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Seizures vs Epilepsy Definitions

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  • pg 1
									  Current Perspectives on Pediatric Care                • MP is a 27 y.o. single 
                                                          mother of 2 who 
                                                          presents in labor at 38 
                                                          weeks. Due to 
                                                          unemployment and 
                                                          recent relocation, MP 
        Doug Allington, Pharm.D.  BCPS                    has not had routine 
                                                          prenatal care. The fetus 
                                                          experiences 
               University of Montana                      decelerations so 
                                                          emergent C‐section is 
                                                          performed.




  • MP delivers LP, a 38 
                                                                      Seizures vs Epilepsy
    week gestational age                                • Seizures result from a 
    neonate born yesterday.                               synchronized discharge of 
    An experienced NICU                                   neurons that result in 
    nurse this morning                                    some change in motor, 
    identified a strange
    identified a strange                                  sensory, or cognitive 
                                                          function.
    ‘facial grimacing’ 
    pattern by LP that 
    persisted for 1‐2                                   • Epilepsy is characterized by 
                                                          multiple seizures (two or 
    minutes on 2 separate                                 more) not precipitated by a 
    occasions.                                            known cause.




Excitatory
Neurotransmitter:                                                              Definitions
Glutamate
                                  Inhibitory
Aspartate                                               • Provoked seizures: due to a recognizable 
                                  Neurotransmitters
Acetylcholine
                                  Dopamine                antecedent event. 
Norepinephrine
                                  GABA                     – Hypoglycemia, intracranial infection, trauma
Histamine
                                  Adequate supply:
                                            yg
                                         oxygen
                                         glucose                  k d i              i h b           f
                                                        • Unprovoked seizures: occur in the absence of 
                                         electrolytes     provoking events.
                                         pH                – Cryptogenic: No known cause
                                                           – Remote symptomatic: 
                                                              • Pre‐existing brain abnormality or insult
                                                           – Idiopathic: genetic




                                                                                                            1
    International Classification of Epileptic Seizures   International Classification of Epileptic 
   • I. Partial                                                         Seizures
       – Simple
       – Complex                                         • I. Partial Seizures
   • II. Generalized                                        – A. Simple (without impairment of consciousness)
       –   Absence                                              • 1. With motor symptoms
       –   Myoclonic                                            • 2. With special sensory or somatosensory symptoms
       –   Clonic
           Cl i
                                                                • 3. With psychic symptoms
       –   Tonic 
       –   Tonic‐clonic                                     – B. Complex (with impairment of consciousness)
       –   Atonic                                               • 1. Simple partial onset followed by impairment of 
                                                                  consciousness (with/without automatisms)
   • III. Unclassified
                                                                • 2. Impaired consciousness at onset – with/without 
   • IV. Status Epilepticus                                       automatisms




           ILAE: Definitions of seizure terms                           Desired Outcomes
• II. Generalized
   – Atonic‐ complete sudden loss                        • General Goals in Epilepsy Therapy
     of muscle tone (drop attacks)                          – Complete control of seizure activity
   – Tonic‐ stiffening of muscles.
   – Myoclonic‐ sudden jerking of muscles                   – Minimal/tolerable adverse effects
     (common during sleep‐ lasts only                       – Normal cognitive development/high quality of life
     seconds)
   – Tonic‐clonic: alternating                           • Duration of Care in Neonates
     stiffening/relaxation of muscle                        – Seizures or Epilepsy
                                                                • Seizures:  typically treated for days or weeks; most 
• III. Unclassified                                               often discontinued before discharge from nursery.
• IV. Status epilepticus                                        • Epilepsy: by definition means repeated seizure activity. 
                                                                  Chronic therapy.




                                                                      Neonatal Seizures Etiologies
             Seizures in First Year of Life              • Hypoxic‐ischemic encephalopathy  
                                                           (35‐42%)
   • Life’s second most 
                                                         • Intracranial hemorrhage or 
     frequent occurrence                                   infarction 15‐20%
     of seizures
   • Seizures may be tonic
     Seizures may be tonic,                                CNS infection (12 17%)
                                                         • CNS infection (12‐17%)
     myoclonic, clonic, or                               • CNS malformation (5%)
     subtle  (chewing, blinking, 
      bicycling)
                                                         • Metabolic/electrolyte 
                                                           abnormality (3‐5%)

                                                         • Inborn errors of metabolism (5‐20%)




                                                                                                                              2
What steps should be used to rule out causes for 
                TM’s seizure?                                                        Epileptic Syndromes
• Basic Laboratory Screen                                         • Neonatal Period
    – Na, Mg, Phosphate, glucose,                                     – Benign familial neonatal 
      tox screen                                                        seizures
•   Sepsis evaluation
    Sepsis evaluation                                                   Early myoclonic 
                                                                      – Early myoclonic
•   Head CT                                                             encephalopathy
•   EEG (often repeat EEGs)                                                • Less than 1%
•   Persistent seizures                                               – Ohtohara’s syndrome
    – Inborn errors of metabolism                                          • 40‐50 cases (incidence/
    – Ammonia ; Lactate; pH                                                  prevalence unknown)
                                                                  http://www.ilae-epilepsy.org/Visitors/Centre/ctf/CTFtable1.cfm




                                                                                 What therapy options are 
           Benign familial neonatal seizures                                      recommended for TM?
• Seizures in term                                                  • Identify/treat 
  infants with normal                                                 underlying acute 
  delivery and no                                                     abnormality
  known cause                                                           – Correct underlying 
                                                                          electrolyte abnormalities
                                                                          electrolyte abnormalities
• Seizures 
                                                                        – Treat infection
  spontaneously remit.
                                                                    • Antiepileptic Agents
• Therapy only for                                                      – Phenobarbital
  persistent seizure                                                    – Phenytoin (fosphenytoin)
  activity                                                              – Benzodiazepine




         Epilepsy in Special Childhood 
                  Populations
                                                                   • JP is a 5 y.o. male who 
•   Children with mental retardation: 25.8%
                                                                     experiences a seizure 
•   Children with cerebral palsy: 13%                                in association with a 
•   Children with mental retardation/CP: 50%                         102.8oF temperature 
•   Children with mothers with epilepsy: 8 7%
    Children with mothers with epilepsy: 8.7%                             li f
                                                                     resulting from a 
•   Children with fathers with epilepsy: 2.4%                        presumed viral 
                                                                     infection. 
• 33% of people who have had a single, 
  unprovoked seizure

                                     www.epilepsyfoundation.org




                                                                                                                                   3
                    Infantile Epilepsy
Febrile seizures (2-5% of                                                                         Febrile Seizures
  children)
Migrating partial seizure of infancy                                               • Most common cause of 
West syndrome                                                                        seizures during 
    Estimated to be about 1 per 2000 to
   4000 live births (Hurst 1994).
                                                                                     childhood
                                                                                   • Characteristics:
Myoclonic epilepsy in infancy (MEI)
  (67 CASES:valproate monotherapy)                                                   – Brief, generalized tonic‐
                                                                                       clonic seizure
Benign infantile seizures
                                                                                   • Simple versus Complex
Dravet syndrome (1:40,000)

Myoclonic encephalopathy in
  non-progressive disorder




                  Simple vs Complex                                                               Febrile Seizures
 Simple                                  Complex                                   • Simple Febrile Seizures
 Generalized seizure less than 15 
           Febrile Seizures              Generalized seizure >15 minutes
                                                                                     – Simple febrile seizures 
 minutes duration                                                                      are benign‐
                                                                                       educate/reassure 
                                                                                               /
 No more than a single seizure per 24    Multiple, recurrent seizures within 24        parents
 hours                                   hours
                                                                                     – Stress general first‐aid 
                                                                                       precautions
                                         Focal seizures




                      Febrile Seizures
• Complex Febrile                                                                  • NB is a 7 y.o. male in 
  Seizures                                                                           the first grade. NB’s 
   – Acetaminophen to                                                                teacher notices that 
     reduce fever
     reduce fever                                                                    he often appears to be 
                                                                                     he often appears to be
   – Rarely, rectal diazepam                                                         ‘daydreaming’ for 5‐15 
                                                                                     seconds at a time, 
                                                                                     multiple times per day. 




                                                                                                                     4
        Practice Parameter: Evaluating the first                                          Practice Parameter: Evaluating the first nonfebrile
            nonfebrile seizure in children.                                                                 seizure in children. (cont.)

 • Goals of immediate evaluation to obtain:                                         • Goals of immediate evaluation to obtain:
        – Detailed history at time of presentation                                            • Lumbar Puncture:  Recommended IF risk of meningitis 
        – Laboratory tests                                                                      or encephalopathy is plausible.
           • Individual basis based upon clinical circumstances
             Individual basis based upon clinical circumstances                               • EEG‐ recommended for children with apparent first 
                                                                                                unprovoked seizure.
             but includes vomiting, diarrhea, dehydration, or                                 • MRI‐ if needed.
             failure to return to baseline alertness. Add toxicology 
             screen as required.

                                                                                    Report of the Quality Subcommittee of the American Academy of Neurology, the Child Neurology 
                                                                                       Society, and the American Epilepsy Society.


 Report of the Quality Subcommittee of the American Academy of Neurology, the
 Child Neurology Society, and the American Epilepsy Society.




                                                                                • NB’s symptoms classic 
  Listing of Childhood                                                            for absence seizures.
  Epilepsies                                                                    • Usual onset for 
                                                                                  absence is 4‐8 y.o.
                                                                                • Simple versus 
Early onset benign childhood occipital epilepsy (Panayiotopoulos type)
                                                                                  complex absence 
                                                                                  complex absence
Epilepsy with myoclonic astatic seizures                                          seizures 
Benign childhood epilepsy with centrotemporal spikes (BCECTS)
Late onset childhood occipital epilepsy (Gastaut type)
                                                                                • Unique, distinctive 
Epilepsy with myoclonic absences                                                  EEG pattern
Lennox-Gastaut syndrome
Epileptic encephalopathy with continuous spike-and-wave during
sleep (CSWS) including Landau-Kleffner syndrome (LKS)
Childhood absence epilepsy (CAE)




                                                                                                             AED: Ranking of Efficacy 
                         Absence Epilepsy                                       Class I      AES/AAN Committee
                                                                                             Prospective, Rand. Controlled Trials 
                                                                                                                                                   ILAE
                                                                                                                                         > 1 RCT or meta‐analysis of RCTs 
                                                                                             (RCT)                                       meeting 6 criteria.
                                                                                             a. Primary outcome defined                  1. Primary outcome efficacy 
Age        AED History     Usually        Alternative                                        b. Inclusion/Excl. defined                  2. Treatment > 48wks
                           Preferred      Agents                                             c. No bias from dropouts                    3. Double blind
                                                                                             d. Relevant & equivalent baselines          4. Superiority or non‐inferiority >
           Initial         Ethosuximide                                                                                                      20% relative difference
Child      Monotherapy     Valproate                                                                                                     5. No forced study exit by # of 
                           L
                           Lamotrigine
                                ti i                                                                                                         seizures
                                                                                                                                         6. Appropriate statistical analysis
           Ethosuximide    Valproate      Zonisamide
           Failure:        Lamotrigine    Topiramate
           Initial         Valproate                                            Class II     Like I, but not randomized, lacking one  >1 RCT or meta‐analysis of RCTs; 
           Monotherapy     Lamotrigine                                                       criteria a‐d                             except: 1. No superiority‐ or‐
Juvenile                                                                                                                                   2. Treatment only 24‐48wks
           Valproate       Lamotrigine    Topiramate
           Failure:                       Zonisamide                            Class III    All other controlled trials                 > 1 RCT or meta‐analysis not meeting 
                                                                                                                                         class I or II
                                                                                Class IV     Uncontrolled studies, case reports,         Evidence, non‐randomize, prospective 
                                                                                             expert opinion                              controlled, uncont., case series or 
                                                                                                                                         experts




                                                                                                                                                                                    5
          ILAE: clinical trial rating, level of evidence and                                        • RT is a 14 y.o. female who recently 
                                                                                                      had a second traumatic head injury 
                               conclusion                                                             while snowboarding.
Combination of clinical trial ratings     Level of evidence    Conclusions
>1 class I studies or meta‐analysis          A                AED established as effective as       • This accident resulted in a 5 minute 
or > 2 Class II studies                                       initial monotherapy                     loss of consciousness and a brief 
1 class II or meta‐anaylsis meeting          B                AED probably effective as initial       tonic‐clonic seizure.
class II criteria                                             monotherapy
>2 class III double‐blind or open‐           C                AED possibly effective as initial     • ED/hospital evaluation DID NOT 
label studies                                                 monotherapy
                                                                                                      reveal any intracranial hemorrhage or 
                                                                                                      reveal any intracranial hemorrhage or
1 class III double‐blind or open‐            D                AED potentially effective as            damage and no AED medication was 
label study                                                   initial monotherapy
                                                                                                      started
>1 class IV clinical studies or expert                        No RCT data available to assess if 
committee report, or expert                  E                AED is effective as monotherapy
opinions, or absence of clinical                                                                    • Subsequent seizure activity occurred 2 
evidence                                                                                              months later
Positive evidence of lack of efficacy                         AED considered ineffective or 
based on class I‐IV or significant           F                significant risk for seizure 
risk of seizure aggravation                                   aggravation




                                                                                                                             AED Selection
                                                                                                       • Historical Agents
  • Trauma‐related epilepsy
                                                                                                           – Carbamazepine
        – Most common cause in                                                                             – Phenytoin
          adolescents 12‐18y.o.
                                                                                                           – Valproic Acid
          Pre puberty/ Puberty is an 
        – Pre‐puberty/ Puberty is an                                                                         Phenobarbital
                                                                                                           – Ph    b bi l
          important consideration in                                                                           • All level C: No class 1 or 2 
          AED selection                                                                                          studies; 14 class 3
                                                                                                       • New agents
                                                                                                           – Topiramate (level C)
                                                                                                           – Oxcarbazempine (level D)




                           Historical Agents
  • Efficacy
  • Chronic Adverse Effects                                                                                             •45,000 children less than 15y.o. diagnosed
                                                                                                                                 with epilepsy each year.
        – Cognition                                                                                                         •(up to 325,000 school aged children
                                                                                                                                 with epilepsy)
        – Metabolic
                                                                                                                        •Slight male to female predominance
        – Endocrine
                                                                                                                        •Incidence higher in African Americans and
  • Drug‐Drug Interactions                                                                                                       socially disadvantaged populations
        – Oral contraceptives                                                                                           •Generalized seizure more common in
                                                                                                                                 children under 10y.o.; afterwards
                                                                                                                                 partial seizures represent half of all
                                                                                                                                 new cases




                                                                                                                                                                          6
                                                Epilepsy during Adolescence
                                        Juvenile absence epilepsy
• NJ is a 16 y.o. male                  (JAE)
  who experienced 
  sudden jerking 
                                        Juvenile myoclonic epilepsy
  movements of his 
                                        (JME)
  neck and shoulders 
  shortly after awaking 
                                        Epilepsy with generalized
  on two occasions 
                                        tonic-clonic seizures only
  over the last week. 
                                        Progressive myoclonus
                                        epilepsies (PME)




          Juvenile Myoclonic Epilepsy             Juvenile Myoclonic Epilepsy
• Commonly presents                        • NO Randomized 
  during puberty or                          Controlled Trials which 
  early adulthood                            meet Class 1, 2, or 3 
           yp
• Generally patients                         ILAE classification
                                             ILAE classification
  have normal 
  intelligence
• Seizures typically 
  well controlled with 
  medications




          Juvenile Myoclonic Epilepsy
                                           • LK is a 19 y.o. college 
                                             student
• Suggested AEDs                              – Dilantin 200mg po bid
   – Lamotrigine*                             – Only 1 seizure in 2 years
   – Levetiracetam                            – Consistent trough serum 
                                                levels: 14‐15mcg/ml.
   – Topiramate                            • Last three months
   – Valproic Acid                            – Two seizures while on 
   – Zonisamide                                 same regimen. 
          • All level D                       – Trough serum levels on 
                                                both occasions‐
                                                10mcg/ml.

  ILAE.




                                                                                7
  Generic substitution in the treatment of epilepsy: case                         Generic substitution in the treatment of 
            evidence of breakthrough seizures
                                                                                epilepsy: patient and physician perceptions.
50 Patients, well-controlled on brand                                         Survey of Patients and Physicians:
AED
                                                                                606 physicians (88%) concerned about
Breakthrough or increased seizure                                                  breakthrough seizures with generic
frequency after switching to generic                                               substitution.
without other provoking factors
                                                                                550 adult patients (65%) of patients concerned
Phenytoin (15 cases); VPA (14)                                                    about efficacy.
CBZ (7); Gabapentin (8);
Zonisamide (8)
       26 cases pre/post levels;                                                Approximately one-half of all physicians extremely
      21/26 had lower serum conc.                                                 or very likely to request NO substitution.
      30 lost driving privileges.
                                                                                               Epilepsy Behav. 2008 Nov;13(4):693-9. Epub 2008 Sep 10.
                                       Neurology. 2008 Aug 12;71(7):525-30.




       Position Statement of American 
                                                                              • TT is a 10 y.o. male 
         Epilepsy Society‐ Nov. 2007                                             – First diagnosed with 
  • AES favors “development and completion of a                                    complex partial seizures: 
    valid controlled, prospective clinical trial, with                             age 5
    protocol approval by the U.S. FDA, studying                                  – TT failed 3 monotherapy 
           p
    the impact of differences between the same                                     trials.
    AED formulations of different manufacturers.”                                – Still has frequent seizures 
  • “….the Society opposes formulation                                             while on combination 
    substitution of antiepileptic drugs for the                                    therapy.
    treatment of epilepsy without physician and                               • TT’s parents are 
    patient approval.”                                                          considering Ketogenic Diet




                                                                                 Ketogenic diet for the treatment of Refractory Epilepsy in 
  • 25‐30% of all epilepsy                                                            Children: a Systematic Review of the Efficacy.
    patients
  • No direct studies of                                                      • Ketogenic diet replaced by 
    Ketogenic diet –vs‐ drug                                                    Phenobarbital/Phenytoin
    therapy
                                                                              • Resurgence in 1980/1990s
  • Ketogenic diet 
         g
     – 1920’s John Hopkins                                                            di    i     9 0
                                                                              • 11 studies since 1970s
       University                                                                – Endpoints of at least a 50% 
     – 4:1 fats:carbohydrate                                                       reduction in seizures frequency
     – 90% of calories from Fats                                                    • 7‐33% of patients seizure free
                                                                                    • >90% reduction: 22‐56% of pts.


                                                                                                                               Pediatrics 2000;105:e46




                                                                                                                                                         8
   Ketogenic diet for the treatment of Refractory Epilepsy in 
        Children: a Systematic Review of the Efficacy.                    Important Co‐Morbidities in 
• Adverse Effects (4‐8%)                                                 Pediatric Epilepsy Populations
   – Lethargy                                                     • Depression/Anxiety
   – Acidosis                                                          – Often ‘overlooked’ in pediatric populations with 
   – Constipation                                                        epilepsy
   – Vomiting                                                            Significant depression scores (26%)
                                                                       – Significant depression scores (26%)
   – Kidney stones – 5%
                                                                       – Significant anxiety scores (16%)
• Noncompliance with Diet
                                                                  • May be due to:
   – 3‐32%
                                                                       – Effects of seizures 
• Placebo response rate was 
  approximately 6‐13%                                                  – Medications
                                                                       – Stigma of having seizures
                                                                       – External locus of control




                                                                                   Mortality and Epilepsy
              Epilepsy and Suicide                                • Death associated with coexisting neurological 
                                                                    compromise
• December 16, 2008, FDA announcement                                  – Poor oral‐motor & pharyngeal function combined 
  concerning suicide warnings will now be                                with GERD
  included on all antiepileptic drugs.                            • Accidental mortality
• FDA statement:
  FDA statement:                                                         Drowning  (reports up to 19% of all deaths)
                                                                       – Drowning (reports up to 19% of all deaths)
                                                                            • 60% in bathtub (Canadian study)
    "This difference was about one additional case of                       • Lower rates of drowning in pools
     suicidal thoughts or behavior for every 500 
     patients treated with antiepileptic drugs or 
                                                                  • Sudden unexplained death
     placebo".                                                         – Central respiratory depression, cardiac, etc
   There may be a 3‐fold risk of death associated with            • Death in association with status epilepticus
     non‐aderence with AED medications. (Faught. 
     Neurology.2008)
                                                                         Breningstall, Mortality in Pediatric Epilepsy. Pediatr Neurol 2001;25:9-16




  Sudden Unexplained Death in Epilepsy (SUDEP)                   American Epileptic Society Website
                                                                           http://www.aesnet.org/go/home
• Definition of SUDEP requires:
   – 1. History of epilepsy                                        • International League Against Epilepsy
                                                                   •   http://www.ilae‐epilepsy.org/Visitors/Centre/ctf/index.cfm
   – 2. Sudden death or cardio‐respiratory compromise 
                                                                        – This site gives comprehensive information 
     not resulting from status epilepticus
                                                                          on all forms of epilepsy to include Epileptic 
   – 3. Unexpected death when no life threatening 
                                                                          Syndromes
     condition is apparent
                                                                             •   Etiology
   – 4. Death this remains unexplained even after post‐
                                                                             •   Pathophysiology
     mortem examination
                                                                             •   Clinical manifestations
                                                                             •   Diagnosis, Prognosis
   – SUDEP may be responsible for 7.5‐17% of all 
                                                                             •   Treatment
     deaths in epilepsy




                                                                                                                                                      9
             Useful Websites
• www.epilepsy.com
  – Useful general information on epilepsy
  – Educational podcasts
  http://www.aan.com/
• htt //            /
  – American Academy of Neurology
  – Long list of Practice Guidelines




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