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Flashcards in Epilepsy Phys and Pharm Deck (56):
1

What is a seizure?

• occasional, sudden, excessive and rapid discharge of gray matter
• Usually consistent with "postive symptoms" of the gray matter involved
• Ie - visual hallucinations if visual cortex involved

2

When do negative symptoms from a seizure come into play?

• Following a seizure the patient will experience negative symptoms, or in other words, a loss of function in the areas of brain involved.
• This is the postictal period.

3

In general, what are the two reasons for the postictal period exhibiting negative symptoms?

The first, neuronal exhaustion; and the second, inhibitory inputs to that area.

4

What does epilepsy even mean?

The term epilepsy implies chronicity and is generally used to indicate a tendency for recurrent seizures because of an underlying brain abnormality. The incidence of epilepsy is 0.7% which is approximately the same as insulin dependent diabetes.

5

What are the key elements in the history with a patient's concern for seizures/epilepsy?

The key elements in the history include: what happened before the seizure (was there any warning)?, what occurred during the spell and what happened afterward? The timeline is also important.

6

How are seizures classified?

The modern classification of seizures is based upon how seizures begin
*This classification scheme has major implications regarding etiology, treatment and prognosis. The major and most important differentiation is between partial seizures and generalized seizures.

7

What is a partial seizure? Does that have anything to do with grand mal seizures?

A partial seizure begins in one area of the cortex. It may remain localized or spread to varying degrees including the whole cortex causing a classic grand mal seizure.
*An analogy I often give patients is that a focal seizure is like a fire which begins in one room of a building and can spread to an entire wing or even further to involve the entire building.
*History of the focal onset is not always present for several reasons; it may begin as a “silent area” of the brain, evolution in to a convulsion may occur too rapidly, and the patient may be amnesic for the focal symptom.

8

What are absence seizures?

In this subgroup are the absence seizures, which involve widespread areas of the cortex but probably not all layers of neurons.
*Many textbooks give the misconception that absence seizures are associated with total unawareness. In reality there are varying degrees of absence seizures, with varying amounts of cognitive impairment during these episodes

9

Are absence seizures only seen in children?

Another common fallacy is that absences are almost exclusively seen in children. They certainly are more common in the pediatric population, but I would estimate that approximately 10% of the patients that come to the adult Seizure Clinic at University Hospital have primary generalized epilepsy and absences.

10

Syncope and near syncope are on the differential for epilepsy. What are the 4 major groups of syncope causes?

A. Circulatory
1. Inadequate vasoconstrictor mechanisms
2. Hypovolemia
3. Reduced venous return to heart
4. Reduced cardiac output (either mechanical in nature or arrhythmic in nature)
5.Altered States of Blood (from hypoxia or anemia or hypoglycemia)

11

Besides syncope or near syncope, which itself has a pretty broad differential, what else is on your mind during an interview for epilepsy concern?

II. Movement Disorders (Especially myoclonus and paroxysmal dyskinesia
III. Fasciculation
IV. Stroke/TA
V. Migraine
VI. Sleep Disorders
*Psychogenic/Behavioral factors as well

12

What are the psychogenic/behavioral factors that may cause epilepsy-type symptoms?

A. Daydreaming
B. Hyperventilation syndrome
C. Hysterical fainting
D. Psychogenic seizures
E. Panic attacks

13

What is the difference between the terms seizure, convulsion and epilepsy?

• Seizure - excessive neuronal discharge characterized as brief, involuntary and episodic
• Convulsion - violent involuntary contraction of voluntary muscles
• Epilepsy - Chronic seizure disorder

14

What is the consequence of a seizure disorder that goes untreated?

• If severe, the oxygen demand and metabolic demand of the brain drastically increases
• If that area of the brain is worked too hard it will be hypoxic
• The hypoxia will alter the microenvironment of that region of grey matter and pre-dispose for more seizures
• Thus, seizures beget seizures

15

We were given what 4 general mechanisms for seizure disorder predilections?

• Abnormal voltage gated channel
○ Leads to focal epileptogenesis
• Abnormal ligand gated channels
○ Can decrease inhibition or increase excitation, thus leading to synchronization AND even focal epileptogenesis
• Alterations in extracellular ionic environment
○ These can lead to either propagation or syncrhonization
• Recruitment of normal neurons via anatomical circuits
○ These can lead to either propagation or syncrhonization

16

What are the steps of seizure progression?

• Focal epileptogenesis
• Synchronization
• propagation

17

What are the common non-primary causes for epilepsy?

• Mechanical causes (trauma or brain tumor)
• Metabolic
○ Hypoxia
○ Hypoglycemia
○ Hypocalcemia
○ alkalosis
• Withdrawal symptoms in CNS
○ Depressant drugs
○ toxins

18

What are the two different kinds of generalized seizure?

• Tonic-clonic and absence (grand mal vs. peri-mal)
• Tonic-clinic
○ 30% and effective drugs are ID'd with the maximal electroshock seizure test (MES)
○ EEG shows high amplitude spikes, 15-40 cycles/sec
○ Loss of postural control, LOC,
○ tonic phase - rigid extension of trunk and limbs)
○ Clonic phase - rhythmic contraction of arms and legs
○ Abnormal behavior, confusion continues even after myoclonus
○ Mechanism - initiation occurs locally with loss og GABA inhibitory tone and propagation is due to degreased GABA tone or increased response to glutamate or just Na channel problems
• Absence - 10%
○ Effective drugs ID'd with pentylenetetrazol (PTZ) test.
○ Usually begins in childhood stops before 20yrs, but not necessarily
○ EEG shows 3 cycles per second
○ Normal muscle tone, impaired consciousness with staring spells
§ With or without eye blinks
○ Function normal after seizure
○ Mechanism - related to oscillatory stimulation of the thalamic-cortical circuitry and inappropriate activation of low-threshold T-type calcium channels

19

what's going on in an absence seizure?

• Absence - 10%
○ Effective drugs ID'd with pentylenetetrazol (PTZ) test.
○ Usually begins in childhood stops before 20yrs, but not necessarily
○ EEG shows 3 cycles per second
○ Normal muscle tone, impaired consciousness with staring spells
§ With or without eye blinks
○ Function normal after seizure
○ Mechanism - related to oscillatory stimulation of the thalamic-cortical circuitry and inappropriate activation of low-threshold T-type calcium channels

20

What's going on in a tonic-clonic seizure?

• Tonic-clinic
○ 30% and effective drugs are ID'd with the maximal electroshock seizure test (MES)
○ EEG shows high amplitude spikes, 15-40 cycles/sec
○ Loss of postural control, LOC,
○ tonic phase - rigid extension of trunk and limbs)
○ Clonic phase - rhythmic contraction of arms and legs
○ Abnormal behavior, confusion continues even after myoclonus
○ Mechanism - initiation occurs locally with loss og GABA inhibitory tone and propagation is due to degreased GABA tone or increased response to glutamate or just Na channel problems

21

What are partial seizures?

• Begin focally and don't spread to the entire cortex
• Simple partial - 10%
○ Key feature is preservation of consciousness
○ Usually of cortical origin in restricted region
○ Jacksonian motor seizures reflect topographic organization of cortex
• Complex partial
○ Loss of or impaired consciousness
○ Psychomotor - involves limbic and temporal/frontal cortex
§ Emotions come into play
• Secondary generalized
• Mechanism - initiation! (rather than propagation) thus more difficult to treat

22

What are the three first line drugs for primary generalized tonic-clonic seizures?

• Valproate OR
• Lamotrigine OR
• Levetiracetam OR
○ Alternatives
○ Carbamazepine
○ Topiramate
○ Zonisamide
○ Oxcarbazepine
○ Phenytoin

23

What are the first line drugs for absence seizures?

• Ethosuximide OR
• Valproate
○ Alternatives
○ Topiramate
○ Zonisamide
○ Clonazepam
○ felbamate

24

What are the first line drugs for Partial seizures?

• Carbamazepine/oxcarbazepine OR
• Lamotrigine OR
• Levetiracetam
○ Alternatives
○ Topiramate
○ Valproate
○ Gabapentin
○ Zonisamide
○ Phenytoin
○ Pregabalin

25

What is the general, overall cellular mechanism of action of anticonvulsant drugs?

• Treatment is aimed at elavating seizure threshold or to stabilize the membrane
• Can also target propagation and aim to limit propagation
○ Reduce synaptic transmission or nerve conduction
• There is more efficacy in limiting propagation and therefore generalized seizures than preventing initiation and partial seizures

26

Phenytoin, carbamazepine, lamotrigine, and topiramate all share a common mechanism of action. What is it?

*block voltage dependent sodium channels and reduce repetitive firing, thus better at controlling tonic-clonic seizures
*Inhibition of sodium channel function [VSSC] can block the sustained high-frequency repetitive firing of action potentials that can initiate seizure formation. Blockade is use-dependent, meaning these agents preferentially block excitation of cells that are firing repetitively, with the higher the frequency of firing (as in an epileptic fit), the greater the block produced.

27

ethosuximide is used in pediatric absence seizures. Why is that?

ethosuximide will Decrease the low-threshold Ca++ (T-type) current (oscillatory responses in thalamic neurons). Abnormal currents are involved in absence seizures;

28

What 4 epilepsy drugs work by enhancing GABA action?

Tiagabine
* blocks the reuptake of GABA at the synapse, resulting in increased GABA levels and enhancement of its action.

Vigabatrin
*inhibits inactivation of GABA by GABA-transaminase

Benzodiazepines and
phenobarbital
*enhance the inhibitory effect of GABA by facilitating the GABA-mediated opening of chloride channels

NOTE - sketchy says gabapentin has nothing to do with GABA, but likely Calcium and release of NT. Micromedex reflects this and says it has nothing to do with GABA. Dr. French's notes DO say that it messes with GABA levels

29

Which drugs may also work by inhibiting excitatory glutamate synapses?

Phenobarbital, lamotrigine, topiramate, and rufinamide may also act by inhibiting excitatory glutamate synapses

30

What does the drug Levetiracetam do?

Levetiracetam binds to and inhibits function of synaptic vesicle protein SV2A in Ca++-mediated neurotransmitter release. Relation to antiseizure action is uncertain

31

Ezogabine is a drug that does what?

Ezogabine is a K+-channel opener-facilitator which stabilizes membrane potential

32

What are the pros and cons to using Carbamazepine?

*remember oxcarbazepine is like the same drug just less toxicity
*Use-dependent sodium channel blocker so it suppresses repetitive action potentials
*Drug-Drug interactions b/c it's a P450 inducer (this is why oxcarbazepine is safer as it doesn't interact with CYP450
*side-efects - diplopia, ataxia, n/v, drowsiness, hyponatremia, Stevens-Johnson syndrome, blood dyscrasias, hepatotoxicity
*need to monitor CBC, platelet count and liver function closely for the first 3 months then periodically after that
*drug of choice for partial seizures (generalized tonic-clonic seizures)
*can be used for trigeminal neuralgia too

33

Main side effects of Carbamazepine/oxcarbazepine?

*side-efects - diplopia, ataxia, n/v, drowsiness, hyponatremia, Stevens-Johnson syndrome, blood dyscrasias, hepatotoxicity
*need to monitor CBC, platelet count and liver function closely for the first 3 months then periodically after that
*drug of choice for partial seizures (generalized tonic-clonic seizures)
*can be used for trigeminal neuralgia too

34

What are the adverse effects/toxicities with phenytoin?

*use-dependent sodium channel blocker like carbamazepine (inhibits the generation of rapid repetetive AP)
*nystagmus, ataxia, sedation
*Rash most common side effect; gingival hyperplasia and hirsutism often develop gradually
*• Overdosage: Nystagmus, ataxia, diminished mental capacity; death results from respiratory and circulatory depression

35

What does an overdose of phenytoin look like?

• Overdosage: Nystagmus, ataxia, diminished mental capacity; death results from respiratory and circulatory depression

36

What is phenytoin used for?

*quite effective for partial seizures and generalized tonic-clonic seizures
*adjunct in neonatal status epilepticus
*fosphenytoin is a water soluble prodrug to be used IV in active seizures

37

What are the adverse effects of levetiracetam?

*biggest are somnolence and dizziness
*Adverse Effects: Fatigue, somnolence, asthenia, and dizziness. Low incidence of cognitive side effects; no reports of life-threatening adverse effects.

38

Levetiracetam is considered quite safe to use. Why is that and what is it used for?

*anti-seizure medication, messes with Calcium channel
*Mechanism unknown (Ca++ channel effects): Binds to and disrupts function of SV2A (synaptic vesicle protein) but uncertain function limits insight into effect on neurotransmission.
*Ineffective against seizures produced by MES or PTZ models, but good activity in kindling model.
*safe b/c Rapid oral absorption, excreted in urine (70%); available in both oral and IV formulations. No P450 drug metabolism, minimal drug interactions with other antiseizure medications, oral contraceptives, or anticoagulants.
* no reports of life-threatening adverse effects

39

Lamotrigine is a broad-spectrum antiseizure med as it doesn't really work at a particular known channel/receptor. What is it used for?

*• As effective as carbamazepine and phenytoin for monotherapy of newly diagnosed partial or generalized seizures; AND is better tolerated. Can be used as initial therapy
• Also used in mania (maintenance treatment of bipolar disorder), migraine

40

Lamotrigine adverse effects

*Similar to phenytoin (dizziness, ataxia, diplopia, sedation, skin rashes, nausea)
*DDIs: Levels increased 2-fold by valproate; decreased by estrogens in oral contraceptives or hormone replacement

41

Topiramate is used as adjunctive therapy in partial seizures. What are it's adverse effects and mechanism of action?

*Mechanism involves block of Na+ channels (similar to phenytoin). May also potentiate GABA actions and depress excitatory actions at glutamate synapses.
*Dose-related dizziness, somnolence, psychomotor slowing / impaired concentration / interference with memory (claimed to be less severe than phenytoin).
*NOT TO BE USED IN PREGNANCY - Teratogenic in animals, so poor choice in women of child-bearing age.

42

What are the adverse effects of zonisamide?

Adverse Effects: Overall very well tolerated, adverse effects transient and self-limited and further reduced by slow dose titration and taking with meals (somnolence, ataxia, dizziness, difficulty concentrating, nausea, diarrhea, rash, agitation. Renal stones possible (mild carbonic anhydrase inhibitor).

43

What is zonisamide used for?

• Appears to have a broad spectrum of activity including infantile spasms; myoclonic, generalized, and atypical absence seizures
• Effective as add-on for both partial and generalized seizures. Used as monotherapy in children.

44

Lacosamide has the use: Adjunctive therapy in partial-onset seizures with or without secondary generalization. Why is it good for partial seizures when so many medications aren't?

Mechanism of Action: Inhibits Na+ channel function via enhancement of slow inactivation without blocking channel directly in contrast to other AEDs that prolong fast inactivation. May also block effects of neurotrophic growth factors.

45

What are the adverse effects of lacosamide?

Adverse Effects: Overall well tolerated, dizziness (> 30%), headache, nausea, diplopia ( 10%).
*Euphoria-like subjective responses and inebriation-like feeling contribute to classification as Schedule V controlled substance.

46

Ethosuximide is the drug of choice for petite mal seizures why?

*absence seizures = petite mal seizures
*unknown mechanism of action but it does suppress brain activity associated with lapses of consciousness common in absence seizures
*likely messes with the T-type calcium channels responsible for causing the absence seizures

47

What are the side effects of ethosuximide?

Most common dose-related effect is gastric distress (pain, nausea, vomiting). Less common effects: Transient lethargy or fatigue, headache, dizziness. Rarely bone marrow depression, tongue swelling, and gum hypertrophy have occurred

48

Which drug is characterized by this clinical use profile?
First-line drug in treatment of generalized tonic-clonic seizures. Also very effective against absence seizures BUT hepatotoxicity prevents being drug of choice; Can also control certain myoclonic and atonic seizures. [Also useful in mania, migraine]

Valproic acid
*mechanism - Unclear, but probably involves some potentiation of GABA function (weak effect on GABA-transaminase) and effects on membrane excitability (similar to phenytoin). Limits activity of T-type Ca++-channels.

49

Valproic acid use can mess with other antiseizure medication by way of metabolism effects. Which ones?

Can inhibit its own metabolism, also inhibits metabolism of phenytoin, lamotrigine, phenobarbital, carbamazepine, ethosuximide.
OTHER:
• Alcohol / CNS depressants: Additive effects
• Anticonvulsants: Increase phenobarbital levels, increase/decrease phenytoin levels. Can increase drowsiness due to clonazepam
• Aspirin / warfarin: Can inhibit platelet aggregation (use cautiously)

50

The benzodiazepines are effective for what type of seizures?

Clonazepam - good for absence seizures (inhibits T-type calcium channels)
Diazepam - good for status epilepticus and as adjunct in atonic, absence, and infantile spasms

51

What are the adverse effects of benzodiazepine use?

*somnolence
*tolerance will develop that limits use
*behavioral problems

52

How does phenobarbital work?

Mechanism of Action: Selectively suppresses firing and spread from abnormal neuronal foci; appears to enhance GABA inhibition and antagonize glutamate excitation.

53

what are the adverse effects of phenobarbital?

• Irritability and overactivity in many children, sedative effects in others (tolerance can develop). May interfere with learning (cognitive deficits)
• Mild ataxia, nystagmus, skin rash, osteomalacia

54

Treatment-resistant epilepsies calls for what drug?

Gabapentin
• Also used in neuropathic pain, anxiety disorders, migraine prophylaxis, movement disorders

55

Status epilepticus is the stat of recurrent major motor seizures between which patient does not regain consciousness. It can be deadly if untreated from respiratory or cv collapse. How do you manage it?

• Initial therapy IV lorazepam (diazepam or midazolam are alternatives), until seizures stop or 20 mg given, then start phenytoin or fosphenytoin NTE 50 mg/min (20 mg/kg IV push or infusion), slow infusion if hypotension
• If seizures persist IV phenobarbital (20 mg/kg, NTE 100 mg/min) then pentobarbital (10 mg/kg) until seizures stop. IF hemodynamically unstable, then midazolam (bolus followed by infusion).
• If seizures still continue, pentobarbital or propofol infusion with pressor support

56

During pregnancy, what are the risks of birth defects with antiseizure medication?

• Risk of birth defects (cleft palates, skeletal abnormalities, CNS/cardiac problems) 2-3-fold higher if mother on anticonvulsants, but > 90% deliver normal babies; difficult to separate medication effect from disease effect, but probably medication. Valproate and phenobarbital may have the highest risk for fetal malformations.
*Among newer agents levetiracetam, oxcarbazepine, and gabapentin have lower rates.
*• Phenytoin, carbamazepine, and phenobarbital can via induction of metabolism can cause vitamin K deficiency and hemorrhage in newborn recommend vitamin K supplementation to mother in final month of pregnancy and for the newborn

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