Download new and newer-Dr. Christos Lambrakis

Epilepsy:
Knowledge is Power
Patient Education Conference
April 28, 2012
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Treating Epilepsy
Antiepileptic Medications
and
New Treatments
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Northeast Regional
Epilepsy Group
Christos Lambrakis M.D.
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‘The goal of therapy is to help the
person with epilepsy lead a full
and productive life….’
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‘…with minimal effects from the
condition or its treatment.’
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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.
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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.
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EEG (Normal)
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EEG (Seizure)
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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.
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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.
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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.
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Treatment Strategies
• Medications
• Surgical
• Dietary
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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.
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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.
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History of Antiepileptic
Medications
1938
• Diphenylhydantoin (Dilantin) was
discovered to have antiepileptic properties.
• Similar effectiveness to phenobarbital.
• Less sedative side effects.
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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.
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History of Antiepileptic
Medications
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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)
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History of Antiepileptic
Medications
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•
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•
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2007: Lyrica (Pregabalin)
2008: Lacosamide (Vimpat)
2008: Rufinamide (Banzel)
2009: Vigabatrin (Sabril)
2011: Clobazam (Onfi)
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History of Antiepileptic
Medications
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History of Antiepileptic
Medications
Extended Release Formulations
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1996: Tegretol XR (Carbamazepine)
2001: Phenytek (Phenytoin)
2002: Depakote ER (Divalproex sodium)
2008: Keppra XR (Levetiracetam)
2009: Lamictal XR (Lamotrigine)
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Extended Release Formulations
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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)
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Mechanisms Of Action
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Mechanisms To Target
Examples
• Dilantin: Blocks sodium channels
• Depakote: Blocks sodium channels
Increases GABA transmission
• Zarontin: Blocks calcium channels
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When to Treat?
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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)?
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When Not to Treat
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Single seizure
No history
Neurologically normal
Young age
Side effect concerns
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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.
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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%.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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Factor Influencing Drug
Selection
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Seizure type
Syndrome
Side effects
Patient age
Lifestyle
Childbearing potential
Other medications
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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.
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Advantages of Monotherapy
• 70-80% of patients are controlled on
monotherapy.
• Fewer side effects.
• No drug interactions.
• Easier dosing = Greater compliance
• Lower cost.
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Antiepileptic Medication
Response
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Advantages of Polytherapy
• May control an additional 30% of patients
that could not be controlled with
monotherapy.
• May provide synergistic effects. (1+1=3)
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Side Effects
• All seizure medications can have side
effects.
• Side effects can be grouped as:
– Dose related
– Dose unrelated (occur at any dosage)
– Idiosyncratic
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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.
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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.
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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).
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Side Effects
Warning Signs
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Prolonged fever
Rash
Severe sore throat
Mouth ulcers
Easy bruising
Pinpoint bleeding
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Weakness
Excessive fatigue
Swollen glands
Lack of appetite
Increased seizures
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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.
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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.
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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.
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FDA Pregnancy Risk
Category C
• Zonisamide
• Gabapentin
• Oxcarbazepine
• Felbamate
• Levetiracetam
• Lamotrigine
• Tiagabine
Category D
• Phenytoin
• Valproic acid
• Carbamazepine
• Phenobarbital
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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.
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Reasons for non-compliance
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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
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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.
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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.
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Factors Associated with Seizure
Recurrence
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Abnormal EEG
Hard to control seizures
Neurologic deficits
Epilepsy type
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Factors Associated with
Non-Recurrence in Adults
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Primary generalized seizure type
Under 30 years of age
Prompt initial control
2-5 years of seizure freedom
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Discontinuing Antiepileptic
Medications
• 65-70% of children who are free of seizures
on antiepileptic medications will remain
seizure free after the drugs are withdrawn.
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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
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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
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Newer Treatments
Antiepileptic Medications
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Sabril (Vigabatrin)
Banzel (Rufinamide)
Vimpat (Lacosamide)
Onfi (Clobazam)
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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).
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Banzel (Rufinamide)
• Approved for the treatment of seizures for
children and adults (> 4 years old) with
Lennox-Gastaut Syndrome (2008).
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Vimpat (Lacosamide)
• Approved as add-on treatment in adults
with partial onset seizures (2008).
• Unique mechanism of action.
• Low side effect profile.
• Rapid effectiveness
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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
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Newer Treatments
Medications in Development
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Carisbamate (Partial seizures)
Retigabine (Partial seizures)
Eslicarbazepine (Partial seizures)
Perampanel (Partial seizures)
Brivaracetam (Generalized tonic seizures)
Fluorofelbamate
JZP-4, PID, Valrocemide, Ganaxolone
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New Treatments
Devices/Surgical
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Vagus Nerve Stimulator
Deep Brain Stimulation
Neuropace
Epilepsy Surgery
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Vagus Nerve Stimulator
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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.
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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
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Newer Treatments
Neuro-stimulators
Deep Brain Stimulation
• Promising new technology for medicallyrefractory seizures.
• Stimulator electrodes are placed deep within
the brain (thalamus or cerebellum) which
are then connected to a pacemaker-like
device in the chest.
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Newer Treatments
Neuro-stimulators
NeuroPace
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Neuro-stimulators
NeuroPace
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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.
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Epilepsy Surgery
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Epilepsy Surgery
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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
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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
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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
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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
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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
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Alternative Treatments
Relaxation Techniques
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Reiki
Yoga
Hypnosis
Deep breathing exercises
Massage therapy
Meditation
Muscle relaxation techniques
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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.
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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.
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