SEIZURES AND EPILEPSY 1

Question 1

An epileptic Seizure

Epilepsy

Answer 1

 An epileptic Seizure
“A transient occurrence of signs and/or symptoms due to
abnormal excessive and synchronous neuronal activity in the
brain”

 Epilepsy
 At least two unprovoked seizures occurring > 24 hours apart
OR
 One unprovoked seizure and a probability of further seizures of at
least 60% occurring over the next 10 years
OR
 Diagnosis of an epilepsy syndrome

Question 2

DEFINITIONS
Epilepsy Syndrome

 Epilepsy is considered to be resolved:

Answer 2

 “A symptom complex the primary feature of which is the
occurrence of electroclinically characteristic epileptic seizures”
Seizures and Epilepsy, 2nd edition. Oxford 2013
 Identified by age at onset, EEG characteristics, seizure types,
genetic observations

 Epilepsy is considered to be resolved:
 For patients who past the age in an age-dependent epilepsy
syndrome
OR
 For patients who are seizure-free for 10 years, with no antiseizure
medications for the last 5 years

Question 3

FOCAL SEIZURES (PARTIAL)
3 classes

describe simple partial
complex partial
Secondarily Generalized

Answer 3

It involves only part of the brain
With or without aura
Classes:
 Simple Partial Seizures
 No impairment of consciousness
 Motor, sensory or autonomic symptoms
 Duration < 60 sec

 Complex Partial Seizures
 Altered consciousness and behavioral arrest
 Duration 1-2 min with postictal confusion
 Motor automatism e.g. chewing or lip smacking

 Secondarily Generalized
 Focal seizure that becomes generalized

Question 4

GENERALIZED SEIZURES
6 classes

describe generalized tonic clonic
absence
myoclonic
tonic
atonic
clonic

Answer 4

 Widespread involvement of the brain
 No Aura
 Can be convulsive or non-convulsive

 Classes:
 Generalized tonic-clonic (grand mal)
 Loss of consciousness with hyperextension of body followed by
rhythmic full body contractions (tonic and clonic phases)
 Duration: 1-2 min with postictal confusion, stupor and headache
seizure extend beyond five-minutes. We worried about life-threatening condition called status epilepticus. If you see someone’s seizing more than 5 min, please call 911

 Absence (petit mal)
 Sudden impairment of consciousness
 Duration: 5-10 sec
 Always starts in childhood

 Myoclonic
 Sudden muscle contractions (jerks) without loss of consciousness
 Duration of jerks: milliseconds

 Tonic
 Bilateral increased tone of the limbs
 Duration: seconds to 1 minute

 Atonic
 Sudden loss of muscle tone
 Durations: few seconds
 Associated with epilepsy syndromes

 Clonic
 Rare

Question 5

ILAE 2017 Classification of Seizure Types Basic Version 1

Answer 5

see slide 12

Question 6

Wording Changes

Answer 6

O L D T E R M N E W T E R M
Unconscious (still used, not in name) Impaired awareness (surrogate)
Partial Focal
Simple partial Focal aware
Complex partial Focal impaired awareness
Dyscognitive (word discontinued) Focal impaired awareness
Secondarily generalized tonic-clonic Focal to bilateral tonic-clonic
Arrest, freeze, pause, interruption Behavior arrest

Antiepileptic Drugs (AEDs) Antiseizure Medications (ASM)

Question 7

 A woman awakens to find her husband having a seizure.
She is able to describe bilateral stiffening followed by
bilateral shaking.
 A 25 year old woman describes seizures beginning with 30
seconds of an intense feeling that “familiar music is
playing.” She can hear other people talking, but afterwards
realizes that she could not determine what they were saying.
After an episode, she is mildly confused, and has
to “reorient herself.”
 A 22 year-old man has seizures during which he remains
fully aware, with the “hair on my arms standing on edge” and
a feeling of being flushed.

Answer 7

1. tonic clonic
2. Focal seizure w/ Imaired awareness = complex partial

3.Focal seizure. w/ retained awareness = simple partial seizrues

it presents with autonomic features.

Question 8

ETIOLOGY

neonates

infants and chilren

Answer 8

Neonates(<1 month) Perinatal hypoxia and ischemia
Intracranial hemorrhage and trauma
Acute CNS infection
Metabolic disturbances (hypoglycemia,
hypocalcemia, hypomagnesemia, pyridoxine deficiency)
Drug withdrawal
Developmental disorders
Genetic disorders

Infants and children (>1 month and <12 years)
Febrile seizures
Genetic disorders (metabolic, degenerative, primary epilepsy
syndromes)
CNS infection
Developmental disorders
Trauma
Idiopathic

Question 9

ETIOLOGY

yougn adults

older adults

Answer 9

Adolescents (12–18 years) Trauma
Genetic disorders
Infection
Brain tumor
Illicit drug use
Idiopathic

Young adults (18–35 years) Trauma
Alcohol withdrawal
Illicit drug use
Brain tumor
Idiopathic
`
Older adults (>35 years) Cerebrovascular disease
Brain tumor
Alcohol withdrawal
Metabolic disorders (uremia, hepatic failure, electrolyte
abnormalities, hypoglycemia, hyperglycemia)
Alzheimer’s disease and other degenerative CNS diseases
Idiopathic

Question 10

RISK FACTORS

Answer 10

 Many factors that could precipitate seizures in susceptible
individuals:
 Sleep deprivation
 Stress
 Drugs - prescribed and recreational (see next slides)
 Alcohol abuse
 Photo-stimulation (flashing lights, rapidly changing images)
 Hormonal changes

Anyone with epilepsy should get a good night’s sleep. They should sleep well. Sleep deprivation is a one of the biggest inducers of seizures

this does not affect everyone, but some, some patient actually, when the exam they’re playing video games, we get seizures.

Catamenial epilepsy: referred to seizure exacerbation in relation to the menstrual cycle. So it happens like when the hormonal levels goes down during the menses.
Treated w progesterone (natural)
Natural not same as synth progestins because natural is metabolized to allopregnanlone which has potent GABA-a mimetic anticonvulstant action, whereas synthethic ones are not metabolized this way

Question 11

DRUG-INDUCED SEIZURES

Answer 11

Alkylating agents (e.g., busulfan, chlorambucil)
Antimalarials (chloroquine, mefloquine)
Antimicrobials/antivirals
* β-lactams, quinolones, acyclovir, isoniazid, ganciclovir
Anesthetics and analgesics
* Meperidine, tramadol, local anesthetics
- Tramadol not to be used with pt w seizures preferably
Higher chance of reducing seizure thresholds, esp in older adult w/ poor kidney fxn

Flumazenil in BDZ-dependent patients

Immunomodulatory drugs
* Cyclosporine, tacrolimus, interferons
Psychotropics
* Antidepressants, antipsychotics, lithium
Sedative-hypnotic drug withdrawal
* Alcohol, barbiturates, benzodiazepines
Drugs of abuse
* Amphetamine, cocaine, phencyclidine, methylphenidate

anti-depressants, anti-psychotics. When you read the warning and Lexi or the drug monographs, all of them saying that they reduced the threshold for seizures

Not abs contraindicated

Question 12

DIAGNOSIS
 Many conditions could be confused with seizures such as
syncope and psychogenic non-epileptic seizure

Answer 12

History
 The most important in diagnosis
 History from the patient and witness
 Presence or absence of aura
 Circumstances surrounded/ could have precipitated the seizure
 History of drug/alcohol abuse
 Past history of childhood epilepsy, childhood illnesses e.g.
meningitis, encephalitis, febrile seizures
 Past history of head injury, stroke, brain tumor or any systemic
conditions that might affect CNS e.g. cancer, electrolyte
abnormalities
 Family history of epilepsy

Physical examination
 Often not helpful
 Evidence of tongue-biting, incontinence, postictal confusion
 Evidence of any neurologic symptoms
Check blood glucose cuz hypoglemia is common

Laboratory
 Comprehensive lab panel to look for any precipitating factors

Electroencephalography (EEG)
 To confirm diagnosis, however it is normal in 20% of patients
an increased risk for seizures because there are some abnormal waves coming from the brain. Saying this abnormal waves do not mean that the patient is having a seizure

Imaging
 CT/MRI brain

Question 13

PATHOPHYSIOLOGY

Answer 13

 Normal neuronal activity: non-synchronized
 Seizures occur when neuronal activity gets
synchronized in an area in the brain
 Imbalance
 ↑↑Excitatory mechanisms
Glutamate receptors (NMDA, AMPA)
Sodium and calcium influx
 ↓↓Inhibitory mechanisms
GABA
Voltage-gated potassium channels
Calcium-dependent potassium channels

Glutamate works in two types of receptors, NMDA and AMPA receptor. They actually excited to the brain. Sodium and calcium influx into the cell can activate the cells as well
when the sodium goes in, the cell becomes depolarized. And calcium influx as well in some types of cells.

Question 14

ANTISEIZURE MEDICATIONS (ASM)

Answer 14

Older Agents
 Phenytoin
 Carbamazepine
 Phenobarbital
 Valproic acid and
divalproex sodium
 Primidone
 Ethosuximide

Newer Agents
 Lamotrigine*
 Oxcarbazepine
 Eslicarbazepine
 Gabapentin
 Topiramate
 Levetiracetam*
 Pregabalin
 Lacosamide
 Vigabatrin
 Clobazam
 Clonazepam
 Perampanel
 Rufinamide
 Stiripentol
 Brivaracetam

Question 15

MECHANISM OF ACTION

Answer 15

 Antiseizure Medications inhibit the abnormal neuronal discharge “Symptomatic”
 No effects on the underlying cause “Not curative”

So the table here you need to know the mechanism of action is those drugs. Why? Because when you’re selecting a drug, you need to combine the mechanism of action like let’s say you want to do a, two agents. Don’t use drugs, the same mechanism of action together,

sodium channel blockers, phenytoin, carbamazepine, oxcarbazepine, all the zippy and family, and then lamotrigine, lacosamide

GABA receptor agonists, the benzodiazepines, globalism and Clonazepam, phenobarbital and primidone (gets metabolized to phenobarb)
- all the drugs that work in gaba, overdose of them can cause respiratory depression. R

Ethosuximide is t type calcium channel blocker. This is a drug that’s used for absence. Seizure.

Broad spec: valproic acid, topiramate
Sv2a modulators actually modulate the gaba transmission. So like the actually affected the gaba release and stuff. (levetiracetam, brivaracetam)

Question 16

ASM AND SEIZURE TYPE

focal

generalized tonic clonic

Answer 16

Focal Seizures Carbamazepine; Lamotrigine; Levetiracetam
Phenytoin
Clobazam; Eslicarbazepine; Gabapentin
Lacosamide; Oxcabazepine; Perampanel
Phenobarbital; Primidone; Topiramate
Valproic acid/divalproex; Vigabatrin; Brivaracetam

Generalized tonic-clonic Carbamazepine; Lamotrigine
Phenytoin, Levetiracetam
Valproic acid/divalproex
Clobazam;; Topiramate; Perampane

Recommendations vary in different guidelines

Question 17

ASM AND SEIZURE TYPE

Answer 17

Recommendations vary in different guidelines
* Phenytoin, carbamazepine are ineffective and may aggravate absence
and myoclonic seizures

Absence* Ethosuximide; Valproic acid/divalproex
Clobazam,
Lamotrigine

Myoclonic* Valproic acid/divalproex
Clobazam
Lamotrigine
Levetiracetam
Rufinamide
Topiramate

Question 18

ABSORPTION
 Bioavailability (F)

It’s very important to have some formulation of intravenous because as I mentioned, some patients might, you need to control the seizures right now. Example, patients with traumatic brain injury and seized on the scene, multiple other seizures might aggravate the brain insult. And we need to stop that.

Answer 18

 The fraction of the administered drug that is absorbed
is called Bioavailability (F) i.e. extent of absorption
 Depends on the drug and the absorption site
 F for iv route is 100% e.g phenytoin, phenobarbital,
lacosamide, levetiracetam and valproic acid
 Clinical relevance: It helps determine the dosage when
switching among different routes e.g. iv to po

most are 100%

Similar to the brain, multiple seizures, the brain will be draining, bring the glucose and oxygen, and the cells will die, and eventually the patient will die.

So like generally, the IV to PO conversion for most anti-seizure medications, 100%, 100 milligram oral phenytoin will be equivalent. Equivalent to 100 mg IV phenytoin. There’s no math involved. Just one-to-one

Gabapentin not avail iv

Question 19

ABSORPTION
salt factor

Answer 19

 Salt factor (S)
Some drugs are available in different salt forms
and/or pro-drugs
Salt factor is the fraction of the prodrug or salt
form that contains the pharmacologically active
drug
Clinical relevance: important for determining the
equivalent dosage of drugs

Phenytoin:
The parenteral product and oral extended release
capsules contain phenytoin sodium salt
Tablets and suspension contain the free
phenytoin acid form
Phenytoin sodium contains 92% of the free
phenytoin acid form (salt factor (S) = 0.92).
However, this difference is not clinically
significant in most patients i.e. use 1:1
conversion

. So phenytoin, it’s an anti-seizure medication, but the issue, it’s highly irritating given by IV. So they created a phosphate ester for this drug. And the goal is for fosphenytoin. And that phosphate ester can be administered so quickly using the IV route. But actually once this drug is goes into the bloodstream, that ester gets cleaved and the active phenytoin released. So like the salt form, it is the amount of phenytoin in this fosphenytoin. This is the S factor.

Question 20

ABSORPTION
 Rate of Absorption

phenytoin
four formulations and probably saw some of them in practice. One is intravenous parenteral formulation, the other is extended release capsule. The third one tablets, and the fourth one is oral liquid.

carbamazepine

Answer 20

Controlled release vs. immediate release formulations
 Clinical relevance: onset of effect, time to peak
concentration and in formulation conversions

 Phenytoin:
 Extended release capsules slowly release the drug in
the GI tract, and so they can be administered on a
once daily basis
 The injectable form, oral liquid and chewable tablets
are immediate release and daily dose needs to be
divided 2-3 times per day

 Carbamazepine:
 CR tablets are dosed less frequently (e.g. BID) than
liquid formulations and regular release formulations
Cannot be crushed
If switching to oral liquid it should be qid or tid
400 mg BID. You can switch it to 200 milligram every 6 h of oral liquid.

Question 21

ABSORPTION
salt factor of fophentoin, divalproex sodium

Answer 21

Fosphenytoin:
 It is a phenytoin prodrug (phenytoin phosphate ester) that is
rapidly metabolized to phenytoin in the body
 1.5 mg fosphenytoin sodium = 1 mg phenytoin sodium = 1 mg
phenytoin equivalent units (PE)
 Dosing of fosphenytoin is presented in phenytoin equivalents
to facilitate conversion

Divalproex sodium:
 It is valproic acid/sodium valproate coordination compound
 Available as enteric-coated formulation with less GI side
effects.
 Valproic acid dose conversion is 1:1

Question 22

ABSORPTION
 Saturable absorption

Answer 22

Absorption is a process that can be saturable
Gabapentin undergoes a saturable absorption i.e.
bioavailability is reduced with increasing doses

Question 23

ABSORPTION
 Drug interaction
Phenytoin absorption and tube feed:

Answer 23

Phenytoin administration through enteral tube
feeds significantly reduces its bioavailability
which may lead to therapy failure
This has been attributed to binding feeds and/or
tubing
 It is recommended to hold tube feed 1-2 h before
and 1-2 h after dosage administration

Phenytoin is one of those drugs that it’s affected by food and phenytoin administration through enteral tubes. Some patient unable to swallow at all. So they have to have nasal gastric tubes. And those nodes, these nasal gastric tubes, if you give Phenytoin with the feeds, actually you’re giving almost nothing to the patient.

bioavailability can go down as low as 80 % a b, let’s just only 20% of the drug will be absorbe

Question 24

most common drug induced seizures

Answer 24

And the big ones, the found bupropion, Wellbutrin, tramadol.
Dimenhydramin (benadriyl)

Bup is not recommended for pt w hx of epilepsy - highest implacted drug that casues it
It is nto an abs contraindication

ramadol tried to find alternatives, if you can. If you can just make sure that this dose correctly given the patient age and renal function.

If necessary, take low amounts of benadryl onlyt