Chapter 9 The Life-Threatening Epilepsies of Childhood and Their Treatment
In this chapter, we will define what the epileptology community usually calls “catastrophic epilepsies” as life-threatening epilepsies. To define them more precisely, we should rather consider the notion of “epileptic encephalopathy.” Epileptic encephalopathies (EE) are conditions in which neurologic deterioration results from the epileptic phenomenon by itself. It is usually considered that EE result from subcontinuous paroxysmal “interictal” activity (such as continuous spikes and waves during sleep), but most authors also include in the spectrum of EE the severe conditions due to seizures themselves (such as Dravet syndrome). To extensively cover the different problems posed by these severe epilepsies at pediatric age, we shall extend childhood to early age, from 1 month to 2 years, usually distinguished as “infancy.”
EE represent about half of the pharmacoresistent epilepsies in childhood, the other half being partial epilepsy. EE disclose several characteristics when compared to adult epilepsies. Most of these characteristics depend on the fact that epilepsy occurs in a developing brain and take into account the following as far as therapeutic trials are concerned:
Rather than an exhaustive review of the life-threatening epilepsies of childhood, we will extensively present four syndromes that differently illustrate the various specificities of EE detailed earlier: infantile spasms (IS), Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and continuous spike waves during sleep (CSWS). They all are highly pharmacoresistent syndromes, but they represent completely different conditions regarding developing drugs. LGS benefited from a significant number of randomized controlled trials with four new drugs approved within the last 15 years. IS has two alternative therapeutic options approved, but DS has only one and CSWS none. The historical approach of the various drug trials within these four syndromes provides a complete view of the problems and the possible solutions for developing new compounds in the life-threatening epilepsies of childhood. Therefore, other life-threatening epilepsies such as myoclonic-astatic epilepsy (MAE), Rasmussen encephalitis, hemimegalencephaly, or Sturge-Weber disease are not included in this chapter.
LGS develops between 2 and 8 years of age. It is a combination of various seizure types, mostly tonic and/or atonic seizures (usually called “drop-attacks” for their risk of falls and recurrent injury) and atypical absences, sometimes appearing as status epilepticus. On electroencephalogram (EEG), bilateral slow spike waves (< 2.5 Hz), generalized with bifrontal predominance, and bursts of rapid (10 Hz) rhythms during slow sleep (often corresponding to subclinical seizures) are most important for diagnosis. Psychomotor delay is present in 90% of cases, with slow behavior and frontal disorders as predominant symptoms. LGS can be cryptogenic in children with a previously normal development or symptomatic of congenital or acquired brain anomalies. Other types of epilepsy, especially IS, may precede LGS. Even if development was delayed prior to the onset of LGS, further mental deterioration is the rule due to persistently high rates of seizures together with interictal abnormal activity. Treating epilepsy has therefore ever been a key point in LGS.
The open antiepileptic drugs (AEDs), the most used in LGS (valproate, benzodiazepines, and phenytoin), as well as ACTH and steroids, or the nondrug treatments, including ketogenic diet, corpus callosotomy, or vagal nerve stimulator, all remain poorly beneficial.2 Felbamate was the first of the new drugs shown to be effective in LGS by using the methodology of double-blind placebo-controlled adjunctive therapy in a randomized controlled trial (RCT).3 The risk of medullar aplasia and hepatotoxicity let the drug be proposed as the third line of treatment in severe cases. Then lamotrigine showed 33% of the lamotrigine group and 16% of the placebo group experienced a more than a 50% reduction in the frequency of all major seizures, including drop attacks. Global evaluations of patients’ functioning in terms of speech, language, and attention were significantly improved in the lamotrigine group.4 The efficacy of topiramate was also demonstrated for tonic seizures, and drop attacks at 3 months5 and maintained at long term in more than 50% of the patients.6 More recently, patients on rufinamide experienced a significant reduction in total seizure frequency and in drop attacks compared to patients on placebo, with 43% of responders for drop attacks compared to 17% on placebo.7
Despite this relatively high number of randomized controlled trials (the highest for an EE in children), the current management of LGS remains somewhat disappointing. The new drugs finally disclosed moderate efficacy (one-quarter to one-third of responders, less than 4% seizure-free patients), and comparative data are not available. Three of the drugs are associated with potentially severe adverse reactions (aplasia and hepatitis with felbamate, skin rash with lamotrigine, cognitive disorders with topiramate). A need remains for new well-tolerated drugs for LGS.
The prevalence of LGS is considered to be a maximum of 1 per 10,000 that meets the prevalence proposed for an orphan indication. The last new drug, rufinamide, was developed as an orphan drug for LGS in Europe, as clobazam currently is in the United States (this benzodiazepine is commonly prescribed in Europe and Canada as adjunctive therapy in LGS).
Several types of seizures coexist in LGS; each of them may be present in types of epilepsy that are not LGS. Clinical trials in LGS should therefore include EEG features in diagnosis criteria and several seizure types as efficacy endpoints to select the drug appropriate for the epileptic syndrome, as opposed to the current approach, which is based on the seizure type. LGS provided the first attempt to perform a trial dedicated to a specific syndrome, using felbamate in 1993.3
LGS is a recognized distinct medical condition, but one of the more challenging aspects of LGS is the distinction from other childhood epilepsies that might mimic either the EEG or clinical pattern. For example, trying to differentiate LGS from MAE may be highly difficult based on age of onset, seizure type (especially in LGS forms with myoclonic jerks and MAE forms with tonic seizures), and slow spike-and-wave patterns on EEG.8 Only one feature is pathognomonic of LGS, the bursts of rapid (10 Hz) rhythms during slow sleep. However, it has not been required as diagnostic criteria for trials until now, mainly because it needed sleep EEG, which could not be systematically performed. As a result, among the patients included in the LGS trials, some likely matched more closely with MAE than with LGS. Further trials should ideally include this EEG feature, at least for stratifying the analysis on a subgroup of “pure” LGS patients.
Another issue is the lack of specific data for the pediatric group in LGS. The trials, which were conducted with felbamate, lamotrigine, and topiramate included both adults and children, but neither the study design nor statistical analysis specifically took into account the pediatric subgroups. Because the syndrome looks different and carries different prognosis in children and in adults, further trials should present the results separately in the two populations, as the last rufinamide trial did.
IS usually occurs between 3 and 8 months of age, with a peak at 4 months. More and more cases have been reported with onset later than 1 year, which seem to be considered separately. Diagnosis lies on the classical triad, which associates a specific type of seizures (epileptic spasms), a specific EEG pattern (hypsarrhythmia), and psychomotor deterioration. In fact, one of the three components may be lacking or be atypical. Epileptic spasms consist of axial contraction in flexion or extension, in clusters that correspond to a large slow wave or to flattening with rapid rhythms on EEG. Spasms may be clinically subtle or even subclinical, particularly at onset of the disease or when they are incompletely controlled, thus making EEG a necessary tool to prove their complete disappearance. The features of spasms may be either symmetric or asymmetric. Video recording is often required for detailed analysis because asymmetry of spasms or a focal discharge combined with them are arguments for a focal cortical lesion to be at the origin of IS. Psychomotor deterioration is usually rapid from epilepsy onset, affecting head control, reaching for objects, defect in visual and auditive attention, and eye–hand coordination.10,11