New and exciting research is ongoing to determine how inflammation may be involved in epilepsy development.
While this area of research is often complicated due to the immune and nervous systems' complex natures, several studies have made significant headway.
With ongoing research, there is great potential for the development of effective therapeutic options.
Lennox-Gastaut syndrome (LGS) is a seizure disorder that can arise from a number of different etiologies, including structural abnormalities of the brain; remote injury to the brain; or genetic variations. In up to 1 in 4 cases the etiology is never determined.
While diagnosis—and treating LGS—can be complicated, there has been significant headway in research over the past few years that has led to advances and potential for new therapeutic options.
Treating LGS means preventing seizures, which generally involves anti-seizure medications. Classically, medications like valproate have been helpful, but over the last few decades many new medications have been studied.
Here is a timeline of FDA-approval for medications to treat LGS:
2018: Prescription cannabidiol (CBD)
Other medications, like levetiracetam, zonisamide, or perampanel may be helpful, but are not yet FDA-approved. Current clinical trials are evaluating safety and efficacy of medications like carisbamate, soticlestat, and retigabine/ezogabine.
Other options for seizures that are resistant to medications include a medical ketogenic diet; surgery, including callosotomy; and vagal nerve stimulation.
Focus on inflammation
It is fascinating that regardless of etiology, LGS presents at a similar age, with similar seizure semiology and similar findings on EEG. Clearly the developmental stage of the brain is important in the evolution and presentation of seizures. Another important factor may be inflammation.
There is a strong connection between inflammation and seizures, particularly in children.
Children under the age of 5 with fevers may have “febrile seizures,” even in the setting of a mild viral illness, which can be accompanied by a rise in levels of inflammatory agents in the cerebrospinal fluid. In older children, respiratory viruses may lower the seizure threshold, even in absence of fever. Infectious meningoencephalitis, antibody-positive autoimmune encephalitis and Febrile Infection-Related Epilepsy Syndrome all cause high levels of inflammation and are associated with frequent intractable seizures.
Seizures may cause inflammation in the central nervous system as well. Signs of chronic inflammation are found in animal models of epilepsy and in human brain tissue resected due to intractable epilepsy—including proliferation of astrocytes, activation of microglia, and cytokine release. It is not clear whether inflammation generated by a seizure is harmful or protective.
In cases of LGS without a clear genetic or structural etiology, some researchers have postulated that the underlying cause may be neuroinflammation.
Some children with LGS have been found to have higher levels of immunoglobulins in the serum and different frequencies of certain HLA-antigens; however, these differences have not been shown consistently across studies.
Some treatments for epilepsies may be immunomodulatory as well. A strict high-fat, low-carbohydrate and low-protein ketogenic diet (KD) is a well-established treatment for seizures intractable to medications, and KD is frequently used in seizure disorders like LGS.
It is unclear exactly how KD works to reduce seizure frequency, but there is some evidence that the diet changes the inflammatory profile of the brain, possibly through effects on the gut microbiome.
What this means for you
The immune system and the nervous system are both incredibly complex. Both change dramatically in the course of pediatric development; both can have rapid and sometimes long-lasting responses to the environment; and outcomes can depend on the location and magnitude of the response. It is therefore incredibly difficult to determine how inflammation may be involved in the development of epilepsy, but it is an exciting avenue of research, with great potential for the development of therapeutic options.