Lennox–Gastaut syndrome (LGS) is a form of encephalopathic generalized epilepsy (EGE) and is a devastating epilepsy syndrome that typically begins within the second and sixth year of life. It is characteristically refractory to antiseizure drugs (ASDs). The diagnostic clinical triad of LGS is (1) multiple mixed seizure types, including tonic, atonic, and atypical absence with high seizure frequency, and often with status epilepticus, (2) impaired intellectual function or behavior disturbance, (3) abnormal EEG background with diffuse slow activity and characteristic epileptiform discharges described as slow spike-and-wave discharges while awake [1]. LGS accounts for approximately 1–4% of all childhood epilepsies [2, 3]. EGE represents approximately 11.6% of all childhood epilepsies [4].

Treatment for LGS includes efforts to manage the underlying cause of their associated cognitive and behavioral dysfunction, attempting to control seizures, and providing support for the patient’s family or caretaker [1]. Despite characteristic drug resistance, ASD therapy is the primary treatment. It is a challenge to optimize seizure control and medication side effects, while maintaining a favorable quality of life. The multiple seizure types in LGS often require broad-spectrum ASDs and combination therapies. Certain medications have proven higher utility in LGS, including valproic acid, lamotrigine, and topiramate [5–7]. Felbamate is effective in seizure reduction and neurocognitive profile but is limited by serious side effects of hepatic failure and aplastic anemia [8]. Clobazam and rufinamide are also approved for LGS, and other ASDs have been reported to have possible benefit but without consistent efficacy, such as levetiracetam, zonisamide, and clonazepam [1, 9, 10]. Oral purified cannabidiol (Epidiolex), the natural cannabidiol from the marijuana plant, is an oral solution that was approved by the US Food and Drug Administration (FDA) for use in LGS in June 2018 and has shown significant effectiveness in clinical trials for refractory seizures [11–14] and for improvement in global functioning of these patients [15–18]. This was also the case for my patient.

My patient has static encephalopathy and spastic quadriplegia with diffuse cerebral volume loss. He was born by cesarean section at 28 weeks and was ventilator dependent. He has been severely delayed since birth, which worsened when his seizures started at 19 months old. His seizure history includes at least four seizure types: type 1, staring blankly then smiles and may drool; type 2, tonic; type 3, generalized tonic–clonic (GTC); type 4, atonic with fall. He had been on lamotrigine and levetiracetam for many years with effectiveness but continued to have daily to weekly seizures with frequent seizure clusters. His current doses are lamotrigine 150 mg three times daily and levetiracetam 1000 mg three times daily and he could not tolerate higher doses. Past medication included phenobarbital, valproic acid, phenytoin, carbamazepine, and topiramate, all of which did not produce significant seizure control or caused side effects.

His mother reports him having a decline in functioning at around 10 years of age. Prior to that he was pulling up and was taking a bottle himself, but after the decline he never walked or talked; a feeding tube was placed for nutritional supplementation and a tracheostomy was placed as a result of repeated aspiration. At that time, he was initiated on primidone for abnormal movements and had remained on a dose of 100 mg three times daily. It was reported that his seizure frequency on lamotrigine, levetiracetam, and primidone was daily of type 1 and weekly seizures of type 2, 3, and 4. He was initiated on rufinamide in the fall of 2010 and titrated according to response to 600 mg twice daily. As a result, his atonic seizures (type 4) resolved completely. Higher doses of rufinamide resulted in increased seizures. A vagus nerve stimulator was considered but felt to be too risky with his respiratory status. There was a lapse in care for several years and he returned to the epilepsy specialist clinic in 2018 following the approval of cannabidiol. At that point, he initially tried clobazam, but had sedation and no reduction in seizures. He was initiated on orally administered cannabidiol in January 2019. Within the first month of treatment on 2.5 mg/kg/dose twice daily his type 1 seizures had resolved, type 2 seizures were reported to be less severe and shorter in duration, and there were no type 3 seizures. His mother reported that he was more awake and alert and was doing more activity. She reported that he was “like he used to be”. He started sleeping through the night and holding himself up better. It also improved his bowel motility. Since that time, his response to titration of cannabidiol has continued to reduce his seizure frequency and improve his functioning. His primary seizure that has remained refractory is type 3, his GTC. His main precipitant is having a bowel movement and stress. These seizures continue to occur approximately two times per month and dosing titration has and will continue, to obtain maximal benefit.

When deciding on medication therapy for this patient, several issues were considered. First and foremost, it is critical to understand and confirm the diagnosis. For this patient, it is unclear why the diagnosis was not confirmed until he was 10 years old, but it seems that this timeframe related to his significant functional decline. Secondly, patient characteristics must be considered to tailor a medication choice. Medications can carry risks to organ systems and to quality of life. For my patient, his mother reports that it took years to make a diagnosis of Lennox–Gastaut and, therefore, treatments tried prior to this had the risk of being suboptimal. Additionally, with LGS the treatment options available are generally ineffective and refractory. As his mother stated, he tried many antiseizure medications and yet remained with excessive seizures. Over the years, certain treatments were found that were both more effective and more tolerable for this patient. With the approval of orally administered cannabidiol, the patient has been able to add its unique mechanism of action to his medication regimen and his seizure frequency has reduced substantially, down to approximately two per month.

To get my patient to a seizure frequency where he is today has not been an easy feat. It often takes trial and error of medications and dosing to obtain success with medications and this is particularly true for devastating epilepsy syndromes. Effective communication with the patient’s response and the caretaker’s input is invaluable to obtain an optimal treatment regimen for a particular patient. I am thankful that my patient has achieved a significant reduction in seizures from baseline and that his care can focus on other aspects of his health. Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed. I look forward to the opportunity to see this progress unfold.