Expert Opinion on the Management of Lennox–Gastaut Syndrome: Treatment Algorithms and Practical Considerations

Abstract

Lennox–Gastaut syndrome (LGS) is a severe epileptic and developmental encephalopathy that is associated with a high rate of morbidity and mortality. It is characterized by multiple seizure types, abnormal electroencephalographic features, and intellectual disability. Although intellectual disability and associated behavioral problems are characteristic of LGS, they are not necessarily present at its outset and are therefore not part of its diagnostic criteria. LGS is typically treated with a variety of pharmacological and non-pharmacological therapies, often in combination. Management and treatment decisions can be challenging, due to the multiple seizure types and comorbidities associated with the condition. A panel of five epileptologists met to discuss consensus recommendations for LGS management, based on the latest available evidence from literature review and clinical experience. Treatment algorithms were formulated. Current evidence favors the continued use of sodium valproate (VPA) as the first-line treatment for patients with newly diagnosed de novo LGS. If VPA is ineffective alone, evidence supports lamotrigine, or subsequently rufinamide, as adjunctive therapy. If seizure control remains inadequate, the choice of next adjunctive antiepileptic drug (AED) should be discussed with the patient/parent/caregiver/clinical team, as current evidence is limited. Non-pharmacological therapies, including resective surgery, the ketogenic diet, vagus nerve stimulation, and callosotomy, should be considered for use alongside AED therapy from the outset of treatment. For patients with LGS that has evolved from another type of epilepsy who are already being treated with an AED other than VPA, VPA therapy should be considered if not trialed previously. Thereafter, the approach for a de novo patient should be followed. Where possible, no more than two AEDs should be used concomitantly. Patients with established LGS should undergo review by a neurologist specialized in epilepsy on at least an annual basis, including a thorough reassessment of their diagnosis and treatment plan. Clinicians should always be vigilant to the possibility of treatable etiologies and alert to the possibility that a patient’s diagnosis may change, since the seizure types and electroencephalographic features that characterize LGS evolve over time. To date, available treatments are unlikely to lead to seizure remission in the majority of patients and therefore the primary focus of treatment should always be optimization of learning, behavioral management, and overall quality of life.

Cannabidiol in patients with Lennox‐Gastaut syndrome: Interim analysis of an open‐label extension study

“…1,2 The median reduction in drop seizure frequency with CBD in the GWPCARE3 and GWPCARE4 studies was 46% from baseline (vs 20% with placebo) 14,15 ; this level of reduction was sustained through 48 weeks of the OLE. 1,2 The median reduction in drop seizure frequency with CBD in the GWPCARE3 and GWPCARE4 studies was 46% from baseline (vs 20% with placebo) 14,15 ; this level of reduction was sustained through 48 weeks of the OLE.…”

“…1,2 The triad of LGS diagnostic criteria are the following: (a) multiple seizure types, mainly generalized, including tonic, atonic, and atypical seizures, with seizure types evolving over time; (b) abnormal electroencephalography (EEG) studies consisting mainly of interictal diffuse slow spike-and-wave complexes <3 Hz occurring during wakefulness and bouts of generalized paroxysmal fast activity; (c) cognitive impairment/intellectual disability. 1,2 The triad of LGS diagnostic criteria are the following: (a) multiple seizure types, mainly generalized, including tonic, atonic, and atypical seizures, with seizure types evolving over time; (b) abnormal electroencephalography (EEG) studies consisting mainly of interictal diffuse slow spike-and-wave complexes <3 Hz occurring during wakefulness and bouts of generalized paroxysmal fast activity; (c) cognitive impairment/intellectual disability.…”

“…2 No monotherapy has high efficacy in the treatment of LGS, with polytherapy being the norm, 4 and long-term seizure control and cognitive outcomes are poor even with polypharmacologic treatment. Valproic acid is also a frequently used first-line therapy, although it is not specifically approved for LGS.…”

A pilot, open‐label study of the effectiveness and tolerability of low‐dose ZX008 (fenfluramine HCl) in Lennox‐Gastaut syndrome

“…Other options include felbamate, clobazam, vagus nerve stimulation (VNS), and ketogenic diet as add‐on therapy. Emergency benzodiazepines are recommended for rescue usage …”

Novel seizure outcomes in patients with Lennox‐Gastaut syndrome: Post hoc analysis of seizure‐free days in rufinamide Study 303

“…Although there is no precise definition of LGS, no biologic marker, and a heterogeneous etiology, LGS is characterized by multiple seizure types, including tonic, atonic, and atypical absence seizures, and key abnormal electroencephalography features consisting primarily of an interictal pattern of slow spike‐wave complexes at <3 Hz that occur during wakefulness . Although commonly observed in LGS and initially considered to be indicative of the syndrome, intellectual disability and behavioral problems are not necessarily present in all patients with LGS at diagnosis, and hence are not included in the diagnostic criteria . In addition, the diagnostic signs of LGS are not pathognomonic of the syndrome and can develop over time, causing uncertainty in distinguishing LGS from other epilepsy syndromes …”