1. Epilepsy: Knowledge is Power
Patient Education Conference
April 28, 2012

2. Treating Epilepsy Antiepileptic Medications and New Treatments

3. Northeast Regional Epilepsy Group Christos Lambrakis M.D.

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

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

7. What is a Seizure?
A seizure begins when one or more cells 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.

8. 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.

9. EEG (Normal)

10. EEG (Seizure)

12. 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.

13. 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.

14. 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.

16. Treatment Strategies
Medications
Surgical
Dietary

17. Antiepileptic Medications
Decreases the frequency or severity of seizures in people with epilepsy.
Treats the symptom of the epilepsy (the seizure) and not the underlying condition (the epilepsy).
Goal is to improve quality of life by reducing the frequency of seizures with minimal side effects.

18. 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.

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

20. 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.

21. 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)

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

23. History of Antiepileptic Medications

24. 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)

25. Extended Release Formulations

26. 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)

28. Mechanisms Of Action

29. Mechanisms To Target Examples
Dilantin: Blocks sodium channels
Depakote: Blocks sodium channels Increases GABA transmission
Zarontin: Blocks calcium channels

30. 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)?

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

32. 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.

33. 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%.

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

35. 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.

36. 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.

37. 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.

38. 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.

39. 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.

41. 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 or changes in the flow of ions (sodium or chloride) across the neuron cell membrane.

42. 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.

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

44. 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.

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

46. Antiepileptic Medication Response

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

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

49. 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.

50. 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 growth, gum growth, and changes in mood.
On occasion these effects are seen at the start of treatment and gradually get better with time.

51. 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).

52. 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

53. 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.

54. 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.

55. Side Effects Pregnancy
Folic acid is frequently prescribed to all women of child baring age as it is believed to protect against some birth defects.
Good news! 90% of women with epilepsy who become pregnant will give birth to normal healthy babies.

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

57. Compliance
The degree to which the patient follows the physicians directions on how and when medications should be taken.
73% of people with epilepsy were found to be compliant with medications.
Compliance is very important in epilepsy treatment as blood levels of medications will fall low if dosages are missed.

58. Reasons for non-compliance
Do not need so much medication
Unpleasant side effects
Making the drug last longer because of cost
Forgetfulness
Confusion about dosages and times
Inconvenience of schedule
Misunderstand directions

59. 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.

60. 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.

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

62. 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

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

64. 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

65. Newer Antiepileptic Medications
Similar effectiveness to established AEDs in the treatment of partial seizures
All AEDs have adverse effects
Not appropriate for all seizure types
Possible teratogenicity
Limited data available for efficacy and safety
Most used as adjunctive therapy

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

67. 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).

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

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

70. 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

71. 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

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

73. Vagus Nerve Stimulator

74. 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.

75. 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

76. 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.

77. Newer Treatments Neuro-stimulators NeuroPace

79. Neuro-stimulators NeuroPace

80. 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.

82. Epilepsy Surgery

83. Epilepsy Surgery

84. 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

85. 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

86. 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

87. 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

88. 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

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

90. 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.

91. 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.