Georges A. Ghacibeh, MD, MS Hackensack University Medical Center Comprehensive Epilepsy Center Overview of Epilepsy Georges A. Ghacibeh, MD, MS

Seizures vs. Epilepsy Seizures Epilepsy A transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain Incidence: approximately 80/100,000 per year Lifetime prevalence: 9% (1/3 benign febrile convulsions) A disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological, and social consequences of this condition Incidence: approximately 45/100,000 per year Point prevalence: 0.5-1% (2.5 million) Cumulative risk of epilepsy: 1.3% - 3.1%

Definition: Seizure vs. Epilepsy Sz Sz Diagnosis Seizure-free No Sz Epilepsy Treatment No Epilepsy Stop Treatment

Classification of Seizures Focal - Onset Simple partial Complex partial Secondarily generalized Generalized - Onset Absence Myoclonic Generalized tonic-clonic Tonic Clonic Atonic

Seizure Types Generalized Focal Focus

Classification of Epilepsy Etiology Primary Secondary Juvenile Myoclonic Childhood Absence Primary GTC Lennox-Gastaut Other developmental disorders Benign Rolandic Benigh Occipital Focal-Onset Epilepsy Generalized Seizure Onset Focal

Epidemiology of Epilepsy Epilepsy: Incidence Rates by Seizure Type* *Data from Rochester, Minn (1935-1979). Adapted with permission from Annegers JF. In: The Treatment of Epilepsy: Principles and Practice. 2nd ed. Baltimore, Md: Williams & Wilkins; 1997:165-172.

Seizure Risk Factor Prenatal and Birth Injury Febrile Convulsions Developmental Delay Head Trauma CNS Infections Brain Tumors Brain Surgery Family History

Evaluation and Diagnosis History from patient and family EEG: standard 20-30 minutes EEG Monitoring: Ambulatory EEG Video EEG Neuroimaging

The Tracing

Video-EEG Monitoring Continuous synchronized EEG and Video recording Monitors patient’s behavior and EEG Scalp: Electrodes Similar to EEG Invasive: Electrodes within or on the surface of the brain.

Paroxysmal Events Epileptic Non-Epileptic: Focal (Partial) onset Generalized onset Non-Epileptic: Psychogenic Cardiac Vasovagal Sleep disorder Migraine…

Partial (focal) Seizures Simple Partial Seizure no loss of awareness Complex Partial Seizure Impaired consciousness w w/o aura Clinical manifestations vary with origin & degree of spread Clinical Manifestations: Automatisms (manual, oral) Bicycling and fencing posture (frontal) Duration (typically 30 seconds to 3 minutes) Amnesia for event Partial Seizure with Secondary Generalization

Primarily Generalized Seizures Absence: Brief staring (<30sec ) Myoclonic: Brief, shock-like muscle contractions Atonic: Loss of muscle tone Tonic: Sustained muscle contraction Tonic-Clonic

Non-Epileptic Events Psychogenic Cardiovascular Syncope Metabolic (glucose, Na, Ca, Mg) Sleep disorders (parasomnias, cataplexy)

New Onset Seizure After the first seizure, no clear indication for treatment Routine EEG is usually of low yield Long term EEG monitoring is sometimes indicated to determine need for long term treatment with AEDs.

What Type of Seizure was it? Information Technology Services 4/19/2017 What Type of Seizure was it? Type Recurrence Risk (2 years) Provoked, no brain injury 3% Provoked, brain injury 10% Single, Unprovoked 42% Recurrent, Unprovoked 70-80% Once a decision has been made that an event was a seizure, one must decide what type of seizure it was *Population based studies indicate that 25-30% of first seizures are “provoked” by some acute event such as trauma, drugs, hypoglycemia, etc. In these situations, the risk of recurrence is generally less. No brain injury- reversible cause like hypoglycemia Brain injury- Abscess or trauma *Its also critical to determine if the “first” was really the “first”- ask the pt about previous absence seizures, myoclonic seizures, auras, etc, as the risk of relapse after the second or third seizure is much higher than after the first Pohlmann-Eden, BMJ, 2006. (C) Copyright, 2000 Yale University. All rights reserved.

Discontinue AEDs Patients who are seizure-free for over 2 years wanting to come-off AEDs Monitoring for 48 – 72 hourse OFF anti-epileptic drugs Seizure activity (spikes) on EEG indicate high risk of seizure recurrence.

Treatment of Epilepsy Medications Diet Therapy Hormonal Therapy Surgical: Resective Multiple Subpial Transaction Vagus Nerve Stimulator Experimental: Deep Brain Stimulation Radiosurgery Cortical Stimulation

Anti-Epileptic Drugs (AED) A drug that decreases the frequency and/or severity of seizures in patients with epilepsy Treats the symptom of seizures, not the underlying epileptic condition Goal—maximize quality of life by minimizing seizures and adverse drug effects

Available AEDs Phenobarbital Mysoline  Primidone Dilantin phenytoin Tegretol carbamazepine Depakote valproic acid Zorantin ethosuxamide Felbatol felbamate Neurontin gabapentin Lamictal lamotrigine Topamax topiramate Gabitril tiagabine Trileptal oxcarbazepine Zonegran zonisamide Keppra levetiracetam Lyrica  pregabaline Frisium  clobazam Klonopin  clonazepam Tranxene  chlorazepate Banzel  rufinamide Vimpat  lacosamide

Rational Use of AEDs Indication / Guidelines by FDA, AES, AAN Seizure type/ Epilepsy syndrome Adverse effects (acute; chronic) Comorbid conditions Cost Age Gender Concomitant medications Social factors Pharmacokinetic profile

Rational Use of AEDs Side Effects Co-morbid Conditions Sleepiness Dilantin Phenobarbital Mysoline Tegretol Depakote Zorantin Felbatol Neurontin Lamictal Topamax Gabitril Trileptal Zonegran Keppra Lyrica Frisium Klonopin Tranxene Banzel Vimpat Side Effects Co-morbid Conditions Sleepiness Cognitive Behavioral Metabolic : Liver Electrolytes Hyperthermia Weight gain Ostioporosis Bone Marrow Co-TRT Avoid Migraine Pain Mood Kidney Stones Psychiatric Liver Disease Bone Marrow Drug Interactions Cytochrome P-450: Steroids Chemotherapy Coumadin Many others… Age / Sex Young Women Elderly

FDA: Use of AEDs Monotherapy Adjunct Therapy Carbamazepine Valproate Ethosuximide Oxcarbazepine Phenobarbital Phenytoin Primidone Felbamate Lamotrigine Topiramate Adjunct Therapy Carbamazepine Lacosimide Levetiracetam Rufinamide Gabapentin Zonisamide Ethosuximide Phenobarbital Oxcarbazepine Phenytoin Tiagabine Primidone Topiramate Valproate Pregabaline Lacosamide

Secondary Generalized AED Treatment Options Partial Generalized Simple Complex Secondary Generalized Tonic- Clonic Tonic Atonic Myoclonic Infantile Spasms Absence Rufinamide ACTH TPM TGB VGB PHT, CBZ, GBP, OXC, TGB, LCS PGB ESX VPA, LTG, TPM, ZNS, LVT, FBM

AED Therapy Trial and Error Method Epilepsy Time First AED Increase Dosage Switch AED Combine AEDs Polytherapy Trial and Error Method

Trial and Error Method TRIAL ERROR Adjust Dosage Recurrent Seizures Change AED Combine AEDs Side Effects

Rational Use of AEDs PharMetrics. April 2002 to June 2003 IMS NPA, Dec 2003. Kwan P, Brodie MJ. N Engl J Med 2000; 342: 314-9.

Success With Antiepileptic Drugs Previously Untreated Epilepsy Patients (N=470) Kwan P, Brodie MJ. N Engl J Med. 2000;342(5):314-319

Common Side Effects Dizziness Sleepiness Drowsiness Ataxia Blurred vision

Diet Therapy

Energy Source: Regular Diet Carbohydrates Fat Glucose Fatty Acids Brain Body

Energy Source: Ketogenic Diet Carbohydrates Fat Ketones Fatty Acids Brain Body

Ketogenic Diet Very High Fat, Low Carbohydate And Protein Diet Fat Used As Alternative Energy Source Goal = Ketosis Why? Elevated Ketones Correlate With Optimal Seizure Control Fluid And Calorie Restricted Based On Ratio – 3:1 or 4:1 Food Must Be Weighed

Ketogenic Diet Admission to the hospital 3-5 days Precise amounts of carbohydrates, proteins and fat All food needs to be weighed Strict monitoring of urine ketones and blood work All medications, including over-the-counter medications, such as Motrin and Tylenol have to be keto-friendly

Modified Atkins Diet Easier than the ketogenic diet Many advantages over ketogenic diet: No admission to the hospital Only carbohydrates are measured and restricted Start at 10 gm per day, then increase to 15-20 gm per day No Protein Restriction No Fluid Restriction No Weighing Food www.atkinsforseizures.com

Compare And Contrast Ketogenic 2% 90% 8% Modified Atkins 6% 64% 30% Carbohydrate Fat Protein Ketogenic 2% 90% 8% Modified Atkins 6% 64% 30% Average American ~50-55% ~25-30% ~10-15%

Low Glycemic Index Diet No Hospital Admission Required Allowance: 40 – 60 grams CHO/day Only Foods With Low Glycemic Index are allowed Foods quantities are not weighed but are based on portion size More Flexible Lifestyle

Hormone Therapies Some women experience increase in seizure frequency around their menstrual period Catamenial seizures This is believed to be due to sudden changes in levels of hormones There are three types of catamenial seizures

Menstrual Cycle Serum Hormone Levels Day of the Cycle Estradiol g/mL E2 P Progesterone ng/mL 150 30 25 100 20 Serum Hormone Levels 15 50 10 5 1 3 5 7 9 11 13 15 17 19 21 23 25 27 Day of the Cycle E2 = estradiol; P = progesterone.

Normal Cycle: Seizures More Frequent With Drop in Progesterone (C1) or With Estrogen Surge (C2) Estradiol g/mL E2 P Progesterone ng/mL 150 30 C2 C1 25 100 20 Serum Hormone Levels 15 50 10 5 1 3 5 7 9 11 13 15 17 19 21 23 25 27 Day of the Cycle C1 = catamenial 1 (seizure pattern); C2 = catamenial 2; E2 = estradiol; P = progesterone. Herzog AG, et al. Epilepsia. 1997;38:1082-1088.

Inadequate Luteal Phase Cycle 1 5 20 10 40 15 60 80 25 100 E2 P 3 7 9 11 13 17 19 21 23 27 Day of the Cycle C3 Estradiol g/mL Progesterone ng/mL Serum Hormone Levels C3 = catamenial 3. Herzog AG, et al. Epilepsia. 1997;38:1082-1088.

Catamenial Epilepsy Katamenios = “monthly” The tendency for increased seizures related to the menstrual cycle Affects 30%-40% of women with epilepsy Note: Catamenial seizure patterns will be apparent only during ovulatory cycles, and 30% of cycles in women with epilepsy are anovulatory Herzog AG, et al. Epilepsia. 1997;38:1082-1088.

Hormone Therapy Supplementation of Progesterone during the period of increased seizures is effective in reducing seizures Oral natural progesterone is the most effective Give for 7 days starting on day 23 of the cycle Treatment with intramuscular progesterone is sometimes effective (Depo-Provera) Some seizure medications shorten the half-life of Depo-Provera and more frequent injections are necessary (every 10 or 8 weeks instead of every 12 weeks)

Herbal Medicines No proven benefits in epilepsy Some herbal medicines may increase the risk of seizures Some herbal medicines may interact with seizure medications If you plan on trying an herbal medicine, first research it thoroughly and consult with your doctor NEVER substitute an herbal medicine for your regular seizure medications http://www.mskcc.org/mskcc/html/11570.cfm

Herbal Medicines Some Herbal Substances Used In Caution Borage Anxiety Caffeine Chamomile Ephedra Evening Primrose Ginkgo Ginseng Herbal Essential Oils Kava Passionflower St. John's Wort Valerian Anxiety Depression Low Energy Arthritis Memory difficulties Caution Some may cause seizures Some may have bad interactions with seizure medications or other medications

Supplements Vitamins: A - E Minerals: Magnesium, Selenium, Zinc… Other: CoQ10, Carnitine, anti-oxidants, …

Supplements: The Rule Most supplements are probably safe if taken at the recommended dose No proven efficacy in treating seizures BUT: Some supplements are recommended in certain metabolic disorders affecting the function of the mitochondria

Mitochondria Mitochondria are small organelles inside the cells, including the brain cells. Their function is to generate energy for the cell

Mitochondria and Seizures Certain mitochondrial diseases can cause seizures It is possible that some patients with epilepsy might have an un-diagnosed mitochondrial disease as a cause of their seizures It is not know if repeated seizures exhaust the energy source of the brain and lead to mitochondrial dysfunction

Supplements In some cases, a combination of supplements and vitamins that support the energy production in the brain might be helpful These are not recommended in everybody, but are safe Some supplements include: Co-Q10, Carnitine, Vitamin B1, B5, B6, C, and E, Lipoic Acid Folic acid is recommended in all women of child-bearing age Vitamin D and Calcium are recommended for all patients taking seizure medications

Sleep and Epilepsy Cognition Sleep Seizures Behavior

Seizures in sleep disorders In patient with epilepsy Evaluation for a sleep disorder should be done if the patient has the right symptoms Treatment of the sleep disorder often leads to marked improvement in seizure control In children, sleep disorder sometimes manifest as behavioral and learning problems. Treatment can improve both.

Sleep in patients with epilepsy Many patients with epilepsy have disrupted sleep This is usually caused by: Nighttime seizures Nighttime seizure activity Side effects of seizure medications Depression and anxiety

Sleep in patients with epilepsy The most common sleep symptoms in patients with epilepsy are: Insomnia: Trouble falling asleep Frequent night time arousals Excessive sleepiness: Frequently due to side effects of medications Sometimes due to sleep disruption form nighttime seizures and seizure activity

Attention The relationship between sleep and seizures is very complex Memory, attention difficulties and sleepiness can be due either to: Seizure medications Lack of proper sleep Nighttime seizures and seizure activity Specific sleep disorder The correct diagnosis is essential!

Nighttime seizure activity In some patients, the EEG reveals very frequent spikes (seizure activity) during sleep, with minimal seizure activity while awake NOTE: Routine 20 minute EEG usually do not reveal this activity Overnight EEG is necessary to capture and quantify this activity

Significance Recent evidence suggests that patients, especially children, with frequent nighttime spikes may develop: Cognitive problems Learning difficulties Behavioral problems

Autism and Seizures About 30% of patients with autism experience seizures About 60% of patients with autism have seizure activity on the EEG The relationship between Autism and Seizures is complex

Seizures, EEG and Autism Seizures in Autistic patients should be treated like any other seizures Some patients with Autism who have frequent spikes (seizure activity) during sleep It is believed that seizure activity can interfere with learning ability, sleep and behavior In some cases, treating the seizure activity can help improve learning ability and behavior Treatment options include medications and diet

Conclusion Epilepsy is a very complex medical condition Many effective treatment options are available Most patients with epilepsy achieve seizure freedom and can live a normal and productive life Seizure medications are the main treatment modality Diet therapy should be considered in some cases Patients who don’t respond well to medications, may consider epilepsy surgery

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