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

     

     

    Status Epilepticus Treatment.png

     

    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
      Focal Generalized
    Older Generation

    1st Line:

    Carbamazepine

        (Oxcarbazepine, Eslicarbazepine (LU) - fewer S/E)

        - Extended release CR (BID) or regular (QID)

        - S/E: memory, SJS, Rash, hypoNa

          (Eslicarbazepine = less S/E)

        - Liver dysfunction (monitor liver enzymes q2m,

          then q1y)

        - Pregnancy: Birth defects (neural tube def.)

           give folic acid 5mg daily

          Reduces efficacy of OCP!!! (enzyme inducer)

    - Phenytoin (Dilantin)

       (do not use >2 weeks, better medicine available)

       - Liver failure, Gum Hypertrophy, Low WBC

       - Hirsutism (esp women), peripheral neuropathy

       - Osteoporosis (Ca, VitD)

    Pregnancy: Fetal Hydantoin Syndrome (fingers malform)

       - Interactions (enzyme inhibitor)

    - Ethylsuccimide

          - only for abscence seizures in pediatric setting

    - Gabapentin

          - Renal metabolism

          - Many argue it is not effective.

          - Safe in Elderly  (due to good S/E profile)

          - Start 100 TID --> titrate up to 300 TID

                         Titrate slowly due to sedation, leg swelling

    1st Line:

    Valproic Acid

           - S/E; weight gain!! (women gain ++ weight)

           - Hair Loss!  Tremor.  PCOS (metabolic synd)

       Pregnancy: teratogenesis (NTD), cognitive changes!

            10 pt IQ drop for >150mg doses, Autism!

     

           - Benefit: Can give IV

    - Dilantin

    - Carbamazepine

    - Vigatotrin (Gabatrin)

        - Gaba-oxidase blocker (Benzo-like effect)

        - Causes retinal damage (needs optho F/U)

        - Only used for "drop attacks"

    - Clobazam

    - Benzo-like drug

    - Limited efficacy (due to tolerance)

    - Good add-on agent for additional control
        (rarely monotherapy if one seizure only)

    - Dosed qHS due to sedation (benzo-effect), or BID

    Newer Generation    

    - Lamotrigine

         - Very good, low S/E profile.  (does not cause classic fatigue, but causes alertness!!)

             (but also has insomnia, dose in AM and early PM.

         - Safe in ELDERLY

         - Cognitively neutral, very potent mood stabilizer

         - Disadvantages:

                 - SJS - warn patients of rash and tell them to stop!

                           - To minimize SJS risk, need to titrate up SLOWLY

                 - Insomnia (move second dose to 5pm if issue)

                 - BID dosing

                 - SLOW titration, takes long time to be theraputic.

           Start (sometimes 12.5mg BID x2w) 25mg BID (25+25) x2 weeks,

                    then 50+25 x2 weeks, then....

                    target: 75-125mg BID

            - Final dose target based on age, weight, and clinical judgement.

            - Can order levels, but take ~2 weeks to come back.

               Often just titrated up until patient gets side-effects.

            Interactions: Valproic acid + Lamotrigine 

            Pregnancy: cleft lip, palate, tetralogy of fallot, transposition (1/1000 --> 1/300)

     

    Topiramate (Topamax) - Weight LOSS! 

     

        Slows thinking and word finding difficulty

    Other indications: migraine, pain, pseudotumor cerebrii

    Rare: Oxalate kidney stones, Glaucoma

    Pregnancy: Cleft lip, palate

     

    - Levetiracetam (Keppra)

        GREAT!  but expensive.  Therapeutic in CSF in 1hr.  Available IV

         - Safe in ELDERLY

         - S/E: 1 in 20 have severe mood S/E (depression, suicidal ideation, anger "KeppRage")

         - Very $$$ - not covered.

         - Start 500mg BID - rapid onset.

         - Brivarecetam also available now. 

     

    Lacosamide (Vimpat)

    - Used if not-responsive to Dilantin with Status Epilepticus

    - BENEFIT Trial = Same as dilantin in acute 

    - Cardiac Arrhythmias: Long PR, long QT, Brugada, 2nd deg AV block

     

     

     

    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
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