Lennox-Gastaut Syndrome Treatment & Management

The goals of treatment for patients with Lennox-Gastaut syndrome (LGS) are the same as for all patients with epilepsy: the best quality of life with the fewest seizures (ideally, none), the fewest adverse treatment effects, and the least number of medications.

A variety of therapeutic approaches are used in LGS, ranging from conventional antiepileptic agents to diet and surgery. ^[9] Unfortunately, much of the evidence supporting these approaches is not robust, and treatment is often ineffective. ^{[10, 11]}

The medical treatment options for patients with LGS can be divided into the following 3 major groups:

• First-line treatments based on clinical experience or conventional wisdom (eg, valproic acid, benzodiazepines [specifically clonazepam, nitrazepam, clobazam ^{[12, 13, 14]} ])

• Treatments suspected to be effective on the basis of open-label uncontrolled studies (eg, vigabatrin, ^[15] zonisamide ^[16] )

• Treatments proven effective by double-blind placebo-controlled studies (eg, lamotrigine, ^[17] topiramate, ^{[18, 19, 20]} felbamate ^[21] , rufinamide ^{[22, 23, 24]} , clobazam ^[25] , cannabidiol ^{[26, 27]} )

The ketogenic diet may be useful in patients with LGS refractory to medical treatment. Surgical options for LGS include corpus callostomy, vagus nerve stimulation, and focal cortical resection. ^[28]

Antiepileptic drugs (AEDs) are the mainstay of therapy for patients with LGS. Unfortunately, no one AED gives satisfactory relief for all or even most patients with LGS. A combination of agents frequently is required. Patients with LGS experience frequent exacerbations of their seizures that may require inpatient adjustment of AEDs.

Patients with LGS have a recognized high risk for status epilepticus. Because of the consequent risk of injury or death, a medication for emergency intervention (eg, rectal diazepam) should be prescribed.

Valproate

Valproate (Depakote, Depakene, Depacon) has been considered the first-line treatment option for children with LGS for the past 2 decades. It is reported to be more effective in patients with cryptogenic LGS than in those with symptomatic LGS.

Lamotrigine

The efficacy of lamotrigine (Lamictal) as adjunctive therapy against seizures associated with LGS was demonstrated in 2 controlled trials and multiple open-label studies. This agent is valuable for patients with LGS, despite its risk of idiosyncratic dermatologic reactions, and its use should be considered as soon as diagnosis of LGS is made. Proper attention to concomitant medications, low starting dose, and very slow titration can minimize the risk of dermatologic reactions.

Topiramate

In a multicenter, double-blind, placebo-controlled trial, topiramate (Topamax) was found to be safe and effective as adjunctive therapy for patients with LGS. ^[20] The target dose was 6 mg/kg/d. In a long-term open-label extension portion of this trial (mean dosage 10 mg/kg/d), drop attacks were reduced by greater than half in 55% of patients, and 15% of patients were free of drop attacks for over 6 mo at the last visit. ^[19]

Felbamate

Felbamate (Felbatol) was found to be safe and effective in patients with LGS in a randomized, double-blind, placebo-controlled adjunctive therapy trial, and 12-month follow-up in patients who completed controlled part of study confirmed long-term efficacy. ^[21] Despite the efficacy of felbamate, the significant risk of idiosyncratic reactions associated with its use make it a third-line or fourth-line drug for LGS.

Zonisamide

The effectiveness of zonisamide (Zonegran) in LGS has been investigated in 3 small open-label studies, with promising results. A multicenter study of zonisamide for long-term adjunctive therapy in 62 children with LGS found that it was safe and effective; 4.8% of children had 100% seizure freedom, and 22.6% had >75% reduction in their seizures, independent of seizure type. ^[16]

Vigabatrin (Sabril)

Vigabatrin (Sabril) was approved by the US Food and Drug Administration (FDA) in 2009 as monotherapy for infantile spasms in patients 1 month to 2 years old, and as adjunctive therapy for adults with refractory complex partial seizures. In 6 open-label studies involving 78 patients with LGS, 15% became completely seizure free and 44% had a >50% reduction in seizure frequency. ^[29]

Rufinamide

The FDA approved rufinamide (Banzel) in 2008 for the adjunctive treatment of seizures associated with LGS in children 4 years and older and adults. In a double-blind, randomized, placebo-controlled trial by Glauser et al, rufinamide produced a statistically significant decrease in total seizure frequency and tonic-atonic seizures in individuals aged 4-30 years. ^[22] A 2009 open-label European study also demonstrated decreased seizure frequency amongst those with LGS. ^[23]

In a multicenter clinical trial of 59 patients with LGS, rufinamide was found to decrease the frequency of tonic-atonic seizures by 24.2%, versus 3.3% with placebo, and total seizures by 32.9%, versus 3.3% with placebo. Adverse events in the rufinamide group included decreased appetite (17.2%), somnolence (17.2%), and vomiting (13.8%). ^[30]

In February 2015, rufinamide was approved in pediatric patients aged 1 to 4 years based on a pharmacokinetic bridging study of a Phase III clinical trial which demonstrated the pharmacokinetic and safety profiles are consistent with those seen in ages ≥ 4 years. ^[31]

Benzodiazepines

Clonazepam (Klonopin) is considered an effective first-line AED therapy for seizures associated with LGS. However, the adverse effects and development of tolerance limit its usefulness over time. Dosing on an every-other-day schedule or alternating 2 benzodiazepines daily may slow development of tolerance. The benzodiazepine clobazam, which is widely used as an anticonvulsant in other countries, was approved by the FDA in October 2011. ^[14] The combination of valproic acid and a benzodiazepine may be better than either drug alone.

In the CONTAIN study of patients with LGS given clobazam, more than 50% of patients had a 50% or greater decrease in weekly drop- and total-seizure frequency. The percentage of patients achieving 100% reduction in drop seizures was 33% for clobazam-treated patients (vs. 7% for placebo) in Quartile 1 (least severe LGS), and 5% of clobazam-treated patients in Quartile 4 (most severe LGS) achieved 100% reduction in drop seizures, versus 0% for placebo. ^[25]

In a second study (OLE study), through 5 years of clobazam therapy, more than 50% of patients in all 4 quartiles (least severe to most severe LGS) demonstrated a decrease of 50% or more in weekly frequency for drop seizures. More than 12% of patients in Quartile 4 achieved 100% reduction in drop seizures from month 3 through year 5. ^[25]

The FDA has issued a warning that clobazam, used as add-on therapy to treat seizures in patients with LGS, may trigger Stevens-Johnson syndrome and toxic epidermal necrolysis, rare but potentially fatal cutaneous reactions. ^{[32, 33]} The risk of developing these disorders is increased during the first 8 weeks of treatment or when treatment is resumed after it is discontinued. This is not typically seen during clinical practice.

Cannabidiol

A purified formulation of cannabidiol (Epidiolex) was approved in June 2018 for seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS). In 2020, it gained approval for seizures associated with tuberous sclerosis complex (TSC) as well as for use in children as young as 1 year (originally approved for aged 2 years or older). Cannabidiol is a structurally novel anticonvulsant and the exact mechanism by which it produces anticonvulsant effects is unknown. It does not appear to exert its anticonvulsant effects through CB1 receptors, nor through voltage-gated sodium channels.

Approval for LGS and DS was based on results from several studies that compared adding cannabidiol added to conventional AEDs to placebo and the incidence of drop seizures from baseline. An international study of 225 patients with LGS (mean patient age 15 years) were randomized to receive cannabidiol 20 mg/kg/day or 10 mg/kg/day, or placebo over 14 weeks. During the 4-week baseline period, the median number of drop seizures was 85 in all groups combined. The median reduction from baseline in drop-seizure frequency per 28 days during the treatment period was 41.9% in the 20-mg cannabidiol group, 37.2% in the 10-mg group, and 17.2% in the placebo group. During treatment, 30 patients (39%) in the 20-mg group, 26 (36%) in the 10-mg group, and 11 (14%) in the placebo group had at least a 50% reduction from baseline in drop-seizure frequency. The odds ratio (OR) for 20 mg vs placebo was 3.85 (95% CI, 1.75 - 8.47; P < 0.001) and the OR for 10 mg vs placebo was 3.27 (95% CI, 1.47 - 7.26; P = 0.003). ^[26]

A study (n=171) conducted in 24 clinical sites in the United States, the Netherlands, and Poland showed a median percentage reduction in monthly drop seizure frequency from baseline was 43.9% (IQR -69.6 to -1.9) in the cannabidiol group and 21.8% (IQR -45.7 to 1.7) in the placebo group. The estimated median difference between the treatment groups was -17.21 (p = 0.0135) during the 14-week treatment period. ^[27]

Approval for use in TSC was based on the GWPCARE6 phase 3 trial (n = 224). Analysis of the 201 patients who completed the study showed that cannabidiol 25 mg/kg/day produced a significantly greater reduction in seizure frequency compared with placebo (49% vs 27%; P = .0009). ^[34]

Corpus callosotomy is effective in reducing drop attacks but is typically not helpful for other seizure types. It is considered palliative rather than curative. Seizure freedom following corpus callosotomy is rare but can occur.

A 2006 study showed a greater than 90% seizure reduction in 52 of 76 patients with LGS who underwent an extended, one-stage, callosal section (splenium intact); 7 of the 76 patients were seizure free. ^[35] The mean follow-up time was 4.7 years. The seizure types most responsive to surgery were atonic and atypical absence.

Vagus nerve stimulation by means of a surgically implanted programmable device is approved by the FDA as an adjunctive treatment for refractory partial-onset seizures in adults and adolescents older than 12 years. In 3 published small studies, approximately three fourths of patients with LGS experienced greater than 50% reduction in seizure frequency with a follow-up period as long as 5 years. ^[36]  

A meta-analysis determined that corpus callosotomy has better outcomes than vagus nerve stimulation for atonic seizures, but that vagus stimulation has comparable benefit to corpus callosotomy for all other seizure types. ^[37]

In rare cases, resection of a localized lesion (eg, vascular lesion, tumor) can improve seizure control in LGS.

The ketogenic diet comprises a high ratio of fats (ketogenic foods) to proteins and carbohydrates (antiketogenic foods). The ratio of ketogenic to antiketogenic foods in the diet ranges from 2:1 to 4:1 or higher. In general, the benefits of the diet for people with epilepsy include fewer seizures, less drowsiness, better behavior, and need for fewer concomitant AEDs.

Based on multiple open-label and, most recently, randomized controlled studies, the ketogenic diet appears to be a useful therapy for patients with LGS. Efficacy appears greatest for atonic, myoclonic, and atypical absence seizures, but other seizure types (tonic-clonic, secondarily generalized tonic-clonic) may also respond.

In a 2008 randomized controlled trial of the ketogenic diet in children with daily seizures who had a poor response to at least 2 AEDs, 38% of the children in the diet arm had a greater than 50% reduction in seizures. Of the 145 children randomized to the ketogenic diet or control, only 14 had LGS. ^[38]

A blinded, crossover study of the ketogenic diet in 20 children with LGS showed a moderate reduction in parent-reported myoclonic-atonic events. Ketosis was not eliminated in the placebo arm; thus, there was no difference observed between the 2 groups regarding reduction in EEG-identified events. When seizure-free patients should be weaned from the diet is not clear. ^[39]

The ketogenic diet is not always successful. The following 3 factors are associated with successful implementation of the diet:

• Dedicated, compliant family willing to alter the entire family's lifestyle

• Family able to follow (without wavering) the strict guidelines of the diet

• Team of professionals (centered around a dietitian) trained and experienced in the use of the diet

Potential serious adverse effects include dehydration, clinically significant metabolic acidosis when the diet is initiated, renal stones, cardiac abnormalities, and abnormal lipid profile.

Some patients with LGS wear protective helmets with face guards to maximize protection of the forehead, nose, and teeth (see the image below). Unfortunately, some patients with LGS do not tolerate the helmet with face guards, and even if tolerated, helmets often are uncomfortable and rarely are cosmetically acceptable. Some families are using head guards, which are marketed for concussion prevention in sports; however, these do not necessarily protect the face and teeth.

Pediatric neuropsychologists can assess intellectual function and educational needs and advise on nonpharmacologic management of behavioral problems. Pediatric psychiatrists can advise on pharmacologic management of behavioral problems. Neurosurgeons can assist in the placement of a vagus nerve stimulator and assess the patient as a candidate for corpus callosotomy or focal resection. Dietitians can assist in the institution and maintenance of the ketogenic diet.