Pediatric benign epileptic syndromes

1. Benign Pediatric Epileptic
Syndromes
Lalit Bansal, M.D.
Children’s Mercy Hospital
08/16/2019

2. Types:
1. Benign Familial Neonatal Seizures
2. Benign Idiopathic Neonatal Seizures
3. Benign Infantile Seizures
4. Childhood Absence Epilepsy
5. Benign Epilepsy of Childhood with Centrotemporal Spikes
6. Panayiotopoulos Syndrome (Benign Partial Epilepsy with Occipital Paroxysms)
7. Idiopathic childhood occipital epilepsy of Gastaut

3. Benign Familial Neonatal Seizures
• Focal clonic seizures, occasionally followed by a GTC component and apnea
• Onset: Usually begin within 2-8 days of birth (54%)
31% have after 1st week of life
Remaining <3.5 months
• Seizure duration 1-2 min; 20-30 episodes per day
• Remits by 16 month
• Familial and self-limiting
• KCNQ2 & KCNQ3 mutation – encodes Voltage-gated K+ channel subunits – responsible for M-currents (neuronal
stability)
• Classified as Idiopathic generalized epilepsies
• No known precipitating factors, normal labs prior or after the seizure.

4. • 11% patients develop other types of seizure later in life
• Syndrome is heterogenous
• Intellectual disability and learning disability – 2.5% (~similar to general population)
• Inheritance – Dominant – penetrance high (85%)
• KCNQ2 – 20q13.3 (can also occur denevo) – BFNS Type 1
• KCNQ3 – 8q24 – BFNS Type 2
• M-currents - large potassium currents – highly expressed in cortex and hippocampus
- slowly activated by depolarization, provides neuronal stability, act as a brake for repetitive AP firing
- reduced by 25% (due to mutation)- causes neuronal exitibility
• After 1st week of life (in rats) – KCNQ2 channel activity decreased
• Also, GABA-mediated responses switch from depolarization to hyperpolarization (Due to increase expression of
potassium-chloride cotransporter KCC2)
• Post-neonatal period – differential expression of K channels, compensatory mech to suppress aberrant M-currents

5. • Incidence : 14.4 per 1,000,000 live births (rare)
• EEG – never shows severe or generalized abnormalities; may show theta pointu alternant pattern
• BFNS patients may show centrotemporal spikes
• Anti-seizure medication – efficacy unknown as most seizure remit spontaneously
• Treatment is short term AED’s (Phenobarbital – most common)
• Retigabine – act on KCNQ2-KCNQ5 with tryptophan residue
• Meclofenamic acid and diclofenac – act as novel KCNQ2/Q3 channel opener – Increases M-current (?help resolve
seizures in neonatal period)

6. • Overlaps with BFNS – as there are rare reports of de nevo KCNQ2 mutation
• Seizure occur between 1st and 5th DOL (80% occur between DOL 4-6)
• Previously called “Fifth-Day fits”
• Seizure are clonic, partial, w/w/o apnea; often unilateral, may change side
• Tonic seizures are extremely rare
• Seizure last 1-3 minutes, occurs in cluster, SE, may persist 2 hour to 3 days
• Even after prolonged SE – complete recovery usually follows
• Etiology: Acute Zn deficiency in CSF (unknown if Zn def is is the cause or after SE)
Viral illness (rotavirus)
• Prevalence – 7% of neonatal seizures
• Most common EEG pattern – 60% have theta pointu alternant
Benign Idiopathic Neonatal Seizures

7. Differences between benign familial neonatal convulsions and benign idiopathic neonatal convulsions:
• Family history is common in benign familial neonatal convulsions but rare (about 2%) in benign idiopathic
neonatal convulsions
• Benign familial neonatal convulsions occurs earlier (days 2-3) than benign idiopathic neonatal convulsions
(days 4-5)
• Persistence of convulsions is longer in benign familial neonatal convulsions
• Occurrence of epilepsy is more frequent in benign familial neonatal convulsions

8. theta pointu alternant pattern
• NOT specific for BFNS (seen w/ hypocalcemia, HIE, meningitis, SAH, BINS)
• characterized by generalized theta activity that is occasionally associated with sharp waves
• frequently asynchronous, discontinuous or in a pattern that alternates with periods of generalized
voltage attenuation
• present during wakefulness and all stages of sleep.
• may be present for several days after seizures have resolved

9. Benign Infantile Epilepsy Syndrome
• Onset 3-12 months (range 6 week to 20 months), remission by 2 year; absence of neurodevelopmental
sequelae
• F:M = 2:1
• Often present as motor arrest, impaired consciousness, staring and convulsions
• Occurs during wakefulness or drowsiness
• Interictal EEG remote from seizure – normal
• Interictal EEG during seizure cluster: lateralized slow wave and spikes in occipito-parietal (familial cases)
• In some patients focal pattern may occur alternating hemisphere (presenting as different semiology)
• Gestational, medical history and metabolic testing and neuroimaging are normal

10. Types:
1. Benign Familial Infantile Seizures – PRRT2 gene mutation (83% cases) [also causes paroxysmal dyskinesia
later in life] (Ch. 16p12-q12) – Autosomal Dominant
2. Benign Familial Infantile Seizure and Choreoathetosis- Pericentromeric region of Ch 16 (80% cases -PRRT2)
and SCN8A mutation
3. Benign Familial Neonatal-Infantile Seizures – SCN2A mutation (present between 1-3 month)
4. Benign Familial Infantile seizure with Familial Hemiplegic Migraine – ATP1A2 (facilitate cortical spreading
depression)
5. Benign Nonfamilial Infantile Seizures - sporadic (rare) de novo PRRT2 mutation
6. Benign Infantile seizures with Mild Gastroenteritis – sporadic cases with associated prolonged episodes of
diarrhea
7. Benign Focal Epilepsy in Infancy with Midline Spikes and Wave during Sleep – midline spikes in sleep

11. Childhood Absence Epilepsy
• Tissot’s first described them as petits acces in 1770 and Poupart as absence seizures in 1775
• Onset 4-10 years of age
• Female > Male; 60-70% female
• 15 – 44% positive family history
• Monozygotic twins (75%) risk of TAS; Dizygotic twins 16 times less common
• Incidence = 6.3-8/100,000
• Genetic mutations associated with CAE: complex inheritance
(GABRG2, CACNA1H –Chinese, CACNG3 – European)

13. Inclusion Criteria
Age at onset between 4 and 10 years and a peak at 5 to 7 years
Normal neurologic state and development
Brief and frequent daily absence seizures with abrupt and severe impairment (loss) of consciousness. Automatisms are frequent but have no significance
in the diagnosis
EEG ictal discharges of generalized high-amplitude spike and-slow wave complexes (2.5 – 4 Hz). They are rhythmic at around 3 Hz with a gradual and
regular slowdown from the initial to the terminal phase of the discharge
Exclusion Criteria
Early onset <4 years
Other than typical absence seizures such as GTCS, or myoclonic jerks before adolescence
Eyelid myoclonia, perioral myoclonia, rhythmic massive limb jerking, and single or arrhythmic myoclonic jerks of the head, trunk, or limbs. However,
mild myoclonic elements of the eyes, eyebrows, and eyelids may be featured, particularly in the first 3 seconds of the absence seizure.
Mild or no impairment of consciousness during the 3 to 4 Hz discharges
Absence seizures > 45 seconds
Onset or offset of absences is not abrupt
Generalized background slowing
Focal slowing seen consistently in one area
Focal spikes consistently in one area

14. • GTCS may appear between 8-15 years of age; or even later 20-30 years of age
• GTCS appear in 30% of cases with early effective therapy and 68% after incorrect therapy
• Later age of onset (9-10 yr) of Absence seizures associated with higher risk for GTCS
• Cessation of Absence may not mean remission. May develop JME (~15%), EMA later in life
• In 90% of cases absences disappear with age
• 7% of CAE continue to have seizure after 12 to 17 years of seizure onset
• In CAE, 25% have subtle cognitive deficits, 43% have linguistic difficulty, 61% psychiatric diagnosis
(ADHD, Anxiety)
• Absence seizures < 4 year of age, 10% have GLUT 1 deficiency (SLC2A1)
• GPFA (generalized paroxysmal fast activity, 6.5%) is an prognostic indicator and is associated with life
long seizures in CAE

15. GPFA

16. • Neuroimaging is normal
• With advance imaging - subtle grey matter volumes loss in frontal gyrus, temporal lobes and
thalami
• If the electroclinical diagnosis of childhood absence epilepsy is established and there are no
atypical features, neuroimaging is not required

17. Treatment:
• Ethoxusamide, sodium Valproate and Lamotrigine – main AED’s
• DBRCT – 16 week therapy: freedom from failure - ETX – 53%, VPA 58%, LTG – 29%
• No significant differences among 3 for discontinuation because of adverse events
• Clonazepam, clobazam, acetazolamide – second line agent
• Levetiracetam – effective with associated GTCS, myoclonic seizures
• Topamax is NOT recommended in CAE, due to lack of efficacy
• AED’s Contraindicated – Vigabatrin, Tiagabine – pro-absence and generate absence status epilepticus
• Carbamazepine, Oxcarbazepine, phenytoin, phenobarbital – may exaggerate absences

18. Benign Childhood Epilepsy with Centrotemporal Spikes
• Most frequent epilepsy syndrome in children between 4-13 year age
• First reported in 1950’s by Gastaut (1952) and Gibbs (1954)
• BCECTS begins between 2-13 year (80% 5-10 years) of age
• Most patients usually recover by age 16 years
• Multifactorial pathogenesis
• Inherited as Autosomal dominant trait with variable penetrance (GRIN2A)
• ~24% of all epileptic seizures in 5-14 year of age
• Annual incidence: 7.1 – 21 per 100,000 children under 15 yr of age
• Slight male predominance
• Prevalence is higher in close relatives with BCECTS – 15% sibling have seizures, 19% sibling have Rolandic spike w/o
Seizures

19. EEG Features
 broad, diphasic, high-voltage 100-300microV
 transverse/horizontal dipole, often followed by slow wave
 Rarely 3Hz GSW may be seen
 Slight hemispheric predominance – Left (boys), right (females)
 HV – reduces frequency of SW
 Ripples (80-250Hz) on Rolandic spikes – marker of epilepsy severity (>2 predictor for seizures, >5 - atypical BCECTS)
 Background is normal, presence of normal sleep architecture
 Rarely focal spikes outside of CT region (midline, parietal, frontal, occipital)

20. CT spike left with horizontal dipole

21. Increase frequency in NREM

22. Ripples

23. BCECTS with 3Hz GSW

24. Clinical Presentation:
• Most patients presents with motor, sensory or autonomic manifestation of face, mouth or throat
• Oropharyngeal and facial manifestations include
 drooling from hypersalivation and swallowing disturbance
 guttural sounds
 involuntary movements or tonic contractions of the tongue or jaw
 unilateral numbness or paresthesia of the tongue, lips, gums, and cheek
 speech arrest
 myoclonic contraction of 1 side of the face
• Sensorimotor phenomenon:
 Leg or half body or miscellaneous abdominal pain
• Generalized seizures are infrequent
• Initial event is hemifacial convulsion, may spread to arm/leg  generalized
• 20-25% children have >1 seizure type

25. • ≥ 50% patients have seizure in sleep (day/night)
• Seizure frequency is usually low (1 seizures in 10% cases)
• 20% children will have several seizures/day
• Predictor for disease: onset < 3 year of age
• Behavioral problems are less frequent than other childhood epilepsy syndromes (ADHD common)
• Deficit in IQ correlates with frequency of SW
• Visual-spatal attention deficit correlate with right rolandic spikes
• Higher SWI during NREM sleep is associated with poorer nonverbal declarative memory consolidation

26. ATYPICAL BCECTS
• Day-time seizures only
• Postictal Todd paresis
• Prolonged seizure, atypical absence seizure, negative myoclonus
• Status epilepticus
• Atypical spike morphology
• Unusual location
• Abnormal background
• Early age of onset-most important feature
• Atypical cases have higher % of learning and behavioral disabilities
• Estimated ~5% of BCECTS cases

27. Prognosis:
• Excellent prognosis
• Difficult to control seizures – in only small number of cases
• Seizure almost always remit spontaneously in late adolescence
• In only 0.02% (3/168 cases) cases seizures occurred in adulthood (7-30 years after cessation of BCECTS)
• Cognitive deficits after cessation of epilepsy: expressive grammar, literacy skills

28. Treatment:
• Drug therapy necessary in ~30% cases
• Carbamazepine, oxcarbazepine, levetiracetam, valproate
• Clobazam – nightly dose for children with seizures only in sleep
• Sulthiame – centrally acting carbonic anhydrase inhibitor (DOC for atypical BCECTS)
• ~14% children may continue to have seizures after initial AED

29. Panayiotopoulos Syndrome
• Childhood partial seizures with ictal vomiting and extraoccipital spikes
• Benign nocturnal childhood occipital epilepsy
• Benign partial epilepsy with occipital paroxysms
• Idiopathic, age-and self-limited, focal autonomic seizures or autonomic status epilepticus
• All other term for this syndrome (PS) are incorrect because:
 Seizure onset is autonomic symptoms (not occipital lobe manifestation)
 Occipital symptoms (only deviation of eyes), rarely occurs at onset. Visual symptoms are rare
 Interictal occipital spikes may never occur (30% cases)
 MEG may show equivalent current dipole clustering in frontal or extraoccipital areas
 Ictal EEG has documented variable onset from posterior or anterior regions
• Prevalence is around 13% of children 3-6 years; 6% of 1-15 years (2-3/1000 children may be affected)
• Genetics – complex/polygenic

30. Clinical Presentation:
• Seizure onset 1-14 years of age (majority 3-6 years)
• Seizures are infrequent in most patients (25% have a single seizure; 50% have ≤6 seizures)
• Seizure usually resolve by 11-13 years of age
• M=F
• Developmental and cognition is normal , although during seizure period subtle deficit in language and executive
function are noted
• h/o febrile seizures in 5-17% patients
• Predominant autonomic features: nausea, retching, vomiting (74%), mydriasis, pallor, cyanosis, thermoregulatory
and cardiorespiratory changes
• 2/3rd of the seizure start in sleep, and are often prolonged (minutes to hours)
• Child may wake up from sleep, vomit, fully conscious or confused, able to speak, feeling sick
• May present as syncope like events (ictal syncope)

31. First clinical symptoms with coughing during autonomic seizure. (Contributed by Dr. C P Panayiotopoulos.)

32. EEG:
• Background is normal
• Multifocal spike/sharp waves – 90% cases; 10 % normal
• All regions affected, but posterior region is common (occipital spikes in 60% cases)
• Eye closure may activate occipital spikes. Sleep activated discharges
• Ictal pattern is unilateral, often posterior with rhythmic slowing
Imaging:
• Normal
Family h/o seizures/epilepsy:
• Absent

33. Idiopathic Childhood Occipital Epilepsy of Gastaut
• Self-limiting childhood epilepsy with onset in later childhood
• Seizures are usually easily controlled, and remission of seizure occurs in 2-4 years from onset (~60% patients)
• Onset between 15 months – 19 years (peak 8-9 years of age)
• Dramatic response to carbamazepine >90% of patients
• M = F
• Development and cognition is normal
• Increased family history of epilepsies (21-37%) or migraine (9-16%), but rare Gastaut type seizures in family
• Prevalence : 0.2 – 0.9% of all epilepsies; 2-7% of benign childhood focal seizures

34. Clinical Presentation:
• Predominant elementary visual hallucinations (lights, color, geometric shapes or indiscrete objects), blindness or
both
• Frequent and diurnal
• Duration seconds 3 min
• Consciousness is intact initially
• Often associated with ipsilateral head turning and deviation of eyes
• Forced eye closure can be seen in 10% patients – with impaired consciousness
• Autonomic manifestations are rare
• Post-ictal headache (orbital) is consistent symptoms in 1/3rd of the children (d/d migraine)

35. Elementary visual hallucinations as illustrated by 3 patients with the complete clinical and EEG features of idiopathic
childhood occipital epilepsy. Note that the visual hallucinations are predominantly multicolored and circular. (Contributed
by Dr. C P Panayiotopoulos.)

36. EEG:
• Occipital spikes
• Occurs with eyes closed (fixation-off sensitivity)
• Rarely generalized discharges can be seen
• No postictal abnormalities
Imaging:
• Normal

37. Occipital paroxysms occur as long as eyes are closed and disappear as long as eyes are open

38. Occipital paroxysms occur as soon and last as long as fixation and central vision are eliminated from both eyes by any means.
These are shown and may be (a) eyes closed in a lit room, (b) covering ordinary commercial underwater goggles with
semitransparent tape, and (c) glasses with lenses that prohibit fixation (Plus 10 spherical glasses) but not sun glasses.
(Contributed by Dr. C P Panayiotopoulos.)

39. Panayiotopoulos syndrome Rolandic epilepsy Gastaut type idiopathic childhood
occipital epilepsy
Prevalence among children 1 to 15 years with afebrile seizures 6% 15% 1% to 2%
Mean age at onset (range) in years 4 to 5 (1 to 14) 8 to 9 (1 to 15) 8 to 9 (3 to 16)
Sex prevalence 54% males 60% males 50% males
Seizure characteristics
Main type of seizure Autonomic and often with emesis Focal sensory-motor Focal visual
Duration Long (usually 9 minutes or longer) Moderate (usually 2 to 4 minutes) Brief (seconds to 1 to 2 minutes)
Focal nonconvulsive status epilepticus (>30 min) 44% Rare Exceptional
Frequency of seizures Infrequent Infrequent Many, sometimes daily
Single seizures only 30% 10% to 20% Exceptional
Circadian distribution Mainly in sleep (64%) Mainly in sleep (70%) Mainly on awake (>90%)
Interictal EEG Multifocal spikes Centrotemporal spikes Occipital spikes
Continuous prophylactic treatment Often not needed Often not needed Needed
Prognosis Excellent Excellent Uncertain
Risk for epilepsy as an adult 2%? 3% 20%?
Remission within 1 to 3 years from first seizure Common Common Uncommon
Similar seizures after remission None Only 1 case is reported Common
Developmental and social prognosis Normal Normal Usually good

40. Thank You