LGS Overview / What's New in LGS?
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Anup Patel shares an overview and updates on Lennox-Gastaut Syndrome at the LGSF's 5th International Conference.
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LGS Overview / What's New in LGS?
- 2. ………………..…………………………………………………………………………………………………………………………………….. Anup Patel, MD • Section Chief Neurology at Nationwide Children’s Hospital • Associate Professor at the Ohio State University College of Medicine • Director Complex Epilepsy Clinic • Chair Professional Advisory Board Lennox Gastaut Syndrome Foundation
- 3. ………………..…………………………………………………………………………………………………………………………………….. Definition of Lennox Gastaut (LGS) • Multiple seizure types, to include tonic, atonic, and atypical absence seizures, with tonic seizures predominantly occurring at night • Abnormal EEG, consisting primarily of an interictal pattern of diffuse, slow spike-wave (SSW) complexes at <3Hz, occurring during wakefulness • Additional features, required as diagnostic by many, include paroxysmal fast rhythms (10–20 Hz) during sleep • Developmental delay or regression
- 4. ………………..…………………………………………………………………………………………………………………………………….. Definition of Epileptic Encephalopathy • Epileptic encephalopathy (EE) is used for conditions in which the epileptic activity itself contributes to mental and neurological decline • First used by Dr. West • West syndrome is the most common EE • Hallmark – most with treatment resistant epilepsy • Many now of genetic etiology
- 5. ………………..…………………………………………………………………………………………………………………………………….. History of LGS • Dates back to the 1960s when Gastaut and colleagues and Sorel recognized the syndrome and published the first reports • Gastaut et al. suggested generously that the syndrome be named “Lennox syndrome” because earlier cases had been reported by Lennox and Davis (1950) • The term “Lennox- Gastaut syndrome” was introduced later • Proposed by Beaumanoir (1985) and adopted by the International League Against Epilepsy (ILAE) Classification Commission in 1989
- 6. ………………..…………………………………………………………………………………………………………………………………….. Challenges • Can have focal seizures and focal findings • EEG patterns change over time • Community/non epilepsy providers not as likely to recognize • Seizures can be hard to differentiate from other events
- 7. ………………..…………………………………………………………………………………………………………………………………….. Challenges • Seizures are brief and often so difficult to count • Difficult to get accurate counts as constant observation needed • High number of treatment resistant patients • Can have events that look like seizures • Can use EEG to help differentiate
- 8. ………………..…………………………………………………………………………………………………………………………………….. Challenges • High frequency of injury due to falls • High care needs • Increased healthcare utilization • Decreased independence
- 9. ………………..…………………………………………………………………………………………………………………………………….. Frequency • Estimated between 1 to 10% of all childhood epilepsies • Onset between ages 1-7 (peak 3-5 years) • 17.5 to 41% of patients had infantile spasms • 66% to 75% of LGS cases are from brain abnormalities • Remainder due to genetic
- 10. ………………..…………………………………………………………………………………………………………………………………….. Why Diagnosis is Challenging? • Multiple causes • Varied clinical presentation • Multiple seizure types can be present • EEG features change with time • Confused with other diagnoses • Disagreement in epilepsy field of importance of diagnosis, criteria, etc.
- 11. ………………..…………………………………………………………………………………………………………………………………….. Why is Diagnosis Important? • Recently, FDA approved treatments for LGS • Data can be monitored, captured, reported as it relates to LGS • Felt early recognition and proper treatment can improve outcomes • Research opportunities can occur • Great Foundation and support group exists
- 12. ………………..…………………………………………………………………………………………………………………………………….. Treatment Options • Previously based on clinical observation and experience • Recent clinical trials and newer FDA approved treatments • Need for broad spectrum treatment coverage • Medications used have higher adverse effect burden
- 13. ………………..…………………………………………………………………………………………………………………………………….. Pharmacological Treatment • FDA approved adjunctive medications: • Felbamate (Felbatol) • Lamotrigine (Lamictal) • Topiramate (Topamax) • Rufinamide (Banzel) • Clobazam (Onfi)
- 14. ………………..…………………………………………………………………………………………………………………………………….. Pharmacological Treatment • Non-FDA approved medications with data: • Valproate (Depakote) • Considered first line in surveys of providers • Clonazepam (Klonopin) • Zonisamide (Zonegran) • Levetiracetam (Keppra) • Less data • Perampamel (Fycompa) • Recent study showing success
- 15. ………………..…………………………………………………………………………………………………………………………………….. Non-Pharmacological Treatment • 50% patients respond to the KD with a > 50% reduction in seizures and some patients may achieve a >90% reduction • 50% of patients respond to Vagus nerve stimulation therapy with a > 50% reduction in seizures, and the response may improve over time • 50% of patients respond to corpus callosotomy with atonic seizures best • Resective surgery may be option underutilized for cortical malformations, etc.
- 16. ………………..…………………………………………………………………………………………………………………………………….. Likelihood of Seizure Freedom • 60% chance first AED will result in seizure freedom • 10% chance second AED will result in seizure freedom • 1-4% chance of third AED will result in seizure freedom • Majority of LGS patients are here
- 17. ………………..…………………………………………………………………………………………………………………………………….. Remission Rates • Vary from 4% to 6.7% • Higher for clobazam patients • As high as 22% • Thought that earlier remission will lead to better outcomes • Not thus proven in literature well • If resective candidate, remission likely higher
- 18. ………………..…………………………………………………………………………………………………………………………………….. How Good Are the Medications?
- 21. ………………..…………………………………………………………………………………………………………………………………….. Majority of causes of LGS • Structural changes to brain • Genetic changes • Metabolic disorders • Can have infantile spasms or West syndrome before
- 22. ………………..…………………………………………………………………………………………………………………………………….. Diagnostic Work-Up • Sleep deprived EEG • Sometimes need overnight studies • MRI brain • If brain MRI normal, should have genetic testing • Urine and blood organic acid testing • Microarray (chromosomes) • Epilepsy Panel • Whole Exome Sequencing (WES) • Whole Genome (not commercially available)
- 24. ………………..…………………………………………………………………………………………………………………………………….. Significant Advances in Genetic Testing • DMN1 • PPP3CA • SCN 2A
- 25. ………………..…………………………………………………………………………………………………………………………………….. Cost of Care Studies • Baseline results suggest a prescribing preference for clobazam in severe LGS patients • Clobazam users had a reduction in seizure-related medical utilization and costs after clobazam initiation • The improvement in medical costs mostly offset the higher prescription costs following clobazam initiation
- 26. ………………..…………………………………………………………………………………………………………………………………….. Connection of Brain Pathways • Suggest that the mediodorsal and ventrolateral thalamus may be the main pathways of seizures for LGS patients • May be targets for changing the abnormal network in LGS • Potential for treatment using thalamic neurostimulation therapies like deep brain stimulation (DBS)
- 27. ………………..…………………………………………………………………………………………………………………………………….. Other Treatments • Emerging evidence suggests that complete callosotomy provides greater improvement in seizures without additional side effects • Tonic seizures • Atonic seizures • VNS has also been shown to have success • Recent study of that some benefit from both
- 28. ………………..…………………………………………………………………………………………………………………………………….. New Drug Application (NDA) • Greenwich Biosciences filed NDA on 10/30/17 • Submitted data that includes Phase 3 data from one Dravet trial and two LGS trials • Attempt is for simultaneous decision on both indications • Waiting on Prescription Drug User Fee Act (PDUFA) date
- 29. ………………..…………………………………………………………………………………………………………………………………….. What is a PFUDA date? • The Prescription Drug User Fee Act (PFUDA) • Deadlines by which the FDA must review new drug applications • Typically calls for a period of 10 months to review applications • Hopefully quicker for Epidiolex
- 30. ………………..…………………………………………………………………………………………………………………………………….. What Does This All Mean? • FDA will determine whether medication can be FDA approved • Then, DEA will have 90 days to reschedule if approved • Would likely be available in any state regardless of law as rescheduling would occur
- 31. ………………..…………………………………………………………………………………………………………………………………….. Summary • Hope exists • LGSF Professional Advisory Board (PAB) planning on research studies • Increased learning occurring • New treatments being developed • Keep Fighting!