Mon. 11/02 - Epilepsy Flashcards
What is epilepsy?
- Chronic neurological disorder characterized by recurrent seizures – hyperexcitable, “irritable” neurons
- One seizure is not epilepsy
What is the neurological substrate of seizures? / Define seizure
Generally neurons fire in specific patterns and in a sort of synchrony. Seizures are the upset of this balance.
Seizure is an episode of sudden, transient disturbance in cerebral excitation, neurons firing rapidly in synchronized bursts.
What is generalization of seizures?
Neurons firing all at the same time
A focus (group) of neurons is hyperexcitable, which can affect other populations of neurons
Differentiate seizures and convulsions:
Convulsions indicate a seizure, but a seizure doesn’t always include convulsions.
True or false: all seizures include a loss of consciousness
False
The population more prone to fever seizures:
Young children
What increases the likelihood of a fever seizure?
How fast the fever increases in a febrile episode
Seizure Classification (3)
Focal (partial)
Generalized
Unknown = anything that does not fit into the other two categories
Sub-types of partial seizures (2)
Simple
Complex
Characteristics of Simple Seizures (4)
- Focal area,
- Unilateral motor or autonomic responses, including convulsion
- Full consciousness
- Difficult to catch/ recognize
Characteristics of Complex Seizures (3-4)
- Focal area,
- Bilateral, resulting in a wide variety of manifestations and bizarre behaviors
- Altered consciousness
(75% originate in the temporal lobe)
What neurological pattern could a generalized seizure follow?
Can start as a partial and spread via the thalamus to affect the entire brain.
Subtypes of Generalized Seizures (7)
- Absence
- Myoclonic
- Tonic -clonic
- Clonic
- Tonic
- Atonic
- Status epilepticus
Describe the two phases of tonic- clonic seizures
Tonic Phase: rigid body, clenched jaw and hands, sustained contraction of all muscles
Clonic Phase: begins with rhythmic jerky movements ending with relaxation of all body muscles
True or false: Tonic-Clonic seizures are associated with major convulsions of the entire body and loss of consciousness.
True
Describe Absence seizure/ Typical Symptoms
Sudden, brief loss of consciousness
motor signs may be absent or may range form rapid eye-blinking to symmetrical jerking movements of entire body
Describe Myoclonic seizure / Typical Symptoms
Sudden, brief “shock-like” contraction (single or multiple) of the muscles in the face and trunk or in one or more extremities;
consciousness may be impaired
Describe Clonic seizure / Typical Symptoms
Rhythmic, synchronized contractions throughout body; loss of consciousness
Describe Tonic seizure / Typical Symptoms
Generalized sustained muscle contraction throughout body; loss of consciousness
Describe Atonic seizure / Typical Symptoms
Sudden loss of muscle tone in the head and neck, one limb or throughout the entire body
consciousness can be maintained or lost briefly
What causes seizures? (6, 7 from G and F, 4 more from Dr. T)
Head injury Fatigue Hypoglycemia Changes in electrolytes Fever (febrile seizures) & illness (infection) Missed medication
From Goodman and Fuller:
- Stress
- Poor nutrition/ skipped meals
- Flickering lights
- Allergies
- Lack of sleep
- Anger, worry, fear
- Heat and humidity
Dr. T also listed congenital, birth trauma, anoxia, and genetic as causes
What is the major role of the thalamus in epilepsy?
-Is the path to the cortex
-If the hyperexcitability affects the electrical activity of the thalamus, this has widespread effects to the cortical areas.
Name the only thalamic nucleus that does NOT project directly to the cortex.
Nucleus Reticularis
What type of cells are found in the Nucleus Reticularis
GABAergic
How does Nucleus Reticularis modulate the activity of the other thalamic nuclei?
The nucleus reticularis, while consisting of inhibitory interneurons, actually works by disinhibition, so it has an overall excitatory effect. This is an example of how a GABAergic cell can have overall excitatory effects.
This nucleus is essential for initiation of movement.
Nucleus reticularis is very impotant in mov initiation -> convulsions in seizures
Name the three antiseizure drug strategies:
- Increase the activity of CNS inhibitory neurons
- Decrease the activity of CNS excitatory neurons
- Stabilize the opening and closing of Na+ or Ca++ channels
Which neurotransmitter is targeted to decrease the activity of excitatory neurons?
Glutamate (excitatory)
Glutamate receptors are a favorite pharmacological target to decrease excitability.
Name the two types of glutamate receptors
- NMDA
2. AMPA
What type of channel does the NMDA receptor open?
Ca++ channels causing depolarization.
What does hyper-excitability lead to?
Hyper-excitability leads to prolonged NMDA receptor activation and large increases in intra-cellular calcium concentration. During the seizure, the neurons will fire continuously (tonic phase). The seizure ends when repolarization of the membrane occurs (clonic phase).
What type of channels do AMPA receptors open?
Na+ channels also cousing depolarization
Which neurotransmitter is targeted to increase the activity of inhibitory neurons?
GABA - Major inhibitory neurotransmitter
What type of channels do GABA receptors open?
Cl- channels causing hyper-polarization
What is the mechanism of GABA receptors?
increase inhibition
What are the barbiturates and benzodiazepines effect over GABA receptors?
Both increase the inhibitory effects of GABA
Barbiturates serve as GABA agonists.
Benzodiazepines work by increasing the amount of chloride that can flow through the channel, so help to further hyper-polarize and increase inhibition.
Can barbiturates and benzodiazepines be prescribed together?
Yes, but definitely don’t drink with these!
What effect does positive ion (Ca++ and Na+) entry have on a neuronal membrane?
Depolarization
True or false: Sodium and calcium channels (not glutamate receptor associated ones), are another pharmacological target for control of seizures.
True
What are the 3 major pharmacological targets for control of seizures?
- Glutamate receptors
- GABA receptors
- Ca++ and Na+ channels
How do you think dehydration could lead to seizure activity?
Dehydration will increase the Na+ concentration inside the cell, increase depolarization (excitation) and precipitate the seizure.
What are the long term effects of seizures?
*Microglial infiltration
*Gliosis - (nonspecific term that basically means inflammation. Gliosis can lead to cell loss)
*Cell loss
*Scarring
Name two diagnostic procedures of choice for epilepsy:
MRI
PET scan
Name two possible findings on MRI image:
- Gliosis
2. Loss of volume
what is the possible finding with PET scan?
PET scan for fluorodeoxyglucose (indicates metabolic activity)
-Dark areas indicate decreased metabolism
What are the % of antiseizures drug effectiveness?
- About 50% of time effective for eliminating seizures;
- 25% for substantial control;
- 25% inadequate medication control
Define status Epilepticus
Continuous seizure for 30 minutes or more, or successive seizures without regaining consciousness
What could cause Status Epilepticus?
- Sudden withdrawal from anti-seizure medications,
- Cerebral infarct,
- Drug/alcohol withdrawal,
- Infection
True or false: Status Epilepticus requires emergency treatment
True
What is the emergency treatment (6)
- Maintain airway, O2,
- Monitor BP/HR,
- Assessing for injury,
- Blood gases,
- Will start toxicology analysis ,
- IV medications
What is the 1st drug used for Status Epilepticus?
1st drugs usually benzodiazepines (Valium or Ativan) via IV
Are benzodiazepines short or long term acting in treatment of Status Epilepticus?
Short
What are the two drugs (and their class) given concurrently with the benzo drugs treatment of Status Epilepticus?
Benzo (Valium or Ativan) concurrent with or followed by phenytoin (Dilantin) or fosphenytoin (Cerebyx)
They are Hydantoins
What else is used if the 1st drug doesn’t work for Status Epilepticus?
What class are these drugs from?
Phenobarbital (Solfoton) or valproic acid (Depakene), also used for anesthesia
Phenobarbitol is a Barbituate
Valproic acid is a Valproate (carboxylic acids in Ciccone)
What’s the next step if phenobarbital or valproic acid doesn’t work for anesthesia during Status Epilepticus?
What class are these drugs from?
If still not resolved, general anesthetics given (midazolam (Versed), pentobarbital (Nembutal), or propofol (Diprivan) – then slow tapering these medication over 12 hours
midazolam is a benzodiazapine
pentobarbital is a barbituate
propofol is a general anesthetic
What is the rational for drug use in seizure treatment?
Most seizures are self-limiting; however, uncontrolled recurrent of seizures may cause further damage to injured neurons, can be potentially harmful to other healthy cells
Name 4 consequences of recurrent seizures? (that would harm other healthy cells)
- Cascade of harmful proteins and oxidative stress
2 .Structural and functional changes in neuronal pathways, - impaired cerebral activity,
- susceptibility to other seizures
Can seizures be fatal?
Yes, Fatal if cardiac irregularities result → cardiac arrest
What is the common goal of anti-seizure drugs?
Suppress excitability of the neurons that are causing the seizure
Name the 4 mechanisms of anti seizure drugs:
↑Inhibitory effects
↓Excitatory effects
↓Na+ entry
↓Ca++ entry
What are the most common side effects of anti-seizure drugs, especially the first generation ones? (3)
Most drugs are sedatives so:
Sleepiness,
Fatigue,
Lethargy
What the 6 chemical classifications of the 1st generation anti-seizure drugs?
Barbiturates Benzodiazepines Hydantoins Iminostilbenes Succinimides Valproates (carboxylic acids in Ciccone)
Name 3 characteristics of Barbiturates (one class of anti-seizures drugs)
Strongly sedative,
Small therapeutic index (benefit to danger ratio)
Overdosing is fatal
2 brand names of Barbiturates
Phenobarbital
Nembutal
Name 2 characteristics of Phenobarbital
Still widely used,
Effective in almost all adult seizures
What’s the purpose of Nembutal?
May be used IV to stop severe, uncontrolled seizures when other drugs are Ineffective – other drugs
(a barbituate)
Adverse effects of barbiturates (8)
- Sedation,
- Nystagmus,
- Ataxia,
- Folate deficiency,
- Vitamin K deficiency,
- Skin problems,
- Paradoxical increase in seizures
- May also increase hyperactivity in children
Name 2 characteristics of Benzodiazepines (another class of anti-seizure drugs)
Sedative
Not always well tolerated
Give 4 examples of Benzo
Ativan (lorazepam)
Valium (diazepam)
Tranxene (Clorazepate)
Klonopin (Clonazepam)
What are Valim and Ativan useful for?
For acute status epilepticus and sun-down syndrome;
not for long-term use
(benzos)
Adverse effects of Benzodiazepines
Behavioral changes
Ataxia,
Sedation,
Name 3 brand names for Hydantoins (another class of anti-seizure drugs)
Dilantin, Phenytek - (Phenytoin is the chemical class)
Cerebyx (phosphenytoin)
Why aren’t other “hideous” - my addition :)- Hydantoins used? (other than Dilantin, Phenytek, Cerebyx)
Not used due to high toxicity
What is the first drug from this class ( Hydantoins) to be used?
Dilantin, Phenytek
What is another condition (different than seizure) that Dilantin, Phenytek is used for?
Used off-label for neuropathic pain, including trigeminal neuralgia
How and what is Cerebyx administered for?
Parenteral by intramuscular or IV injection
for short period (5 days or less) or status epilepticus
What are the adverse effects of Hydantoins? (9)
Gastric irritation, Confusion, Sedation, Dizziness, Headache, Cerebellar signs (nystagmus, ataxia, dysarthria), Gingival hyperplasia – overgrowth , Hirsutism, Skin disorders
Name two Iminostilbenes (another class of anti-seizure drugs)
Tegretol, (carbamazepine)
Trileptal (oxcarbazepine)
Whats the mechanism of work for Tegretol and Trileptal?
Work by slowing recovery of Na+ channels firing too rapidly
They are iminostilbenes
Name the adverse effects of Tegretol and Trileptal? (8)
iminostilbenes
Dizziness, Drowsiness, Ataxia, Blurred vision, Anemia, Water retention (abnormalities with ADH, anti-diuretic hormone release), Cardiac arrhythmias, CHF
What’s the only Succinimides (another class of anti-seizure drugs)used for seizures? What type of seizures is it used for?
Only one in use is Zarontin (Ethosuximide), for absence seizures
What are the adverse effects for Zarontin? (7)
GI distress (N&V), Headache, Dizziness, Fatigue, Lethargy, Dyskinesias and bradykinesia, Skin rash/itching
Name 3 Valproates (last class):
What other disorder are these 3 used for?
(valproic acid)
Depakene,
Depakote
Depacon,
Also used to treat bipolar disorder
What are the adverse effects for Depakene, Depakote, Depacon? (4)
GI distress,
Temporary hair loss,
Weight gain/loss,
Impaired platelet function
Why were 2nd generation drugs introduced and how are they used in reference to the 1st generation?
While single drug therapy is always easier, the 2nd gen drugs offer better control for patients who do not respond well to a single drug
Frequently used as an “add-on” to a 1st generation drug
What are some of the advantages of the 2nd generation drugs? (2-5)
More favorable pharmacokinetic characteristics
- Absorption,
- Distribution,
- Metabolism
Relatively mild side effects
Name Some of the second generation drugs: (7 lines)
Felbatol Rufinamide (Banzel), Topiramate (Topamax) Gabapentin (Neurontin) Vimpat, Lamictal Levetiracetam (Keppra) Pregabalin (Lyrica) Vigabatrin (Sabril)
Name the three drugs used to treat used in Lennox-Gastaut and some of these drugs characteristics:
Felbatol
- can be severely toxic causing aplastic anemia, liver failure
- used only when other therapies have failed
Rufinamide (Banzel), Topiramate (Topamax) – not as toxic
What is Lennox-Gastaut syndrome?
A difficult to treat childhood epilepsy,
onset 2-6 years of age
what else is Gabapentin used for? (off label)
Chronic/neuropathic pain
What are the adverse effects of Gabapentin? (4)
Fatigue,
Ataxia
Dizziness,
Sedation,
What are the 3 well tolerated 2nd generation drugs?
Vimpat, Lamictal
Levetiracetam (Keppra)
Name another drug that is also used for chronic pain
Pregabalin (Lyrica) – also used for chronic pain (fibromyalgia, diabetic peripheral neuropathy, post-herpetic neuralgia)
What are the adverse effects of Lyrica? (3)
Dizziness,
Drowsiness,
Peripheral edema (inhibits Ca++ channels)
what are the adverse effects of Vigabatrin (Sabril)?(8)
Damage to retina, Suicidal thoughts, Confusion, Drowsiness, Fatigue, In-coordination, Weight gain, Joint pain
How are anti-seizure drugs selected and dosed? (3)
Case-by-case basis;
very individualized
Daily oral doses usually divided into 3-4 equal quantities;
When should we schedule therapy for patients with seizures?
If possible, schedule therapy for about an hour after a dose
Are these drugs a threat for pregnancy?
Pregnancy precautions – risks of congenital malformations increased
What are the factors predicting successful withdrawal from anti-seizure medication? (4)
Free of seizures for at least 2 years on meds
Good control of seizures within 1st year after seizures start
Normal neuro exam prior to withdrawal
Initial onset of seizures during childhood
What is the recommended amount of time to taper the medication off?
3-6 months
What is the % of Pt that can remain seizure-free after meds withdrawn?
60-70%
What percentage of U.S. Population have epilepsy?
~3%
