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 Epilepsy concepts Diagnosing Epilepsy What causes Epilepsy Treating Epilepsy New developments

Epilepsy Concepts What is epilepsy? What is a seizure?

Incidence Epilepsy 0.5-1% Seizures 5-10%

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

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

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

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

Idiopathic Partial Epilepsy Benign Rolandic Epilepsy Benign Occipital Epilepsy

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

Symptomatic Partial Epilepsy Temporal Lobe Epilepsy Frontal Lobe Epilepsy Parietal Lobe Epilepsy Occipital Lobe Epilepsy

Type of Epilepsy The importance of knowing

Diagnosis of Epilepsy Medical History Physical exam

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

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

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

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

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

Non-epileptic events Physiologic (other medical conditions) Fainting, low sugar, changes in electrolytes, toxins, fever. 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: TIAs, complicated migraines, movement disorders, sleep disorders, anxiety/panic disorder, vertigo, cardiac disorders, rage attacks, breath-holding spells,

What causes of Epilepsy? The seizure threshold 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

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

Seizure Control I discussed on the earlier slide drug resistant epilepsy, or seizures that are hard to controll with medicine, puts a person at higher risk for SUDEP. About 1/3 of people with epilepsy have drug resistant epilepsy. The definition of DRE is where seizures keep occuring despite 2 good trials of seizure medication. A good trial of a seizue medication means that an appropriate medication was used for the patient’s epilepsy and an appropriate dose was achieved. The medication failed because of persistent seizures and not side effects. For example, if the patient was still in the procress of increasing the medication to the target dose, and then had to stop it because of side effects, we wouldn’t call this a drug failure. Also, there are many types of epilepsy, and not all doctors specialize in epilepsy. Different medications work for each type of epilepsy. Sometimes doctors, despite their best intentions, prescribe the wrong seizure medication for a patient’s epilepsy. For example, tegretol for absence seizures, which can make it worse. So, a patient is only drug resistant only if they have tried two or more appropriate medications for their epilepsy and failed them because of persistent seizures.

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

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

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

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

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

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

Medication choices based on epilepsy type…

AED’s for Partial Epilepsy All but Zarontin and Banzel

Best AED’s for Generalized Epilepsy Depakote Keppra Lamictal Topamax Zonegran 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 Ezogabine (Potiga) Perampanel Vertex Emergency Treatment Intranasal Midazolam

Potiga Potassium Channel Opener Partial Seizures Rare but serious side effects Trial and Error: Every pt is different. We don’t now until we try which will be the right receptors to open and right ones to block Side effects: when you block too many neurotransmitters, channels- you disturb normal brain function and you get side effect. For example if too many NT are blocked you get sleepy and dizzy 1/3: New medication are not any better than old

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

Vx-765 for Partial Epilepsy New approach to Epilepsy Rx Anti-Inflammatory Short Duration of therapy (weeks instead of years) Oral Medicine Early Clinical Trials Completed Early results encouraging but longer treatment duration to be studied Headache, dizziness, GI most common side effects Only studied for 6 weeks

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

Intranasal Midazolam Easy to give Preferred route Can be self-administered or given by caretaker Under study Efficacy and Side Effects unknown

Advances in Treatment Newermedications Brivaracetam Carisbamate Clobazam Eslicarbazepine Ganaxalone Losigamone Nitrfazepam Perampanel Piracetam Progabide Remacemide Retigabine Seletracetam Stiripentol

For patients that do not respond to medication Ketogenic diet Surgeries

Ketogenic Diet (@1920) High fat, low carbohydrate/protein diet Requires hospitalization to start it NPO until patient in ketosis Parent education Meds to be taken into account Recommended mainly for young children due to compliance and efficacy

Epilepsy Surgery The goals are: To determine where the seizures are coming from To make sure is safe

Epilepsy Surgery To determine where the seizures are coming from Video-EEG monitoring MRI MRS: PET: SPECT: MEG:

Epilepsy Surgery To make sure that it is safe Wada test: to study speech and memory Neuropsychological testing: mental functions (IQ, memory, attention) and personality assessment Psychological evaluation Ophthalmologic evaluation

Epilepsy Surgery Some cases in which the localization is not clear or where function could be affected will require INVASIVE ELECTRODES Depth electrodes Subdural electrodes

Types of Epilepsy Surgery Temporal Lobectomy Extratemporal Resections Hemispherectomy Corpus Callosotomy

Outcome after epilepsy surgery Anterior temporal lobectomy 70-80% seizure free Neocortical resection With lesion: 50-80% seizure free Without lesion: 30-50% seizure free Hemispherectomy Significant improvement Corpus Callosotomy Significant improvement for drop attacks

Complications of surgery Low rate of complications Infections Bleeding Anesthesia Function

Vagus Nerve Stimulator (1997) Intractable epilepsy patient without focus or desires interim step before epilepsy surgery Goal is to reduce amount/severity of seizures vs. cure Device surgically implanted in left chest/axilla area Coils around left vagus nerve Stimulation is automatic; patient can additionally stimulate device if aura