Management of Difficult to Treat Epilepsy in Children Northeast Regional Epilepsy Group

Advances in the Diagnosis and Treatment of Epilepsy Marcelo E. Lancman, M.D. Director, Epilepsy Program Northeast Regional Epilepsy Group

Advances in the Diagnosis and Treatment of Epilepsy Advances in the Diagnosis and Treatment of Epilepsy Epilepsy concepts Epilepsy concepts Diagnosing Epilepsy Diagnosing Epilepsy What causes Epilepsy What causes Epilepsy Treating Epilepsy Treating Epilepsy New developments New developments

Epilepsy Concepts What is epilepsy? What is epilepsy? What is a seizure? What is a seizure?

Incidence Epilepsy Epilepsy0.5-1% Seizures Seizures 5-10%

Classification of Seizures Partial PartialSimpleComplex Secondary Generalized Generalized Generalized Absence Atonic Clonic Tonic Tonic-clonic Myoclonic

Classification of Epilepsy By Localization By Localization –Partial –Generalized By Cause By Cause –Idiopathic (unknown) –Symptomatic

Classification of Epilepsy Idiopathic Partial Epilepsy Idiopathic Partial Epilepsy Symptomatic Partial Epilepsy Symptomatic Partial Epilepsy Idiopathic Generalized Epilepsy Idiopathic Generalized Epilepsy Symptomatic Generalized Epilepsy Symptomatic Generalized Epilepsy

Idiopathic Generalized Epilepsy Benign Neonatal Familial Epilepsy Benign Neonatal Familial Epilepsy Benign Myoclonic Epilepsy of Infancy Benign Myoclonic Epilepsy of Infancy Generalized epilepsy with febrile seizures plus Generalized epilepsy with febrile seizures plus Epilepsy with myoclonic absence Epilepsy with myoclonic absence Epilepsy with myoclonic-astatic seizures Epilepsy with myoclonic-astatic seizures Childhood absence epilepsy Childhood absence epilepsy Juvenile absence epilepsy Juvenile absence epilepsy Epilepsy with GTCS only Epilepsy with GTCS only

Idiopathic Partial Epilepsy Benign Rolandic Epilepsy Benign Rolandic Epilepsy Benign Occipital Epilepsy Benign Occipital Epilepsy

Symptomatic Generalized Epilepsy Infantile spasms (West syndrome) Infantile spasms (West syndrome) Dravet syndrome Dravet syndrome Lennox-Gastaut syndrome Lennox-Gastaut syndrome

Symptomatic Partial Epilepsy Temporal Lobe Epilepsy Temporal Lobe Epilepsy Frontal Lobe Epilepsy Frontal Lobe Epilepsy Parietal Lobe Epilepsy Parietal Lobe Epilepsy Occipital Lobe Epilepsy Occipital Lobe Epilepsy (Tuberous Sclerosis Complex, Neurofibromatosis) (Tuberous Sclerosis Complex, Neurofibromatosis)

Special types of Epilepsy Neonatal seizures Neonatal seizures Landau-Kleffner syndrome Landau-Kleffner syndrome ESES (electrical status epilepticus during sleep) ESES (electrical status epilepticus during sleep) Reflex Epilepsy Reflex Epilepsy

Type of Epilepsy The importance of knowing The importance of knowing

Diagnosis of Epilepsy Medical History Medical History Physical exam Physical exam

Testing Testing Testing –EEG, AEEG, VEEG –Labs –Genetics Imaging Imaging –CT, MRI (high definition)

Diagnosis Diagnosis is clear: treatment is initiated Diagnosis is clear: treatment is initiated Diagnosis unclear: Video-EEG Diagnosis unclear: Video-EEG

Video-EEG Monitoring Continuous EEG monitoring along with continuous audio-video recording Continuous EEG monitoring along with continuous audio-video recording Mostly requires inpatient admission Mostly requires inpatient admission

Goals of Video-EEG Monitoring Epilepsy vs. non- epileptic events Epilepsy vs. non- epileptic events Characterize epilepsy type Characterize epilepsy type Pre-surgical evaluation Pre-surgical evaluation

Non-Epileptic Events 20 to 30% of patients referred with diagnosis of intractable epilepsy 20 to 30% of patients referred with diagnosis of intractable epilepsy Events that do not have electrical source in brain Events that do not have electrical source in brain May have physical or psychological causes that are not epilepsy May have physical or psychological causes that are not epilepsy But CAN also occur in patients who have epilepsy But CAN also occur in patients who have epilepsy

Non-epileptic events Physiologic (other medical conditions) Physiologic (other medical conditions) –Fainting, low sugar, changes in electrolytes, toxins, fever. Psychological Psychological –Referred to psychiatry and neuropsychologist who work with this type of stress-seizure –Psychiatric medication, psychotherapy, education

Non-epileptic events Conditions that may look like seizures: Conditions that may look like seizures: –TIAs, complicated migraines, movement disorders, sleep disorders, anxiety/panic disorder, vertigo, cardiac disorders, rage attacks, breath-holding spells,

Diagnostic Advances Magnetoencefalography Magnetoencefalography

What causes of Epilepsy? The seizure threshold The seizure threshold Causes: Causes: –Genetics, head injury, stroke, tumors, infections, malformations, metabolic disorders (diabetes, thyroid, parathyroid, adrenal), degenerative disorders, perinatal factors and other less common (cardiac, GI, blood, inflammatory, poisons, etc)

Seizure Triggers Alcohol, stress, environmental temperature, lights, fever/illness, hormonal changes, hyperventilation, sleep deprivation, medications and supplements, missing medication doses and travel across time zones Alcohol, stress, environmental temperature, lights, fever/illness, hormonal changes, hyperventilation, sleep deprivation, medications and supplements, missing medication doses and travel across time zones

Treating Epilepsy What is intractable epilepsy? What is intractable epilepsy? Despite medical management, patient continues to have frequent, debilitating seizures

Seizure Control

Options for the Intractable Seizure Patient Medications (combinations) Medications (combinations) Diets Diets Surgical procedures Surgical procedures –Stimulators –Resections

Medications Choices based on epilepsy type, patient profile, side effect profile, cost Choices based on epilepsy type, patient profile, side effect profile, cost Best to have patient on single antiepileptic drug (AED) Best to have patient on single antiepileptic drug (AED) May need polytherapy (combination of medications) May need polytherapy (combination of medications) Adding meds requires going up slowly with the new agent before discontinuing previous drug Adding meds requires going up slowly with the new agent before discontinuing previous drug Polytherapy requires deep knowledge of interactions Polytherapy requires deep knowledge of interactions

How to use polytherapy rationally Pharmacodynamics (what the medication does to the body) Pharmacodynamics (what the medication does to the body) Pharmacokinetics Pharmacokinetics (what the body does to the medications) (what the body does to the medications) –Absorption –Distribution –Elimination Half life Half life Liver Liver Kidneys Kidneys

How to use polytherapy rationally Side effects Side effects –Dose-related –Idiosyncratic (each person is different)

Older Medications Carbamazepine (Tegretol) Carbamazepine (Tegretol) Phenobarbital Phenobarbital Ethosuximide (Zarontin) Ethosuximide (Zarontin) Phenytoin (Dilantin/Cerebyx) Phenytoin (Dilantin/Cerebyx) Valproic acid (Depakote) Valproic acid (Depakote) Primidone (Mysoline) Primidone (Mysoline)

Newer AED’s Gabapentin (Neurontin) Gabapentin (Neurontin) Lamotrigine (Lamictal) Lamotrigine (Lamictal) Topiramate (Topamax) Topiramate (Topamax) Felbamate (Felbatol) Felbamate (Felbatol) Diastat (Diazepam) Diastat (Diazepam) Vigabatrin (Sabril) Vigabatrin (Sabril) Ezogabine (Potiga) Ezogabine (Potiga) Oxcarbazepine (Trileptal) Oxcarbazepine (Trileptal) Pregabalin (Lyrica) Pregabalin (Lyrica) Zonisamide (Zonegran) Zonisamide (Zonegran) Levetiracetam (Keppra) Levetiracetam (Keppra) Lacosamide (Vimpat) Lacosamide (Vimpat) Rufinamide (Banzel) Rufinamide (Banzel) Clobazam (Onfi) Clobazam (Onfi)

Medication choices based on epilepsy type…

AED’s for Partial Epilepsy All but Zarontin and Banzel All but Zarontin and Banzel

Best AED’s for Generalized Epilepsy Depakote Depakote Keppra Keppra Lamictal Lamictal Topamax Topamax Zonegran Zonegran Banzel Banzel

Future Medications –Brivaracetam –Carisbamate –Eslicarbazepine –Ganaxalone –Losigamone –Nitrfazepam –Perampanel –Piracetam –Progabide –Remacemide –Retigabine –Seletracetam –Stiripentol

What Are Some Promising New Medical Treatments? Maintenance Treatment Maintenance Treatment –Ezogabine (Potiga) –Perampanel –Vertex Emergency Treatment Emergency Treatment –Intranasal Midazolam

Potiga Potassium Channel Opener Potassium Channel Opener Partial Seizures Partial Seizures Rare but serious side effects Rare but serious side effects

Peramapanel Glutamate Blocker Glutamate Blocker Effective in trials for partial seizures Effective in trials for partial seizures Side effects: Dizziness, Sleepiness Side effects: Dizziness, Sleepiness Approved in Europe Approved in Europe Under study in US for Generalized Seizure types Under study in US for Generalized Seizure types Under FDA review for Partial Seizures Under FDA review for Partial Seizures

Vx-765 for Partial Epilepsy New approach to Epilepsy Rx New approach to Epilepsy Rx –Anti-Inflammatory –Short Duration of therapy (weeks instead of years) –Oral Medicine Early Clinical Trials Completed Early Clinical Trials Completed –Early results encouraging but longer treatment duration to be studied –Headache, dizziness, GI most common side effects

Emergency Treatment Rectal Diastat Rectal Diastat –Clinically proven –Hard to give –Adults don’t like –Can’t self administer

Intranasal Midazolam Easy to give Easy to give Preferred route Preferred route Can be self- administered or given by caretaker Can be self- administered or given by caretaker Under study Under study

For patients that do not respond to medication Ketogenic diet Ketogenic diet Surgeries Surgeries

Epilepsy Surgery

Rates of Surgical Success* Temporal Lobectomy 70-80% Temporal Lobectomy 70-80% “Lesion” Resection 70-80% “Lesion” Resection 70-80% “Non-Lesional” Resection 30-50% “Non-Lesional” Resection 30-50% Medical Management 5% Medical Management 5% * Absence of Disabling Seizures

Visualase Laser Treatment Evaluation is same as for epilepsy surgery No need for open brain operation

Visualase Implant Probe inserted in OR Transferred to MRI Treatment Laser Treatment MRI monitors safety of Laser Rx real-time Follow up Probe Removed Patient can leave same day

Neuromodulatory Treatments Device implanted to alter instead of destroy brain tissue Device implanted to alter instead of destroy brain tissue Range of treatment possible: Electrical, Cooling, local medications Range of treatment possible: Electrical, Cooling, local medications –Limit body/brain side effects Improve brain function? Improve brain function?

NeuroPace Implant Device under skull Leads to seizure focus Treatment Detects seizure Electrical treatment delivered Follow up MD reviews Fine tunes treatment

Deep Brain Stimulation (DBS)

What will Epilepsy Care Look Like in Future? Personalized Medical Choices based on genetics Personalized Medical Choices based on genetics Truly Anti-epileptic therapy Truly Anti-epileptic therapy Treatment directed right at the seizure focus Treatment directed right at the seizure focus