A look at Neonatal Epilepsy Syndromes

1. OVERVIEW OF NEONATAL EPILEPSY
SYNDROMES
PRESENTER: DR. OLIELO
FEACILITATOR: DR. OYIEKE

2. SELF-LIMITED (FAMILIAL) NEONATAL EPILEPSY (SELNE)
Incidence of 5.3 per 100,000 live births
characterized as a channelopathy, caused in
most cases by pathogenic variants in
voltage-gated potassium channel genes
KCNQ2 and KCNQ3
Inheritance :autosomal dominant pattern
15 percent of those who carry a variant may
not have recognized seizures

3. SELF-LIMITED (FAMILIAL) NEONATAL EPILEPSY (SELNE)
Clinical features
Seizures occur within the first seven days of life, 90% between days 4
and 6, and resolve within six weeks to six months. Some can occur as
late as 3 months
The incidence is similar for males and females.
Focal tonic, involving the head, face, and limbs
Focal clonic seizures may also occur
Clusters: frequent as 20–30 per day.

4. SELF-LIMITED (FAMILIAL) NEONATAL EPILEPSY (SELNE)
Evaluation and diagnosis –
Diagnosis of exclusion
Diagnostic criteria for SeLNE require focal tonic seizures at onset and a
nonlesional brain MRI in an infant delivered after a normal pregnancy
and labor.
The ictal EEG is not distinctive from other electrical or electroclinical
seizure types.
The interictal EEG background may be normal or mildly abnormal burst
suppression multifocal sharp waves.
Neuroimaging is mandatory
Where available, genetic testing should confirm a pathogenic variant in
KCNQ2 or KCNQ3

5. SELF-LIMITED (FAMILIAL) NEONATAL EPILEPSY (SELNE)
Benzodiazepine, Valproate Carbamazepine or oxcarbazepine can be
effective treatments
Antiseizure medications can often be stopped once the infant is beyond
the usual six-week period of recurrence risk.

6. SELF-LIMITED (FAMILIAL) NEONATAL EPILEPSY (SELNE)
Clinical course and outcomes:
Seizures abate by age six months, typically by age six weeks.
(68% during the first 6 weeks. However, 10–14% may later develop other
types of febrile (5%) or afebrile seizures. Idiopathic generalised seizures
are more common. There have also been accounts of SeLECTS.
Development is typically normal.
Prevalence of mental disability and learning disability is reported to be
approximately 2.5%

7. SELF-LIMITED FAMILIAL NEONATAL-INFANTILE EPILEPSY
(SeLFNIE)
The seizures typically occur within day 1 to 21 months: with a mean
onset at 11 weeks (median 13 weeks).
Inherited in an autosomal dominant pattern and is caused by
pathogenic variants in the SCN2A gene
Rare cases are associated with pathogenic variants of the KCNQ2 gene

8. SELF-LIMITED FAMILIAL NEONATAL-INFANTILE EPILEPSY
(SELFNIE)
Clinical features – SeLFNIE is characterized by focal tonic or focal clonic
seizures, a family history of neonatal seizures, and no other neurologic
abnormalities
(normal physical examination and neuroimaging are required).
At onset, seizures are focal tonic with head and eye deviation.
Seizures may last from 20 seconds to 4 minutes, but often occur in
clusters
The interictal EEG is typically normal. EEG slowing or focal discharges in
central and posterior regions may be seen during periods of active
seizures

9. SELF-LIMITED FAMILIAL NEONATAL-INFANTILE EPILEPSY
(SeLFNIE)
Treatment
Carbamazepine is considered a first-line
Clinical course and outcomes –
Seizure frequency is variable
seizures cease by 12 to 24 months and do not recur later in life

10. EARLY INFANTILE DEVELOPMENTAL AND EPILEPTIC
ENCEPHALOPATHY (EIDEE)
incidence of 10 per 100,000 live births
EIDEE is characterized by early onset, frequent seizures, abnormal
neurologic examination, with a burst-suppression pattern, slowing, and
abundant multifocal discharges on EEG, along with developmental
impairment.
EIDEE incorporates the epilepsy syndromes classified as [6]:
•EIEE (Ohtahara syndrome)
•Early myoclonic encephalopathy (EME)
Infants with EIDEE may evolve to develop infantile epileptic spasms
syndrome (IESS), and then, in childhood, they may develop LGS

11. EARLY MYOCLONIC ENCEPHALOPATHY
Onset: first weeks of life
More than 60% start before 10 days of age and rarely
after the second month.
Boys and girls are affected equally.
• Erratic, focal, rarely generalized myoclonic and tonic
Erratic myoclonus affects the face or limbs.
It is often restricted in a finger, a toe, the eyebrows, eyelids or lips,
occurring in the same muscle group and often migrating elsewhere,
usually in an asynchronous and asymmetrical fashion.
• High incidence of consanguinity
• Sometimes IEMs

12. EARLY MYOCLONIC ENCEPHALOPATHY
Manifests with a triad of intractable seizures.
Erratic myoclonus appears first followed by simple focal seizures and
later by tonic epileptic (infantile) spasms.
There may be marked truncal hypotonia, limb hypertonia,
disconjugate eye movements, dyspnoea, or opisthotonic or
decerebrate posturing.

13. EARLY MYOCLONIC ENCEPHALOPATHY
Eitiology
Inborn errors of metabolism – most common
• Non ketotic hyperglycinemia, propionic aciduria, Methylmalonic
acidemia, D glycericacidemia, sulfite & xanthine oxidase
deficiency, Menkes disease
• Some cases- AR inheritance
• Cases with Early Myoclonic encephalopathy with suppression burst
pattern- responds to pyridoxine

14. EARLY MYOCLONIC ENCEPHALOPATHY

15. EARLY MYOCLONIC ENCEPHALOPATHY

16. EARLY MYOCLONIC ENCEPHALOPATHY
Investigations & Prognosis
• MRI Brain OFTEN NORMAL : BUT CAN show periventricular/ cortical
atrophy/ asymmetrical ventricular enlargement
A thorough metabolic screening is mandatory.
• Metabolic screening- serum levels of amino acids-glycine & glycerol
metabolites, organic acids & amino acids in CSF
• More than ½ die within weeks/months
Psychomotor development may be abnormal from the onset of
seizures or arrests and deteriorates rapidly afterwards.
• Those who survive develop severe mental deficits

17. EARLY MYOCLONIC ENCEPHALOPATHY
Treatment
• No effective treatment
• ACTH and AED are of no benefit
• NKHG- Reduction in dietary protein and sodium benzoate -120mg/kg
• Trial with pyridoxine should be done

18. EIEE:
• Onset in the first weeks of life (around the first 10 days of life,
sometimes within the uterus or up to 3 months after birth)
• Characteristic repetitive ‘tonic spasms’ - focal or generalized
• Commonly associated with structural brain abnormalities
• EEG burst suppression pattern, > in sleep, evolves to hypsarrythmia
• Intractable to AEDs
• Neurological outcome is very poor, early death
• Evolves to WS, LGS

19. EIEE:
Etiology
• Malformation of cortical development- Hemimegalencephaly,
porencephaly, Aicardi syndrome, agenesis of mamillary bodies, FCD
• Metabolic cause – rare
• No familial cases
• Neuropathology- most severe in Ohtahara
• EEG – Burst suppression pattern -pseudorhythmicity

20. EIEE: OHTAHARA SYNDROME
Treatment
• No effective treatment
• ACTH and AED are generally not effective
• Case reports show response to zonisamide & vigabatrin
• Neurosurgery- FCD

21. EIEE

22. EIEE
Half the patients die within weeks or months of onset and the
others soon develop permanent severe mental and neurological
deficits.
In survivors, the clinical and EEG patterns change to those of
West syndrome within a few months of onset and may also change
to those of LGS if patients reach the age of 2 or 3 years.

23. EARLY INFANTILE DEVELOPMENTAL AND EPILEPTIC
ENCEPHALOPATHY (EIDEE)
Ohtahara syndrome Early myoclonic encephalopathy
Tonic spasms Erratic myoclonus, focal seizures, cluster spasms
Malformation of Cortical development Genetic and metabolic
Suppression burst both sleep and awake Accentuated by sleep
Burst Longer • Shorter
Suppression Shorter • Longer
Transformation to WS as a RULE • Common but transient

24. KCNQ2-DEE
In contrast to self-limited familial neonatal epilepsy, some individuals
with de novo missense KCNQ2 pathogenic variants develop KCNQ2-DEE.
Infants with KCNQ2-DEE present in the first week of life with an
abnormal neurologic examination (encephalopathy, hypotonia, and lack
of visual attentiveness) and severe, treatment-resistant

25. KCNQ2-DEE
Clinical features – Seizures typically begin in the first days of life in an
infant with encephalopathy and an abnormal neurologic examination.
The seizures often have a tonic semiology, myoclonic and/or focal
seizures are also seen.
Neonates with gain of function KCNQ2 variants may have prominent
nonepileptic startle-like myoclonus, in addition to encephalopathy and
severely abnormal interictal EEG background patterns.

26. KCNQ2-DEE
Evaluation and diagnosis – The interictal EEG can have abundant
multifocal negative sharp waves and/or can meet criteria for burst
suppression.
Brain MRI may reveal subtle abnormalities (T1 and T2 hyperintensity) in
the basal ganglia and thalami that can resolve after the neonatal period
No other specific imaging abnormalities are reported.
Genetic testing for KCNQ2 pathogenic variants is necessary to confirm
the diagnosis.

27. KCNQ2-DEE
●Treatment – While seizures are resistant to treatment, limited data
suggest that patients with KCNQ2 pathogenic variants may respond best
to antiseizure medications that act on sodium channels (eg,
oxcarbazepine, carbamazepine, or phenytoin)
●Clinical course and prognosis – The seizures resolve within a few
months to years in over half of patients, but affected children typically
have moderate to severe global neurodevelopmental disabilities

28. PD-DEE AND P5PD-DEE
●Pyridoxine-dependent (ALDH7A1) developmental and epileptic
encephalopathy (PD-DEE) and the related disorder, pyridoxamine 5'-
phosphate oxidase deficiency (PNPO) developmental and epileptic
encephalopathy (P5PD-DEE)
Clinical features – Most develop seizures in-utero or shortly after birth
and have co-occurring encephalopathy.
A later presentation, typically in the first three years of life, is seen in up
to one-quarter of patients, with rare patients presenting in adolescence.
Seizure types are variable: multifocal myoclonus, focal seizures, epileptic
spasms, and generalized tonic-clonic seizures.

29. PD-DEE AND P5PD-DEE
●Evaluation and diagnosis –
EEG: a burst-suppression pattern and abundant multifocal epileptiform
discharges.
Brain MRI may be normal or show white matter edema in the setting of
severe encephalopathy
Metabolic testing should not delay treatment, but biochemical
evaluation with measurement of urine and plasma alpha-aminoadipic
semialdehyde (alpha-AASA) and/or plasma pipecolic acid can aid the
diagnosis.
Genetic testing is useful to detect pathogenic variants in the ALDH7A1
or PLPB genes in PD-DEE, or the PNPO gene in P5PD-DEE.

30. PD-DEE AND P5PD-DEE
Treatment –
Seizures respond rapidly to treatment with pyridoxine and pyridoxal-5'-
phosphate. Trials of pyridoxine (100 mg IV injections, repeated every 5 to
15 min (max of 500 mg) with continuous EEG monitoring, or 15 to 30
mg/kg per day orally in three divided doses.
If there is no response to pyridoxine or PLP, leucovorin (2.5 mg IV) may
be administered. Unresponsiive to AED
Early initiation of a lysine-restricted diet may result in improved long-
term outcomes; L-arginine therapy is also a component of therapy for
this syndrome
Clinical course and prognosis – Patients can have a normal
neurodevelopmental outcome with early, appropriate treatment, but
many will experience neurodevelopmental delays.

31. QUESTION 1
(A) GABRG2 gene
(B) CHRNA4 gene
(C) SCN1A gene
(D) KCNQ3 gene
(E) LGI1 gene
A 5-day-old boy presents with clonic activity
of the arms. Complete blood count, basic
metabolic panel, blood cultures, and CSF
analysis are all normal. Lumbar puncture and
results are likewise normal. Magnetic
resonance imaging (MRI) of the brain is
performed and is also normal. On further
history, it is revealed that his father had similar
episodes when he was less than 1 week old
that spontaneously resolved before the age of
6 months. Genetic workup on the infant is
most likely to reveal a mutation within the

32. QUESTION 2
Epileptic encephalopathy with suppression
bursts is characterized by
(A) paroxysmal choreoathetosis
(B) paroxysmal polyspikes lasting several
seconds alternating with episodes of low-
amplitude tracing
(C) a spike followed by a bell-shaped slow
wave
(D) a favorable prognosis
(E) mutation in voltage-gated sodium
channels