Overcoming Challenges in the Diagnosis of Rare Childhood-onset Epilepsies

Lennox-Gastaut syndrome (LGS) and Dravet syndrome are two rare, childhood-onset epilepsy disorders that pose considerable challenges to patients, families and clinicians. Striking infants, toddlers and young children, and persisting throughout life, LGS and Dravet syndrome have several complex symptoms, including life-threatening seizures. Compounding the burden of both of these debilitating conditions is the difficulty in achieving an accurate diagnosis to support patient care.

Complex Diagnosis and Disease Management

While LGS and Dravet syndrome share common features, the characteristics of each syndrome and the variability of symptoms over time present unique challenges to the proper diagnosis and optimal care of each disease. 

In LGS, the first signs of the disease typically present between two and eight years of age (peak onset between three and five years old) and include a triad of clinical features: multiple seizures, a signature EEG pattern, and developmental delay. The evolving nature of the condition, however, and the presence of comorbid, non-seizure factors such as other neurological problems and mobility issues, combine to create a high bar for identifying LGS. In fact, it is not unusual for the diagnosis of LGS to be missed until later in life, including adulthood.

“The root of the challenge in diagnosing LGS is its variability since not all children present with the characteristic symptoms at onset or at any one time,” said Mary Holmay, national director, medical science liaisons at Greenwich Biosciences. “As they get older, their symptoms can also change. Patients also present with cognitive impairment, which is consistent with other epilepsy syndromes. These factors can make a clear cut diagnosis very challenging.” 

Progress in Genetic Testing

Although it shares overlapping signs with LGS, Dravet syndrome presents earlier – within the first year of life – and usually in a developmentally normal infant. The initial presentation of Dravet syndrome usually includes prolonged, recurrent convulsive seizures. Patients with Dravet syndrome are typically highly sensitive to increased body temperature. And while initial seizures may be triggered by fever or infection, they may also be misdiagnosed as more benign febrile seizures in an infant with a normal EEG. 

One factor that is aiding the diagnosis of Dravet syndrome is genetic testing. Unlike LGS, approximately 85 percent of patients with Dravet syndrome have the mutation of the SCN1A (sodium voltage-gated channel alpha subunit 1) gene. While a confirmatory genetic diagnosis is helpful in identifying the syndrome at a young age, there is caution on exclusively relying on the test. 

“The field of epilepsy has come a long way with the advent of genetic testing for Dravet syndrome,” said Tyler Story, senior director, medical affairs at Greenwich Biosciences. “But there is a risk in relying too much on lab values and genetic tests when diagnosing the syndrome. The presence of SCN1A and other Dravet-related mutations without clinical signs is not sufficient by itself for diagnosis; and the absence of an SCN1A mutation does not definitively rule out Dravet syndrome.”

Bearing the Burden

Difficulty diagnosing LGS and Dravet syndrome early-on can result in years of uncontrolled seizures and long-lasting adverse consequences on patient learning, behavior and socialization. Moreover, lacking an accurate diagnosis, patients are frustratingly often out of reach of the medications that may help control their seizures. In the case of Dravet syndrome, mis-diagnosis is burdensome for patients since most show limited response to antiepileptic therapies approved for other syndromes.1,2 Holmay notes that the wrong medications can even make the condition worse. 3 
Beyond the clinical realm, the consequences of under- and mis-diagnosis of LGS and Dravet syndrome have a dramatic impact on the quality of life of patients and their families.

“Without a specific diagnosis, families can’t get connected to the patient communities in LGS and Dravet syndrome where they can engage with others who share similar experiences,” said Story. “It’s so important that families feel they are not alone – that they can connect within a community to gain support, learn about medications and gain advice on managing the physical and emotional toll of these conditions.”

Power of Collective Voice

Today, while LGS and Dravet syndrome remain a challenging clinical diagnosis, there is positive change that is bringing optimism to patients, families and clinicians.

“I’ve worked in the field of epilepsy for over 20 years and have seen firsthand the progress made by advocacy groups and others in amplifying the voice of patients,” said Holmay. “This dialogue has helped make rare diseases like LGS and Dravet syndrome more top of the mind within the clinical community. This is bringing improvements in clinical diagnosis, promoting research on appropriate medications and driving the productive social engagement that benefits patients. We have come a long way.”

Story adds, “The rare disease community has shown a great example of what can be achieved if academia, industry and government collaborate to amplify the voice of patients. There is a lot of power in all of us working together.”

For additional information on Lennox-Gastaut syndrome and Dravet syndrome, visit www.takeonepilepsy.com

  1. Wirrell EC, Laux L, Donner E, et al. Optimizing the diagnosis and management of Dravet syndrome: recommendations from a North American consensus panel. Pediatr Neurol. 2017;68:18-34 e13.
  2. Chiron C, Dulac O. The pharmacologic treatment of Dravet syndrome. Epilepsia. 2011;52 Suppl 2:72-75.
  3. de Lange IM, Gunning B, Sonsma ACM, et al. Influence of contraindicated medication use on cognitive outcome in Dravet syndrome and age at first afebrile seizure as a clinical predictor in SCN1A-related seizure phenotypes. Epilepsia. 2018;59:1154–1165.