Seizures

Classification

• Seizures can be:
  • Partial vs. Generalized
  • Convulsive vs. Non-Convulsive
  • Tonic, vs. Clonic, vs. Myoclonic
    • Tonic - Sustained muscle contraction
    • Clonic - Rhythmic movements with regular amlitude and frequency
    • Myoclonic - Vary in amplitude and frequency
    • Automatisms - Chewing or lip smacking
• Focal Seizures
  • Temporal Lobe - produce motionless stare (+ repetitive chewing or lip smacking
  • Epilepsia Partialis Continua - tonic-clonic movements of the facial and limb muscles on one side of body
• Status Epilepticus
  • > 30min of continuous seizure activity  (any variety)
  • Typically most seizures terminate by 5min, if still goes > 5min, then less likely to self-terminate.
  • Requires medications to terminate (otherwise if lasts > 60min can cause permanent brain damage)

• Absence	Focal Dyscognitive
  NO Aura	Aura
  < 30s	>1min
  Daily, frequent	Weekly
  Sudden onset	Gradual onset
  NO post-ictal state	Post-Ictal State
  Inducible (Hyperventilation and Photic)	Not inducible

Status Epilepticus

Source: Dr. Lomax (Queen's University)

Glauser T et al Epilepsy current 2016

• A condition resulting either from failure of mechanisms responsible for seizure termination or from the initiation of mechanisms which lead to abnormally prolongued seizures. 
• Causes LONG TERM EFFECTS (memory, future seizures, brain damage, emotional scarring - PTSD, etc..). 

• Definition of "Status Epilepticus" >5min of continuous activity OR ≥2 sequential seizures without full recovery of consciousness between seizures approximately 30min.

• Must act quickly on status epilepticus --> do not wait!!! "time is brain"
• Mortality 22%
• Classification
  • Prominent Motor Features
    • Convulsive SE (aka tonic-clonic SE)
    • Myoclonic SE  (continuous jerks) with coma or without coma)
    • Focal motor
    • Tonic Status (tonic seizure)
    • Hyperkinetic 
  • No Prominent Motor Features
    • With coma
    • Without Coma 
• Management:
  • ABCs
  • Initiate ECG monitoring
  • Check Glucose
  • Check ECG (PR interval < 200mg, QTc < 460ms) 
  • Medications:
    • First Line
      • 4mg of IV ativan x2
      • Nasal midazolam works well 
      • Lacosamide 400mg IV load (LU code 430) [DO NOT USE IF QT > 460 or PR > 200]
    • Second Line
      • Phenytoin 15-20mg/kg max infusion 50mg/min (Cardiac monitoring)
      • Valproate 40mg/kg IV rapid loading at 3-6 mg/kg/min
      • Levetiracetam 60 mg/kg, max 4.5g/dose single dose
    • Third Line
      • Propofol and Midazolam IV

Acute Management

• ABCs
• Initiate ECG monitoring
• Check Glucose (if glucose < 60mg/dl or <3.3 mmol/L)
  • Adults: Thiamine 100mg IV then 50mL of D5W IV
  • Children ≥ 2y: 2ml/kg D25W IV
• Check ECG (PR interval < 200mg, QTc < 460ms) 
• Medications:
  • First Line
    • 4mg of IV ativan x2
    • Nasal midazolam works well 
    • Lacosamide 400mg IV load (LU code 430) [DO NOT USE IF QT > 460 or PR > 200]
  • Second Line
    • Phenytoin 15-20mg/kg max infusion 50mg/min (Cardiac monitoring)
    • Valproate 40mg/kg IV rapid loading at 3-6 mg/kg/min
    • Levetiracetam 60 mg/kg, max 4.5g/dose single dose
  • Third Line
    • Propofol and Midazolam IV

Epilepsy

• Definition

  • Epilepsy Definition A tendency to recurrent unprovoked seizures AND the associated psychological and social consequences 2 unprovoked seizures occurring >24hr apart OR 1 seizure and abnormal imaging or an abnormal ECG

• Workup of "first seizure"
  • History
    • Prev seizures?
    • Ask if they have "myoclonic jerks" -> i.e. putting butter on toast and knife went flying.
      • Can be considered seizures
    • Ask if FOCAL SEIZURES?? (ask what happens right before)
      • Dejavu, stared, started in body part?
    • Auras? (visual? smells? any smells no one else can smell?)
  • Investigations
    • CT scan --> negative. 
    • EEG (usually normal)
  • After first seizure (negative investigations) --> Risk of repeat seizure is 50%  
    • Higher risk of seizures if: (raises risk to 80% = recommend antiseizure therapy)
      • 2 seizures >24hr apart = 80% risk of more seizures
      • EEG demonstrates epileptiform activity
  • Decide if Focal or Generalized
    • Focal = Usually lesional (sclerosis, dysplasia, vascular malformations, tumours, stroke, concussion)
      • Important because --> can cure with surgery
    • Generalized = 70% remission at least 2 epileptic medications.
      • Important because --> IF focal meds are used --> can worsen seizures

• Levetiracetam (Keppra)
  • Indicated as adjunctive therapy for patients with:
  • FOCAL OR GENERALIZED
  • Dose: range 250mg to 3000mg bid
  • Route: IV and PO
  • Metabolism:
    • Excreted unchanged in urine, no hepatic metabolism
    • Does not interact with other drugs
    • Therapeutic CSF level in 1hr 3min.
  • LU code defined now!!!
  • Efficacy: 30-40% responder rate for focal seizures or focal onset generalized tonic clonic
  • S/E:
    • 15% experience behavioral/mood side effects.  (anger, depression etc..)
      • Counsel, esp careful if developmental delay, or hx of aggression.
  • NEW: Brivaracetam (Brivlera) - cheaper
    • Newer levetiracetam engineered to remove mood changes. (less GABA activity).
      • 5% mood disturbance
    • Quicker therapeutic levels than levetiracetam if given as IV load
    • Downside:
      • Hepatically metabolized 
      • Interacts with chemo agents, oral contraceptives!!
• Eslicarbazepine (Aptiom)
  • Like carbemazepine, but the active metabolite (with less side effects)
  • FOCAL SEIZURES
  • Adjunctive treatment of focal onset seizures
  • Dr. Lomax uses as primary, but we should not!
  • LU code 430
  • 24hr dosing (easier to take)
  • Metabolism:
    • Weak inducer of CYP 3A4 (decreases Estrogen and coumadin)
    • Weak inducer of 2C19 (increases phenytoin)
  • S/E:
    • Dizziness, drowsiness, ataxia, double vision (13-18%)
    • etc..
    • 3% risk of Rash (small risk SJS)
• Lacosamide (Vimpat)
  • Adjunctive therapy of focal onset seizures in pts > 18yo
  • FOCAL SEIZURES (90% are focal onset)
  • LU code 430
  • Route: IV and PO
  • Dosing:
    • Start 50mg QHS increase by 50mg q2w up to max 200mg BID
    • (causes some dizziness/sedation, so slowly titrate)
  • Metabolism
    • No hepatic metabolism (no interactions)
    • Excreted in urine
  • S/E:
    • Long QT and long PR ---> Sudden deaths reported
    • 25% dizziness
    • QT > 460ms and PR >200 --> CONTRAINDICATED
    • Associated with atrial fibrillation (on monograph)
  • TRENDS study --> Lacosamide is non-inferior to phenytoin. (data not completed unfortunately)
• Perampanel (Fycompa)
  • Very effective - for refractory epilepsy!
  • PARTIAL OR GENERALIZED
  • Route: Oral only
  • Dose: 4-12mg daily (start at 2-4mg)
  • Pharmacology
    • 70H halflife
  • Downside:
    • Homicidal ideation (BLACK BOX WARNING)
    • Excessive scratching and grooming
    • Dizziness 25-50%
    • Somnolence 25-50%
• Rufinamide (Banzel)
  • Indicated or Lennox-Gastaut Syndrome in children (>4yo) and adults)
    • Triad of:
      • Classic EEG feature (2.4hz slow spike an wave)
      • Seizures (GTC, Tonic, Atonic, atypical absence)
      • Intellectual Disability
  • No LU code
  • Must have failed many other meds
  • Metabolism:
    • Decreases levels of CBZ and PHB and pheny by 30-45%
    • Decreases OCP efficacy
    • VPA increases rufinamide levels by 70%
    • Drowsiness, somnolence dizziness, nausea/vomiting. 
    • Shortens QT
• Medical Marijuana
  • Weakly effective anticonvulsant
  • In vitro: has evidence
  • Cannabidiol (CBD) has anticonvulsive effects
  • Does not have psychoactive effects of THC (but THD also has anticonvulsive properties)
  • Studies:
    • 124 patients with resistant epilepsy
    • Open label trial (33 Dravet syndrome, 31 Lennox Gastaut Syndrome)
    • 79% adverse events (12% severe) [most studies adverse events: 20-25%]
    • Only 3% stopped study (despite adverse effects)
    • 36.5% reduction in seizure frequency
    • 0% responder rate (Responder = 50% decrease in frequency of seizures)
• Ketogenic Diet
  • in early 1900's --> starved patients causing ketosis
  • High fat, low carb diet. (90% calories from fats)
  •  

Anti-Seizure Therapy

• Dilantin
  • Many Side Effects
  • No longer used in practice out of hospital, b/c so may better drugs available as O/P:
  • S/E:
    • Osteoporosis
    • Gingival hypertrophy
    • Cerebellar atrophy (Unable to walk)
    • Large fiber neuropathy
    • SJS up to 15%

• Note: Nearly all have S/E of (fatigue, weight gain, dizziness, ataxia, blurred vision, memory)
• Note: Nearly all act on sodium channels as their mechanism

Ones safe in ederly

• Elderly
  • Keppra  (psychosis, agitation, anxiety)
    • - avoid in anxiety/ impulsive cases
    • $$$, and not covered.
    • Start 500 BID - good dose... fast onset.
  • ***Lamotrigine
    • Very good, low S/E profile.
    • Most cognitively neutral, mood stabilizer.
    • Disadvantages
      • SJS - warn patients of rash.. stop.
      • Causes insomnia, second dose at 5pm if issue.
      • Prescribed BID
      • Uptitrate slowly 25mb BID x2 weeks, then 50-25 for 2 weeks... target 75-125 BID.
        • Target based on patient's age, weight, what you feel is important.
        • Can order levels, but comes back 2 weeks.  Levels don't matter, can uptitrate until S/E.
  • Gabapentin
    • Renal metabolism.
    • Some people say gabapentin is not that effective.
    • 100 TID --> uptitrate to 300 TID.
      • Titrate slowly due to sedation, leg swelling.
    • Good for ederly b/c S/E aren't a big issue.
  • Clobazam
    • Thought to be not as effective? but no evidence?
    • Good add-on drug to another.
    • I.e. patient has one seizure on
    • qHS due to sedation (benzo-like drug).
    • Can do BID.

• First time epilepsy
  • Seizure hx (onset, trigger, etc...)
  • Risk factors:  Birth hx, develtopmental hx, seizure risk factors (febrile seizures), head injuries with LOC, CNS infections, family history of epilepsy.
  • W/U; EEG + MRI (focal cortical dysplagia, lesions).
    • Usually CT not enough... just structural lesions.
    • Get regular EEG, yield is higher the closer to seizure.  (pseudoseizure?).
      • Initial EEG pick it up in 1/3 of patients.  In 2/3 that remain.. sleep deprived picks up in 1/3 of those.. of 2/3 that remain.... 1/3 be picked up as ambulatory EEG (~48hrs)... then admit, take away seizure meds, sleep deprive..
• Seizure Mgmt in Pregnancy
  • NEEDS to be PLANNED.
  • Recommendation: seizure free x9 months before getting pregnant. (risk lowest).
  • Has to be planned.
  • Do not use valproic acid, phenobarbital (teratogens).  [Most data is databases, RCT unethical].
  • All drugs teratogenic...
    • Usually risk dose dependent, but MUCH worse with dual therapy.
    • Try to get them on monotherapy.
  • all antiepileptic are teratogenic.
    • Ones least likely, Keppra, lamotrigine (Less than 300mg daily).
    • Recommend stable dose of antiepileptic... until seizure free x9mo.
    • Before getting prengnat, get lamotrigine level (to ensure that is level they are seizure free).
      • Once pregnant, lamotrigine metabolism increases, need to increase to target that level.
  • Folic Acid ... 5mg?/g
  • Risk of seizure in pregnancy;
    • Trauma from fall
    • Fetal hypoxia.
  • After birth
    • Decrease lamotrigine back to a dose close to what they were before, but slightly higher b/c new mother are sleep deprived.

• Notes:
  • If switching... I.e. target lamotrigine (on dilantin).  Uptitrate lamotrigine first to target dose.  Then a week in between where they are on both.  Then downtitrate the other one slowly.

Driving Guidelines

• Must be seizure free >6mo

Pregnancy

• Until 1980, some US states had laws that forbid women with epislepsy from marrying
  • 50% of pregnancies unplanned in epilepsy patients (20% general population)
• Brain development 5 weeks, Major organs 10 weeks.
• General Population: Rate of teratogenesis is 1-3% (significant morbidity)
• AED rate: 4-7 - 13.8
• Low Risk (Recommended)
  • Lamotrigine
  • Levetiracetam
  • Carbamazepine (but avoid in young women)
• Intermediate Risk:
  • Phenytoin
  • Topiramate
• High RIsk:
  • Valproic Acid
• Folic Acid - 5mg daily (write a prescription!) - decreases miscarriage rate
• SUDEP (Sudden Unexpected Death in Epilepsy Patients)
• Pregnancy does not increase risk of epilepsy and labour
• Usually pregnancy decreases anti-epilepsy drug levels (usually increase dose)
• Breast feeding protects fetal IQ in epilepsy