1. health and fitness
2. disease
3. epilepsy

How to make simple things complex
-Update 2009
Financial disclosure - None
z OffOff-label disclosure - Most
z References - Apology
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How to Make Simple Things Complex
-Childhood Epilepsy Update 2009
Suresh Gurbani MD, PhD
Child Neurologist, LMOLMO-OCMSA
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Know your facts
Then you may twist them as you want
-Mark Twain
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Definitions of epileptic seizures
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Seizure is caused by a paroxysmal, excessive, hypersynchronous
electrical discharge of cortical neurons due to changes in the
electrical function of the brain.1,2
Seizure may be manifested clinically by an impairment or loss of
consciousness, abnormal motor activity, sensory disturbances,
behavioral and emotional abnormalities, or autonomic dysfunction.
dysfunction.1,2
Epilepsy affects almost 2.3 million people in the United States.3
-Third most common neurological disorder in the United States.
-Direct + Indirect cost is $ 25 billions/year.
1 Kandel ER, et al. Principles of Neural Science. 4th ed. 1991:910935.
2 Hauser AA, Hesdorffer D. Epilepsy: Frequency, Causes &
Consequences. Epilepsy Foundation of America; 1990.
3 Begley CE, et al. Epilepsia. 2000;41:342-351.
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The ILAE proposed definition of epilepsy: “a disorder of the brain
characterized by an enduring predisposition to generate epileptic
epileptic seizures
and by the neurobiological, cognitive, psychological, and social
consequences of this condition. A definition of epilepsy requires
requires the
occurrence of at least one epileptic seizure”
seizure”
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This definition represents a conceptual change, in that it defines epilepsy
not as recurrent epileptic seizures but as a condition where seizures
seizures reflect
the existence of an enduring epileptogenic disturbance with the potential to
generate further seizures.
seizures.
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This new definition recognizes the neurobiological, cognitive, psychological,
and social consequences of epileptic seizures,
seizures, which are important parts of
the diagnostic and therapeutic approaches to people with epilepsy.
epilepsy.
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Reactive seizures (febrile convulsions or alcoholic withdrawal seizures are
usually generalized) can be partial when prepre-existing localized cerebral
disturbances make one area of the brain more epileptogenic than others.
Definitions of epileptic seizures
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A fixed operational definition specifying number of seizures, risk of
recurrence, or duration of inter-seizure intervals, is impractical and
unworkable.
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Operational definition: 2 or more unprovoked seizures.
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Operational definition of epilepsy for certain epidemiologic studies, or for
specific research purposes could be different.
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For general purposes of clinical diagnosis and treatment, each patient
should be considered individually.
AgeAge-Specific Incidence of Seizures in Rochester,
MN (1935(1935-1984)
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New cases of epilepsy Approximately 30% are among
those >65 years of age
Medical conditions affecting elderly
increase risk for seizures and
epilepsy
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Incidence per 100,000
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Definitions of epileptic seizures
GeneralizedGeneralized-onset seizures
PartialPartial-onset seizures
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80
60
40
20
0
0
20
40
Age (y)
60
80
- Hauser WA, et al. Epilepsia.
Epilepsia. 1993;34:4531993;34:453-468.
.
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Classification of Seizures
Classification of Seizures
International Classification of Epileptic Seizures 19811981- ILAE
Etiological Classification – Shinnar
I Partial Seizures:
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Acute symptomatic
Remote symptomatic
Cryptogenic
Idiopathic
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A -Simple partial (with motor, sensory, autonomic, or psychic signs).
signs).
B 1 & B2 - Complex partial
C - Partial with secondary generalization.
II Generalized Seizures:
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Absence (petit mal)
Atonic
Clonic
Myoclonic
Tonic
TonicTonic-clonic (grand mal)
III Unclassified Seizures:
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Classification of Seizures
Classification of Seizures
Proposed ILAE diagnostic scheme for people with epileptic
seizures and with epilepsyepilepsy- Engel 2001
Semiologic Classification of Seizures 1998 - Luders
1 Aura
2 Autonomic Seizures
3 Dialeptic Seizures
4 Motor Seizures
Simple: Myoclonic,Tonic,Epileptic spasm,Clonic,TonicClonic,Versive
Complex: Hypermotor,
Hypermotor, Automotor,
Automotor, Gelastic
5 Special Seizures
Atonic,Astatic,Hypomotor,Akinetic,Negative myoclonic,Aphasic
6 Paroxysmal Event
Organic, Psychogenic
Axis I : Ictal Phenomenology
Axis II : Seizure Type
Axis III : Syndrome
Axis IV : Etiology
Axis V : Impairment WHO ICIDH -2
Proposed ILAE diagnostic scheme for people with epileptic
seizures and with epilepsyepilepsy- Engel 2001
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This diagnostic scheme is divided into 5 parts, or axes, organized
organized to facilitate a logical
clinical approach to the development of hypotheses necessary to determine the
diagnostic studies and therapeutic strategies to be undertaken in
in individual patients.
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Axis 1:Ictal phenomenology – from the Glossary of Descriptive Ictal Terminology, can
be used to describe ictal events with any degree of detail needed.
needed.
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Axis 2:Seizure type – from the List of Epileptic Seizures. Localization within the brain
brain
and precipitating stimuli for reflex seizures
seizures should be specified when appropriate.
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Axis 3:Syndrome – from the List of Epilepsy Syndromes, with the understanding that
that
a syndromic diagnosis may not always be possible.
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Axis 4:Etiology – from a Classification of Diseases Frequently Associated with
Epileptic Seizures or Epilepsy Syndromes when possible, genetic defects, or specific
pathological substrates for symptomatic focal epilepsies.
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Axis 5:Impairment – this optional, but often useful, additional diagnostic parameter
parameter
can be derived from an impairment classification adapted from the
the WHO ICID.
Infantile spasms
Neonatal
Summary of key recommendations from the Commission on
Classification and Terminology – ICE, Budapest – June 30, 2009
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1. Mode of seizure onset and Classification of Seizures:
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Generalized seizures can be asymmetric. Generalized epileptic seizures originate at
some point within, and rapidly engage, bilaterally distributed networks. Such bilateral
networks can include cortical and subcortical structures, but do not necessarily
include the entire cortex. Although individual seizure onsets can appear localized, the
location and lateralization are not consistent from one seizure to another.
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Focal epileptic seizures originate within networks limited to one hemisphere, which
may be discretely localized or more widely distributed. For each seizure type, ictal
onset is consistent from one seizure to another with preferential propagation patterns,
which can involve the contralateral hemisphere. In some cases, however, there is
more than one epileptogenic network, and more than one seizure type, but each
individual seizure type has a consistent site of onset.
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Summary of key recommendations from the Commission on
Classification and Terminology – ICE, Budapest – June 30, 2009
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1. Mode of seizure onset and Classification of Seizures:
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Specific changes recommended to the 1981 classification of seizures are as follows:
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1) The category of unclassified epileptic seizures has been eliminated. Neonatal
seizures will no longer regarded as a separate entity.
2) The previous subclassification of absence seizures has been simplified and
altered. Myoclonic absence seizures and eyelid myoclonia are now recognized.
3) Epileptic spasms are now included and are classified under generalized seizures.
Note, however, that spasms may be associated with focal pathology and seizure
initiation, thus spasms could potentially exist in either category.
4) Under focal seizures the distinction between the different types (e.g. complex
partial and simple partial) is eliminated. It is important however to recognize that
impairment of awareness or other dyscognitive features, localization, and progression
of ictal events can be of primary importance in the evaluation of individual patients
and for specific purposes (e.g. randomized trials, surgery). Nothing in this
recommendation precludes describing focal seizures according to these features.
5)Myoclonic atonic (sometimes referred to as myoclonic astatic) seizures are now
recognized.
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Summary of key recommendations from the Commission on
Classification and Terminology – ICE, Budapest – June 30, 2009
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1. Mode of seizure onset and Classification of Seizures:
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Recommended classification of seizures
GENERALIZED SEIZURES
-Tonic clonic (in any combination)
-Absence 1.Typical
2. Atypical
3. Absence with special features
Myoclonic absence
Eyelid myoclonia
-Myoclonic 1. Myoclonic
2. Myoclonic atonic
3. Myoclonic tonic
-Clonic
-Tonic
-Atonic
-Epileptic spasms
FOCAL SEIZURES
-These can be further described as a function of seizure severity, putative site of origin, elemental
sequence of events, or other features.
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-Syndromes themselves will no longer be classified as being focal (or localization-related or
partial) versus generalized.
Classification of Seizures
Summary of key recommendations from the Commission on
Classification and Terminology – ICE, Budapest – June 30, 2009
Proposed ILAE diagnostic scheme for people with epileptic
seizures and with epilepsyepilepsy- Engel 2001
COMMISSION REPORT
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Axis I : Ictal Phenomenology
Axis II : Seizure Type
Axis III : Syndrome
Axis IV : Etiology
Axis V : Impairment WHO ICIDH -2
For Correspondence:
Anne T. Berg, Ph.D.
Department of Biology
Northern Illinois University
DeKalb, IL 60115 , USA
Phone: 815-753-1644
E-mail is [email protected]
Epilepsy Syndromes
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CSWS (Epilepsy with continuous spikespike-wave during
slowslow-wave sleep)
Doose syndrome
Dravet syndrome
Gastaut syndrome
LandauLandau-Kleffner syndrome
LennoxLennox-Gastaut syndrome
Panayiotopoulos syndrome
Rasmussen’
Rasmussen’s syndrome
West syndrome
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Classification of Epilepsy Syndromes
Idiopathic (Primary/Genetic)
z Being neonatal convulsions
z Benign childhood epilepsy with centrotemporal spikes
z Absence epilepsy (pyknoepilepsy
(pyknoepilepsy))
z Juvenile myoclonic epilepsy.
Symptomatic (Secondary)
z LennoxLennox-Gastaut syndrome
z Mesial Temporal Lobe Epilepsy Syndrome
Epileptic Syndromes in Infancy, Childhood and
Adolescence – 4 th Edition - 2005
Epileptic syndromes in neonates
By J Roger, M Bureau, Ch Dravet. P Genton,
Genton, Ca Tassinari,
Tassinari, P Wolf
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Epileptic syndromes in neonates
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Epileptic syndromes in infancy and early childhood
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Epileptic syndromes in childhood
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Epileptic syndromes in older children and adolescents
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Genetically defined epileptic syndromes and specific
etiologies
Epileptic syndromes in neonates
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BNSBNS-Benign familial neonatal seizures (BFNS)
-Incidence: 15/100,000 live births
-GeneticsGenetics- EBN1EBN1-20q13.320q13.3-KCMQ2, EBN2EBN2-8q248q24-KCNQ3
-A diagnosis by exclusion of anoxicanoxic-ischemic ,metabolic or infectious
causes, reinforced by the familial history of neonatal seizures.
seizures.
-S/S: full term infant with good Apgar scores who develops tonic
seizures with apnea on day 2 or 3 of life with multiple seizures in a
day but normal interictal neurological examination.
-interictal EEG may be normal, discontinuous with focal or multifocal
abnormalities. Ictal EEG may show seizures starting with
generalized flattening of the background activity followed by
localized or generalized spikes or slow waves.
--seizures
--seizures respond well to phenobarbital which may be discontinued
after a few months.
Benign familial neonatal seizures (BFNS)
Benign idiopathic neonatal seizures (BINS)
Symptomatic neonatal seizures
Severe neonatal epilepsies with suppressionsuppression-burst pattern
Epileptic syndromes in neonates
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Benign familial neonatal seizures (BFNS)
Benign idiopathic neonatal seizures (BINS)
Symptomatic neonatal seizures
Severe neonatal epilepsies with suppressionsuppression-burst pattern
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Epileptic syndromes in neonates
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BNSBNS-Benign idiopathic neonatal seizures (BFNS)
- fifth day fits in French fraternity
-mostly partial and or apneic,
apneic, clonic but never tonic seizures starting
between day 1 and day 7 of life.
- interictal EEG may be normal, discontinuous with focal or multifocal
abnormalities.
-Ictal EEG shows rhythmic slow waves or spikes. They can be strictly
strictly
unilateral or immediately generalized, or first localized and then
then generalized.
- treatment options include phenobarbital, clonazepam,
clonazepam, diazepam
Epileptic syndromes in neonates
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Epileptic syndromes in neonates
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Severe neonatal epilepsies with suppressionsuppression-burst pattern
-Early infantile epileptic encephalopathy with burstburst-suppression (Ohtahara
syndrome/EIEE)
-rarest of the 3 age dependent epileptic encephalopathies
(Ohtahara syndrome, West syndrome and LennoxLennox-Gastaut syndrome)
-usual onset at 1 to 3 months of age, chronic spasms occur in clusters
clusters
or singly, both in the awake state and during sleep
-hemihemi-convulsions, or erratic focal seizures can occur
-no myoclonus
-burstburst-suppression pattern on EEG with 22-6 second long high voltage
slow wave bursts intermingled with spikes followed by suppression
suppression
phase lasting for 33-5 seconds with unchanging pattern in both waking
and sleeping records
-majority have brain structural anomaly or damage
-majority die in infancy or develop West syndrome
Epileptic syndromes in neonates
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Epileptic syndromes in infancy and early childhood
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Febrile seizures
Idiopathic and/or benign localizationlocalization-related epilepsies in infants and young
children
NonNon-idiopathic benign localizationlocalization-related epilepsies in infants and young
children
Infantile spasms and West syndrome
Benign myoclonic epilepsy in infancy
Severe myoclonic epilepsy in infancy (Dravet syndrome)
Myoclonic astatic epilepsy (Doose syndrome)
The LennoxLennox-Gastaut syndrome
Malignant migrating epilepsy in infancy
Myoclonic status in nonnon-progressive encephalopathies
Benign familial neonatal seizures (BFNS)
Benign idiopathic neonatal seizures (BINS)
Symptomatic neonatal seizures
Severe neonatal epilepsies with suppressionsuppression-burst pattern (EIEE and EME)
Severe neonatal epilepsies with suppressionsuppression-burst pattern
-Early (neonatal) myoclonic encephalopathy (EME or NME)
-usually starts in the neonatal period
-partial or fragmentary erratic myoclonus involving face or limbs with a
migratory pattern, partial motor seizures, massive myoclonus and
and often
delayed occurrence of repetitive tonic spasms
-burst lasting for 11-5 seconds followed by almost complete suppression
lasting 33-10 seconds is a characteristic pattern of EEG which is enhanced
during sleep
- antianti-epileptic agents, corticosteroids and ACTH not effective
-nonketotic hyperglycinemia is common co morbidity
Epileptic syndromes in infancy and early childhood
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Febrile seizures
Idiopathic and/or benign localizationlocalization-related epilepsies in infants and young
children
NonNon-idiopathic benign localizationlocalization-related epilepsies in infants and young
children
Infantile spasms and West syndrome
Benign myoclonic epilepsy in infancy
Severe myoclonic epilepsy in infancy (Dravet syndrome)
Myoclonic astatic epilepsy (Doose syndrome)
The LennoxLennox-Gastaut syndrome
Malignant migrating epilepsy in infancy
Myoclonic status in nonnon-progressive encephalopathies
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Febrile Seizures
Epileptic syndromes in infancy and early childhood
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Febrile seizures : An event in infancy or early childhood ,
usually occurring between 3 months and 5 years of age,
associated with fever but without evidence of intracranial
infection or defined cause.
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Complex febrile seizures : Febrile seizures lasting more
than 15 minutes, multiple within 24 hours, or focal.
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Seizures with fever : Seizure with fever in children who have
suffered a previous nonnon-febrile seizure.
Factors influencing predictions in febrile seizures
F/H/O febrile seizures in a first degree elective
Developmental delay or neurologic problems
Complex febrile seizure( focal, prolonged,
multiple)
Age of onset < 18 months
Level of temperature at first seizure
(low temperature)
Duration of illness before seizure
(short duration)
Attendance at daycare
first febrile seizure
+
+
+
recurrence after a
first febrile seizure
-life time risk of seizure of any kind - 8%, 44-5 % is due to febrile seizures
-partial seizure seen in 8%
-prolonged seizure(> 20 minutes) seen in 5%, higher coco-relation with
MTS (with MTS epilepsy p/h/o febrile seizures 30%)
-risk of a recurrent febrile seizure after a first one is 3030-40%
-risk of subsequent epilepsy is only 22-5%
-in most longlong-term outcome for school performance, behavior and later use of
healthcare resources is same as normal population
-fanatical use of antipyretics does not reduce the rate of recurrent
recurrent febrile seizures
-vaccine induced febrile seizures do not affect the overall outcome
outcome
-incidence of DPT related febrile seizures has dropped by 80% after
after introduction of DTaP.
DTaP.
-Children vaccinated with DTP vaccine are at most risk for seizures
seizures on the day of the
vaccination.
-FeverFever-related seizures tended to occur 8 to 14 days after getting the MMR vaccine.
-MMR + V > MMR causes febrile seizures
-Human herpes virus 6 ( HHV 6) causes direct viral invasion of brain
brain causing initial febrile
seizure and its reactivation during subsequent febrile illness leads to recurrent febrile
seizures (neurotropic
(neurotropic virus)
Epilepsy after a first febrile
seizure
+
+
+
+
+
+
+ (15%)
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American Academy of Pediatrics Practice Parameter:
LongLong-term Treatment of the Child with Simple Febrile Seizures
The risk of recurrent simple febrile seizures:
-Children < 12 months - 50% recurrent febrile seizures
-Children > 12 months - 30% recurrent febrile seizure
-of those that do have a second febrile seizure, 50% have a chance
chance of having at least 1 additional
recurrence
PEDIATRICS Vol. 103 No. 6 June 1999, pp. 13071307-1309
Risk of CPS at 25 yrs
Presence of number of predictive factors versus risk of seizure recurrence at 2 years after first febrile seizure.
0 = 14%
1 = 21%
2 = 32%
3 = 62%
4 = 76%
- Berg AT et al, a prospective study of recurrent febrile seizures. N Eng J Med 1992, 327:1122327:1122-1127.
American Academy of Pediatrics Practice Parameter:
LongLong-term Treatment of the Child with Simple Febrile Seizures
- Phenobarbital and Valproic Acid are effective in preventing the recurrence of simple
febrile seizures.
- Phenobarbital reduced the rate of subsequent febrile seizures from
from 25 % per year to
5 % per year.
- Valproic Acid reduced the rate of subsequent febrile seizures from 35 % per year to
4 % per year.
- Carbamazepine and Phenytoin are not effective in preventing the recurrence of
of
simple febrile seizures.
- Antipyretic agents, in the absence of anticonvulsants, are not effective in preventing
recurrent febrile seizures.
- A 44% reduction in the risk of febrile seizures per personperson-year was seen with
intermittent use of diazepam.
-but a seizure could occur before a fever is noticed.
-sedation associated with this therapy could mask evolving signs of a central
nervous system infection.
-acute recurrent seizures
- No study has demonstrated that treatment for simple febrile seizures
seizures can prevent the
later development of epilepsy.
Febrile seizures – Points to ponder
-most common convulsive event in humans
- simple febrile seizures - 2%
- focal febrile seizures - 8%
- > 30 min seizures
- 20%
- multiple factors
- 50% (focal, prolonged, multiple)
American Academy of Pediatrics Practice Parameter:
LongLong-term Treatment of the Child with Simple Febrile Seizures
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Based on the risks and benefits of the effective therapies, neither
neither continuous nor
intermittent anticonvulsant therapy is recommended for children with 1 or more
simple febrile seizures.
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The American Academy of Pediatrics recognizes that recurrent episodes
episodes of febrile
seizures can create anxiety in some parents and their children, and, as such,
appropriate education and emotional support should be provided.
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PEDIATRICS Vol. 103 No. 6 June 1999, pp. 13071307-1309
PEDIATRICS Vol. 103 No. 6 June 1999, pp. 13071307-1309
8
Febrile Seizures
Molecular Genetics of Idiopathic Epilepsies
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Epilepsy Syndrome
Linkage
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Epilepsies with complex inheritance
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Idiopathic generalized epilepsy, unspecified
Juvenile myoclonic epilepsy
Persisting absence with later myoclonic epilepsy
Persisting absence with tonictonic-clonic seizures
Generalized epilepsy with febrile seizures plus
Febrile seizures
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8q/3p
6p/15q
1p
8q
2q/19q
8q/19p
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Baram et al
In rat pup (10 days old= 11-2 yr child)
Hyperthermia causes transient hippocampal
CA1 injury, but no permanent cell loss at 3
months.
Dube et al
Prolonged seizure in animals can cause
permanent lowering of seizure threshold
Scott et al
Prolonged febrile seizure in very young
children causes MRI changes after 2 days
which resolve in 44-8 months
Febrile Seizures
Serial MRI after experimental febrile seizures: altered T2 signal
signal without neuronal death.
Ann Neurol.
Neurol. 2004; 56(5):70956(5):709-14 (ISSN: 03640364-5134)
Dubé
Dubé C; Yu H; Nalcioglu O; Baram TZ
Department of Anatomy and Neurobiology, University of California at Irvine, Irvine, CA 92697926974475, USA.
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Febrile Seizures
-
J. Takanashi et al. Diffusion MRI abnormalities after prolonged febrile
seizures with encephalopathy. Neurology. 2006; 66(9): 13041304-09.
Seventeen patients ( 10 months to 4 years age)
Prolonged febrile seizure (more than 1 hour in 12 patients) as initial
initial
symptom
Clusters of complex partial seizures were seen after 44-6 days in 16
patients
MRI within 2 days showed no abnormality
Subcortical white matter lesions were observed between 3 and 9 days
days
in all 17 patients which disappeared between 9 and 25 days
experimental prolonged febrile seizures in immature rats
abnormal MRI signal in "temporal lobe" structures at 24 hours in
in 75% , and at 8 days in 87.5%
altered T2 values in dorsal hippocampus (75%), the piriform cortex
cortex (87.5%), and the amygdala
(25%)
no evidence of neuronal injury or death in these regions.
synaptic reorganization of granule cells, and transient and longlong-term alterations in the expression
of specific genes.
changes denote pathological cellular processes that promote epileptogenesis
persistently modified hh-channels after complex febrile seizures convert the seizureseizure-induced
enhancement of inhibition to hyperexcitability
GEFS + Syndrome
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The term "generalized epilepsy with febrile seizures
seizures plus" (GEFS+) was first
used by Scheffer and Berkovic to describe "a genetic disorder with
heterogeneous clinical phenotypes" (Scheffer and Berkovic 1997).
1997).
large AngloAnglo-Australian extended family
febrile seizures, often of unusual duration or severity
Simple febrile seizures constituted the most common manifestation.
manifestation.
However, these often tended to occur beyond the usual upper limit
limit of 4 to 5
years
afebrile generalized seizures of various types, mainly generalized tonictonicclonic ones, but in some cases, myoclonic attacks, myoclonicmyoclonic-astatic
epilepsy, or even episodes of status epilepticus occurred in some
some pedigree
members
transmitted as a autosomal dominant inheritance
the term "febrile seizures plus" (FS+) was proposed
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GEFS + Syndrome
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Generalized epilepsy with febrile seizures plus (GEFS1+) -19q (SCN1B)
(sodium channel B1 subunit)
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sodium channel 1 A subunit (GEFS2+)
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gaba receptor gamma 2 subunit (GEFS3+)
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-(SCN1A)
extended spectrum of GEFS+ ?
Epileptic syndromes in infancy and early childhood
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Febrile seizures
Idiopathic and/or benign localizationlocalization-related epilepsies in infants and young
children
NonNon-idiopathic benign localizationlocalization-related epilepsies in infants and young
children
Infantile spasms and West syndrome
Benign myoclonic epilepsy in infancy
Severe myoclonic epilepsy in infancy (Dravet syndrome)
Myoclonic astatic epilepsy (Doose syndrome)
The LennoxLennox-Gastaut syndrome
Malignant migrating epilepsy in infancy
Myoclonic status in nonnon-progressive encephalopathies
Severe myoclonic epilepsy in infancy (Dravet syndrome)
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First described by Dravet in 1978, 445 cases published by 2002 per
per review by Dravet.
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In 1989, the revised classification of the ILAE "epilepsies and syndromes
undetermined as to whether they are focal or generalized," as the
the syndrome shows
both generalized and localized seizure types and EEG paroxysms.
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In the last proposal by the ILAE,
ILAE, the Dravet syndrome is considered an “epileptic
encephalopathy,”
encephalopathy,” defined as a condition in which the epileptiform abnormalities
themselves are believed to contribute to the progressive disturbance
disturbance in cerebral
function.
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However, it is not proved that the cognitive decline observed in the first stage of the
disease is only the consequence of the epilepsy.
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Variable mutations in the sodiumsodium-channel gene SCN1A has been described in
patients of Dravet Syndrome both with and without myoclonia.
myoclonia.
Severe myoclonic epilepsy in infancy (Dravet syndrome)
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starts during the first year of life, development is normal prior
prior to the onset of seizures
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In many cases, the first seizure, focal or generalized, is associated
associated with fever with normal EEG.
These seizures in these cases often recur in 6 to 8 weeks, often changing sides
sides and may be
prolonged, leading to status epilepticus and are commonly treated
treated with phenobarbital.
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Dravet syndrome (interictal EEG abnormalities)
Other convulsive seizures, both febrile and afebrile, occur in the
the following months, manifesting as
(1) generalized clonic and tonictonic-clonic or unilateral hemiclonic,
hemiclonic, initially predominating in the head
and face and then evolving to variable bilateral localization and
and loss of consciousness which can
be characterized as “unstable”
unstable” seizures. EEG now shows polymorphic changes.
(2) Myoclonic seizures involving the body axis and proximal part of the limbs appear accompanied
by generalized spike and waves, and polyspike and waves in the EEG.
These myoclonic seizures are often associated with interictal segmental
segmental myoclonus.
(3) Absence seizures, which are atypical and of rather short duration,
duration, with more or less rhythmical
generalized spike waves in the EEG.
(4) complex partial seizures with atonic or autonomic features as well as automatism, with
occasional secondary generalized lesion.
(5) frequent convulsive (often febrile) status, or nonconvulsive (obtundation) status with
associated fragmentary or segmental erratic myoclonias. Convulsive seizures can initiate,
occurred during or terminate these statuses which can last for several hours or days. The EEG
shows a diffuse dysrhythmic slow waves, intermixed with focal and diffuse spikes.
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Dravet Syndrome- interictal myoclonias increased by movements
Epileptic syndromes in infancy and early childhood
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Febrile seizures
Idiopathic and/or benign localizationlocalization-related epilepsies in infants and young
children
NonNon-idiopathic benign localizationlocalization-related epilepsies in infants and young
children
Infantile spasms and West syndrome
Benign myoclonic epilepsy in infancy
Severe myoclonic epilepsy in infancy (Dravet syndrome)
Myoclonic astatic epilepsy (Doose syndrome)
The LennoxLennox-Gastaut syndrome
Malignant migrating epilepsy in infancy
Myoclonic status in nonnon-progressive encephalopathies
Myoclonic astatic epilepsy (Doose
(Doose syndrome)
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Prior to the onset seizures, 84% show normal development; the remainder
remainder show
moderate speech related psychomotor retardation.
Usually begin between 2 and 5 years of age, Boys (74%) are more often affected
than girls.
The first seizures are often prolonged, recurring frequently and daytime
generalized tonictonic-clonic type (50%), and rarely myoclonic, astatic,
astatic, myoclonicmyoclonicastatic,
astatic, or absence seizures. After a few weeks or months, soso-called daily "minor
motor seizures”
seizures” appear, consisting of myoclonic seizures,
seizures, absences, and drop
attacks which can last for 11-3 years.
The most common and characteristic seizure type, is the myoclonic-astatic seizure
with symmetrical myoclonic jerks immediately followed by loss of muscle tone
(postmyoclonic atonia). Lapse of consciousness accompanied by myoclonic and
astatic seizures occurs in 62% of the cases. The pure myoclonic, pure astatic, or
combined myoclonic-astatic seizures occur in 100% of the affected children.
Avoid CBZ (OXC), PHT, VGB – as it may worsen seizures. Rx- LTG + VPA, KD.
Predictors of unfavorable outcome
(1)
(2)
(3)
(4)
Epileptic syndromes in childhood
z
Epilepsy with centrocentro-temporal spikes and related syndromes
Panayiotopoulos syndrome and Gastaut type idopathic childhood occipital
epilepsy
Non idiopathic partial epilepsies of childhood
The HHE syndrome (sequential Hemiconvulsions,
Hemiconvulsions, Hemiplegia, Epilepsy)
Electrical status epilepticus during slow sleep (ESES or CSWS) including
including
acquired epileptic aphasia (Landau ==-Kleffner syndrome)
Childhood absence epilepsy and related syndromes
z
The syndrome of myoclonic absence
z
z
z
z
z
Frequent generalized tonic clonic,
clonic, tonic or clonic seizures during the early phase
Nocturnal generalized tonictonic-clonic seizures
Myoclonic, astatic,
astatic, myoclonicmyoclonic-astatic , or absence status epilepticus
Failure to suppress EEG abnormalities (4(4-7 Hz rhythms, and spike and wave discharges)
Benign Occipital Epilepsies Childhood (BOEC)
Syndrome Panayiotopoulos
Syndrome
Features
Age at onset
Seizures - frequency
4 (1(1-14) yrs
Gastaut
Syndrome
8 (3(3-16) yrs
infrequent
frequent
- duration
prolonged
brief
- timing
nocturnal
daytime
- first symptoms
autonomic s/s
visual s/s
- LOC
yes
rare
- post ictal headache
no
yes
Not needed/
mono AED
Required – 2-3
poly AED
In 22-3 yrs
In 33-5 yrs
Treatment
- remission
Epileptic syndromes in childhood
z
Epilepsy with centrocentro-temporal spikes and related syndromes
Panayiotopoulos syndrome and Gastaut type idopathic childhood occipital
epilepsy
Non idiopathic partial epilepsies of childhood
The HHE syndrome (sequential Hemiconvulsions,
Hemiconvulsions, Hemiplegia, Epilepsy)
Electrical status epilepticus during slow sleep (ESES or CSWS) including
including
acquired epileptic aphasia (Landau ==-Kleffner syndrome)
Childhood absence epilepsy and related syndromes
z
The syndrome of myoclonic absence
z
z
z
z
z
11
Criteria of CAE as defined by Panayiotopoulos
Epileptic syndromes in childhood
z
Childhood absence epilepsy and related syndromes
z
AbsencesAbsences-a lapse of consciousness, at times associated with minor
movements such as eye blinking or facial twitching.
- typical, or petit mal: brief (usually less than 10 seconds), with
with sudden
onset and offset, and associated with a characteristic 33-3.5 Hz spikespikeandand-wave EEG pattern.
- atypical: longer duration with some postictal confusion and less
less
regular EEG features.
- absence with myoclonus
- absence with eyelid myoclonus
z
inclusion criteria:
-frequent, brief typical absences
-age at onset between 4 to 10 years
-high amplitude 33-Hz spikespike-wave with single spikes, or no more than a
double spike per complex with an abrupt onset, gradual slowslow-down,
-duration of 4 to 20 seconds.
z
exclusion criteria:
-presence of prominent myoclonia,
myoclonia,
-stimulus sensitivity (photic sensitivity)
-arrhythmical and multispike complexes
-predominant brief discharges of <4 seconds duration
-frontal dominance or leadlead-in.
Childhood Absence Epilepsy: Evolution and Prognostic Factors.
Recent Developments in Absence Epilepsy
- Grosso S, Galimberti D, et al: Epilepsia; 2005; 46 (November): 17961796-1801
z
119 children with typical absence seizures were identified.
z
62 met the stricter criteria as defined by Panayiotopoulos for CAE and were
assigned to group 2; and were compared to 57 patients assigned to
to group 1
who did not meet these criteria.
z
Compared to group 1 patients, group 2 had higher rates of seizure
seizure control
(95% vs 77%) and terminal remission (82% vs 51%); fewer generalized
convulsive seizures (8% vs 30%); and shorter mean periods of treatment
(2.2 vs 3.8 years).
z
Hippocampal Volume in Childhood Complex Partial Seizures and Absence
Absence Epilepsy
z
Small number : CPSCPS- 24; CAECAE- 9; controlcontrol- 21
z
Quantitative MRI
z
Significantly smaller anterior hippocampal volumevolume- CPS<CAE when compared to control
- Caplan R et al – AES December 2005
-Fewer patients in group 2 required polytherapy (11% vs 47%) and had
relapses following discontinuation of therapy (0 vs 22%).
-Specific factors that predicted an unfavorable prognosis included
included
generalized tonictonic-clonic seizures during the period of absence occurrences,
myoclonic seizures, eyelid or perioral myoclonia,
myoclonia, and atypical EEG features.
Don’
Don’t Worry Be Happy !
Proposed Planned Physician Preparation Paradigm
Axis I : Ictal Phenomenology
Phenomenology
Axis II : Seizure Type
Axis III : Syndrome
Axis IV : Etiology
Axis V : WHO ICIDH -2 Impairment
12
Why Oh Why !
Why Oh Why !
z
z
Evolution of EpilepsyEpilepsy-
Evolution of EpilepsyEpilepsy-Same injury at different developmental ages may results in different
different
epilepsy syndromes
- “Double Hit Theory”
Theory” (Substrate + Insult)
-Different injury at same developmental age may cause same
epilepsy syndrome
- Substrate – genetic trait, hippocampal dysgenesis, or prior prolonged seizures
seizures
- Insul - initial precipitating injury (IPI) which include 1) birth trauma
trauma – HIE
-sequential development of receptors
GABAA -> NMDA -> AMPA -> KA
2)CNS infection
3)head trauma or
4) prolonged febrile seizure,
etc, etc, etc
-Epilepsia 46 (supplement 7), 2005
Neurogenesis and Migration
Neurogenesis and Migration
z
z
z
z
z
z
z
Transfection of genetically engineered retrovirus
Reporter gene green fluorescent protein (GFP) in
developing rat brain and time lapsed video microscopy
It is not true that glial and neuronal cells are separate
cell lines from separate lineages
In ventricular zone (VZ) of dorsal telencephalon, radial
glia neuronal stem cells generate excitatory pyramidal
neurons and radial glial cell through asymmetric cell
division (80%), which is determined by the intrinsic
determinant factor “Numb”
Numb”. Neuron cells migrates to
subventricular zone (SVZ) and acts as a progenitor cell
for symmetric division
In SVZ symmetric cell division produces two daughter
neurons
Rapid and symmetrical expansion of neuroepithelium
leads to expansion of the neural tube and formation of
the neural axis
Neurogenesis is the period of time during which neural
cell are generated, predominantly during embryonic age
Neurogenesis mainly occurs in 1st and 2nd trimester, is
mostly complete by birth; but a small population of
neural stem cell remain in the hippocampus and
subependymal region which continue to produce neuron
through adulthood
Neurogenesis and Migration
Why Oh Why !
z
z
z
z
GABAergic inhibitory neurons are generated in mesial ganglionic eminence in ventral
telencephalon, migrate tangentially to the cortex, 70 % dive down
down to VZ and then
migrate radially to the appropriate laminae
GABA signaling plays a tropic role in proliferation, migration and
and differentiation of
cells.
Radial glial cells have GABAA receptors during embryonic phase .
Evolution of EpilepsyEpilepsy-Same injury at different developmental ages may results in different
different
epilepsy syndromes
-Different injury at same developmental age may cause same epilepsy
epilepsy
syndrome
sequential development of receptors
GABAA -> NMDA -> AMPA -> KA
-Epileptic Syndrome = Developmental Age + Type/Severity of Insult
Insult +
Genetic Substrate
13
Same injury at different developmental ages may
results in different outcome
Birth Defects
Teratogen Exposure
z
PrePre-implant (Fertilization):
: Abortion/Normal
z
Implantation :
: Abortion/Normal
z
Organogenesis:
: Malformation
z
Fetal period :
z
Evolution of EpilepsyEpilepsy-
z
z
z
z
Histogenesis:
Functional maturation
: Growth retardation
: Functional loss
: Malformation
z Teratogen Exposure
AEDs are most common teratogens
VPA – Most potent teratogen
AEDs cause 2 –3 fold increase in birth defects, higher
with polypharmacy
If NO AEDs during pregnancy NO increase in birth
defects i.e. epilepsy does not cause increase in birth
defects
Why Oh Why !
-Same injury at different developmental ages may results in different
different epilepsy
syndromes
-Different injury at same developmental age may cause same epilepsy
epilepsy syndrome
sequential development of receptors
GABAA -> NMDA -> AMPA -> KA
-Epileptic Syndrome = Developmental Age + Type/Severity of Insult
Insult + Genetic
Substrate
-Epileptogenesis depends on – genetic risk, maturation program, early pathology,
prolonged seizures, treatment regimen success
Cure Epilepsy 2000 Conference
No Seizures
No Side Effects
No Compromise in QOL
Epilepsy Polytherapy
CURE ?
14
Epilepsy Polytherapy
Epilepsy Polytherapy:
AEDS
Ketogenic
Diet
AEDS
Brain
Stimulation
Resective
Surgery
Research
Identifiable mode of action
Optimal AED Therapy
z
z
z
z
z
z
Identifiable mode of action
Simple pharmacokinetics
Clearly defined therapeutic range
Minimal adverse effects, interactions, toxicity
Wide safety window
Easy to use through routes
z
z
GABA:
Receptor targets
GABA A -
pentameric structure
chloride channel
GABA, barbiturates, ethanol,
neurosteroids, benzodiazepines
GABA B – potassium ion efflux
GABA Receptors
Millennium Minute
z
z
Receptor targets
Glutamate: Inotropic – 4 AMPA (GluR1(GluR1- GluR4)
5 Kainate(GluR5 - GluR7
KA1 – KA2)
5 NMDA (NMDA R1
NMDA R2 A – D)
Metabotropic – m Glu 1-8 in 3 sub groups
Combination of subunits make a glutamate receptor
15
Glutamate Receptors
Optimal AED Therapy
z
z
z
z
z
z
Identifiable mode of action
Simple pharmacokinetics
Clearly defined therapeutic range
Minimal adverse effects, interactions, toxicity
Wide safety window
Easy to use through routes
Protein Binding of FirstFirst- and SecondSecond-Generation AEDs
Millennium Minute
z
z
z
z
z
z
Agent
First-Generation
Carbamazepine
Phenobarbital
Saturation Kinetics
Phenytoin
: Zerokinetics
Valproic Acid : Faster rise in level > 100ug/ml
Gabapentin : No transport > 100 mg/kg/dose
Zonisamide : RBC saturation @ 200200-400 mg/day
Agent
First-Generation
Carbamazepine
Phenobarbital
Phenytoin
Primidone
Valproate
>90%
Valproate
>90%
Gabapentin
Lamotrigine
Levetiracetam
Oxcarbazepine
(monohydroxy derivative)
Tiagabine
Topiramate
Viagabatrin
Zonisamide
Site of Clearance of FirstFirst- and SecondSecond-Generation
AEDs
Second-Generation
Felbamate
Gabapentin
50% hepatic, 50% renal
Gabapentin
Lamotrigine
Levetiracetam
Oxcarbazepine (monohydroxy derivative)
100% renal
85% hepatic
66% renal
45% hepatic,45% renal
Tiagabine
Topiramate
90% hepatic
30-50% hepatic, 50%-70% renal
Zonisamide
>90% hepatic
significant
0%
55%
minimal
40%
>90%
15%
0%
40%
Optimal AED Therapy
Clearance
>95% hepatic
75% hepatic
25%renal
>90% hepatic
50% hepatic
50% renal
>95% hepatic
significant
significant
Phenytoin
Second-Generation
Felbamate
Hepatic metabolism -P 450 vs nonnon-P450
Protein Binding
z
z
z
z
z
z
Identifiable mode of action
Simple pharmacokinetics
Clearly defined therapeutic range
Minimal adverse effects, interactions, toxicity
Wide safety window
Easy to use through routes
16
Optimal AED Therapy
Millennium Minute
z
z
z
z
z
z
z
z
z
z
Therapeutic Range
Felbamate
Gabapentin
Lamotrigine
Levetiracetam
Oxcarbazepine
Topiramate
Zonisamide
60 – 180 mcg/ml
12 – 25
10 – 20
20 – 40
12 – 35 ( as MHD)
8 – 25
20 - 30
z
z
z
z
z
Identifiable mode of action
Simple pharmacokinetics
Clearly defined therapeutic range
Minimal adverse effects, interactions, toxicity
Wide safety window
Easy to use through routes
Optimal Concentration Range and NOT
Therapeutic Range
Optimal AED Therapy
Summary of AED related Adverse Reactions:
z
General: Mood Modifying Medications
PB: cognitive interference, hyperactivity in children, sedation/clouding
sedation/clouding in
adults
PHT: lymphadenopathy,
lymphadenopathy, ataxia, cosmetic side effects
CBZ: skin rash/SJS, bonebone-marrow toxicity
OXC: Hyponatremia
ETX: Lupus
VPA: hepatic/pancreatic toxicity, obesity, alopecia, PCOS
FBM: hepato + bonebone-marrow toxicity, insomnia, GI disturbance, weight loss
GBP: weight gain, depression
LTG: SJS & TEN, psychosis
LTC: behavioral and mood issues
ZNS : renal stone, oligohydrosisoligohydrosis-hyperthermia, learning issues, weight loss
TPM: same as ZNS + anomia, speech dysfunction, glaucoma
z
Children do not read books – FBM , VPA, Benzodiazepines
z
z
z
z
z
z
z
z
z
z
z
z
Effects of FirstFirst-Generation AEDs Added to
SecondSecond-Generation AEDs
Gabapentin
Lamotrigine
Topiramate
Tiagabine
Levetiracetam
Zonisamide
z
z
z
z
z
z
Identifiable mode of action
Simple pharmacokinetics
Clearly defined therapeutic range
Minimal adverse effects, interactions, toxicity
Wide safety window
Easy to use through routes
Effects of SecondSecond-Generation AEDs Added to
FirstFirst-Generation AEDs
Oxcarbazepine
(MHD)*
Gabapentin
Carbamazepine
None
None
Phenobarbital
None
None
Phenytoin
None
None
Primidone
None
None
Valproate
None
None
None
None
None
Phenytoin
Carbamazepine
Valproate
Phenobarbital
Primidone
None
None
None
None
None
Lamotrigine
None
None
25%
None
None
Levetiracetam
None
None
None
None
None
Oxcarbazepine
May
None
None
Slight
None
Tiagabine
None
None
None
None
None
Topiramate
May
None
11%
None
None
Zonisamide
None
None
None
None
None
Slight
17
Optimal AED Therapy
z
z
z
z
z
z
Identifiable mode of action
Simple pharmacokinetics
Clearly defined therapeutic range
Minimal adverse effects, interactions, toxicity
Wide safety window
Easy to use through routes
Practice Parameter Update: Management issues for women with
epilepsy—
epilepsy—focus on pregnancy (an evidenceevidence-based review)
Practice Parameter Update: Management
issues for women with epilepsy—
epilepsy—focus on
pregnancy (an evidenceevidence-based review)
Report of the Quality Standards Subcommittee and the
Therapeutics and Technology Assessment Subcommittee of the
American Academy of Neurology and the American Epilepsy
Society
C. L. Harden, MD; P. B. Pennell,
Pennell, MD; K. J. Meador, MD, FAAN; W. A. Hauser, MD, FAAN; G.
S. Gronseth,
Gronseth, MD, FAAN; J. A. French, MD, FAAN; S. Wiebe,
Wiebe, MD; D. Thurman, MD, MPH; B.
S. Koppel, MD, FAAN; J. Hopp,
Hopp, MD; T. Y. Ting, MD; C. A. Hovinga,
Hovinga, PharmD;
PharmD; B. Gidal,
Gidal,
PharmD;
PharmD; P. W. Kaplan, MB, FRCP, FAAN; J. N. Robinson, MD; A. N. Wilner,
Wilner, MD, FACP,
FAAN; B. Vazquez, MD; L. Holmes, MD; A. Krumholz,
Krumholz, MD, FAAN; R. Finnell,
Finnell, PhD; P. O.
Shafer, RN, MN; D. Hirtz,
Hirtz, MD; C. Le Guen
z
z
z
z
It is estimated that three to five out of every 1,000 births are to
women with epilepsy (WWE).
If a woman is seizure free nine months before she becomes
pregnant, it's likely that she will not have any seizures during the
pregnancy.
Women with epilepsy are not at a substantially increased risk of
having a cesarean section, late pregnancy bleeding, or premature
contractions or premature labor and delivery.
Levels of seizure medications in the blood tend to drop during
pregnancy, so checking these levels and adjusting the medication
doses should help to keep the levels in the effective range and the
pregnant woman seizure free.
-released April 27, 2009
Practice Parameter Update: Management issues for women with
epilepsy—
epilepsy—focus on pregnancy (an evidenceevidence-based review)
z
z
z
Valproate - increased risk for fetal malformations and decreased
thinking skills in children, whether used by itself or with other
other
medications
consider avoiding the epilepsy drugs phenytoin and phenobarbital in order
to prevent the possibility of decreased thinking skills in children.
children.
Women with epilepsy be warned that smoking may increase substantially
substantially
the risk of premature contractions and premature labor and delivery
delivery during
pregnancy.
AEDs and Birth Defects
Teratogen Exposure
z
PrePre-implant (Fertilization):
: Abortion/Normal
z
Implantation :
: Abortion/Normal
z
Organogenesis:
z
Fetal period :
z
AEDs are most common teratogens
AEDs cause 22-3 fold increase in birth defects, higher with polypharmacy
If NO AEDs during pregnancy NO increase in birth defects i.e. epilepsy
epilepsy does not
cause increase in birth defects
All 4 old AEDs and LTG, TPM, ZNS have similar birth defect rates – 7%
VPA – Most potent teratogen!
z
z
z
z
: Malformation
Histogenesis:
Functional maturation
: Growth retardation
: Functional loss
: Malformation
18
Practice Parameter Update: Management issues for women with
epilepsy—
epilepsy—focus on pregnancy (an evidenceevidence-based review)
Practice Parameter Update: Management issues for women with epilepsy
epilepsy
-focus on pregnancy (an evidenceevidence-based review)
Recommendations:
z
z
Conclusion:
Conclusion:
The fact that PB, PRM, PHT, CBZ, LVT, VPA, GBP, LTG, OXC
and TPM cross the placenta may be factored into the clinical
decision regarding the necessity of AED treatment for a woman
with epilepsy (Level
(Level B for PB, PRM, PHT, CBZ, LVT, and VPA
and Level C for GBP, LTG, OXC, and TPM).
VPA, PB, PHT, and CBZ may be considered as not transferring
into breast milk to as great an extent as PRM, LVT, GBP, LTG,
and TPM (Level
(Level B when compared to PRM and LVT and Level
C when compared to GBP, LTG and TPM).
z
There is no evidence to determine if indirect exposure to
maternally ingested AEDs has symptomatic effects on the
newborns of WWE.
Recommendation:
Recommendation:
z
No recommendation is made (Level
(Level U).
U).
Optimal AED Therapy
z
z
z
z
z
z
Identifiable mode of action
Simple pharmacokinetics
Clearly defined therapeutic range
Minimal adverse effects, interactions, toxicity
Wide safety window
Easy to use through routes
Vimpat (lacosamide) Tablets and Injection approved on October 28, 2008
z
z
z
z
z
z
z
z
z
z
z
z
z
z
z
z
z
z
z
z
z
1912 - Phenobarbital
1935 - Mephobarbital
1938 - Phenytoin
1946 - Trimethadione
1947 - Mephenytoin
1949 - Paramethadione
1950 - Phenthenylate
1951 - Phenacemide
1952 - Metharbital
1952 - Benzchlorpropamide
1953 - Phensuximide
1954 - Primidone
1957 - Methsuximide
1957 - Ethotoin
1960 - Aminoglutethimide
1960 – Ethosuximide
1968 – Diazepam
1974 – Carbamazepine
1975 – Clonazepam
1978 - Valproate
1981 - Clorazepate
z
1992 - Felbamate
1993 - Gabapentin
1994 - Lamotrigine
1997 - Topiramate
1998 - Tiagabine
1999 - Levetiracetam
2000 - Oxcarbazepine
2000 - Zonisamide
2005 - Pregabalin
2009 - Rufinamide
2009 -Lacosamide
z
OrphanOrphan- Brivaracetam
z
P III - Vigabatrin
P III - Eslicarbazepine
P III - Brivaracetam
P III - Carisbamate
P III - Retigabine
P III - Clobazam
z
z
z
z
z
z
z
z
z
z
z
z
z
z
z
z
Lacosamide acts by enhancing slow inactivation of voltage gated sodium channels.
channels. Voltage gated
sodium channels are the membrane proteins responsible for generating
generating the neuronal action
potential,
potential, the all or none electrical event which causes neurons to release
release neurotransmitter.
During an action potential voltage gated sodium channels undergo fast inactivation,
inactivation, a process
which takes a few milliseconds. This inactivation prevents the channel
channel from opening, and helps
end the action potential.
z
Many typical antiepileptic drugs, like carbamazipine or lamotrigine,
lamotrigine, slow the recovery from
inactivation and hence reduce the ability of neurons to fire action
action potentials. As inactivation only
occurs in neurons firing action potentials, this means that drug that modulate fast inactivation
selectively reduce the firing in active cells.
z
Slow inactivation is a similar processes, except that it does not
not produce complete blockade of
voltage gated sodium channels, and it occurs over the course of hundreds of milliseconds or
more, and recovery from this state takes equally as long. Lacosamide
Lacosamide makes this inactivation
happen at less depolarized membrane potentials. This means that lacosamide only effects
neurons which are depolarized or active for long periods of time,
time, typical of neurons at the focus of
an epileptic focus.
z
Lacosamide does not affect AMPA,
AMPA, kainate,
kainate, NMDA,
NMDA, GABAA,
GABAA, GABAB or a variety of
dopaminergic, serotonergic, adrenergic, muscarinic or cannabinoid
cannabinoid receptors and does not block
potassium or calcium currents
19
Rufinamide for Generalized Seizures Associated With LennoxLennox-Gastaut
Syndrome.
Glauser T, Kluger G, et al: Neurology; 2008; 70 (May 20): 19501950-1958
z
On November 20, 2008 The U.S. Food and Drug Administration approved Banzel
(rufinamide), for use as an adjunctive (add-on) treatment for seizures associated with
Lennox-Gastaut syndrome.
z
The principal mechanism of action of rufinamide is considered to be the modulation of
the activity of sodium channels and, in particular, prolongation of the inactive state of
the channel.
z
Rufinamide was granted orphan drug designation by the FDA.
(A drug is eligible for orphan drug designation if it is intended to treat a disease or
condition that affects fewer than 200,000 people in the United States.)
z
Rufinamide, at a dose of 45 mg/kg per day, in a single four-month clinical trial
studying patients 4 to 30 years old, improved seizure control with a 41 percent
reduction of tonic plus atonic seizure frequency over placebo and 20 percent
reduction of total seizure frequency over placebo.
z
Common adverse reactions reported by patients using Rufinamide in clinical trials
included headache, dizziness, fatigue, drowsiness, gait disturbance, double-vision,
nausea and vomiting.
Status epilepticus in children
z
Status epilepticus (SE) occurs in an estimated 40 per 100,000 children per year.
z
Seventy percent of children younger than 1 year who are subsequently diagnosed with epilepsy
present with SE as the initial symptom.
z
In children with epilepsy, 20% have SE within 5 years of diagnosis.
z
Five percent of children with febrile seizures present with SE.
z
SE is defined as recurrent or continuous seizure activity lasting longer than 30 minutes in which
the patient does not regain baseline mental status.
z
Pathophysiology: Prolonged seizures are associated with cerebral hypoxia, hypoglycemia, and
hypercarbia and with concurrent and progressive lactic and respiratory acidosis. When cerebral
metabolic needs exceed available oxygen, glucose, and metabolic substrates (especially during
status epilepticus), neuronal destruction can occur and may be irreversible.
z
Hypoxia, hypercarbia, hyperthermia, tachycardia, hypertension, hyperglycemia, hyperkalemia,
and lactic acidosis result from massive sympathetic discharge.
Status epilepticus in children
Status epilepticus in children
Status epilepticus in children
z
Use intraosseous (IO) infusion if intravenous access is not immediately available in
the children < 6 years of age.
z
Phenobarbital (20-25 mg/kg intravenously/IO) is effective for febrile and neonatal status
epilepticus and may be infused after benzodiazepines if the child is likely to have these types of
seizures.
z
Infuse D5NS at 20 ml/kg over 1 hour.
z
Obtain serum anticonvulsant levels prior to administering additional long-acting anticonvulsants
such as phenytoin or fosphenytoin.
z
Consider treatment with 25% dextrose at 0.25 g/kg (max 25 gm/dose) – low sugar;
Naloxone 0.1 mg/kg (IV,IM,SC) – narcotics overdose; Antibiotics – meningitis etc.
z
Phenytoin (20 mg/kg intravenously/IO) or fosphenytoin (20 pe/kg intravenously/IO). Phenytoin and
fosphenytoin are effective for most idiopathic generalized seizures and for posttraumatic, focal, or
psychomotor status epilepticus. Use a slow rate of infusion (Phenytoin =<1 mg/kg/min or <50
mg/min, and fosphenytoin <3 mg/kg/min or <150 mg/min).
z
Lorazepam (0.05-0.1 mg/kg intravenously/IO slowly infused over 2-5 min) has rapid
onset and longer duration of action.
z
General anesthesia
z
For patients without parenteral access, use intramuscular midazolam (0.1-0.2 mg/kg).
z
Pentobarbital (5-10 mg/kg intravenously/IO loading dose followed by 0.5-3 mg/kg/h) or midazolam
(0.2 mg/kg intravenously/IO loading dose followed by 0.75-10 mcg/kg/min)
z
For patients without parenteral access, per rectal diazepam (0.3-0.5 mg/kg /age)
z
All children must be intubated and paralyzed, have continuous cardiorespiratory and EEG
monitoring, and be in a pediatric critical care setting.
20
DiffusionDiffusion-Weighted Magnetic Resonance Imaging in Patients With Partial
Status Epilepticus.
Status epilepticus in children
Di Bonaventura C, Bonini F, et al: Epilepsia;
Epilepsia; 2009;50 (January): 4545-52
z
Refractory status epilepticus (RSE) is defined as a seizure lasting longer than
60 minutes despite adequate treatment with intravenous benzodiazepines and other
antiepileptic drugs (AEDs). Refractory status epilepticus occurs in approximately 30%
of patients with SE. Approximately 9% of status epilepticus cases in children are
refractory
z
Patients who experience RSE have high morbidity and mortality. Neurological
morbidity has been reported in up to 57% of these children , and the mortality is as
high as 32%. Outcomes often correlate with underlying etiologies but are also
impacted by seizure duration.
z
Nonconvulsive SE and focal motor seizures at onset are risk factors for RSE.
z
Current recommendations for the management of RSE include the use of intravenous
midazolam, pentobarbital, propofol, thiopental, levetiracetam and valproic acid.
z
Lacosamide?
z
DiffusionDiffusion-weighted MRI imaging (DWI) can detect changes in the distribution
distribution of water
molecules in brain regions affected by various pathologies. Status
Status epilepticus can
cause vasogenic and cytoxic brain edema with shift in water molecules and signal
alterations on DWI.
z
Significant signal alterations in different brain regions on DWI correlated with location
of ictal activity. Acute phase signal abnormalities resolved in all patients with DWI and
FLAIR signals returning to normal in 9 to 30 days.
z
Prolonged overactivity of epileptic neurons increases local glucose and oxygen
requirements leading to regional hyperperfusion.
hyperperfusion. When this can no longer
compensate, anaerobic glycolysis and lactic acid accumulation occur, leading to
cytotoxic edema, decreased extracellular volume, and bloodblood-brain barrier breakdown
with vasogenic edema and water diffusion. This accounts for the changes on DWI.
DWI.
DWI is useful for showing areas of hemodynamic and metabolic involvement with
electrical SE.
LongLong-Term Risk of Epilepsy After Traumatic Brain Injury in Children
Formulation Changes of AEDs Associated With Increased Risks
and Young Adults: A PopulationPopulation-Based Cohort Study.
z
Design: Retrospective, populationpopulation-based, cohort review.
Participants: 1,605,216 people born in Denmark over a 2525-year period
(1977 to 2002).
Methods: FollowFollow-up data for a for a total of 19,527,337 personperson-yrs.
z
Relative to no brain injury, risk of epilepsy over time was 2 times
times higher
after a mild brain injury, 7 times higher after severe brain injury,
injury, and 2 times
higher after skull fracture (all statistically significant).
The relative risk of epilepsy after TBI was highest during the first
first 6 months
following the injury, but remained significantly higher for >10 years.
Risk for epilepsy after TBI increases with increasing age ( >15 yrs), female
gender, and a positive family history of epilepsy.
z
z
z
z
z
z
z
Unfortunately, we have no established prophylactic therapy at this
this time for
the prevention of epilepsy in TBI patients.
z
Christensen J, Pedersen MG, et al: Lancet; 2009; (February 23)
Epilepsy Polytherapy:
CaseCase-Control Analysis of Ambulance, Emergency Room, or Inpatient Hospital
Hospital Events
for Epilepsy and Antiepileptic Drug Formulation Changes
-Zachry WM III, Doan QD, et al: Epilepsia; 2008
Methods: Cases and controls were identified from a large geographically diverse
diverse
database that includes Medicare, Medicaid, and commercially insured
insured patients with
dependents (Ingenix
(Ingenix LabRx Database).
Results: There were 416 cases and 1,248 controls for matched analyses and 5,562
controls for nonnon-matched analyses.
-Zonisamide was the most commonly associated medication with cases
cases (42.4%). The
next 3 medications were gabapentin (15.2%), phenytoin sodium extendedextended-release
(13.6%), and clonazepam (18.2%).
-A majority of patients experiencing AA-rated formulation changes did so within 2
months of their index date.
Conclusions: Patients who utilized urgent services (Emergency department,
ambulance, or inpatient) for their epilepsy had 81% greater odds of having had an AArated AED switched within the last 6 months.
Reviewer's Comments
This study demonstrates patients switched from one AED formulation
formulation to another are
at increased risk of requiring emergency medical services. What concerns this
reviewer is that many more patients are on lamotrigine, levetiracetam,
levetiracetam, and valproic
acid than on zonisamide. –J. Layne Moore, MD, MPH).
-Oakstone Medical Publishing
History of Fasting and Ketogenic Diet in the Treatment of Epilepsy
Epilepsy
-Circa 30 ADAD-The Bible states that Jesus Christ recommended fasting associated
associated
with prayer for convulsing demon possession (Mark 9:149:14-29).
-1911 “La cure du Dr. Guelpa”
Guelpa” was defined as fasting followed by a restrictive and
vegetarian diet (Guelpa and Marie 1911).
1911).
Ketogenic Diet
- 1921 Wilder published his preliminary report on the ketogenic diet in the treatment
of seizures (Wilder 1921).
1921).
- 1971 Huttenlocher described the mediummedium-chain triglyceride diet (Huttenlocher et al
1971).
1971).
-1989 Schwartz shortshort-term metabolic effects and clinical efficacy of the “classical”
classical”
ketogenic diet and the mediummedium-chain triglyceride diets (Schwartz et al 1989a).
1989a).
- 1996 Freeman and colleagues extensively described the classic ketogenic diet
method (Freeman et al 1996).
1996).
- October 1994 Ketogenic diet on NBC Dateline & February 1997 A televised movie.
Unfortunately, the lay public was left with the impression that most children taking
anticonvulsant medications are plagued with adverse side effects and that the diet is
the only option leading to a “cure”
cure” of epilepsy.
21
Ketogenic Diet in the Treatment of Epilepsy
z
A study from the Mayo Clinic mentioned that patients with symptomatic
symptomatic
epilepsy might respond less well to the diet than patients with idiopathic
idiopathic
epilepsy (Keith 1963).
1963).
z
Livingston, summarizing the experience from Johns Hopkins University,
University,
mentions exactly the opposite opinion, stating that patients with
with idiopathic
epilepsy respond less well to the ketogenic diet, and the patients with
myoclonic and akinetic epilepsies (which are commonly due to symptomatic
epilepsy) have the best response to the diet (Livingston 1972).
1972).
z
Schwartz and colleagues showed that the seizure type may not be
important because, at least with shortshort-term followfollow-up, no particular seizure
type showed a significantly better response to the diet (Schwartz et al
1989a).
1989a).
z
These results were later confirmed by a prospective study of 150
patients by Freeman and colleagues (Freeman et al 1998b).
1998b).
Contraindications to Ketogenic Diet
-Fatty acid oxidation defects:
- A history of episodes of weakness or muscle cramps precipitated by fasting or prolonged
exercise is suggestive of a disturbance in the fat oxidation metabolism
metabolism (Haas and Marsden 1996).
1996).
-Other phenotypes include history of myopathy and Reye syndromesyndrome-like episodes (Haas and
Marsden 1996).
1996). The latter are characterized by encephalopathy, elevated liver transaminases,
transaminases,
and hyperammonemia.
hyperammonemia. Many of these patients will have family histories of unexplained
unexplained sudden
infant death syndrome (Bale and Bennett 1992; Haas and Marsden 1996)
-MiddleMiddle-chain acyl dehydrogenase deficiency is the most common form of betabeta-oxidation
enzymatic deficiency (Haas and Marsden 1996).
1996). In some specific enzymatic disturbances, such
as longlong-chain acyl dehydrogenase deficiency, a diet using middlemiddle-chain fatty acids may be
tolerated, because it bypasses the faulty system.
With the exception of glucose transportertransporter-1, pyruvate dehydrogenase complex, and
phosphofructokinase deficiencies ketogenic diet for other inborn errors of metabolism such as
organic acidurias,
acidurias, urea cycle defects, or even mitochondrial disease,
disease, should be avoided.
-Static encephalopathy and cerebral palsy tend to be used as a “waste basket”
basket” diagnosis. One
should always be suspicious of the accuracy of these 2 nosological entities
- Also attempted is a screening for the social situations that make
make the ketogenic diet an
impossibility, such as a completely unstable family structure.
NonNon-pharmacologic Treatments of Epilepsy
-
Ketogenic Diet:
- fast vs slow initiation
- MCT vs Cream diet
- KD vs LGID
- Modified Atkins diet
- response in pediatrics versus adults
The “Classic”
Classic” Hopkins Ketogenic Diet Protocol
• Initial fasting for 1 to 3 days until 4(+) ketonuria.
ketonuria.
• Initial feeding: - One third of total calculated caloric intake on the first day after
after 4(+)
ketonuria.
ketonuria.- Two thirds of total calculated caloric intake on the second day after 4(+)
ketonuria.
ketonuria.- Three thirds of total calculated caloric intake on the third day
day after 4(+)
ketonuria.
ketonuria.
• Total caloric intake (full diet) is 75% of the total daily allowance
allowance for age and weight.
• Total protein intake is 1 g/kg per day.•
day.• Initial ratio is 4 to 1 (4 g of fat for each g of
carbohydrate or protein).
• Carbohydrate or protein intake is one tenth of the total caloric
caloric intake).
• Add vitamins and calcium supplements.
• Supplement carnitine if serum levels are low.
The Ketogenic Diet in the Management of
AEDAED-Refractory Epilepsy
Nonfasting Mayo Clinic Ketogenic Diet Protocol
z
The diet is initiated as an outpatient regimen without fasting in
in a 1 to 1 ratio and increased
gradually to a 4 to 1 ratio over a period of 1 to 3 weeks (Williams et al 1997).
1997).
z
Buchhalter and colleagues achieved a 4 to 1 ratio in 9 days without any complications
complications
(Buchhalter et al 1996).
1996).
z
Huse and Wilder reported no problems with immediate initiation of a 3 to 1 diet (Wilder
1921;Huse 1994)
z
The disadvantages of this approach include slower onset of ketosis
ketosis and the lack of the initial
“boost”
boost” of seizure control seen with fasting. Some families are also reassured
reassured by the faster onset
of seizure control associated with fasting and prefer fasting, in
in spite of the initial inconvenience of
hospitalization, fingersticks,
fingersticks, and other problems.
z
At times, a faster onset of seizure control is medically desirable,
desirable, as in cases of infantile spasms.
z
z
The lack of the initial period of teaching during the hospitalization
hospitalization for fasting has to be substituted
by a lecture in the “outpatient setting.”
setting.”
z
z
Efficacy similar to that seen with the classical ketogenic diet (Williams et al 1997).
1997). These results
have been recently replicated with other nonnon-fasting protocols (Bergqvist et al 2005; Hood 2006)
z
z
z
z
z
z
‘First Do No Harm’
Harm’
Hypoglycemia
Hyperlipidemia
Hypercalciuria
Hyperuricemia
Protein deficiency
Diarrhea (MCT Oil) ; Constipation (Classic)
Rarely, renal calculi, impaired neutrophil function
22
Results from a KD Prospective Multicenter Study:
Johns Hopkins, Monteflore,
Monteflore, Harvard/Boston’
Harvard/Boston’s Children’
Children’s, University of
Texas, University of Kentucky, Dalhousie University
Vining EP et al. Arch Neurol(1998);55:1433Neurol(1998);55:1433-47
z
z
z
z
z
z
z
z
z
Number of patients:
51
Age range:
1-8 years
Seizure frequency:
230 per month
Follow3,6,and 12 month
Follow-up:
Outcome analysis:
Intent to treat
Seizure free at 1 year:
10% (5/51)
> 50% Seizure reduction:
40%
Continuing on diet:
47%
D/C diet due to AE: lethargy,infection,constipation,vomiting
dehydration/acidosis,behavioral changes
Neurotechnology
-Brain Stimulation
z
z
z
z
z
z
Epilepsy Polytherapy:
Repetitive Transcranial Magnetic Stimulation
(rTMS)
rTMS) -nonnon-invasive method to reduce cortical
excitability, there by reducing both the severity
and frequency of seizures in the patients with
refractory epilepsy
SubSub-acute Temporal Lobe Stimulation
Deep Brain Stimulation (DBS)
Intercept Epilepsy Control System (IES)
Responsive Neuro Stimulator (RNS)
Vagus Nerve Stimulation (VNS)
Surgery
Brain Stimulation
Deep Brain Stimulator (DBS)
z
DeepDeep-brain stimulation of the
anterior thalamus, evaluated in
the SANTE trial, showed
improved seizure control in
most patients (findings
presented by Dr. Robert Fisher
at the 2008 American Epilepsy
Society meeting in Seattle).
Brain Stimulation
Brain Stimulation
Intercept Epilepsy Control System (IES)
Responsive Neurostimulator System (RNS)
z
z
Consistent Electronic Signals
to stabilize brain activity.
The trial includes approximately
150 patients in a prospective,
randomized, doubledouble-blind study
at approximately 15 sites in the
U.S. and Canada. All patients
will be implanted and monitored
for 13 months following
implant, with longlong-term followfollowup until the device is approved
or the study is stopped.
z
An investigational
implantable responsive
neurostimulator system –
‘”NeuroPace
‘”NeuroPace RNS,”
RNS,” is being
evaluated in a multicenter,
multicenter,
andomized,
andomized, doubledouble-blinded
trial for the treatment of
medically refractory epilepsy
-(Sun et al 2008).
2008).
23
Brain Stimulation
Brain Stimulation
Vagus nerve stimulation (VNS)
Vagus nerve stimulation (VNS)
z
z
z
Vagus nerve stimulation is used as a safe
adjunctive therapy to intractable seizures.
Complex partial seizures with secondary
generalizations respond well to this therapy
with significant reduction in seizures as well
as improvement in alertness (Buoni et al
2004).
2004). Vagus nerve stimulation involves
repeated stimulation of the left vagus nerve
through implanted electrodes. Despite
studies in animals and man, which show
changes in brain electrophysiology,
metabolism, and neurochemistry, the mode
of action remains uncertain. Stimulation is
delivered via a programmable generator,
allowing variation in current, pulse,
frequency, and dutyduty-cycle. Complications of
this treatment can be divided into: adverse
events related to surgery, late complications,
and stimulationstimulation-induced effects. Adverse
surgical outcomes are acceptably low in
experienced hands (Tecoma and Iragui
2006).
2006).
z
VNS Summary :
z
First new mode of antianti-epilepsy therapy
OnOn-going and Abortive therapy
Seizure control @ 24 mth >12 mth > 6 mth
Less than 10% seizure free
Seizure Control - > 75% : 34%; >50% : 60%
z
z
z
z
Buoni S, Mariottini A, Pieri S, et al. Vagus nerve
stimulation for drugdrug-resistant epilepsy in children
and young adults. Brain Dev 2004;26:1582004;26:158-63.
Tecoma ES, Iragui VJ. Vagus nerve stimulation use
and effect in epilepsy: what have we learned?
Epilepsy Behav 2006;8:1272006;8:127-36.
In the Final Analysis:
z
z
z
z
The role of VNS In the foreseeable future :
VNS as an adjunct to a rationally chosen AEDs before
subjecting patients to intolerable side effects
VNS before more invasive procedure with limited
benefits such as callosotomy
VNS before invasive monitoring and resections in the
nonnon-lesional, extraextra-temporal, partial epilepsies
Caveat: Duty Cycle; Lead Fibrosis/Fracture at higher output current?
current?
Epilepsy Polytherapy:
When to do surgery:
z
z
Resective
Surgery
z
z
z
z
z
The potential for becoming seizure – free is the most important
factor that tilts the scale
The price is the risk associated with craniotomy and the potential
potential for
neurologic deficit from the resection
If the probability of freedom from seizures is < 50%, a trial with
with VNS
before undertaking craniotomies may be reasonable in such cases
Lesionectomy - AV malformation, DNET, MTS
Hemispherectomy - SturgeSturge-Weber Syndrome,
- Rasmussen Syndrome
NonNon-lesional resection
Corpus Callosotomy
24
Surgery for Epilepsy in Children With DNET (Dysembryoplastic
(Dysembryoplastic
Neuroepithelial Tumor:) Clinical Spectrum, Seizure Outcome,
Neuroradiology,
Neuroradiology, and Pathology.
z
DNET in children is commonly associated with refractory partial onset
seizures.
z
MRI typically reveals a well demarcated lesion that usually does not
enhance significantly following contrast administration.
z
Pathological classification usually WHO Grade 1.
z
Rare malignant transformation.
z
Methods: 29 consecutive patients who had DNET between 1994 and 2007.
z
70% localized to the temporal lobes, 30 % extratemporal.
extratemporal.
z
Outcome was complete seizure freedom or Engel Class IA in 27 (>90%)
(>90%)
and Engel Class IB in the remaining 2 patients. Recurrence of seizures
seizures
occurred in 8 patients with residual tumor, and a second surgery,
surgery, with
resection of the residual tumor resulted in seizureseizure-freedom in all 8.
Anterior Temporal Resection Outcome:
z
z
z
Complete seizure control in 78% with MTLE and 85%
with temporal lobe tumors, 1 year after ATMR in Yale
experience (Spencer DD, 1998)
Similar results from Mayo. Cleveland and UCLA
ContraContra-lateral upper quadrant visual field defect
-Bilginer B, Yalnizoglu D, et al: Childs Nerv Syst;
Syst; 2009;25 (April): 485485-491
ExtraExtra-temporal Neocortical Resections
z
z
z
z
In lesional cases, outcome depends on the
completeness of removal of lesion + mapped
epileptogenic region
NonNon-lesional cases generally require invasive monitoring
prior to surgery
SeizureSeizure-free rate for nonnon-lesional, extraextra-temporal cases
( overall UCLA 19861986-19901990- 44%;Engel – 1990)
Montreal Series:
Frontal lobectomy:
23%( 1975)
Parietal lobe resection : 45%(1992)
Occipital resections:
46%(1997)
Hemisherectomy for SturgeSturge-Weber Syndrome
z
z
z
z
Hemisherectomy Outcome at UCLA
z
z
z
z
z
Chugani et al(1993):
N = 23; 65% sz free; 78% had > 90% sz reduction
Peacock et al(1996):
N = 58; 88% had a sz reduction of > 90%
Asarnow et al(1997):
Developmental outcome at 2 years was better than
those in other series where patients received medical
treatment for symptomatic infantile spasms
Early onset seizures( < 1 years) usually associated with
significant hemiparesis and significant mental retardation
Later surgery outcome associated with IQ of 3030-60 range
Surgery performed < 1 year of age associated with IQ of
9090-99.
Hoffman et al. Child’
Child’s Brain(1979), 5:2335:233-48.
Callosotomy
z
z
z
z
z
Atonic and tonictonic-astatic seizures(‘
seizures(‘drop attacks’
attacks’) benefit
significantly from the procedure
Partial seizures deteriorate as transtrans-callosial fibers have
inhibitory effect
No improvement in neurocognitive development
following procedure
Procedure is not curative; rather it is palliative at the best
VNS may offer equal or greater benefits without
craniotomy or associated risks
25
Epilepsy Polytherapy
GammaGamma-knife Radiosurgery
z
z
z
A Multicenter,
Multicenter, Prospective Pilot Study of Gamma Knife Radiosurgery for Mesial
Temporal Lobe Epilepsy: Seizure Response, Adverse Events, and Verbal
Verbal Memory.
Barbaro NM, Quigg M, et al: Ann Neurol;
Neurol; 2009;65 (February): 167167-175.
Results: Both groups had significant reductions in seizures by 1 year after
after treatment.
At the 3636-month followfollow-up evaluation, 67% of subjects were seizureseizure-free for the prior
12 months (77% in the highhigh-dose group and 59% in the lowlow-dose group), prevalence
of verbal memory impairment was 15%; 12% of subjects had verbal memory
improvement. Subjects often experienced a transient increase in auras. This effect
receded as seizures came under better control. Higher RS dose resulted
resulted in increased
steroid prescribing, new headaches, and visual field defects.
z
Three of 30 subjects did not complete the 36 month study: 1 was lost to
followfollow-up, 1 required urgent temporal lobe surgery because of massive
brain edema, and another underwent temporal lobectomy at 24 months.
months.
z
Temporal lobectomy - most common surgery for intractable epilepsy, 11-year seizureseizurefree rate of 65% after temporal lobectomy. Adverse events can include
include verbal
memory deficits, mood disorders, psychosis (rarely) after this costly
costly open surgery.
Ketogenic
Diet
AEDS
Brain
Stimulation
Mode of Action of Current AEDs
5 molecular targets : Na+, Ca++, GABA, GABAGABA-T,
GABA uptake, Glutamate
z
z
z
Novel mechanisms under investigation
z
z
z
z
Facilitation of K+ channel opening
Inhibition of K+ channel inactivation
Blockade of mGlu7 receptor
Modulation of forebrain nicotinic receptor
Research
Genomics!
Millennium Minute
z
Resective
Surgery
z
Genome Project - 3 billion genes
initiation, cessation, protection, vaccine gene
PharmacoPharmaco-genomics: Genetics of Human
response to study efficacy/safety of drugs
genome microchip
Syndrome/Seizure Type specific AEDs
1990s - Decade of the Brain
z
z
z
z
z
z Epilepsy Genes
- sodium channel a1 subunit(GEFS2+)
- calcium channel b4 subunit (sz
(sz & ataxia)
- nicotinic cholinergic receptor b
subunit(ADNFLE)
neuroserpin (progressive myoclonic epilepsy)
-gaba receptor gamma 2 subunit(GEFS3+)
1990s - Decade of the Brain
z
z
z
z
z
z
z
z Epilepsy Genes
- benign familial neonatal convulsions:20q, 8q
- benign familial infantile convulsions:19q, 16
- nocturnal frontal lobe epilepsy AD:20q
- juvenile myoclonic epilepsy - 6p, 15q
- progressive myclonic epilepsy - 21q 22.3
- persisting absence & myoclonic seizures:1p
- febrile seizures:8q, 19p
26
UCLAUCLA-Kaiser Permanente Research
z
z
z
z
z
z
z
Publications
Daley, M.D., Siddarth,
Siddarth, P., Levitt,
Levitt, j., Gurbani, S., Shields, W.D., Sankar,
Sankar, R., Arthur
Toga, A., and Caplan,
Caplan, R. Amygdala volume and psychopathology in childhood
complex prtial seizures. Epilepsy and Behavior 2008;13:2122008;13:212-7
Daley, M., Levitt,
Levitt, J., Siddarth,
Siddarth, P., Mormino,
Mormino, E., Hojatkashani,
Hojatkashani, C., Gurbani, S.,
Shields, W.D., Sankar,
Sankar, R., Toga, A., and Caplan,
Caplan, R. Frontal and temporal volumes in
children with complex partial seizures. Epilepsy and Behavior 2007;10:470
2007;10:470--6.
Caplan,
Caplan, R., Levitt,
Levitt, J., Siddarth,
Siddarth, P., Taylor, J., Daley, M., Wum K.W., Gurbani, S.,
Shields,SW.D.
Shields,SW.D. and Sankar R. Thought disorder and frontofronto-temporal volumes in
pediatric epilepsy. Epilepsy and Behavior 2008;13;5932008;13;593-9.
Caplan,
Caplan, R.,
R., Siddarth,
Siddarth, P., Stahl, L., Lanphier,
Lanphier, E., Vona,
Vona, P., Gurbani, S., Koh,
Koh, S.,
Sankar,
Sankar, R. Donald, W.D. Childhood absence epilepsy: Behavioral, cognitive, and
linguistic comorbidities.
comorbidities. Epilepsia 2008;49:18382008;49:1838-46.
Caplan,
Caplan, R., Siddarth,
Siddarth, P., Vona P, Stahl, L., Bailey, C., Gurbani, S., Shields, W.D.
Language in pediatric epilepsy Epilesia (in press)
Caplan,
Caplan, R., Siddarth,
Siddarth, P., Vona P, Wu, KN, Gurbani, S., Sankar.
Sankar. Frontal and temporal
volumes in childhood absence epilepsy Epilepsia (in press).
UCLAUCLA-Kaiser Permanente Research
z
z
z
z
z
z
z
z
z
Neurotechnology
Imaging the Developing Brain
UCLAUCLA-Kaiser Permanente Research
z
z
z
z
z
z
z
Abstracts
Tosun,
Tosun, D., Siddarth,
Siddarth, P. Toga, A., Caplan,
Caplan, R., and Hermann, B. The
neurodevelopmental relationship between intelligence and cortical morphometry is
altered in children with complex partial seizures. Annual Meeting
Meeting of American
Epilepsy Society, Seattle, December 2008 .
Caplan,
Caplan, R., Siddarth,
Siddarth, P., Vona P, Stahl, L., Bailey, C., Gurbani, S., Shields, W.D.
Language in pediatric epilepsy. Annual Meeting of American Epilepsy
Epilepsy Society,
Seattle, December 2008.
Caplan,
Caplan, R., Siddarth,
Siddarth, P., Vona P, Wu, KN, Gurbani, S., Sankar.
Sankar. Frontal and temporal
volumes in childhood absence epilepsy. Annual Meeting of American
American Epilepsy
Society, Seattle, December 2008.
Caplan,
Caplan, R., Siddarth,
Siddarth, P., Bailey, C., Gurbani, S., Koh,
Koh, S. Language in pediatric
epilepsy. Annual Meeting of American Academy of Child and Adolescent
Adolescent Psychiatry,
Chicago October 2008.
Siddarth,
Siddarth, P, Gurbani, S., Lanphier,
Lanphier, E., Bailey, C., Stahl, L., Vona,
Vona, P. and Caplan,
Caplan, R.
Language deficits in pediatric epilepsy. Annual Meeting of International
International League
Against Epilepsy, Singapore, July 2007.
Siddarth,
Siddarth, P., Gurbani, S., Vona,
Vona, P., Koh,
Koh, S. and Caplan,
Caplan, R. Vulnerability for linguistic
deficits in pediatric epilepsy. Annual Meeting of American Epilepsy
Epilepsy Society,
Philadelphia, 2007
Imaging the Developing Brain
Publications (continued)
Tosun,
Tosun, D., Caplan,
Caplan, R., Siddarth,
Siddarth, P., Gurbani, S., Toga, A, and Hermann, B. The
neurodevelopmental relationship between intelligence and cortical morphometry is
altered in children with complex partial seizures (under review).
review).
Caplan,
Caplan, R., Siddarth,
Siddarth, P., Levitt,
Levitt, J.G., Taylor, J., Daley, M., Wu, K.W., Gurbani, S.,
Sankar,
Sankar, R. Donald, W.D. Language and frontofronto-temporal volumes in pediatric
epilepsy (in preparation).
Jones, J.E., Siddarth,
Siddarth, P., Gurbani S., Shields, W. D., Caplan,
Caplan, R. FollowFollow-up study of
comorbidities in pediatric epilepsy (in preparation).
Jones, J.E., Siddarth,
Siddarth, P., Gurbani S., Shields, W. D., Caplan,
Caplan, R. Suicidal ideation
and brain volumes in pediatric epilepsy (in preparation)
Smith, K., SIddarth,
SIddarth, P., Gurbani S., Shields, W. D., Caplan,
Caplan, R. Psychopathology,
cognition, and language in siblings of children with epilepsy (in
(in preparation)
Tosun,
Tosun, D., Hermann, B., Siddarth,
Siddarth, P., Gurbani, S., Toga, A. and Caplan,
Caplan, R. Cortical
morphometry in childhood absence epilepsy (under review).
SchreibmanSchreibman-Cohen, A., Daley, M., Siddarth,
Siddarth, P., Levitt,
Levitt, J., Gurbani, S., Altshuler,
Altshuler, L.
and Caplan,
Caplan, R.
R. Amygdala voumes in childhood absence epilepsy (in preparation).
A
z
z
z
z
z
Standard Head Coil with 1.5 Tesla – Macrostructure of brain
Phased array technology at 1.5T significantly improves SNR (signal
(signal to noise
ratio) – detection of subtle macrostructural changes
3T phased array allows visualization at 300300-400 micron level
7 T phased array allows visualization at 100 micron level
23 phased array coils available and 92 coil prototype is being tested
tested
Imaging the Developing Brain
1.5 T
7 T, at experimental stage, needs extended scanning time.
1.5 T four coil phased array images showing left frontal lobe dysplasia
dysplasia not
seen in 1.5 T head coil image.
27
Imaging the Developing Brain
z
z
Diffusion Tensor Imaging ( DTI)
z
Provides rate, magnitude, and directionality of
water diffusion in the brain
FA (fractional anisotropy) is a measure of
directional bias of diffusion that is influenced by
white matter maturation, myelination, density, type,
and coherence
More tightly packed is the tract with fewer vs many
directions, brighter will be signal
Increases in FA are associated with the
development of ion channels and precede the
appearance of myelin by electron microscopy
Decreases in T1 signal signify an increase in the
concentration of cholesterol and glycolipids around
external myelin membrane
Decreases in T2 signal signify a tightening of
axonal myelin due to changes in protein
configuration
Decreases in ADC (apparent diffusion coefficient)
occur as the size of neurons and glia increase
FA values can help Dx changes related to MS, TSC
and TLE ( both mesial as well neocortical)
Decreased FA value with MTS
Decreased FA value correlates with cognitive
impairment in TSC
z
z
z
z
z
z
z
z
z
In the Final Analysis:
White Matter Organization
z
z
z
z
z
In the foreseeable future :
AEDs will remain a major tool in the treatment of
epilepsies
Monopharmacy is insufficient and so embracing
polypharmacy is a necessity to achieve seizure control
Complications of AEDs increase sharply as we use
polypharmacy in medically refractory patients
I've gotten over it,
yet here it comes again,
nothing can make me,
become a great fan.
It could be worse,
they could not know,
why i am not like them,
why i am slow.
“ One who is confronted with the task of controlling
seizures in a person with epilepsy grasps at any straw “
- William G. Lennox, MD. 1928
I do worry,
about my life,
how i will grow up,
with all my strife.
What i do know is that,
no matter how hard it gets,
or how bad,
i will always have my mom and dad.
28
Know your facts
(Then you may twist them as you want)
-Mark Twain
IRAQ
Weapons
of
Mass Destruction
IRAN/N.KOREA
GOD BLESS AMERICA!
29