SEIZURE TYPES: GENERALIZED by HC120209052552

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									Cortical dysfunction: Epilepsy

        Michael Privitera, MD
      Professor and Vice Chair
             Neurology
Neural activity and
electroencephalography
   Measuring Cortical Activity
      ability to assess the collective behavior of cortical
        neurons is important for the study of arousal,
        wakefulness, sleep and dreaming, and for the diagnosis
        of epilepsy and coma
      ensemble properties of the cerebral cortex can be
        examined with techniques that record the activity of
        many cortical neurons simultaneously
   electroencephalogram (EEG): recorded noninvasively with scalp
    electrodes;
      EEG is probably not the result of action potentials, but
        instead the sum of slow changes in the membrane
        potential (EPSPs and IPSPs) of dendrites in superficial
        cortex
   electrocorticogram (EcoG): recorded from the cortical surface
    when exposed during surgery
   an EEG component related to a specific sensory stimulus is
    called a sensory evoked potential or event related potential
What does EEG do well?
   Detects, characterizes (focal vs
    generalized), and localizes epileptiform
    abnormalities
   Assesses degree of generalized
    slowing- especially helpful in the
    unresponsive patient
   Identifies “subtle” status epilepticus-
    critical in the unresponsive patient with
    twitching
   Localizes focal slowing
   Detects somewhat specific patterns
    (PLEDS, FIRDA, CJD, triphasics, SSPE)
Focal spikes

 This is an example of a focal
 spike on EEG (arrow).
Generalized
spike/wave

This is an example of a
generalized spike/wave.
    Temporal structure of sleep
       stepwise descent from wakefulness to stage 1
        through to stage 4 sleep, followed by an ascent back
        upward
:
-      first REM episode 70-90 minutes after sleep onset
       as night progresses, cycle repeats with less delta
        sleep and longer REM episodes
Patient history: Part 1
A 36 yo male has had seizures since age
17. The seizures start with an unusual
feeling in his abdomen, followed by
speech arrest and some difficulty
understanding what people are saying to
him; these symptoms may then continue
and cause alteration of consciousness and
amnesia for the event. Observers say he
stares and makes chewing movements for
1-2 minutes, then has about 5 minutes
where he has trouble speaking normally.
     Definitions
1.
        Seizure: The clinical manifestation of an
         abnormal, hypersynchronous discharge of a
         population of cortical neurons. (subjective
         symptoms or objective signs)
        Epilepsy: A disorder in which there is a
         tendency to have recurrent seizures.
        Medication-resistant epilepsy: cases where
         medication fails to fully control siezures- up to
         25% of all cases
   Pathophysiology of Generalized
    Tonic-Clonic Seizures (GTCS)
Secondarily                    Generalized
Generalized                    from Onset
  Focal                          Seizure
  onset                         threshold



Inhibition                     Generalized
of seizure                       onset
 spread

                Clinical
              manifestation:
                 GTCS
Seizure classification - Partial
 Simple partial seizures (consciousness
  intact)
 Complex partial seizures
  (consciousness impaired)
 Partial seizures with secondarily
  generalization
Simple Partial Seizure
 No alteration of consciousness
 Involves focal area of cortex
 Clinical manifestation depends on area
  of cortex involved
     Sensory
     Motor
            sensory: visual, auditory
     Special
     Autonomic: fear, tachycardia
     Memory
    Typical temporal lobe
    complex partial seizure
   Aura of autonomic, psychic, epigastric, or
    olfactory sensation
   Arrest of movement common
   Oroalimentary or extremity automatisms
   Duration 60-90 seconds
   Postictal language disturbance when
    seizures originate in dominant hemisphere
   Often confusion with gradual recovery
   Amnesia for event
Techniques to Localize
Seizures
 Structural
 Functional
 Electrophysiologic         (EEG)

            to differentiate ictal from interictal
   Important
   abnormalitites
Neuroimaging in epilepsy:
Structural
   CT scanning reserved for emergency use
    when structural abnormality (i.e. hemorrhage)
    suspected
   MRI is diagnostic procedure of choice for
    seizures BEST TEST TO EVALUATE
    POSSIBLE STRUCTURAL LESION
   Seizure protocol MRI
     Superior to routine MRI for detecting mesial
      temporal lobe abnormalities
MRI scan with arteriovenous malformation
Interictal temporal lobe hypometabolism on PET
Visual stimulus and occipital activation on functional MRI
Electroencephalography
   Patients with epilepsy, first EEG: 29-50%
    have epileptiform abnormalities, multiple
    EEGs increase yield 59-92%
   Normal EEG does not “rule out” epilepsy
   Multiple normal EEGs in setting of
    uncontrolled seizures – suspect nonepileptic
    seizures
     Definitive   diagnosis: ictal EEG recording
    Antiepileptic Drug
   A drug that decreases the frequency
    and/or severity of seizures in people
    with epilepsy

   Treats the symptom of seizures, not the
    underlying epileptic condition

   Goal—maximize quality of life by
    minimizing seizures and adverse drug
    effects
    Cellular Mechanisms of
    Seizure Generation

   Excitation (too much)
                 Na+, Ca++ currents
     Ionic-inward
     Neurotransmitter: glutamate, aspartate
   Inhibition (too little)
                 Cl-, outward K+ currents
     Ionic-inward
     Neurotransmitter: GABA
   Synchronization abnormalities (max in
    hippocampus)
The GABA Story (highlights)
 Known older antiepileptic drugs (eg,
  phenobarbital or diazepam) work at
  same site as GABA
 GABA blockers cause seizures
 GABA system manipulation has led to
  new medications
     Mechanisms to Know
 Carbamazepine and phenytoin (2 of the
  older medications) both work by
  modulating Na channels.
 Tiagabine (a new medication) works by
  specifically inhibiting GABA reuptake
  into the neuron
 Topiramate (a new medication) works
  by multiple mechanisms
Steps in Antiepileptic Drug
Development
 Development usually based on
  mechanism
 Screen in multiple animal seizure
  models
 Pilot studies for safety and efficacy in
  humans
 Large randomized controlled trials in
  humans with epilepsy
     **$800 million and ~8-10 years**
  Treatment Strategies in Epilepsy
                                              EPILEPSY

      Genetics

                                    Structural /
Initiating      Critical            Functional     Seizures
  Event        modulators            changes

         Age




             Disease Modification                  Symptomatic
                   (future)                         treatment
                                                     (current)
  The Hope

Advances made in recent years at
the genetic and molecular level,
coupled with new developments in
imaging techniques, will clearly play
a critical role in our ability to
ultimately develop a “CURE” for
epilepsy.
Patient history: Part 2
He has tried and failed all the available
antiepileptic drugs. His MRI is normal.
His EEG shows epileptiform
abnormalities from the left temporal
region. He is admitted for video/EEG.
      Patient History: Part 3
 Video/EEG determined the seizures
  were coming from left temporal lobe but
  precise relationship to cortical language
  areas could not be determined.
 Grid of electrodes implanted over
  fronto-temporal region for seizure
  localization & language/motor
  localization
Key language areas
Electrode grid for cortical recording and stimulation
Electrodes on cortex after craniotomy
Results of stimulation mapping
   Our Patient: Outcome

 No  postoperative seizures for 5
  years
 Medications reduced but not
  eliminated
 No postoperative language or
  motor disturbances other than
  some word-finding difficulties

								
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