LGS Comorbidities
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Lennox-Gastaut syndrome (LGS) is a developmental and epileptic encephalopathy that begins in childhood. It is associated with significantly elevated morbidity and mortality. It remains an extremely rare disorder, accounting for around 5% of all childhood epilepsies. 

LGS is a highly heterogeneous disease, both in terms of initial presenting symptoms and the way the disease progresses. Typically, LGS manifests when a child is between 3 and 5 years of age; however, this condition can have a late onset, though in most cases, symptoms appear before 12 years of age. 

Read more about LGS etiology 

LGS does not have a universally agreed-upon definition. Nevertheless, clinicians tend to recognize a triad of symptoms associated with LGS: refractory seizures, electroencephalographic abnormalities, and cognitive impairment. With regards to seizures, tonic seizures are “a hallmark of LGS,” according to Strzelcyzk and Schubert-Bast in CNS Drugs. Atonic seizures are also characteristic of LGS, though they are slightly less common. 

Atonic seizures can be dangerous because the sudden loss of muscle tone can often result in patients falling. This increases the risk of injuries, especially if they occur on unstable ground. In addition to the risk of poor seizure control, patients with LGS are known to develop intellectual disability and behavioral problems, making it difficult for young patients to adjust to a classroom setting and interact with their peers. 

“Most adults with LGS are unable to live independently due to their intellectual disability, together with seizures that usually continue into adulthood,” Strzelcyzk and Schubert-Bast wrote. “The burden of care for families can take its toll on physical, mental, and emotional health.” 

LGS is an incurable disease; associated symptoms may be partially relieved but never fully resolved. LGS is a condition that is highly drug-resistant. For example, valproate, which is among the first-line medications for this condition, is partially effective against atonic and myoclonic seizures, as well as atypical absences. However, it is teratogenic, and contraception is encouraged among female users of childbearing potential. 

Lamotrigine is among the second-generation antiseizure drugs used to treat LGS. Studies indicate that it can reduce the frequency of all major seizures, and there is some evidence that it has synergistic properties when used with valproate. However, this drug is associated with childhood rash, which may worsen with age. 

Rufinamide represents a prominent third-generation antiseizure treatment licensed for LGS. It works by prolonging the inactive state of sodium channels, which reduces seizure frequency and severity. Although it is generally well-tolerated, it is associated with adverse effects such as somnolence and vomiting. 

The Role of Antiseizure Therapies 

The main point about the current arsenal of LGS therapies is that it is lacking on many fronts. All LGS medications, from first-generation to third, are associated with significant adverse effects, and none are curative. LGS is notorious for being resistant to various antiseizure medications, despite seizures being the most pressing manifestation of the disease.

“Despite recent breakthroughs, with newly approved and upcoming treatments, patients continue to experience a significant burden,” Strzelcyzk and Schubert-Bast wrote. 

Read more about LGS treatment 

 In Developmental Medicine & Child Neurology, Zhang and colleagues revisited this issue by comparing and ranking the efficacy and safety of antiseizure medications commonly prescribed in LGS. 

They reviewed a total of 8 randomized controlled trials involving 1171 patients with LGS, focusing on 6 antiseizure medications, some of which have been previously discussed: lamotrigine, rufinamide, cannabidiol, topiramate, clobazam, and felbamate. 

The research team discovered that, compared to placebo, all 6 antiseizure medications achieved a significantly higher response rate. In other words, despite known deficiencies, antiseizure medications can generally help manage seizures in LGS—the more important question is the margin at which they do so. 

Zhang and colleagues identified rufinamide, cannabidiol, and topiramate as antiseizure medications that have a 50% or more probability of reducing the occurrence of drop seizures. The research team identified topiramate as the drug that has the greatest likelihood of helping patients achieve seizure freedom. 

Nevertheless, the safety profile of all 6 antiseizure medications leaves much to be desired; suffice it to say that there is much room for improvement in developing any future LGS therapeutics. And this sets the tone for the direction of travel in laboratories across the globe working to develop new therapies for LGS: forward-facing, focused on minimizing symptoms and daily disruptions and keeping adverse events to the bare minimum. 

According to Zhang et al, “no monotherapy drug treatment has been shown to be highly effective for this syndrome,” and it is most suitable to describe currently available antiseizure medications as “adjunctive” as opposed to “therapeutic” in the strict sense of these words. So the world looks to new LGS therapeutics, a task made more difficult in that LGS tends to manifest in childhood, making recruiting study subjects much more challenging. Nevertheless, the successful treatment of a myriad of childhood illnesses indicates that this, too, can be overcome, given space and time. 


Strzelczyk A, Schubert-Bast S. Expanding the treatment landscape for Lennox-Gastaut syndrome: current and future strategiesCNS Drugs. Published online January 21, 2021. doi:10.1007/s40263-020-00784-8

Zhang L, Wang J, Wang C. Efficacy and safety of antiseizure medication for Lennox-Gastaut syndrome: a systematic review and network meta-analysisDev Med Child Neurol. Published online September 30, 2021. doi:10.1111/dmcn.15072