by Edwin Trevathan, M.D., M.P.H.
Dr. Trevathan is Associate Professor of Neurology & Pediatrics at Washington University School of Medicine and Director of the Pediatric Epilepsy Center at St. Louis Children's Hospital .
Lennox-Gastaut syndrome (LGS) accounts for only about 4% of all childhood epilepsy, yet LGS is a very important epilepsy syndrome because of resistance of the seizures to treatment with routine anti-epileptic drugs (AEDs) and the severe co-morbidities. Injuries due to falls from seizures are common, over 90% of children with LGS have some degree of mental retardation, and cerebral palsy occurs in about half of children with LGS. In addition children with multiple seizure types but who do not meet diagnostic criteria for LGS comprise another 5% of children with epilepsy; therapies proven useful for LGS are the same treatments typically used for all children with multiple seizure types.
History and diagnostic criteria
In the early 1930's William Lennox described the clinical features of ‘epileptic encephalopathy' - an entity that included those with multiple seizure types and mental deficiency. In late 1930s Lennox and Gibbs described ‘slow spike and wave' that was thought to be a variant of the spike and wave they had previously described in petit mal epilepsy. Lennox in 1945 and Lennox and Davis in 1950 published the symptomatic triad of; (1) slow spike and wave on EEG, (2) ‘mental deficiency', and (3) three seizure types (that we now refer to as atypical absence seizures, myoclonic seizures, and head drop attacks evolving to axial spasms and falls). In 1966 Gastaut expanded upon the original observations of Lennox and Davis. Gastaut's contribution, largely derived from the thesis of Charlotte Dravet, incorporated more clinical details, verified the EEG findings reported by Lennox, and documented the poor cognitive outcome. Based upon the contributions of Lennox and colleagues and Gastaut, Dravet and colleagues of the Marsielles school, the term ‘Lennox-Gastaut Syndrome' was adopted.
Clinical investigators have refined the diagnostic criteria of LGS over the last thirty years, but the essential elements of the syndrome have remained unchanged since Lennox and Davis' publication in 1950. The syndrome is currently defined by several criteria:
(1) multiple seizure types including atypical absence and seizures resulting in falls (axial tonic, massive myoclonic, and atonic seizures);
(2) EEG demonstrating slow spike and wave (< 2.5 hertz) and bursts of fast rhythms at 10-12 hertz during sleep (see figures below); and
(3) static encephalopathy and learning disabilities, most often associated with profound mental retardation.
Other seizure types usually are present including generalized tonic-clonic seizures and partial seizures.
Distinguishing LGS from other epilepsy syndromes may be particularly challenging; comparing the diagnostic criteria used for LGS between different clinical series and clinical trials is somewhat frustrating, as it is often unclear as to whether consistent application of the terms is used between authors. Some authors have considered that there is a continuum between the more severe generalized epileptic encephalopathies with multiple seizure types (e.g., LGS) and cases of myoclonic astatic epilepsy (MAE) who typically enjoy a much better prognosis. Other authors have considered LGS to be a symptomatic epilepsy and MAE to be genetically determined.
Figure A. Slow spike-wave associated with Lennox-Gastaut syndrome
Figure B. An electrodecremental response associated with tonic or atonic seizures in Lennox-Gastaut Syndrome
Figure C. ‘Fast recruitment rhythms' associated with Lennox-Gastaut syndrome
LGS represents about 5% of childhood epilepsy, with a prevalence of about 2.6 per 10,000 children at 10 years of age. The presence of slow spike-wave on EEG among children with multiple seizure types predicts the co-existence of profound mental retardation. Children with LGS are also more likely to have cerebral palsy than children with multiple seizure types but without slow spike-wave on EEG and multiple seizure types. Oguni and colleagues documented the progressive decline in IQ and progressive gait disturbances with age that were associated with worsening of the epileptic encephalopathy of LGS. In an analysis of 101 patients with LGS, Hoffmann-Riem and colleagues reported that non-convulsive status epilepticus significantly increased the odds of severe mental retardation. The risk of serious injuries from falls associated with seizures is high. Up to 10% of children with LGS die prior to age 11 years.
Before the introduction of valproic acid in the 1970's a variety of AEDs were used in the treatment of seizures associated with LGS. Phenytoin (Dilantin®) is probably helpful for the axial spasms, but may exacerbate the frequency of absence seizures. Barbiturates have some apparent efficacy, but are associated sedation and anecdotal reports of exacerbation of seizures in some patients. Likewise, benzodiazepines (e.g., clonazepam, lorazepam) have long been used to treat seizures associated with LGS, especially clusters of seizures that often accompany even the most minor of febrile illness or minor physical stress. Rare anecdotes suggesting an increased risk for development of tonic status epilepticus among children with LGS have limited the use of benzodiazepines by some epileptologists. Clobazam and nitrazepam, each available in Canada and Europe but not marketed in the USA, have reduced the frequency of seizures among children with LGS in an open label study. Some authors have reported that clobazam is better tolerated than other benzodiazepines such as clonazepam or nitrazepam, but comparative studies have not been published.
Succinimides, especially methsuximide (Celontin®), may have an adjunctive role in the treatment of atypical absence, tonic and myoclonic seizures associated with LGS. Ethosuximide may reduce the frequency of atypical absence seizures in some patients. Trimethadione (Tridione®) is a rarely used drug with considerable efficacy in absence seizures, and possible efficacy, myoclonic, and atonic seizures of LGS. There have been no controlled trials of methsuximide or of trimethadione in LGS. Unfortunately trimethadione is only available now via a compassionate use protocol. Bromides have not been shown to be effective in LGS, yet on a few occasions I've found bromides to be apparently effective in open label treatment of refractory clonic seizures associated with LGS.
Acetazolamide (Diamox®) is typically well-tolerated has been shown to have efficacy against multiple types of seizures. The role of acetazolamide among patients with LGS may deserve further study, especially since another carbonic anhydrase inhibitor (topiramate) has recently been proven to reduce atonic seizures in children with LGS.
ACTH has been reported to benefit patients with LGS, but side effects and lack of objective data regarding benefit have limited interest in ACTH. Roger and colleagues have suggested that if corticosteroids are given early in the course of LGS that long-term benefit may be achieved, but controlled data are not available.
Valproic acid was approved for use in the 1970s. Although randomized clinical trials have never been conducted to prove efficacy of valproate in LGS, most epileptologists have viewed valproate as a first-line drug for LGS since the early 1980's because of: (1) VPA's efficacy against partial seizures and generalized seizures (including absence); (2) lack of exacerbation of any of the seizure types associated with LGS; and (3) relative lack of sedative side-effects compared to barbiturates. The major risks of VPA are increased risk of neural tube defects in the offspring mothers taking VPA during the first trimester of pregnancy, idiosyncratic hepatic failure, and pancreatitis. All females of child-bearing age with LGS should receive adequate birth control and folate supplementation.
In the early 1980's anecdotal reports of the possible efficacy of cinromide in the treatment of LGS led to the first major multi-center clinical trial of treatment for LGS. Seventy-three patients entered the double-blind, placebo-controlled trial that was terminated prematurely because of no efficacy. The cinromide study was important for two reasons. First, the cinromide study documented the "enormous commitment by investigators and their staff, by consultants, by the sponsor, and most notably by the patients' parents" in terms of time, documentation, and patient recruitment and retention in controlled trials of this complex patient population. Defining and recruiting a homogenous population of patients with LGS was difficult, requiring multiple centers. Identifying and quantifying seizures activity in LGS is very difficult; many of these patients have seizures that are difficult to classify, and their frequent seizures (especially myoclonic and atypical absence) are often difficult to quantify. Second, the cinromide study demonstrated an unexpectedly large placebo response, much like all subsequent clinical trials of LGS, emphasizing the importance of viewing open-label studies with a degree of skepticism and making clinical decisions when possible based upon the results of well-designed controlled clinical trials.
Felbamate (FBM) efficacy among children and adults with LGS was documented in a double-blind, placebo-controlled trial. Seizure frequency was assessed by guardian report and by serial 4-hour EEG-video monitoring sessions during the course of the study. FBM significantly reduced the number of atonic seizures compared to placebo in both the treatment and the maintenance phases of the study, and there was a significant reduction of all seizure types among FBM-treated patients. A dose-response relationship was demonstrated for reduction of atonic seizures, with a linear reduction in the number of atonic seizures per day with increasing plasma FBM levels; 5 patients had no atonic seizures during the maintenance phase. In an open-label follow-up FBM study, patients who converted from placebo to FBM had the same degree of improvement on FBM as those who received FBM during the trial. At the end of the double-blind trial only 2 of the 22 subjects randomized to placebo had experienced a > 50% reduction in atonic seizure. However, during the first month that these patients from the placebo group were treated with FBM 12 of the 22 subjects (55%) had a > 50% reduction in atonic seizures.
In a study of the efficacy of FBM as add-on therapy to VPA in LGS, VPA was found to have a significantly reduce the frequency of drop attacks after controlling for the effect of FBM. The authors concluded that the therapeutic effect of FBM on drop attacks is due in part to increased VPA levels, but that a synergistic effect of the two drugs likely resulted in a reduction in overall seizure frequency.
No pattern of serious adverse events due to FBM was apparent at the time of FDA approval in 1993. By the summer of 1994 120,000 patients had been exposed to FBM and reports of both aplastic anemia and hepatic failure had been reported to Wallace Laboratories and the FDA. After letters had been sent to over 200,000 physicians in the USA informing them of these new risks, most patients were withdrawn from FBM. Recent analyses have led to better estimates of the risk of FBM. Kaufman, et.al. reviewed all case reports of aplastic anemia among patients treated with FBM. The incidence of aplastic anemia among those treated with FBM was estimated to have a lower limit of 1 per 37,037 patients and an upper limit of 1 per 4784 patients, with a "most probable" incidence of 1 per 7874 patients treated. Pellock and Brodie estimated the incidence of hepatotoxicity to be about 1 per 26,000-34,000 patients treated with FBM131 - similar to the recently reported risk of hepatotoxicity for valproate (VPA). At the time of this writing, no children under the age of 13 years have been reported to have FBM-related aplastic anemia. Female sex, history of immune disorders (e.g., systemic lupus erythematosis), a history of prior blood dyscrasias, and allergic reactions to medications are probably associated with increased risk for FBM-associated aplastic anemia. These factors may prove helpful in selecting patients for FBM therapy.
Apparent efficacy of lamotrigine (LTG) in open-label studies led to clinical trials among children with LGS. A large double-blind, placebo-controlled trial of LTG and LGS with collaborators from 40 different epilepsy centers in the U.S.A. and Europe documented LTG's efficacy in LGS. Following a single-blind baseline in which all study patients received placebo, 169 patients (ages 3 to 25 years) were randomized to placebo or LTG added to their baseline AEDs for 16 weeks. Thirty-three percent of the LTG group and 16% of the placebo group experienced a > 50% reduction in frequency of all major seizures (generalized tonic-clonic, tonic, atonic, and major myoclonic seizures. Thirty-seven percent of those treated with LTG and 22% of those who received placebo had a > 50% reduction in frequency of drop attacks (atonic, tonic, and/or major myoclonic seizures that resulted in falls). Forty-three percent of LTG-treated patients and 20% of placebo-treated patients had a 50% or greater reduction in frequency of generalized tonic-clonic seizures. The only clinically significant adverse event was serious rash in two patients, both of whom were not only receiving VPA but also had LTG dose-escalation rates that are faster than current recommendations. Global evaluations of patient's functioning in terms of speech, language, and attention were significantly improved in the LTG group.
Eriksson and colleagues published a randomized, double-blind, crossover study of LTG as add-on therapy in 30 children with severe generalized epilepsy, 20 of whom had LGS. LTG was more effective than placebo during the double-blind crossover phase in reducing the frequency of tonic, tonic-clonic, and atonic seizures (p<0.0001). Thirteen of the 20 children with LGS improved in the open phase of the study and entered the double-blind phase; seven of the 20 children (35%) responded to LTG treatment with a > 50% seizure frequency reduction. Two children with LGS became seizure free on LTG. No apparent relationship between LTG blood level and response was noted; none of the children improved on placebo, and none developed a rash.
LTG's efficacy against typical absence seizures has been documented in a placebo-controlled trial, but no well-designed clinical trials of any drug have been reported for atypical absence seizures. EEG-video monitoring is required to quantify atypical absence seizures in children with LGS.
The efficacy of topiramate (TPM) has been reported for tonic-clonic seizures, tonic seizures, and drop attacks associated with LGS. In the LGS study topiramate was associated with only a 14% reduction in the frequency of drop attacks compared to baseline, but this reduction was significantly better statistically than the placebo group. This reduction in drop attacks was maintained in an open label follow-up study after completion of the placebo-controlled trial. As with the FBM and LTG trials, the TPM trial was not designed to appropriately determine whether TPM is effective in atypical absence. However, unlike LTG there are no published data that document efficacy of TPM in simple absence or atypical absence.
TPM has been associated with impairment of cognitive processing, especially language processing. Just as a slow dose-titration is required with LTG to reduce the risk of rash, a slow dose-titration schedule is also required with TPM to avoid problems with cognition - especially expressive language processing. Recent reports of glaucoma associated with TPM use are of uncertain significance as the rate of glaucoma among patients taking TPM is not significantly different from the rate of glaucoma in the general population. However eye pain or eye erythema among patients on TPM warrant immediate referral to an ophthalmologist for evaluation.
Comparative trials of TPM, LTG, and FBM have not been published. Currently available safety data suggest that TPM may have safety that is comparable to or better than LTG, with primary risks of TPM being problems with language processing and a risk of renal stones. However, there is still significantly less post-marketing surveillance experience with TPM than LTG. Therefore, the recent reports of glaucoma and liver failure associated with TPM will require further investigation. Preliminary reports and our experience suggest that TPM may be useful in combination with LTG.
Zonisamide (ZON), approved for treatment of partial seizures in adults in the US, has been shown to have efficacy among children with multiple seizure types and myoclonic seizures. Although controlled trials of ZON among children with LGS have not reported, zonisamide is likely helpful and has been considered by most epileptologists as a treatment option for patients with LGS.
The ketogenic diet has been used in children with refractory seizures of multiple types since the late 1920's. Over the last decade there has been a resurgence of interest in the ketogenic diet, as more open-label data have become available on the ‘classical diet' that appears to offer better results with fewer side effects than the MCT oil diet introduced in the 1970's. Recently a multi-center open-label study of the ketogenic diet has reproduced the good results previously reported by the Johns Hopkins group. Fifty-one children (ages 1-8 years) with multiple seizure types and generalized epileptiform abnormalities on EEG who had failed to respond to at least 2 AEDs were placed on the classical ketogenic diet. Fifty-four percent of children on the diet at 3 months had a greater than 50% decrease in seizure frequency. If the placebo-controlled trial of the ketogenic diet (in progress at Johns Hopkins) confirms efficacy demonstrated in the open-label studies, the place of the diet in the armamentarium of the child neurologist may depend upon the frequency of adverse events, which may or may not be comparable to AEDs. The absence of surveillance for adverse events associated with the ketogenic diet makes comparison of the risk of the ketogenic diet with the risk of AEDs very difficult. Practically, children over the age of 10 years (unless severely impaired and fed via gastrostomy tubes) are not usually able to comply with the ketogenic diet.
Vagus nerve stimulation (VNS) has been approved for treatment of intractable partial seizures in the United States. A Swedish group has recently reported a possible reduction in seizure frequency among children with LGS treated with VNS. As expected, sedative side effects are less severe with VNS than with AEDs in children, but other significant adverse events have been reported.
Patients with intractable atonic or tonic seizures that result in falls may benefit from a corpus callosotomy. Various epilepsy centers have used slightly different approaches to selecting patients for this procedure. However as long as seizures resulting in severe falls with associated injuries are targeted, a significant number of patients can achieve palliative improvement and a reduction in drop attacks. Some authors have suggested that VNS should be performed prior to corpus callosotomy, primarily because the perceived morbidity risk is less with VNS. However, our experience has been that patients who are properly selected for corpus callosotomy tend to have a more dramatic reduction in drop attacks than those with LGS who are implanted with a VNS. Therefore the decision of whether to place a VNS or perform a corpus callosotomy in a child or young adult with LGS should consider the following issues:
(1) whether the seizures that result in falls are clearly primarily generalized (by careful EEG-video monitoring), in which case the corpus callosotomy may be more effective in reducing or eliminating the drop attacks;
(2) the general medical condition and size of the child, which influence anesthesia and operative risks;
(3) other factors that influence perceived benefit of each procedure.
Decisions regarding whether to perform a corpus callosotomy or place a VNS first will continue to be made based upon subjective data until and unless a comparative trial is performed.
In the absence of head-on comparative studies, the choice of initial therapy is debatable. My approach is to use as primary anti-epileptic drugs those that have been shown effective against multiple seizure types and/or LGS in clinical trials (LTG, TPM, and FBM) as well as VPA and ZON, with the hope of limiting the number of primary drugs to no more than 2-3. Whether I use ZON, TPM, LTG, or VPA first or second is dependent upon individual patient characteristics and the estimated risk:benefit ratios for the patient. I usually do not use FBM unless these initial drugs fail, but I tend to use FBM prior to considering surgical procedures like VNS or corpus callosotomy. (The likely risk of general anesthesia with a surgical procedure is probably greater than the risk of felbamate in most children.)
Children with LGS almost always have exacerbation of seizure frequency when they have viral illnesses or experience some other type of physical stress. I try to use short-term benzodiazepines to bridge these periods of seizure frequency and duration exacerbation rather than add another primary drug. Clinicians with access to clobazam should probably consider the use of this drug, given the impression of several experienced clinicians that it produces fewer adverse events than other benzodiazepines. The use of benzodiazepines only on a short-term basis, and minimizing the use of barbiturates, may enhance the effect of benzodiazepines used for the treatment of prolonged seizures or clusters of seizures in order to prevent status epilepticus, a common complication of LGS and a possible contributor to cognitive decline.
The therapeutic options for treatment of LGS and IS have expanded during the last decade. Yet we need more options for the treatment of these devastating childhood epilepsy syndromes.
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