Lennox-Gastaut syndrome (LGS), one of the catastrophic epilepsies of childhood, is classified by the International League Against Epilepsy as a symptomatic generalized epilepsy syndrome. Originally described in 1966, this “epileptic encephalopathy” requires 3 components for diagnosis.1
First, children must exhibit multiple seizure types. Tonic seizures (especially during sleep), atonic (astatic or drop attacks) seizures, and atypical absence seizures are most commonly observed; some patients also develop myoclonic, generalized tonic-clonic, or partial seizures. Nonconvulsive status epilepticus is quite frequent, occurring in over 50% of LGS patients. The second feature required by the definition is an interictal awake electroencephalogram (EEG) pattern consisting of slow spike wave discharges (less than 3 Hz), usually with a generalized distribution. Another characteristic EEG feature is paroxysms of low voltage fast activity at about 10 Hz during sleep. The third component of the definition of LGS is cognitive impairment involving moderate to severe mental retardation and behavioral disorders including aggression and autistic features.
Over 75% of children with LGS have an identifiable cause (symptomatic or presumed symptomatic/cryptogenic). These include numerous congenital or acquired etiologies, such as cortical maldevelopment, perinatal hypoxia-ischemia, CNS infection, or neurometabolic disorders. About 20% of children with LGS have prior infantile spasms (West syndrome) and evolve into LGS with age. The typical age of onset of LGS is between 2 and 5 years; boys are affected about 5 times more often than girls.5
The prognosis of LGS is poor, with regard to both seizures and cognitive outcome. Risk factors for a poor cognitive prognosis include symptomatic etiology, history of nonconvulsive status epilepticus, prior infantile spasms, and early age of seizure onset.6
Due to the encephalopathic nature and multiple seizure types, LGS is notoriously difficult to treat.7
Many drugs reduce seizures initially, only to lose effectiveness over time. Children often end up on polypharmacy with numerous anticonvulsants, which adds to the cumulative side effects and drug–drug interactions.3
Furthermore, the seizures themselves are thought to contribute to the cognitive impairment and behavioral comorbidities.
Difficulties in diagnosing LGS are discussed in detail in a recent review.4
Sometimes the classic clinical and EEG features are not present at the onset of the syndrome. Due to the heterogeneous causes, the diagnosis may be delayed or uncertain, at least initially. Some aspects of the seizure semiology can be confusing. For example, it can be difficult to differentiate between spasms and tonic seizures and to identify and quantify atypical absence seizures accurately. Some rapidly secondarily generalized seizures can also mimic seizure types seen in LGS.
Many treatment attempts in LGS are anecdotal and empirical. Systematic difficulties complicate performance of drug trials in LGS, including the very frequent occurrence (often nearly uncountable) of atypical absence seizures, the inaccuracy of parental reports of seizure semiology and frequency, the wide range of etiologies, and the evolution of seizure types over time.
A few randomized, double blind, placebo-controlled trials of single agents have been performed in LGS.5
reduced the occurrence of atonic and tonic-clonic seizures in children with LGS. All of these studies entailed addition of the study drug to other medications, and the studies varied considerably in their experimental design and patient selection criteria. No head-to-head trial comparing more than one drug has been published.
Even with the new generation of anticonvulsants, valproic acid is considered the most useful initial medication of choice for drop attacks, atypical absences and myoclonic seizures in LGS.5
Although there are no controlled studies, valproic acid is reportedly effective against multiple LGS seizure types including atypical absence, myoclonic, and other situations in which slow spike-wave discharges are found on EEG. Caution must be exercised in using valproic acid in children under the age of 2 years, especially if they are receiving several other anticonvulsants, because of the risk of hepatotoxicity. In that age group, it has been recommended to try topiramate or lamotrigine first.11
Felbamate could also be considered as an alternative to valproic acid, because felbamate lacks the sedative side effect seen with other anticonvulsants (eg, topiramate, benzodiazepines), which exacerbates seizure occurrence. Owing to the risk of aplastic anemia and hepatoxicity with felbamate use, this medication must be used with caution and appropriate patient monitoring of blood levels, liver function, and hematologic indices. Caretakers must be provided detailed information about the potential risks of felbamate. The effects of benzodiazepines are variable. A recent study showed that clobazam significantly reduced both drop and non-drop seizures in a dose-dependent manner in patients with LGS.13
Clobazam reportedly has less sedative effects than other benzodiazepines, making it an attractive potential adjunctive treatment for LGS.
An animal model of LGS does not exist, hampering progress in design of therapeutics. It is not surprising that there is no experimental model, since LGS comprises so many distinct seizure types and lacks a consistent underlying etiology. Treatment of rats with a cholesterol synthesis blocker produces atypical absence seizures with slow spike waves, providing an opportunity to study the mechanism of this specific seizure type, which appears to involve GABAB
These observations have not yet been exploited therapeutically.
Some general treatment considerations include recommendations to use as few anticonvulsants concurrently as possible to avoid side effects from polytherapy, avoid excessive drowsiness which exacerbates several of the seizure types in this syndrome, and consider the cognitive and psychological comorbidities which result from both LGS and its treatment. Clearly, a multidisciplinary approach is required to address the medical and psychosocial aspects of LGS. At present, authorities recommend valproic acid as the first line medication, followed by one or two of the second-line agents (lamotrigine, rufinamide, topiramate, clobazam, felbamate, levetiracetam).5
If those therapies fail to achieve treatment goals, zonisamide, the ketogenic diet, vagus nerve stimulation, or corpus callosotomy can be tried (the latter targeting drop attacks). Of note, carbamazepine and gabapentin can exacerbate some of the seizure types in LGS.11
The role of newer anticonvulsants such as vigabatrin and zonisamide remain undetermined in LGS.