Understanding the Epilepsy Spectrum Through Genes and Linked Diseases May Transform Epilepsy Management

The links between epilepsy and other diseases offer clues for early treatment. Frances E. Jensen, MD, past AES president and professor at Cornell Medical School, describes these links, and what they mean for future epilepsy treatment modalities.

The links between epilepsy and other diseases offer clues for early treatment. Frances E. Jensen, MD, past AES president and professor at Cornell Medical School, describes these links, and what they mean for future epilepsy treatment modalities.

At the 68th Annual Meeting of the 2014 American Epilepsy Society (AES), Frances E. Jensen, MD, past AES president and professor at Cornell Medical School, discussed some of the advances in the understanding of the pathophysiology of epilepsy. Increasingly, epilepsy is being understood as a spectrum of disorders that are linked with other neurologic diseases, including autism, multiple sclerosis, and major depression.

Epilepsy is increasingly recognized as a mainstream medical condition. With up to 1 in 26 people developing epilepsy at some point in their lifetime, and with 2.2 million people in the United States affected by the condition, Jensen noted, “We should all recognize the dominance of epilepsy.”

In addition to being a surprisingly common disease, epilepsy has far more symptoms than seizures alone. A broad spectrum of associated nonictal symptoms of epilepsy, with different etiologies and severity levels also underlie the disorder, including attention-deficit/hyperactivity disorder, cognitive deficits, psychiatric disorders, and dementia.

Understanding and treating these nonictal symptoms will depend on finding relationships between epilepsy and other neurologic disorders, such as multiple sclerosis, traumatic brain injury, Alzheimer's disease, autism, and Parkinson's disease. Several pathophysiologic mechanisms link these conditions, including excitotoxicity, deficiencies of ion channels, and the presence of amyloid protein, Tau, and synuclein. In addition, across all of these neurologic diseases, inflammation plays an important role.

Many psychiatric and cognitive conditions have shared neurochemistry with epilepsy. Mood and attentional disorders, for instance, share dysregulated signaling pathways involving serotonin, norepinephrine, dopamine, acetylcholine, gamma-aminobutyric acid (GABA), glutamate, and corticotropin-releasing hormone.1

Epilepsy is also linked with depression, both in terms of higher rates of epilepsy in patients with depression, and in terms of higher rates of depression in patients with epilepsy. This bidirectional relationship, in addition to some of the structural similarities between anticonvulsant medications and antiepileptic drugs, suggests an important biochemical link. Further supporting the link, toxic illegal substances such as MDMA (ecstasy) can cause depression and seizures. Similarly, treatments such as vagal nerve stimulation are effective in treating depression as well as seizure disorders.

Another disease strongly linked to epilepsy is autism. Not only do patients with these conditions share more than 9 genetic factors, including MeCP2, TSC1/TSC2, FMR1, and Shank3, but approximately 40% of children with autism also have epilepsy. Further, up to 70% of children with autism have epileptiform electroencephalogram patterns. Emerging from this link is the role of synaptic plasticity in the development of both conditions.

Synaptic plasticity relies on signaling between synapses that strengthens when signaling occurs more frequently. As a synapse fires more, the synapse grows, and the connection between neurons is strengthened, which is the biological basis for memory. Synapse growth in response to continued signaling requires functioning gene transcription and translation. When those genes are mutated or errant, the excitability of the synapse may be inappropriately high, even in the absence of long-term potentiation. As a result, learning and memory functions are compromised, as in autism, and overactivation of the nervous system may increase the risk of developing a seizure disorder.2

Such changes to the synapse signaling pathway have been documented in several genetic conditions related to autism, including West's syndrome, Fragile X syndrome, and Angelman syndrome. In all of these conditions, changes to channels in the synapse affect neuronal excitability, linking the pathophysiology of autism with the pathophysiology of epilepsy.

The links between epilepsy and other neurologic diseases also offer clues to how epilepsy develops over time, indicating a cascade of pathologic events that include early changes preceding the initial seizure event by years. Increased ion channel activation, posttranslational changes, transcriptional events, neuronal death, and inflammation may be some of the early events that ultimately lead to later pathophysiologic effects of epilepsy, such as neuronal sprouting, network reorganization, and gliosis.3

Encouragingly, approximately 35 medications and devices already exist for targeting some of the changes in the early, intermediate, and late pathways that are thought to ultimately lead to epileptic seizures. Potentially, understanding epilepsy as a spectrum of events may lead to earlier treatment. Through the identification of early changes in the early stages of epilepsy pathogenesis, patients may receive preventive treatments before a seizure ever occurs.

According to Jensen, the growth in the understanding of epilepsy hinges on “the intersection of genomics, computational neurophysiology, and basic neuroscience with signaling pathways, gene expression, and cell fate.” With discoveries coming from many disciplines, and the start of translation of these discoveries into clinical care, Jensen called the current status of research and discovery “an extraordinarily amazing time.”


1. Adelöw C, Andersson T, Ahlbom A, Tomson T. Hospitalization for psychiatric disorders before and after onset of unprovoked seizures/epilepsy. Neurology.2012;78(6):396-401.

2. Lamprecht R, LeDoux J. Structural plasticity and memory. Nat Rev Neurosci. 2004;5(1):45-54.

3. Rakhade SN, Jensen FE. Epileptogenesis in the immature brain: emerging mechanisms. Nat Rev Neurol. 2009;5(7):380-391.