Although a prompt and accurate diagnosis of Lennox-Gastaut syndrome (LGS), a rare and severe form of epileptic encephalopathy, is necessary to effectively manage this condition, diagnosing it is difficult for various reasons.

While treatment options are limited, knowing how to spot the signs of LGS can help physicians diagnose and manage this disorder in young people.

 

A diagnosis that flies under the radar

LGS is an uncommon disease that can easily be missed initially. The clinician needs to always keep LGS on the differential when encountering a patient with treatment-resistant epilepsy with multiple seizure types and intellectual disability.

The prognosis for LGS is poor, with a 5% mortality rate and 80%–90% continuing to experience seizures into adulthood with the types of seizures evolving with time, according to an article published in Epilepsia.

Bourgeois BF, Douglass LM, Sankar R. Lennox-Gastaut syndrome: a consensus approach to differential diagnosis. Epilepsia. 2014;55 Suppl 4:4–9.

 

The epileptiform features of LGS can lead to progressive dysfunction. One study cited by the Epilepsia authors found that the risk of mortality in children with LGS was 14 times greater than that of the general population.

LGS can stem from various etiologies, its clinical presentation varies, and it exhibits variable seizure types and EEG findings that change over time. LGS has no biomarkers and the greater medical community debates various factors of its pathology and diagnosis.

Clinicians should keep in mind that due to its polymorphic nature and variable presentations, a systematic approach is needed for the evaluation and diagnosis of LGS. This condition is often mistaken for others, which delays diagnosis and appropriate treatment, according to the Epilepsia research. Additionally, often the most characteristic clinical features are absent or subtle at the beginning of the disease, and often the disease is unrecognized resulting in a delayed diagnosis. 

 

How LGS presents

LGS affects 1–2 births per million, and is more common in males.

Lennox-Gastaut syndrome. MedlinePlus. Updated September 14, 2022.

 

Often, patients will have other epilepsy syndromes (West Syndrome or infantile spasms) that evolve into LGS.

Although patients demonstrate multiple types of seizures, the most common type is tonic, resulting in the uncontrollable bilateral contraction of extremities, which often occurs during sleep. When these seizures occur during waking hours, they may increase the risk of falls.

Another common form of seizure in these patients is atypical absence seizures, which can result in a brief partial or complete loss of consciousness.

Drop attacks can also present, which lead to sudden falls and serious/life-threatening injuries. These attacks are characterized by a sudden loss of muscle tone (ie, atonic) followed by abnormal muscle contraction (ie, tonic).

More than two-thirds of patients experience prolonged periods of seizure activity (ie, status epilepticus). Brief seizures tend to cluster in episodes.

LGS has a characteristic regression or plateau of neurodevelopmental milestones that is progressive. Intellectual disability is characteristic in children with LGS, with learning issues evident even before the onset of seizures.

These concerns can worsen over time—especially if the seizures are frequent or severe. Concomitant neurological abnormalities and behavioral problems, as well as delayed development of motor skills such as walking/crawling, can also occur.

 

Diagnosing LGS

The classic diagnostic triad for LGS involves multiple seizure types, slow (≤2.5 Hz) spike-wave patterns on the interictal EEG, and cognitive impairment.

Even adults can be diagnosed with LGS. Furthermore, normal or abnormal imaging doesn’t play a big role in diagnosis, according to the Epilepsia research.

LGS is often preceded by West syndrome (infantile spasms), which can delay diagnosis. Symptoms of LGS most often occur due to neuronal damage from prenatal/perinatal insults, malformations, infections, neurocutaneous syndromes, or tumors. Specifically, cortical dysplasia, or abnormalities to the cerebral cortex, can result in LGS, according to Epilepsia.

LGS can consist as part of a “constellation” of pathology such as tuberous sclerosis complex. Various mutations have been linked to LGS, but these only occur in small pockets of individuals. Most mutations that yield LGS are sporadic, although family history for epilepsy is positive in 3%–30% of patients.

According to an International League Against Epilepsy position paper published by Epilepsia, as many as 25% of patients have a history of infantile spasms, while as many as 40% of children have no known etiology.

Specchio N, Wirrell EC, Scheffer IE, et al. International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: Position paper by the ILAE Task Force on Nosology and Definitions. Epilepsia. 2022;63(6):1398–1442.

 

 

Prognosis and treatment

Most people with LGS require lifelong assistance with activities of daily living due to seizures and intellectual disability, although a minority of them can live independently. There is no known cure for LGS, and normal development and complete resolution of seizures are uncommon.

Valproate is generally considered first-line therapy for various seizures, with other options including clobazam, felbamate, lamotrigine, rufinamide, fenfluramine, and topiramate.

Cannabidiol (Epidolex) was approved in 2018 to treat LGS seizures in patients aged 2 years or more. This drug contains only minimal psychoactive ingredients, and no resulting euphoria has been documented. Randomized trials have found cannabidiol to be most effective in reducing the overall frequency of drop attacks by as much as 44%, according to research published by Lancet.

Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (Gwpcare4): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391(10125):1085–1096.

 

Non-pharmacologic strategies for LGS cited in research published by the National Institute of Neurological Disorders and Stroke include the ketogenic diet, vagus nerve stimulation, and corpus callosotomy.

Lennox-Gastaut syndrome. National Institute of Neurological Disorders and Stroke. Updated July 25, 2022.