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Pediatric Epilepsy

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					       Seizures and Epilepsy:
           Epidemiology

• Incidence of epilepsy: 40/100,000/yr in
  children birth-16 yrs of age
• About 1 % of children will have at least one
  afebrile seizure by age 14 yrs
• 0.4 %-0.8 % will have epilepsy by age 11 yrs
• Epilepsy is the most common neurologic
  problem in childhood
         Seizures vs Epilepsy

• A seizure is a sudden, involuntary, time-
  limited alteration in neurologic function
  (movement, behavior) secondary to
  abnormal discharge of neurons in the CNS
• Epilepsy is a chronic condition
  characterized by 2 or more unprovoked
  seizures.
Beta, Alpha, Theta and Delta are
the four types of brain waves. The
electrical frequencies emitted by
the brain. These frequencies can
be seen on an electro-
encephalograph machine.
NEONATAL SEIZURES
                              Definition

 A stereotypic, paroxysmal spell of
  altered neurologic function
  (behavior, motor,and/or autonomic
  function)
                                Definition


 Neonatal period limited to :
    - first 28 days for term infants
    - 44 weeks gestational age for
       pre-term
                            Frequency

 In US – incidence has not been
  established clearly
 Estimated frequency of 80-120 per
  100,000 neonates/year
 1-5:1000 live births
     Why do neonatal seizures have such
                unusual presentations?



 Immature CNS cannot sustain a
  synchronized, well orchestrated
  generalized seizure
     Perinatal Anatomical and Physiological
      Features of Importance in Determining
          Neonatal Seizure Phenomena

ANATOMICAL
Neurone outgrowth—dendritic and axonal ramifications—in
 process
Synaptogenesis not complete
Deficient myelination in cortical efferent systems

Volpe JJ.Neonatal Seizures :Neurology of the Newborn.4th ed.
Perinatal Anatomical and Physiological Features
 of Importance in Determining Neonatal Seizure
                   Phenomena

PHYSIOLOGICAL
In limbic and neocortical regions—excitatory synapses develop
   before inhibitory synapses ( N-methyl-D-aspartate receptor
   activity, gamma-aminobutyric acid excitatory)
Immature hippocampal and cortical neurons more susceptible to
  seizure activity than mature neurons
Deficient development of substantia nigra system for inhibition of
  seizures
Impaired propagation of electrical seizures, and synchronous
  discharges recorded from surface electroencephalogram may
  not correlate with behavioral seizure phenomena
______________________________________________________________________
  Volpe JJ.Neonatal Seizures.In:Neurology of the Newborn.4th ed.
 Probable Mechanisms of Some Neonatal
              Seizures

PROBABLE MECHANISM                                       DISORDER

Failure of Na + -K + pump secondary to              Hypoxemia, ischemia,
  adenosine triphosphate                              and hypoglycemia
Excess of excitatory neurotransmitter
(eg.glutamic acid—excessive excitation)              Hypoxemia, ischemia
                                                        and hypoglycemia
Deficit of inhibitory neurotransmitter             Pyridoxine dependency
  (i.e., relative excess of excitatory
   neurotransmitter)
 Membrane alteration—  Na +                 Hypocalcemia and
   Permeability                                hypomagnesemia
_________________________________________________________________
Volpe JJ.Neonatal Seizures:Neurology of the Newborn.4th ed.
    Classification of Neonatal Seizures


    Clinical

    Electroencephalographic
                      Classification
I. Clinical Seizure
 Subtle
 Tonic
 Clonic
 Myoclonic
                            Classification
II. Electroencephalographic seizure


   Epileptic

   Non-epileptic
                Clinical Classification

1. Subtle
   More in preterm than in term
   Eye deviation (term)
   Blinking, fixed stare (preterm)
   Repetitive mouth and tongue movements
   Apnea
   Pedaling and tonic posturing of limbs
                  Clinical Classification
2. Tonic
   Primarily in Preterm
   May be focal or generalized
   Sustained extension of the upper and
    lower limbs (mimics decerebrate posturing)
   Sustained flexion of upper with extension of
    lower limbs (mimics decorticate posturing)
   Signals severe ICH in preterm infants
                  Clinical Classification
3. Clonic
   Primarily in term
   Focal or multifocal
   Clonic limb movements(synchronous or
    asynchronous, localized or often with no anatomic
    order of progression)
   Consciousness may be preserved
   Signals focal cerebral injury
                  Clinical Classification
4. Myoclonic
   Rare
   Focal, multifocal or generalized
   Lightning-like jerks of extremities
    (upper > lower)
              Jitteriness Versus Seizure
CLINICAL FEATURE                                              JITTERINESS                    SEIZURE

Abnormality of gaze or eye                                                O                        +
  movement
Movements are stimulus                                                   +                         O
  sensitive
Predominant movement                                                Tremor                         Clonic jerking

Movements cease with passive                                              +                            O
  flexion
Autonomic changes                                                         O                            +
------------------------------------------------------------------------------------------------------------------
                                        Etiology

 It is critical to recognize neonatal seizures, to
  determine their etiology, and to treat them for
  three major reasons:

 1. Seizures are usually related to significant
  illness, sometimes requiring specific therapy
                                     Etiology

2.Neonatal seizures may interfere with
  important supportive measures, such as
  alimentation and assisted respirations for
  associated disorders.

3.Experimental data give some reason for
  concern that under certain circumstances the
  seizure per se may be a cause of brain injury.
                                     Etiology

 Clinical history provides important clue
 Family history may suggest genetic
  syndrome
 Many of these syndromes are benign
 In the absence of other etiologies, family
  history of seizures may suggest good
  prognosis
                                      Etiology

 Pregnancy history is important
 Search for history that supports TORCH
  infections
 History of fetal distress, preeclampsia or
  maternal infections
                                        Etiology

   Delivery history
   Type of delivery and antecedent events
   Apgar scores offer some guidance
   Low Apgar score without the need for
    resuscitation and subsequent neonatal
    intensive care is unlikely to be associated
    with neonatal seizures
                                    Etiology

 Postnatal history
 Neonatal seizures in infants without
  uneventful antenatal history and delivery may
  result from postnatal cause
 Tremors may be secondary to drug
  withdrawal or hypocalcemia
 Temperature and blood pressure instability
  may suggest infection
          Comparison of prominent etiologic diagnoses of
          seizures in the newborn period. (Data modified
           from Mizrahi and Kellaway, 1987; Rose and
                         Lombroso, 1970)
             Malformation
            Hypoglycemia
            Hypocalcemia
                 Meningitis
                       Stroke                                                                             1970
                     Trauma                                                                               1987

              Hemorrhage
      Hypoxia-ischemia

                                  0           10          20          30           40          50
                                                        Incidence (%)
Fanaroff A, Martin R.Neonatal seizures. In:Neonatal and Perinatal Medicine, Diseases of the Fetus and Infant,6th ed
Laboratory Studies to Evaluate Neonatal
                                Seizures

Indicated

Complete blood count, differential, platelet count;
  urinalysis
Blood glucose (Dextrostix), BUN, Ca, P, Mg,
  electrolytes
Blood oxygen and acid-base analysis
Blood, CSF and other bacterial cultures
CSF analysis
EEG
 Laboratory Studies to Evaluate Neonatal
                                 Seizures

Clinical Suspicion of Specific Disease

Serum immunoglobulins, TORCH antibody titers, and
  viral cultures
Blood and urine metabolic studies (bilirubin,ammonia,
  lactate, FeCl³, reducing substance.)
Blood and urine toxic screen
Blood and urine amino and organic acid screen
CT or ultrasound scan
                                  Treatment

 Identify the underlying cause:
   hypoglycemia - D10 solution
   hypocalcemia - Calcium gluconate
   hypomagnesemia- Magnesium sulfate
   pyridoxine deficiency- Pyridoxine
   meningitis- initiation of antibiotics
                                   Treatment

 To minimize brain damage
 Some controversy when to start
   anticonvulsants
 If seizure is prolonged (longer than 3
   minutes), frequent or associated
   with cardiorespiratory disturbance
  Drug Therapy For Neonatal Seizures
Standard Therapy
AED           Initial Dose        Maintenance Dose                         Route
Phenobarbital 20mg/kg              3 to 4 mg/kg per day                  lV, lM, PO
Phenytoin      20 mg/kg            3 to 4 mg/kg per day                  lV, POª
Fosphenytoin 20 mg/kg phenytoin 3 to 4 mg/kg per day                      lV, lM
               equivalents
Lorazepam²      0.05 to 0.1 mg/kg   Every 8 to 12 hours                   lV
Diazepam²´      0.25 mg/kg          Every 6 to 8 hours                     lV

AED= andtiepileptic drug; lV= intravenous; lM= intramuscular; PO= oral
ªOral phenytoin is not well absorbed.
²Benzodiazepines typically not used for maintenance therapy.
³Lorazepam preferred over diazepam.
        Acute therapy of neonatal seizures

 If with hypoglycemia- Glucose 10%: 2ml/k IV
 If no hypoglycemia- Phenobarbital:20mg/k IV
     loading dose
     If necessary : additional phenobarbital:
     5 mg/kg IV to a max of 20 mg/kg
     (consider omission of this additional
      Phenobarbital
      if with baby is asphyxiated)
      Phenytoin: 20 mg/kg, IV (1 mg/kg/min)
      Lorazepam:0.05-0.10 mg/kg, IV
                Pharmacological properties of
                              Phenobarbital

 Enters the CSF/brain rapidly with high efficiency
 The blood level is largely predictable from the dose
  administered
 It can be given IM or IV(more preferred)
 Maintenance therapy accomplished easily with oral
  therapy
 Protein binding lower in newborn—free levels of drug
  are higher
 Entrance to the brain increased by local acidosis
  associated with seizures
             Determinants of Duration of
      anticonvulsant therapy for neonatal
                                  seizures


 Neonatal neurological examination

 Cause of neonatal seizure

 Electroencephalogram
      Duration of anticonvulsant therapy-
                              Guidelines

Neonatal period
 If neonatal neurological examination
  becomes normal discontinue therapy
 If neonatal neurological examination is
  persistently abnormal,consider etiology and
  obtain EEG
 In most such cases- Continue phenobarbital
                     - Discontinue phenytoin
                     - Reevaluate in 1 month
      Duration of anticonvulsant therapy-
                              Guidelines

One month after discharge
 If neurological examination has become
  normal, discontinue phenobarbital
 If neurological examination is persistently
  abnormal,obtain EEG
 If no seizure activity on EEG, discontinue
  phenobarbital
                                   Prognosis
Two most useful approaches in utilizing outcome

 EEG

 Recognition of the underlying neurological
  disease
                           Complications

   Cerebral palsy
   Hydrocephalus
   Epilepsy
   Spasticity
   Feeding difficulties
Epilepsy In Childhood
    Epilepsy In Childhood: Objectives
•   Review the international classification of
    seizures .
•   Review some epilepsy syndromes that occur
    during infancy and childhood
•   Discuss the evaluation process of seizures in
    children
•   Discuss the medications used to treat pediatric
    seizures
•   Discuss alternative therapies for intractable
    epilepsy
          Pediatric Epilepsy

Steps in evaluation:
• 1. Is the spell a seizure event?
• 2. What is the differential diagnosis?
• 3. Is it epilepsy?
• 4. Is it part of an epilepsy syndrome?
• 5. What tests are needed?
• 6. What is the therapy?
International Classification of Sz types


   I-Partial Seizures          II-Generalized Seizures
    Arise from specific foci      Diffuse onset
   1. Simple: No change in
       consciousness
   2. Complex:
       Consciousness is
       impaired or lost
                Partial Seizures

– Simple Partial Seizures
    • With motor signs
    • with somatosensory or
      special sensory symptoms
    • With autonomic symptoms
    • With psychic symptoms
– Complex Partial sz (CPS)
    • Simple partial followed by
      impaired consciousness
    • Consciousness impaired at


                                   Epilepsy.flv
      onset
– CPS evolving to secondary
  generalized
         Generalized Seizures
–   Myoclonic seizures
–   Tonic seizures
–   Absence seizures
–   Tonic-clonic seizures
–   Atonic seizures
       Mimics of Childhood Epilepsy
•   Syncope
•   Breath-holding spells
•   Cataplexy
•   Behavioral staring
•   Movement disorders( e.g. tics)
•   Parasomnias( night terrors, sleep walking,..)
•   Migraine
•   Benign myoclonus
•   Gastro esophageal reflux disease
        Seizure Type Vs Epileptic
                Syndrome
• A seizure type is determined by the patient’s behavior and
  EEG pattern during the ictal event
• An epileptic syndrome consists of a complex of signs and
  symptoms that occur together in a child with epilepsy more
  often than would be expected by chance
• An epileptic syndrome is defined by:
   –   Seizure type(s)
   –   Natural history
   –   EEG(ictal and inter ictal)
   –   Response to AEDs
   –   Etiology
                     Infantile Spasms
•   Peak onset : 4-6 mo ( 90 % before
    12 mo)
•   Clinically characterized by spasms,
    which can be flexor, extensor or
    mixed
•   Spasms occur in clusters and are
    more common on awakening, or
    when the infant is tired
•   West syndrome = infantile spasms,
    mental retardation and
    hypsarhythmia
•   Treatment:
    Hormonal,anticonvulsants, surgery
•   Prognosis: overall poor
Hypsarrhythmia
    Lennox- Gastaut Syndrome
• Age of onset:1-8 yrs ( 3-6 more common)
• Clinically, A Triad:
  1. Multiple seizure types(tonic most common)
  2. Cognitive/ motor impairment
  3. Slow spike and wave
• Etiology: Usually symptomatic
  – 30 % of patients with infantile spasms develop
    LGS.
      Lennox- Gastaut Syndrome
• Treatment:
  – AED (Valproate, benzodiazepines, lamotrigine.
    Topamax, Felbamate…)
  – Nonpharmacologic (Ketogenic diet, Vagus nerve
    stimulator)
  – Surgery
• Prognosis: Very poor
  – Less than 15 % are seizure free
  – Impaired cognition and cerebral palsy are common
Lennox-Gastaut syndrome
      Benign partial epilepsy of childhood
      with centro-temporal spike (BECTS)
•   Also called Benign Rolandic Epilepsy
•   The most common focal epilepsy in
    childhood
•   Represents 15 % of childhood epilepsy
•   Onset: 3-13 years( peak 6-8 yrs)
•   Typical seizures are nocturnal, partial
    with secondary generalization in a
    neurologically and cognitively normal
    child
•   The typical partial seizure involves:
     – Unilateral parasthesias of the tongue, lips,
       gums and cheeks
     – Unilateral clonic or tonic activity of above
     – Speech arrest, salivation and vocalization
       with preserved consciousness
Benign rolandic epilepsy
                       BECTS

• EEG:Central-temporal spikes.
• Treatment:
  Almost every AED is effective
  Gabapentin has been studied in randomized trials
• Prognosis:
  – Has the best prognosis of all epilepsies!
  – By mid teens the disorder resolves in almost all patients
    Childhood Absence Epilepsy
              (CAE)

• Onset: 4-10 years
• More common in females
• Normal neurologic and developmental status
• Multiple seizures daily
• Seizures last 5-15 second
• EEG: Classical 3 Hz diffuse spike and wave discharges with
  normal background.
• The seizures and the discharges are activated by
  hyperventilation.
• Treatment: Ethosuximide, valproate, lamotrigine
Absence epilepsy
   Juvenile Myoclonic Epilepsy
             (JME)
• Onset: commonly 12-18 yrs (8-26 yrs)
• Seizures: 3 types:
      1. Myoclonic
      2. GTC
      3. Absence (in 15-40 %)
• Seizures frequently occur upon awakening
• Precipitating Factors:
   – Lack of sleep
   – Emotional stress
   – Alcohol consumption
   Juvenile Myoclonic Epilepsy-
              EEG
• Genetics: multiple loci: 6p, 15q14, 8p,1p
• EEG:Background is normal. Generalized 4-6 Hz
  polyspike and slow wave complexes; Some have
  3-4 Hz spike and slow wave complexes.
• Treatment:
      Valproate, Lamotrigine,Topiramate
• Prognosis:
  – Seizures are controlled in the majority of patients.
  – JME is one form of epilepsy in which discontinuation
    of pharmacotherapy cannot be recommended
  – 90 % relapse rate of seizures after AEDS are
    discontinued
juvenile myoclonic epilepsy
    Etiology of Epilepsy in Childhood
•   Idiopathic/Genetic
•   CNS malformations, neurocutaneous disorders
•   Hippocampal sclerosis
•   Vascular disease
•   CNS infection
•   Toxic disorders
•    Metabolic disorders
•   CNS neoplasm(less than 1 %)
•   Prenatal/perinatal injury
•   Trauma
•   Miscellaneous: demyelinating disorders, vasculitis
 Epilepsy And Seizures: Evaluation

• Detailed History
• Physical Examination
• Supportive Investigations:
  –   EEG/ Video EEG
  –   Neuroimaging
  –   Metabolic work up
  –   Lumbar puncture
    Pediatric Epilepsy: Treatment

• 1. Anticonvulsant medications
• 2. Nonpharmacologic treatments
  – Ketogenic diet
  – Vagus nerve stimulator
• 3. Epilepsy Surgery
      History of AED Therapy in US
•   1857- Bromides        • 1993- Felbamate
•   1912- Phenobarbital            Gabapentin
•   1937- Phenytoin       • 1994- Lamotrigine
•   1944- Trimethadone    • 1997- Topiramate
•   1954- Primidone                Tiagabine
•   1960- Ethosuximide    • 1999- Levetiracetam
•   1974- Carbamazepine   • 2000- Oxcarbazepine
•   1975- Clonazepam               Zonisamide
•   1978- Valproate       • 2005- Pregabalin
                          • Pending- Vigabatrin
                    Phenobarbital
• Maintenance dose(mg/kg/day) 2-5(neonate); 3-7(child)
• Advantages
   –   IV formulation
   –   Can quickly load and bolus
   –   Once daily dosing if needed
   –   Widely available and inexpensive
• Disadvantages
   –   Hyperactivity in younger children
   –   Cognitive concerns
   –   Hepatic enzyme inducer
   –   Rash and hypersensitivity reactions
                             Phenytoin
• Maintenance dose mg/kg/day 5-15 neonate/infant (high range if
  PO); 3-7 child
• Advantages
   –   IV formulation
   –   Can quickly load and bolus
   –   Once daily dosing if needed
   –   Widely available and inexpensive
• Disadvantages
   –   Hepatic enzyme inducer
   –   Unpredictable pharmacokinetics
   –   Difficult to maintain therapeutic levels with PO dosing in infants
   –   Rash and hypersensitivity reactions
   –   Cosmetic side effects with long-term use
                   Carbamazepine
• Maintenance dose mg/kg/day 10-40
• Advantages
   –   Improved tolerability over phenobarbital and phenytoin
   –   Possible mood stabilization
   –   Sustained-release formulation
   –   Relatively inexpensive
• Disadvantages
   –   Rare idiosyncratic leukopenia and aplastic anemia
   –   Hepatic enzyme inducer
   –   May aggravate generalized epilepsies
   –   No IV formulation
   –   Rash and hypersensitivity reactions
                           Valproate
• Maintenance dose mg/kg/day 15-60
• Advantages
   –   Broad spectrum
   –   Possible mood stabilization
   –   Migraine prevention
   –   Extended-release formulation
   –   Can normalize epileptiform EEG
   –   IV formulation
   –   Widely available and relatively inexpensive
• Disadvantages
   – Idiosyncratic hepatic failure, especially in children under 2 years with
     polypharmacy
   – Idiosyncratic pancreatitis
   – Dose-related thrombocytopenia or platelet dysfunction
   – Weight gain
   – Menstrual irregularities
   – Tremor
   – Hepatic enzyme inhibitor
                        Gabapentin
• Maintenance dose mg/kg/day 30-90
• Advantages
   –   Well tolerated
   –   Rapid escalation if needed
   –   Used for neuropathic pain
   –   No effect on hepatic enzymes
• Disadvantages
   –   Efficacy only in focal-onset epilepsy
   –   Three times daily dosing
   –   Possible weight gain
   –   No IV formulation
                      Lamotrigine
• Maintenance dose mg/kg/day 5-15(with inducer);1-5(with
  VPA);2-8(monotherapy)
• Advantages
   –   Favorable CNS profile
   –   Twice daily dosing
   –   Broad spectrum
   –   Possible mood stabilization
   –   Can normalize epileptiform EEG
• Disadvantages
   –   Slow titration
   –   Interaction with valproic acid
   –   Rash and hypersensitivity reaction
   –   May exacerbate myoclonic epilepsy
   –   No IV formulation
                Levetiracetam
• Maintenance dose mg/kg/day 20-80
• Advantages
  – Rapid titration if needed
  – Twice daily dosing
  – No effect on hepatic enzymes
• Disadvantages
  – Less data in children and generalized epilepsies
  – May exacerbate behavioral problems
  – No IV formulation
                   Oxcarbazepine
• Maintenance dose mg/kg/day 20-50
• Advantages
   – Twice daily dosing
   – Possible mood stabilization
   – Improved tolerability over phenytoin
• Disadvantages
   –   Limited spectrum
   –   Hyponatremia
   –   Rash and hypersensitivity reaction
   –   May exacerbate generalized epilepsies
   –   No IV formulation
   –   May induce oral contaceptive at doses >1200 mg
                        Topiramate
• Maintenance dose mg/kg/day 2-20 (infants); 2-10
  (children)
• Advantages
   –   Broad spectrum
   –   Migraine prevention
   –   Twice daily dosing
   –   Weight loss
• Disadvantages
   –   Possible idiosyncratic or dose-related cognitive adverse effects
   –   Weight loss
   –   Renal stones
   –   Decreased sweating
   –   Metabolic acidosis
   –   Rare acute angle closure glaucoma
   –   No IV formulation
   –   Induces oral contaceptives at doses >200 mg
                    Zonisamide
• Maintenance dose mg/kg/day 5-20
• Advantages
  –   Once or twice daily dosing
  –   Weight loss
  –   May be effective in progressive myoclonic epilepsies
  –   No effect on hepatic enzymes
• Disadvantages
  –   Less data in children and generalized epilepsies
  –   Possible dose-related cognitive adverse events
  –   Weight loss
  –   Renal stones
  –   Decreased sweating
  –   No IV formulation
      Treatment of Pediatric Epilepsy

• Goal: Seizure control without side effects
• Appropriate therapy requires accurate diagnosis:
  – Seizure type
  – Epilepsy syndrome
               Treatment of Seizure Types
                    Traditional AED
       Primary Generalized                                  Partial Onset
Absence        Myoclonic    Tonic-Clonic          Simple Complex Secondary
           Atonic,Tonic                           Partial   Partial   Generalized




Ethosuximide    Benzodiaz   Carbamazepine, Phenytoin, Phenobarbital, Primidone
                -epines

                                    Valproate
             Treatment of seizureTypes
                   AEDs, 2005
       Primary Generalized                                 Partial Onset
Absence     Myoclonic     Tonic-Clonic            Simple Complex Secondary
           Atonic,Tonic                          Partial   Partial   Generalized




Ethosuximide Benzodiaz    Carbamazepine, Phenytoin, Phenobarbital, Primidone
            -epines           Gabapentin,Oxcarbazepine, Tiagabine, Pregabalin

     Valproate, Felbamate, Lamotrigine, ?Levetiracetam, ?Zonisamide, ?Topiramate
      Factors affecting AED choice
• Side effect profile
• Titration schedule
• Other medications already on, tried
   – Drug-drug interaction
   – Mechanism of action
• Overall clinical experience
• Physician’s personal experience
• Cost
  Alternatives to Anticonvulsant
            Treatment
• Medically intractable seizures
  (Pharmacoresistant epilepsy)
  - Seizures that are not controlled by
  anticonvulsant medication, or are only
  controlled by medications that have
  significant side effects
• It is estimated that 20-30 % of patients with
  epilepsy have medically intractable seizures
                            (Hauser, 1991)
  Alternatives to Anticonvulsant
            Treatment

• Ketogenic diet
• Vagus nerve stimulator
• Epilepsy Surgery
              Conclusions

• Seizures in children are a common cause of
  neurological morbidity
• Mimics of epilepsy are common
• Detailed history and physical examination
  are essential for accurate diagnosis
• Many treatments options are available
Thank You

				
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