Juvenile myoclonic epilepsy

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Epilepsyfor the students

• Amir M. Arain, M.D.
• Vanderbilt University

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Definitions

• Epileptic seizure
• The clinical manifestations(symptoms and signs)
  of excessive and hypersynchronous, usually self
  limited, activity of neurons in the cerebral
  cortex.
• Epilepsy
• A chronic disorder characterized by recurrent
  (more than 2) unprovoked seizures.

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The ILAE classification of seizures

• I. Partial (focal, local) seizures
• A. Simple partial seizures(consciousness not
  impaired)
• B. Complex partial seizures (with impairment of
  consciousness)
• C.partial seizures evolving to generalized
  seizures

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Simple partial seizure
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Simple Partial seizure
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Complex Partial seizureTemporal lobe
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Partial secondarily generalized
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The ILAE classification of epileptic seizures

• II. Generalized seizures
• A. Absence seizures
• 1. Absence seizures
• 2. Atypical absence seizures
• B. Myoclonic seizures
• C. Clonic seizures
• D. Tonic seizures
• E. Tonic-clonic seizures
• F. Atonic seizures (astatic seizures)
• III. Unclassified seizures

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Myoclonic seizure generalizing
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Absence seizure
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Absence seizure complex
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Atonic seizure
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The International League Against Epilepsy
classification of epilepsies and epileptic
syndromes

• I. Localization-related (focal, local, partial)
  epilepsies and syndromes
• A. Idiopathic (with age-related onset). At
  present, two syndromes are established1. Benign
  childhood epilepsy with centrotemporal spike
• 2. Childhood epilepsy with occipital paroxysms
• B. Symptomatic. This category comprises syndromes
  of great individual variability.

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The International League Against Epilepsy
classification of epilepsies and epileptic
syndromes

• II. Generalized epilepsies and syndromes
• A. Idiopathic (with age-related onset, in order
  of age appearance) 1. Benign neonatal familial
  convulsions 2. Benign neonatal convulsions 3.
  Benign myoclonic epilepsy in infancy 4.
  Childhood absence epilepsy (pyknolepsy, petit
  mal) 5. Juvenile absence epilepsy 6. Juvenile
  myoclonic epilepsy (impulsive petit mal) 7.
  Epilepsy with grand mal seizures on awakeningB.
  Idiopathic, symptomatic, or both (in order of age
  of appearance) 1. West's syndrome (infantile
  spasms)
• 2. Lennox-Gastaut syndrome 3.
  Epilepsy with myoclonic-astatic seizures 4.
  Epilepsy with myoclonic absences

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The International League Against Epilepsy
classification of epilepsies and epileptic
syndromes

• C. Symptomatic1. Nonspecific cause. Early
  myoclonic encephalopathy2. Specific syndromes.
  Epileptic seizures may complicate many disease
  states. Under this heading are included those
  diseases in which seizures are a presenting or
  predominant feature.
• III. Epilepsies and syndromes undetermined as to
  whether they are focal or generalizedA. With
  both generalized and focal seizures 1.Neonatal
  seizures 2. Severe myoclonic epilepsy in
  infancy 3. Epilepsy with continuous spikes and
  waves during slow-wave sleep 4. Acquired
  epileptic aphasia (Landau-Kleffner syndrome)
• B. Without unequivocal generalized or focal
  features

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Frontal Lobe seizure Orbitofrontal
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Frontal lobe seizure
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Pseudoseizure
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The International League Against Epilepsy
classification of epilepsies and epileptic
syndromes

• IV. Special syndromesA. Situation-related
  seizures 1. Febrile convulsions 2. Seizures
  related to other identifiable situations, such as
  stress, hormones, drugs, alcohol, or sleep
  deprivationB. Isolated, apparently unprovoked
  epileptic eventsC. Epilepsies characterized by
  the specific modes of seizures precipitatedD.
  Chronic progressive epilepsia partialis continua
  of childhood

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Seizure precipitants

• Stress, emotion
• Sleep/sleep deprivation
• Hyperventilation
• Fever
• Medications, metabolic disturbance
• Reflex epilepsy
• Photic stimuli TV, flashing lights, visual
  patterns
• Startle, music, reading, eating

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Case

• 18yr female admitted in the Epilepsy lab for
  evaluation of recurrent spells.These atypical
  spells are associated with lightheadedness.
  Without warning he would become unresponsive and
  go limp. Myoclonic jerks were noted in the
  upper extremities. The pt. typically did not have
  vocalization, urinary or fecal incontinence or
  tongue biting

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Case

• Neurologic exam ---- normal
• EEG ---- normal
• MRI ---- normal
• EKG episodes of asystole were recorded with
  patients typical spell
• Patient became asymptomatic after implantation of
  a cardiac pacemaker.

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All that jerks is not a seizure

• Syncope
• Hyperventilation/panic attacks
• Migraine and migraine equivalents
• Paroxysmal movement disorders.
• Sleep disorders
• TIAs
• TGA

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Syncope
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Syncope
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• Non epileptic seizures
• PPt by stress
• Quivering, side-to-side movements of the head,
  pelvic thrusting, and uncontrolled flailing,
  thrashing, or asynch. rhythmic mov.of the limbs
• Variable features
• Eyes closed
• No post-ictal change
• Refractory to adequate AED levels
• Prolonged duration
• Normal prolactin
• Rare but do occur

• Epileptic seizures
• Can be ppt by stress
• Stereotypical
• Constant features
• Usually eyes open
• Post ictal state
• Responsive to AEDs
• Seconds to minutes
• Elevated prolactin
• Self-injury and incontinence of urine or stool

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Pseudoseizure
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Generalized Absence (GA) vs Complex partial (CP)
sezures
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Case

• 22y male developed seizure disorder at 15yrs of
  age. Prior neurologic exam was unremarkable. Over
  the years patient has experienced GTC shortly
  after awakening, often precipitated by sleep
  deprivation and excess alcohol use. In the early
  morning hours after awaking body jerks would
  appear, interfering with eating and dressing

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Juvenile myoclonic epilepsy

• This is a common idiopathic generalized epileptic
  syndrome that occurs in 5 to 10 of patients
  with epilepsy.
• A study in the United Kingdom demonstrated a mean
  interval of 14.5 years between onset of symptoms
  and diagnosis of JME.
• Characterized by myoclonic seizures GCTC
  seizures in about 90 of patients, and absence
  seizures ( 30 ).
• Seizure precipitants Emotional stress, alcohol,
  and recreational drug use can also increase
  seizure frequency in JME, and, to a lesser
  extent, flickering lights and menstruation.
• Sleep deprivation is another common seizure
  precipitant. late nights of studying or parties
  frequently result in morning myoclonic seizures
  or GTCS.

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JME Management

• Lifestyle modification avoidance of sleep
  deprivation, alcohol.
• For the majority of patients, JME is usually a
  lifelong condition and cessation of medication
  leads to relapse in 80-90 of patients.
• The drug of choice is sodium valproate.
• Clonazepam is an effective alternative, but its
  cognitive side effects, especially with long term
  use, make it less accepted by patients.
• Lamotrigine is effective, both as add-on therapy
  and monotherapy, especialy if VPA side effects of
  weight gain, tremor and hair loss can not be
  tolerated

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Workup of a first unexplained seizure.

• High resolution MRI
• EEG
• 1 Unexplained seizure does not necessitate AED
  treatment except
• Recognized epileptic syndrome with high
  probability of recurrence.
• Focal brain lesion.

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Treat or not to Treat

• The risk of recurrence of seizures is about
  30-35 after the first unprovoked seizure
• The risk of recurrence is about 70 after second
  seizure

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EEG yield

• 1st EEG 50
• With repeated EEG and activation procedures the
  yield can go up to 90
• No benefit after the fourth EEG, as it gives
  maximum yield

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Drug Therapy basic principles

• Use a single drug whenever possible.
• Start low and go slow
• Increase the dose of that drug to either seizure
  control or toxicity (decreasing the dose if
  toxicity occurs).
• If a drug does not control seizures without
  toxicity, switch to another appropriate drug used
  alone, and again increase the dose until seizure
  control occurs or toxicity intervenes.

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Drug Therapy basic principles

• Remember that the "therapeutic range" is a
  guideline and not an absolute. Some patients
  achieve seizure control with blood concentrations
  below the range, and others tolerate
  concentrations above the range without toxicity.
• Consider using two drugs only when monotherapy is
  unsuccessful. Keep in mind that some patients may
  have more seizures when taking two drugs rather
  than one drug because of drug interactions.

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Drug Therapy basic principles

• Be aware that the ability to metabolize
  anticonvulsant drugs is different in the young,
  the elderly, pregnant women, and people with
  certain chronic diseases, especially hepatic and
  renal disease, than in healthy, nonpregnant
  adults.

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Pharmacokinetic overview of classical AEDs
PHT
CBZ
VPA
PHB
PMD
ESX
CZP
Bioavailability
gt90
75-85
gt90
gt90
gt90
gt90
gt80
Protein binding
90
75
90
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lt20
lt10
86
Metabolism
95
gt95
gt96
lt80
Metabolism site
Liver
Liver
Liver
Liver
Liver
Liver
Liver
7-42
6-20
5-15
65-110
8-15
30-60
30-40
T1/2
no
yes
no
no
no
no
no
Autoinduction
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Classical AEDs idiosynchriatic toxicity
Rash, lymphadenopathy
PHT
Rash, other hypersensitivity
CBZ
Liver failure, pancreatitis (rare)
VPA
PHB
Rash, connective tissue disorders
Connective tissue disorders
PMD
Blood dyscrasias
ESX
-
CZP
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Pharmacokinetic overview of newer AEDs
FBM
GPN
LTG
TOP
TGB
LEV
OXC
ZNS
Absorption dose dependent bioavailability Tmax
(hrs)
no
yes
no
no
no
no
no
no
gt90
60
gt98
gt80
gt89
100
99
100
1-4
2-3
1.4-4.8
1-4
0.9-2.6
1
4-6
2-6
Protein binding
25
0
55
15
96
0
40
40
18-24
5-8
12-70
20-30
2-9
6-8
9
63
T1/2
no
no
slight
no
no
no
no
no
Autoinduction
applies to monohydroxyderivative (MHD), the
main active metabolite
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Pharmacokinetic overview of newer AEDs - continued
FBM
GPN
LTG
TOP
TGB
OXC
ZNS
LEV
Metabolized?
50
no
90
20-50
98
99
65
40
Metabolism site
hepatic
NA
hepatic
hepatic
hepatic
liver
liver
blood
Elimination
urine
urine
urine
urine
feces (2/3)
urine
urine
urine
urine (1/4)
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Effect of newer AEDs on blood concentration of
established AEDs
AED serum concentration with add-on
FBM GPN LTG TPM TIA LEV OXC ZNS
CBZ

PHT
VPA
an increase in PHT level may occur at high OXC
doses
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Effect of established AEDs on blood concentration
of newer AEDs
AED serum concentration with add-on
CBZ PHT VPA
FBM
GPN
LTG
TPM
TGB
LEV
OXC
ZNS
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New AEDs most concerning toxicity
Aplastic anemia, liver failure
FBM
-
GPN
Skin rash
LTG
TPM
Agitation, psychosis, speech disorder
Encephalopathy, psychosis
TGB
LEV
-
Rash, hyponatremia
OXC
Agitation, psychosis
ZNS
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Case

• A 27 yr women with history of epilepsy has just
  received her positive pregnancy test. She is on
  Carbamazepine. Her seizure frequency is 1-2
  seizures in six months.
• She in concerned about teratogenic effects of the
  medication.
• Should we take her off the medication?

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GUIDELINES FOR THE MANAGEMENT OF EPILEPSY DURING
PREGNANCY

• Baseline antiepileptic drug (AED) levels
  (total/free) and folate (serum/RBC)
• Folate supplementation level 1-4 mg/day
• Maternal alpha-fetoprotein level at week 15-16
• AED levels and fetal ultrasound at 18-19 weeks
• Repeat fetal ultrasound at 22-24 weeks
• AED levels at 34-36 weeks. Make adjustments to
  ensure therapeutic drug levels at term.
• Vitamin K 20 mg/day during eighth month or 10
  mg IV 4 hours before birth
• and 1 mg IM to newborn at birth
• Monthly AED levels postpartum for 12 weeks

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Drug therapy

• Partial and Secondarily
• Generalized Seizures
• Carbamazepine, phenytoin, and valproic acid are
  the first-line agents among most specialists for
  partial and secondarily generalized seizures
• Gabapentin, lamotrigine, oxcarbazepine,
  tiagabine, topiramate, and vigabatrin are new
  anticonvulsants that are recommended for
  treatment of partial seizures.

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Generalized seizures

• Primary Generalized Seizures
• Ethosuximide and valproic acid are equally
  effective for treating absence seizures, but
  ethosuximide is not effective for treatment of
  primary generalized tonic-clonic seizures.
• Other AEDs
• lamotrigine topiramate
• felbamate tiagabine
• zonisumide

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Case

• 30yr male with history of epilepsy has been
  seizure free on valproate for the last 2.5 years.
  He is not having any side effects. He is
  wondering if we can take him off medication.
• What should we do?

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Discontinuing AEDs

• Seizure free 2-5 years on AEDs
• Single type of partial or generalized seizures
• Normal neurologic examination and normal IQ
• EEG normalized with treatment
• Relapse 31.2 children, 39.4 adults

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What is status epilepticus?

• Epileptic seizure that is prolonged or so
  frequently repeated as to create a fixed and
  lasting epileptic condition.
• 30 min.

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The Treatment of Generalized Convulsive Status
Epilepticus

• Amir M. Arain, M.D.
• Department of Neurology
• Vanderbilt University Medical Center

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VUMC Status Epilepticus Pathways-Phase I 0-15
min (ED)- Goals

• Treatment initiated immediately on arrival
• Neuro resident evaluates patient ASAP
• Seizures to be controlled ASAP
• Plan transfer to NCU/ MICU
• If seizures not controlled in 10-15 minutes,
  advance to phase II per physicians judgement

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VUMC Status Epilepticus Pathways-Phase I 0-15
min (ED)- Treatments

• IV access
• Pulse Oximetery
• Cardiac monitor

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VUMC Status Epilepticus Pathways-Phase I 0-15
min (ED)- Labs

• Blood glucose at bedside
• SMA 6, SMA 12
• CBC with diff and platelets
• If on AEDs check AED levels
• Hold urine and serum specimen

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VUMC Status Epilepticus Pathways-Phase I 0-15
min (ED)- Tests

• CXR if indicated when status controlled
• EKG if indicated when status controlled
• Schedule CT without contrast if status not
  explained by
• AED withdrawal
• Metabolic or toxic disorder
• CT can be done when status is controlled prior to
  transfer to NCU

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VUMC Status Epilepticus Pathways-Phase I 0-15
min (ED)- Meds/IV

• IV- NS at KVO
• If blood glucose low 1 amp D50 (50 cc IVP) and
  start second IV with D5NS
• Thiamine 100 mg IVP if
• given D50
• cachectic/ malnourished
• alcoholic

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VUMC Status Epilepticus Pathways-Phase I 0-15
min (ED)- Meds/IV

• If actively seizing
• 1) Diazepam IV, max 20 mg at lt 5 mg/min
• or
• Lorazepam IV, max 10 mg at lt 2mg/min

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VUMC Status Epilepticus Pathways-Phase I 0-15
min (ED)- Meds/IV

• 2) Fosphenytoin (Cerebryx)- max delivery
  rate150mg/min, total dose 20 mg/Kg (marketed in
  phenytoin equivalent)
• Do not use if status is due to a metabolic cause
  unlikely to respond to phenytoin
• Reduce delivery rate if AV block or hypotension
• Current treatment with phenytoin is not a
  contraindication

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VUMC Status Epilepticus Pathways-Phase I 0-15
min (ED)- Meds/IV

• Magnesium sulfate may be used if appropriate
• If not actively seizing, fosphenytoin may be
  given without a benzodiazepine

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VUMC Status Epilepticus PathwaysPhase II 15-60
min (ED-NCU) Goals

• For continued uncontrolled seizures
• Intubate and ventilate patient
• Control seizures ASAP
• Complete EEG
• For patient with decreasing seizures
• Additional dose of fosphenytoin
• Transfer to NCU or MICU when stable

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VUMC Status Epilepticus PathwaysPhase II 15-60
min (ED-NCU) Treatments

• Continuing
• IV access
• pulse oximetery
• New
• Foley catheter
• Intubate for uncontrolled seizures
• Ventilate

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VUMC Status Epilepticus PathwaysPhase II 15-60
min (ED-NCU) Labs

• Phenytoin level 30 minutes after loading dose
  completed

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VUMC Status Epilepticus PathwaysPhase II 15-60
min (ED-NCU) Tests

• CT (without contrast) when seizures controlled
• EEG (not necessary if patient wakes up). Contact
  EEG tech at time of ED admission
• LP if indicated

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VUMC Status Epilepticus PathwaysPhase II 15-60
min (ED-NCU) Meds/IV

• For patients with decreasing seizures after
  fosphenytoin load additional 10 mg/Kg of
  fosphenytoin
• For patients continuing to seize, who require
  intubation
• Thiopental succinylcholine (avoid if possible)
• Consider additional dose of fosphenytoin 10mg/Kg,
  or phenobarbital/pentobarbital

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VUMC Status Epilepticus PathwaysPhase II 15-60
min (ED-NCU) Meds/IV

• For continuing seizures post-intubation
  phenobarbital load or pentobarbital coma
• phenobarbital 20 mg/Kg at lt 100 mg/min
• if hypotensive, decrease rate of delivery
• pentobarbital 5 mg/Kg loading dose (to achieve
  burst suppression pattern on EEG with interburst
  interval of 7sec. Repeat load as necessary to
  max of 15 mg/Kg, then maintain at 1-3 mg/Kg/hr
  x6-12 hours, then reevaluate

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VUMC Status Epilepticus PathwaysPhase III 1-24
hrs (NCU) Goals

• EEG is completed within 1 hour of call
• Maintain hemodynamic stability
• Treat hyperthermia
• Identify etiology of seizures and develop
  appropriate plan of care
• Patient returns to normal level of consciousness
  post seizures

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VUMC Status Epilepticus PathwaysPhase III 1-24
hrs (NCU) Treatments

• Neuro checks
• Admission weight
• Aspiration precautions
• VS on admission and Q 4 hours
• Rails up and safety checks Q 2 hours
• Pad side rails

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VUMC Status Epilepticus PathwaysPhase III 1-24
hrs (NCU) Labs

• Bedside glucose at 2 hours for patient continuing
  to seize

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VUMC Status Epilepticus PathwaysPhase III 1-24
hrs (NCU) Meds/IV

• Maintenance AEDs as indicated, such as
• Phenytoin 200-400 mg/day, or
• Carbamazepine 200 mg bid, then increase by 200 mg
  Qod to 7-15 mg/Kg/day or
• Phenobarbital 60-120 mg Qhs or
• Divalproex 10-15 mg/Kg/day in 3 divided doses,
  then increase by 5-10 mg/Kg/day to 15-45 mg/Kg/day

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VUMC Status Epilepticus PathwaysDay 2 (NCU
11S) Goals

• Disposition plan developed
• If ETOH/drug induced detox referral
• If known epilepsy and seizures back to
  baseline/acceptable level, plan D/C for early am
  day 3
• If meningitis/stroke/metabolic/other cause
  identified, transfer to appropriate path and
  manage accordingly

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VUMC Status Epilepticus PathwaysDay 3 (11S
D/C) Goals

• Patient to be D/Ced from VUMC when following
  criteria are met
• awake
• back to baseline LOC/functioning
• Source of seizures is identified and appropriate
  disposition planned
• Maintenance AEDs initiated (when indicated)
• Patient agrees with plan

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Case

• A 65yr. Old female is acting confused for the
  last 1 week. The confusion fluctuates and its
  nadir she is unable to recognize any of her
  family members.
• O/E she can not recall her address or DOB
• She is afebrile and neck is supple
• No history of epilepsy

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Case

• Labs
• CBC, SMA 7 normal
• Head CT normal
• Spinal Tap normal
• EEG continues ictal discharge were seen
• Diagnosis Non Convulsive Status Epilepticus

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Do not miss non-convulsive status

• Non convulsive status epilepticus is a term used
  loosely to describe absence status, complex
  partial status and end stage convulsive S.E.
• Do not give paralytics for patients with
  convulsive status epilepticus. This may abolish
  the outward expression of the seizures while the
  brain continues to have epileptic activity.

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Ketogenic diet

• Ketosis improves seizure control
• The basic protocol calls for a diet with a
  fat-tocarbohydrate-plus-protein ratio of 4 to 1
  on a caloric basis. A modification of the diet
  uses medium-chain triglyceride (MCT) oil and
  allows for a greater amount of carbohydrate. The
  MCT oil diet is not clearly more beneficial, nor
  is it better tolerated.
• beneficial in a subset of patients who have not
  responded to antiepileptic drugs. It is used
  predominantly in children.

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Epilepsy surgery

• Approximately 2030 of patients with epilepsy do
  not respond to anticonvulsant drugs
• Selection Criteria
• A precise diagnosis of seizure type and exclusion
  of patients with nonepileptic events.
• Documented failure of seizure control on adequate
  blood concentrations of appropriate
  anticonvulsant drugs.
• The seizure focus is defined in a part of the
  brain that can be resected with a low probability
  of causing a functional impairment that is worse
  than the intractable seizures.

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Epilepsy surgery

• Adequate time to establish that seizures are
  refractory to medical treatment. In adults, this
  is usually 6 months to 2 years, but in special
  circumstances, such as epilepsia partialis
  continua, less time is needed. In children,
  shorter waiting periods are indicated when
  seizures are causing developmental delay.

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Epilepsy surgeryPresurgical evaluation.

• EEG-CCTV
• MRI
• PET/ ictal SPECT
• Neuropsycholgical testing
• Wada test

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Epilepsy surgery Surgical Procedures

• Focal Cortical Resection
• In general, an anterior temporal lobectomy is
  performed for mesial temporal lobe seizures, but
  variations include an anterior medial resection
  or, in some cases, an amygdalohippocampectomy.
  When a specific structural lesion is identified,
  such as a tumor or malformation, the goals of
  surgery are removal of the abnormality and
  resection of epileptogenic tissue with careful
  attention to sparing functional tissue.
• Extratemporal cortical resections are less common
  because extratemporal epileptic foci are less
  common and more difficult to localize, and
  resection is more likely to cause a functional
  deficit.

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Epilepsy surgery

• Hemispherectomy Sturge-Weber syndrome, diffuse
  cortical dysplasias, hemimeganencephaly,
  unilateral congenital injuries, and Rasmussen's
  encephalitis. Because the involved cortex is
  already dysfunctional, hemispherectomy usually
  does not significantly increase motor, sensory,
  or cognitive impairment.
• Corpus Callosotomy
• Generalized seizures, especially atonic seizures,
  show the greatest benefit from callosal section.

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Epilepsy

• Epilepsy is a treatable condition and
  epileptic patients can live a normal and healthy
  life. Epilepsy should not be a social taboo

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