Epilepsy Essentials: Screening for Lennox-Gastaut Syndrome

Lennox-Gastaut syndrome (LGS) is a developmental and epileptic encephalopathy with typical onset at age 3-5 years, although rare late-onset cases have been described.^1-3 Diagnostic delay is common, however, and individuals may be older at diagnosis.¹ LGS is characterized electroclinically (ie, with EEG pattern and clinical characteristics).¹ Incidence is approximately 1 in 50,000.

The Challenge of Diagnosing LGS

As with many rare epilepsy syndromes LGS does not have a specific or individual biomarker, but rather is diagnosed by recognizing a constellation of symptoms. Genetic testing cannot confirm the diagnosis but may be helpful in differentiating other potential causes of seizures.⁴ In LGS, the classic triad of symptoms is: 1) having multiple seizure types (eg, drop seizures, generalized tonic-clonic seizures, and myoclonic seizures); 2) developmental delays; and 3) slow spike and wave discharges on EEG. However, that classic triad is not present in every person with LGS. Children may have a small amount of each or a large amount of 1 of these 3 symptoms and almost none of another.

Symptoms of LGS also change over time and this is important to recognize, considering that there can be a delay between symptom onset and diagnosis of LGS. As individuals with LGS age, some symptoms may “drop-out” or cease occurring (eg, having only 1, rather than multiple, seizure types). Developmental delays also increase with age, which can make it more difficult to ascertain just what symptoms a person is experiencing.² Changes in the EEG are not always present at onset. EEG patterns change further with age as slow spike-and-wave discharges evolve into a generalized slowing.⁵ EEG changes may be part of the natural history of the disease but could also be a result of the many antiseizure medications (ASMs) that are typically used for LGS.^6,7

Because not all 3 symptoms must be present for diagnosis and severity of each symptom can range from mild to severe, diagnosing LGS requires not only considering and understanding the full spectrum for each of these 3 different symptoms, but also being able to differentiate the presentation of these symptoms from other epilepsies with overlapping symptomatology.

Seizure Semiology

Among the keys to diagnosis for neurologists is listening to the semiology, or story, of the seizure by asking the questions in Table 1.

It is important to elicit the full seizure semiology for different types of seizures that a person experiences or is witnessed to experience. People and care partners may have difficulty remembering all aspects of seizure episodes or not be aware of different types of seizures occurring. Additionally, if clinicians focus on 1 type of seizure too early, they may miss the bigger picture and mistake LGS for another type of epilepsy in which multiple seizure types do not occur. VideoEEG or even videos taken on a cell phone by a care partner can be very helpful in identifying seizure semiology when witnesses have difficulty describing seizure episodes for any reason.

LGS Is a Syndrome With Multiple Etiologies

Among the most important reasons to pay such close attention to seizure semiology and whether there are multiple seizure types, developmental delays, and slow spike-and-wave discharges or slowing on EEG is that there is no 1 diagnostic test for LGS. This is because LGS is a syndrome—a pattern of symptoms and signs—not a single disease or a specific etiology. In fact, LGS can be caused by any of multiple etiologies.^8,9

There are multiple pathogenic genetic variations that lead to LGS.⁴ Often, children who spent time in the neonatal intensive care unit with severe anoxic encephalopathy or had infantile spasms develop LGS. Neurometabolic diseases such as cobalamin deficiency and amino acid or pyridoxine metabolism disorders, which are typically not diagnosed until later, can also present with LGS. Cerebral dysgenesis and neuronal migration differences have also been implicated as causes of LGS.

A Screening Tool for LGS

Because the complexities of LGS can complicate diagnosis, which can result in suboptimal treatments, colleagues and I used a Delphi consensus process to create a screening tool for LGS (Table 2) in any person with drug-resistant epilepsy (DRE): the Refractory Epilepsy Screening Tool for LGS (REST-LGS).⁹

The screening tool includes major issues as well as items a neurologist may not remember to ask in every encounter, such as whether the person wore a helmet during childhood. These kinds of questions may also be less familiar to adult neurologists or those who see pediatric patients less often, making the screening tool helpful for remembering to ask these questions while taking a history from someone with DRE. The developmental delay that is seen with LGS also makes it important to ask care partners these questions. The LGS foundation estimates LGS diagnosis can take 12 to 15 years and that some people are not diagnosed until their early 30s. Both pediatric and adult neurologists need to be aware not only of the symptomatic triad of LGS but also that symptoms evolve over time.

Expert and nonexpert raters used REST-LGS to evaluate 200 diagnosis-blinded medical records of people with DRE. Moderate-to-good agreement (κ, 0.41-0.60) occurred with expert vs nonexpert evaluators. Although 81% to 85% of the cases reviewed met 1 to 3 major criteria of REST-LGS (Table 2, Items 1-5), the majority of LGS cases met 3 major and 2 to 3 minor criteria (Table 2, Items 6-8). In contrast, cases of nonLGS DRE met 1 or no major criteria and 1 to 2 minor criteria.¹⁰

Why Specific Diagnoses of DRE Matter

Although there are many ASMs approved for treatment of LGS that reduce seizure frequency, with any DRE it is typical that individuals with LGS continue to have seizures while taking multiple ASMs. This might lead clinicians to consider a specific label as less important than finding the best combination of ASMs. However, for people with LGS, there are ASMs—the sodium channel blockers—that often worsen seizures, which is a key reason to differentiate LGS from other DREs.^11,12

Having a specific diagnosis and label can also be extremely meaningful for the family of a person with LGS, allowing them to access specific resources and join in advocacy efforts. The burdens of LGS for families is high and having access to other families and advocacy efforts can reduce the impact of LGS on their quality of life.

Finally, standardizing the questions that are asked during history taking can not only help individual patients and their families, but can also help improve research and understanding of LGS. Better and standardized identification of patients with LGS may also help identify appropriate people for clinical trials to aid development of better treatments for LGS.

Summary

LGS is a complex epilepsy syndrome with multiple causes and requires careful history taking for both current clinical features and how the condition has evolved since onset. Screening both children and adults with DRE for LGS can potentially improve outcomes for patients and their families and care partners. Standardization of such screening may aid in research of the condition and development of new treatments.