020/04/01;23:487-499.
  5. Sandoval Karamian AG, Wusthoff CJ, Boothroyd D, Yeom KW, Knowles JK. Neonatal genetic epilepsies display convergent white matter microstructural abnormalities Epilepsia. 2020 Dec;61:e192-e197.
  6. Knowles JK, Xu H, Soane C, Batra A, Saucedo T, Frost E, et al. Maladaptive myelination promotes generalized epilepsy progression Nature Neuroscience. 2022 2022/05/01;25:596-606.
  7. Albuja A.C. KGQ. Absence Seizure. [Updated 2021 Dec 13]. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing 2022.
  8. Guerrini R, Marini C, Barba C. Generalized epilepsies Handb Clin Neurol. 2019;161:3-15.
  9. Musgrave J, Gloor P. The role of the corpus callosum in bilateral interhemispheric synchrony of spike and wave discharge in feline generalized penicillin epilepsy Epilepsia. 1980 Aug;21:369-378.
  10. Fogerson PM, Huguenard JR. Tapping the Brakes: Cellular and Synaptic Mechanisms that Regulate Thalamic Oscillations Neuron. 2016 Nov 23;92:687-704.
  11. Jiruska P, de Curtis M, Jefferys JGR, Schevon CA, Schiff SJ, Schindler K. Synchronization and desynchronization in epilepsy: controversies and hypotheses J Physiol. 2013;591:787-797.
  12. Li MCH, Cook MJ. Deep brain stimulation for drug-resistant epilepsy Epilepsia. 2018 Feb;59:273-290.