Epilepsy: Knowledge is Power Patient Education Conference October 16th, 2013

Treating Epilepsy Epilepsy Diagnosis and Treatment Options

Northeast Regional Epilepsy Group Christos Lambrakis M.D.

‘The goal of therapy is to help the person with epilepsy lead a full and productive life….’

‘…with minimal effects from the condition or its treatment.’

What is a Seizure? A seizure begins when one or more neurons (cells in the brain) send electrical messages that cause an inappropriate burst of electrical activity. This can cause surrounding neurons to generate their own electrical discharges which can spread throughout the entire brain.

What is a Seizure? Abnormal discharge of brain cells resulting in a change of behavior, movement, sensation or awareness. During a seizure a person may feel, move, think or act differently. This is because a seizure can temporarily disturb many of the brains normal functions.

EEG (Normal)

EEG (Seizure)

What is Epilepsy? Epilepsy is the term applied to the state of recurrent seizures. A condition of the brain, of various causes, which predisposes the patient to recurrent epileptic seizures. Epilepsy is a tremendously variable condition in terms of its cause, seizure types and response to treatment.

Epilepsy Our understanding of epilepsy has increased dramatically over the last 20 years. Accurate seizure characterization has aided in determining prognosis and selection of medication Several new anti-epileptic medications provide excellent seizure control with less side effects than older medications. Advances in surgery and vagal nerve stimulation.

Epilepsy Statistics Epilepsy is one of the most common neurologic diseases. Affects approximately 1% of the population (2 million people in the USA). Approximately 10% of the population will have a seizure at some point in their lifetime.

Treatment Strategies Medications Surgical (neurostimulators and resective) Dietary

Antiepileptic Medications Decreases the frequency or severity of seizures in people with epilepsy. Treats the symptom of the epilepsy (the seizure). Goal is to improve quality of life by reducing the frequency of seizures with minimal side effects.

History of Antiepileptic Medications 1912 Phenobarbital was the primary medication used for seizures. Used for generalized tonic-clonic and to a lesser extent partial seizures. No effect on absence seizures. Sedative effect occurred in many people. Hyperactivity noted in children.

History of Antiepileptic Medications 1938 Diphenylhydantoin (Dilantin) was discovered to have antiepileptic properties. Similar effectiveness to phenobarbital. Less sedative side effects.

History of Antiepileptic Medications 1960-1974 U.S. Food and Drug Administration (FDA) imposed new regulations on pharmaceutical companies. Medications were now required not only to be safe but they had to be proven effective against the illness it was designed to treat. Only one medication for seizures was developed during this time. Valium was found to be an effective treatment for status epilepticus.

History of Antiepileptic Medications 1974: Carbamazepine (Tegretol) 1978: Valproic acid (Depakote) 1993: Felbamate, Gabapentin (Neurontin) 1995: Lamotrigine (Lamictal) 1996: Fosphenytoin (Cerebyx) 1997: Topiramate (Topamax), Tiagabine (Gabitril) 1999: Levetiracetam (Keppra) 2000: Oxcarbazepine (Trileptal), Zonisamide (Zonegran)

History of Antiepileptic Medications 2007: Lyrica (Pregabalin) 2008: Lacosamide (Vimpat) 2008: Rufinamide (Banzel) 2009: Vigabatrin (Sabril) 2011: Clobazam (Onfi)

History of Antiepileptic Medications

History of Antiepileptic Medications Extended Release Formulations 1996: Tegretol XR (Carbamazepine) 2001: Phenytek (Phenytoin) 2002: Depakote ER (Divalproex sodium) 2008: Keppra XR (Levetiracetam) 2009: Lamictal XR (Lamotrigine)

Extended Release Formulations

Key Concepts in Antiepileptic Treatment Mechanism of Action How do medications work? For many medications this is still not well understood Proposed mechanisms involve increasing the amount of inhibitory neurotransmitters, decreasing the amount of excitatory neurotransmitters or changes in the flow of ions (sodium or chloride) across the neuron cell membrane.

Antiepileptic Medications How they work? Mechanisms To Target Excitation (Too much) - Flow of Sodium or Calcium into neuron - Neurotransmitters (Glutamate, Aspertate) Inhibition (Too little) -Flow of Chloride in, or Potassium out of neuron -Neurotransmitter (GABA)

When to Treat? Are the episodes really seizures? EEG: Normal or abnormal? Frequency and type of episodes? Are there other neurologic problems? What is the cause of the seizures? Can the underlying problem be treated rather then treating the symptom (i.e. the seizure)?

When Not to Treat Single seizure No history Neurologically normal Young age Side effect concerns

First Seizure Studies have shown that a otherwise normal child who had a single seizure has a 15% chance of having a second seizure if left untreated. Physicians will typically wait until a second or third seizure before initiating treatment with antiepileptic medication.

First Seizure For a child who is neurologically abnormal or has an abnormal EEG- the risk of subsequent seizures is substantially increased to between 50-60%.

When to Treat? Risk-Benefit Ratio In determining whether to treat physicians consider many factors. The benefits of preventing further seizure activity is weighed against the risk of potential side effects of the antiepileptic medications. The decision to treat is a highly individualized one.

Key Concepts in Antiepileptic Treatment -Metabolism- The process by which medications are broken down and eliminated by the body. Most antiepileptic medications are metabolized by the liver. Some antiepileptic medications are metabolized by the kidneys.

Key Concepts in Antiepileptic Treatment -Metabolism- Children generally have a faster metabolism and thus require higher then expected dosages of medications to maintain adequate blood levels. Older people typically have slower metabolisms and thus require less medication. Often they can become toxic on ‘normal’ dosages of medication.

Key Concepts in Antiepileptic Treatment Half-life The time it takes your body to eliminate half the medication in your body. After one half-life the amount of medication in your body will decrease by 50 %. After 5 half-lives 95% of the medication will be removed from your body. Half-lives vary greatly among seizure medications.

Key Concepts in Antiepileptic Treatment Steady State A balance obtained when the amount of medication you take into your body equals the amount being eliminated. May take days to reach a steady state when starting or changing doses of medications. Full therapeutic effect of a medication is not reached until steady state is achieved.

Key Concepts in Antiepileptic Treatment Therapeutic Range The blood levels of medication that for most people will provide an adequate seizure reducing effect without excessive side effects. Treat the person not the range! Everyone responds differently. Some people can be effectively treated with blood levels above or below the therapeutic range.

Factor Influencing Drug Selection Many antiepileptic medications are effective against specific seizure types. It is very important to know the specific type or types of seizures a patient is having so that the appropriate medication can be chosen. On occasion the wrong medication can actually make seizures worse.

Factor Influencing Drug Selection Seizure type Syndrome Side effects Patient age Lifestyle Childbearing potential Other medications

Factor Influencing Drug Selection Monotherapy or Polytherapy Monotherapy is usually the preferred treatment. A single drug is prescribed in increasing increments until seizures are controlled or toxicity occurs. If the drug is ineffective or side effects occur, the drug is slowly withdrawn while another medication is slowly introduced.

Advantages of Monotherapy 70-80% of patients are controlled on monotherapy. Fewer side effects. No drug interactions. Easier dosing = Greater compliance Lower cost.

Antiepileptic Medication Response

Advantages of Polytherapy May control an additional 30% of patients that could not be controlled with monotherapy. May provide synergistic effects. (1+1=3)

Side Effects All seizure medications can have side effects. Side effects can be grouped as: Dose related Dose unrelated (occur at any dosage) Idiosyncratic

Side Effects Dose related Some effects are dose related. That is they become more likely as the amount of medication is increased. Sleepiness, slurred speech, and unsteadiness are common effects of seizure medications at higher doses.

Side Effects Dose unrelated (Common at any dose) Some side effects can occur at any dosage. Examples include double vision, weight gain, hyperactivity, sleep disturbances, irritability, hair changes, gum growth, and changes in mood. On occasion these effects are seen at the start of treatment and gradually get better with time.

Side Effects Idiosyncratic A rare side effect that occurs because of a patients individual sensitivity or allergic reaction to a particular medication. Examples include: Liver failure, aplastic anemia, severe rashs (Steven Johnson Syndrome).

Side Effects Warning Signs Prolonged fever Rash Severe sore throat Mouth ulcers Easy bruising Pinpoint bleeding Weakness Excessive fatigue Swollen glands Lack of appetite Increased seizures

Side Effects Pregnancy All seizures medication pose some risk to the developing fetus. None of the commonly used seizure medication are absolutely contraindicated in pregnancy. Possible side effects include cleft palate/lips, cardiac abnormalities, and spinal tube defects.

Side Effects Pregnancy Antiepileptic medications can reduce the effectiveness of certain birth control pills. It is important to tell your doctors about all the medications you are taking so that potential interactions can be discussed and avoided.

FDA Pregnancy Risk Category C Zonisamide Gabapentin Oxcarbazepine Felbamate Levetiracetam Lamotrigine Tiagabine Category D Phenytoin Valproic acid Carbamazepine Phenobarbital

Effectiveness of Treatment 75-80% of patients with epilepsy will have reliable long term control of their seizures with currently available medications. For the remainder of patients with intractable seizures other options exist such as epilepsy surgery, neuro-stimulators and the ketogenic diet.

Discontinuing Antiepileptic Medications Antiepileptic medications may not have to be taken for a lifetime. When seizures have been controlled over a period of time (usually one to two years), there is a good chance that withdrawal of medication will be successful.

Factors Associated with Seizure Recurrence Abnormal EEG Hard to control seizures Neurologic deficits Epilepsy type

Factors Associated with Non-Recurrence in Adults Primary generalized seizure type Under 30 years of age Prompt initial control 2-5 years of seizure freedom

Discontinuing Antiepileptic Medications 65-70% of children who are free of seizures on antiepileptic medications will remain seizure free after the drugs are withdrawn.

Newer Treatments Antiepileptic Medications Research has provided insight into the pathophysiology of epilepsy at the molecular and genetic level enabling medications to be developed that target these mechanisms Not just ‘more of the same’ Unique mechanisms of action Improved pharmacokinetics

Newer Antiepileptic Medications Similar effectiveness to established AEDs in the treatment of seizures All AEDs have adverse effects Not appropriate for all seizure types Most used as adjunctive therapy (add-on therapy)

Newer Treatments Antiepileptic Medications Sabril (Vigabatrin) Banzel (Rufinamide) Vimpat (Lacosamide) Onfi (Clobazam)

Sabril (Vigabatrin) Approved as monotherapy for patients 1 month to 2 years of age with infantile spasms. Approved as add-on therapy for adults with complex partial seizures. Can cause eye injury (Retinal damage).

Banzel (Rufinamide) Approved for the treatment of seizures for children and adults (> 4 years old) with Lennox-Gastaut Syndrome (2008).

Vimpat (Lacosamide) Approved as add-on treatment in adults with partial onset seizures (2008). Unique mechanism of action. Low side effect profile. Rapid effectiveness

Onfi (Clobazam) Approved in 2011 Adjunctive (add-on) treatment for seizures associated with Lennox-Gastaut syndrome in adults and children 2 years of age and older. Atonic (“drop seizures”), tonic, or myoclonic seizures

Newer Treatments Medications in Development Carisbamate (Partial seizures) Retigabine (Partial seizures) Eslicarbazepine (Partial seizures) Perampanel (Partial seizures) Brivaracetam (Generalized tonic seizures) Fluorofelbamate JZP-4, PID, Valrocemide, Ganaxolone

New Treatments Devices/Surgical Vagus Nerve Stimulator Deep Brain Stimulation Neuropace Epilepsy Surgery

Vagus Nerve Stimulator

Vagus Nerve Stimulator FDA approved in 1997 (Seizures), 2005 (Depression) Electrical stimulus applied to the Vagus Nerve and has been found to reduce seizure frequency Typically reserved for patients with difficult to control epilepsy. Implantation takes 1-2 hours under general anesthesia.

Vagus Nerve Stimulator Patients/Caregivers can turn the device on by using hand held magnet Low side effects: Cough/ deepening of voice during stimulation. After one year: 1/3 have excellent response (90% reduction) 1/3 have good response (50% reduction) 1/3 little to no response

Newer Treatments Neuro-stimulators Deep Brain Stimulation Promising new technology for medically-refractory seizures. Stimulator electrodes are placed deep within the brain (thalamus or cerebellum) which are then connected to a pacemaker-like device in the chest.

Newer Treatments Neuro-stimulators NeuroPace

Neuro-stimulators NeuroPace

Newer Treatments Epilepsy Surgery Certain patients in whom medication has failed to provide seizure control are evaluated for epilepsy surgery Surgery is restricted to those patients whose seizures originate from an identifiable focus in the brain.

Epilepsy Surgery

Epilepsy Surgery

Newer Developments MEG (Magnetoencephalography) Measures the small electrical currents arising inside the neurons of the brain. Similar to EEG but provides greater accuracy. Used to locate where seizures are coming from within the brain. Can be used to map brain functions

Alternative Treatments Ketogenic Diet Developed in the 1920’s High fat, low carbohydrate, adequate protein diet (4:1 ratio) Forces body to burn fats producing ketones Effective in half the patients who try it

Alternative Treatments Ketogenic Diet Not easy. Requires careful weighing and calculating of food calories Complications: Growth delay, bone fractures, kidney stones and elevated cholesterol levels

Alternative Treatments Relaxation Techniques Reiki Yoga Hypnosis Deep breathing exercises Massage therapy Meditation Muscle relaxation techniques

Alternative Treatments Biofeedback Method of using relaxation or imagery to change body functions such as breathing, heart rate, and blood pressure These functions are monitored A stressful situation is presented and relaxation techniques are utilized Patient is able to view these functions and the see the differences between stressed and relaxed states

Alternative Treatments Biofeedback Has been shown to help people with high blood pressure, headaches, and pain. Patients who have seizures triggered by anxiety or stressful situations may benefit

Alternative Treatments Melatonin Natural hormone produced by the pineal gland in the brain Frequently used as a sleep aid Study results with respect to helping seizures have been inconclusive.

Alternative Treatments Vitamins Necessary for good health, however…… Large doses of vitamins have not been shown to be of any benefit in reducing seizure frequency Patients on seizure medication may require supplements of calcium and Vitamin D for bone health.

Medical Marijuana

Medical Marijuana Marijuana comes from the Cannabis Sativa herb. Contains over 100 compounds (Phytocannabinoids). Two of these compounds are Tetrahydrocannibinol (THC) and Cannabidiol CBD.

Medical Marijuana THC Responsible for psychoactive properties. Used medicinally to treat nausea, pain and stimulates appetite. Most common form of ‘Medical Marijuana’.

Medical Marijuana CBD Does NOT have psychoactive properties. Low toxicity and high tolerability. Some animal studies have shown it can reduce certain types of seizures. Very few studies involving humans.

Medical Marijuana In The News Several case reports and surveys have attested to a positive effect of either THC or CBD reducing seizure frequency. Scientific, peer-reviewed studies are still lacking.

Medical Marijuana Laws and Research Due to strict laws, it is difficult to study C. Sativa. Several pharmaceutical companies in UK and Japan are studying various phytocannabinoids.

Medical Marijuana New Jersey Law Physician must be registered with NJ’s medical marijuana program. Physician-patient relationship must have existed for 1 year and at least 4 office visits. Patient must have ‘medically refractory epilepsy’. Patients must register with the state.

Medical Marijuana New Jersey Law Regulations for kids are more strict, however…. September 10th, 2013 Gov. Christie signed into law that children with severe epilepsy syndromes can now have access to medical marijuana.

Medical Marijuana New Jersey Law NJ currently has Medical Marijuana available in bud or lozenge forms. Laws are changing rapidly!!!

Medical Marijuana New York Law On June 3, 2013 the NY State Assembly passed a bill that would legalize medical marijuana with 99 Assembly members voting Yes and 41 Voting No. It was delivered to the Senate and has yet to be voted on. Three bills currently in process in New York Senate (SB 1682, SB 4406, AB 6357).