IDT Fall26 Seizure Disorders

   What is the difference between seizure, epilepsy, status epilepticus, PNES?

a.      Seizure- abnormal electrical activity in brain

b.      Epilepsy-recurrent unprovoked seizure (2 seizures >24h apart)

c.      Status Epilepticus-prolonged seizure (>10/ >30 min; functional >5min - start giving meds)

d. PNES Psychogenic Nonepileptic Seizure- no abnormal electrical brain activity - often has eyes open + aware of what’s happening; tx is referral to therapist/psychiatrist NOT AED

Epidemiology - prevalence, incidence, trends

60mil worldwide

68/100,000

low-middle class

Bimodal- childhood, older adults (stroke/brain injury/hemorrhage)

1.      Understand common etiologies of provoked seizures?

a.      Often provoked by CVD**

b.      Electrolyte abn (Na Ca Mn, vGlucose)

c.      TBI, brain surgery

d.      Brain tumor

e.      Alc**/benzo withdrawal

f.        Infection

g.      Inflammation

h.      Fever (esp in children)

1.      What are the medications that can lower seizure threshold?

a.      Opioids (tramadol, Meperidine)

b.      Cocaine

c.      Fluoroquinolones

d.      Carbapenems

e.      Cephalosporin (beta lactamase inhibitors!!)

f.        Penicillin

g.      Bupropion,, SSRI lesser (switch?)

h.      Antipsychotics (clozapine)

i.        TCA

j.        Lithium

1.      Understand general classification of epileptic seizures

a.      Focal or Generalized

b.      Observable vs Non-observable

                                                                i.      Motor vs Non-motor (Tonic-stiff muscle, Atonic-sudden loss of muscle strength, Myoclonic-short quick jerking, Clonic (rhythmic jerking), Absence

c.      Preserved vs Impaired consciousness

                                                                i.      Awareness and responsiveness

                                                              ii.       Postictal confusion

If unknown type of seizure?

Reach for cross spectrum ASM

GTC

General Tonic Clonic Seizure

Generalized seizures

GTC, Absence, Myoclonic, Tonic/Atonic

Imaging

EEG - rule out PNES ; 3Hz spike/wave = absence

Video recording

CT (urgent setting), MRI (more detailed)

-Inject dye for imaging -Ictal SPECT for focal seizures

Lab Workup

CMP (Na, Ca, Mn, Glu), Renal / Hepatic Fx

CBC - infection?

Lumbar puncture

Pregnancy - most ASMs are teratogenic

UDS - withdrawals

Anti-seizure drug levels

Pharmacotherapy Principles

Seizure type - gen/focal?

Comorbidity** - some rx treat multiple conditions

AR** -

Drug interactions**

Pt preference - ins, access

Broad Spec

Focal and Gen:

Valproate,

Lamotrigine,

Levetiracetam - LEAST DD INTERACTION, easy dosing, 1:1 po:iv

Topiramate,

Zonisamide,

Perampanel,

Rufinamide,

Felbamate,

Clonazepam

Absence Seiz: Ethosuximide

Narrow Spec list

Focal seizures:

Carbamazepine

Oxcarbazepine

Eslicarbazepine

Phenytoin

Gabapentin

Pregabalin

Tiagabine

Vigabatrin

1.      What class of ASM that should not be used for myoclonic, absence, tonic/atonic seizures? Why?

Narrow Spectrum ASMs may exacerbate seizures

GTCs RX

1st line: (Broad Spectrum) Lamotrigine, Levetiracetam, Valproate

*Add on: +clobazam, lamotrigine, levetiracetam, perampanel, valproate, topiramate, brivaracetam, lacosamide, phenobarbital, primidone, zonisamide

Focal Seizure RX

1st line: Broad spec Lamotrigine, Levetiracetam

2nd Line: Narrow spec - +carbamazepine, oxcarbazepine, zonisamide, lacosamide

+Add-on: carbamazepine, oxcarbazepine, lamotrigine, levetiracetam, zonisamide, lacosamide, brivaracetam, cenobamate, eslicarbazepine, perampanel, pregabalin, phenobarbital, phenytoin, tiagabine, vigabatrin

Absence Seizure RX

+1^st line: ethosuximide - uncommonly stocked and rare type of seizure

+2^nd line or add-on: lamotrigine, levetiracetam, valproate

Myoclonic Seizure TX

ONLY BROAD SPEC

+1^st line: levetiracetam, valproate

+2^nd line or add-on: brivaracetam, clobazam, clonazepam, lamotrigine, phenobarbital, topiramate, zonisamide

Comorbidity Bipolar

Lamotrigine, Valproate

Caution in Comorbidity GAD/MDD

NO Levetiracetam, Parampanel

Comorbidity w Migraine

Topiramate, Valproated

Meds for Comorbidity Obesity

Topiramate, Zonisamide

Comorbidity Underweight

Valproate, Pregabalin

Comorbidity Hepatic impairment

Cl: Valproic acid, Felbamate

AVOID: Carbamazepine, Phenytoin, Tiagabine

General ASM AE

+Hypersensitivity

+Steven-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS)

+CNS/psychiatric effects: sedation, dizziness, somnolence, ataxia, memory impairment, confusion, depression, suicidal ideation, agitation, ataxia

+Hepatotoxicity

+Bone loss

+Supplement with calcium and vitamin D

Cyp Enzyme Inducers (names/ drugs affected)

•Carbamazepine

•Oxcarbazepine

•Phenytoin

•Fosphenytoin

•Phenobarbital

•Primidone

-WARFARIN

-HORMONAL CONTRACEPTIVES

Cyp Enzyme Inhibitor

•Valproic acid

Therapeutic Drug monitoring - use?

-PT SPECIFIC- Titrate pts up to when seizures stop; Measure when AE show

+Carbamazepine

+Therapeutic range: 4-12 mg/L

+Phenobarbital

+Therapeutic range: 10-40 mg/L

+Phenytoin

+Therapeutic range: 10-20 mg/L (total); 1-2 mg/L (free)

+Primidone

+Therapeutic range: 5-12 mg/L

+Valproic acid

+Therapeutic range: 50-150 mg/L (total); 5-15 mg/L (free)

Avoid in Pregnancy

+Avoid clonazepam, phenobarbital, primidone, phenytoin, carbamazepine, valproate, etc.

+Valproate has the highest risk**

+Contraindicated in patients with child-bearing potential who do not have effective contraception

+Can cross placenta – congenital malformation and neurodevelopmental disorders

+Levetiracetam is preferred in pregnancy**

1.      Which drug is the safest to use in pregnancy?

Levetiracetam

1.      Which drugs have hyponatremia as adverse effects?

Carbamazepine

Oxcarbazepine

Eslicarbazepine

Switching ASMs

-Lower first ASM while titrating next ASM (overlap)

Discontinuing ASM

-+ASMs should not be stopped abruptly

+NICE guideline, 2022: assess risk of seizure recurrence if ASMs are discontinued when patient is seizure-free for 2 years**

+Discontinue ASMs one at a time

+High risk of seizure recurrence in juvenile myoclonic epilepsy, structural abnormalities or with co-existing neurodegenerative and other neurological conditions 

Non-Pharm Tx

+Laser ablation of seizure focus

+Vagal nerve stimulation

+Deep brain stimulation

+Ketogenic diet (4:1 ratio fat-carbohydrate)

+Ketosis state can reduce seizure frequency

+Can be considered for those with childhood epilepsy syndromes

Common Childhood Epilepsy Syndromes

-JME- Juvenile Myoclonic Epilepsy -

•Triad of myoclonic jerks, GTCS, and absence seizures

•Most have normal cognitive ability

-Lennox-Gastaut Syndrome -

•Combined generalized and focal epilepsy

•Developmental and epileptic encephalopathy

-Dravet Syndrome

•Previous named “Severe Myoclonic Epilepsy of Infancy” (SMEI)

•Genetic epileptic syndrome, triggered by fever

Juvenile myoclonic epilepsy treatment

1st Line: Valproate

2nd Line:

•Lamotrigine

•Levetiracetam

•Topiramte

•Zonisamide

Lennox-Gastaut syndrome treatment

1st Line: Valproate

2nd Line:

•Lamotrigine

•Rufinamide

•Topiramate

•Clobazam

•Flenfluramine

•Felbamate

•Cannabidiol

Dravet syndrome treatment

1st Line: Valproate

2nd Line:•Triple therapy: stiripentol + clobazam + valproate

•Fenfluramine

•Cannabidiol + clobazam

•Levetiracetam

•Topiramate

Rufinamide

Benzel

+MOA: prolongs inactive state of Na channels

+Dose: 400-800 mg/day, titrate up to max 3.2 g/day in 2 divided doses

+Contraindication: familial short QT syndrome

+Adverse effects: CNS depression, DRESS, leukopenia

 2nd Line Lennox-Gastaut

Felbamate

Felbatol

+MOA: multiple - NMDA antagonism, enhance GABA, Na & Ca channel blockers

+Dose: initial 1200 mg/day in 3-4 divided doses, max 3600 mg/day

+BBW: aplastic anemia, hepatic failure

+Adverse effects: loss of appetite, N/V, insomnia, fatigue

2nd Line Lennox-Gastaut

Fenfluramine

Fintepla

+MOA: unknown – agonist activity on serotonin receptors

+Dose: initial 0.1 mg/kg bid, titrate up to max 26 mg/day

+BBW: valvular heart disease, pulmonary hypertension

+Available through restricted REMS program

+Adverse effects: weight loss, angle-closure glaucoma

2nd Line Dravet

2nd Line Lennox Gastaut

Stiripentol

Diacomit

+Dose: 50 mg/kg/day given in 2 or 3 divided doses

+MOA: enhance GABA neurotransmission

+Adverse effects: weight loss, decreased appetite, CNS depression, neutropenia and thrombocytopenia

2nd Line Dravet with Clobazam and Valproate

Status epilepticus Tx

+Status epilepticus is seizure that lasts >5 mins

+Medical emergency

+Treat underlying causes: electrolyte abnormality, alcohol withdrawal, cardiovascular diseases, etc.

+First line therapy (Level A evidence, AES 2016 guideline)

+IM: midazolam**

+IV : lorazepam, diazepam

Benzodiazepine

+MOA: Enhance GABA effects

+Controlled substance (C-IV)

+Multiple formulations: IV, IM, rectal, nasal spray

+BBW: Sedation, respiratory depression especially when used with opioids

Diazepam Rectal Gel

rph have to lock correct dose collar

Status Epilepticus Treatment algorithm

1.      What is the BBW of vigabatrin?

Permanent vision loss

1.      What is the dosing of lamotrigine? What does it depend on?

+Dose: 25 mg daily for 2 weeks > 50 mg daily for 2 weeks > titrate 50 mg/day q2 weeks to usual maintenance dose of 225-375 mg in 2 divided doses

+If taking valproic acid: 12.5 mg daily for 2 weeks > 25 mg daily for 2 weeks > titrate 25-50 mg/d q2 weeks to usual maintenance dose of 100-200 mg in 2 divided doses

+If taking enzyme inducers, including contraceptives: 50 mg daily for 2 weeks > 100 mg daily for 2 weeks > titrate 100 mg/d q2 weeks to usual maintenance dose of 300-500 mg in 2 divided doses

DOSE BASED ON DRUG INTERACTION

1.      Which drug has metabolic acidosis and glaucoma as AE?

Topiramate

1.      Which drugs can worsen psychiatric symptoms?

Levetiracetam / Brivatiracetam

Parampamel

1.      Which drug has BBW for hepatic failure, pancreatitis, and teratogenicity?

Valproate

1.      Which drugs have hyperammonemia with or without encephalopathy as AE?

Zonisamide

Valproate

1.      Which drugs can cause physical dependence?

Clobazam

Phenobarbital/ Primidone

Gabapentin

Pregabalin

1.      Which drugs can cause cardiac arrythmia?

Lacosamide

Phenytoin

1.      Which drugs can cause hepatotoxicity?

Levetiracetam

Cannabidiol

Cenobamate

Phenytoin

Valproate!

Felbamate!

1.      Which drug has the least drug-drug interactions?`

Levetiracetam

1.      Which drug has risk of Purple Glove Syndrome? What is the syndrome?

Phenytoin

+Extravasation and Purple Glove Syndrome - even if filtered**

+-Weak acid -Crystalizes -Dilute only in NS, requires a filter**

SS: limb edema, discoloration, pain

1.      What are common AEs of gabapentinoids?

+Somnolence

+Peripheral edema

+Weight gain

1.      Which drug has high risk of cardiotoxicity with rapid infusion?

Phenytoin

+BBW: Cardiovascular toxicity (hypotension, arrythmia) associated with rapid infusion

+IV use is contraindicated in bradycardia, heart block

+IV admin limit: 1-3 mg/kg/min or ≤50 mg/min***, whichever is slower

Which ASM is associated with gingival hyperplasia

Phenytoin

1.      Which drugs would you need to concern if patient has low albumin level?

Phenytoin

Valproate

1.      Which drugs should be used in caution in Asian population with variant HLA-B*1502 allele and variant HLA-A*3101 allele?

Carbamazepine

1.      Which drugs have blood dyscrasia as adverse effects?

Aplastic anemia + Agranulocytosis: Carbamazepine, Ethosuximide, Oxcarbazepine, Felbamate

Thrombocytopenia: Valproate

1.      What are the general ASM’s adverse reactions?

+Hypersensitivity

+Steven-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS)

+CNS/psychiatric effects: sedation, dizziness, somnolence, ataxia, memory impairment, confusion, depression, suicidal ideation, agitation, ataxia

+Hepatotoxicity

+Bone loss

+Supplement with calcium and vitamin D