This document provides information on epileptic encephalopathies that onset in infancy, including definitions and classifications. It describes several specific syndromes - Early Myoclonic Encephalopathy (EME), Ohtahara syndrome, West syndrome, and Dravet syndrome. EME is characterized by erratic myoclonus, focal seizures, and spasms in the first weeks of life, along with a burst suppression pattern on EEG. Ohtahara syndrome involves tonic spasms in the first months with a continuous burst suppression EEG. West syndrome consists of epileptic spasms, developmental delay/regression, and a hypsarrhythmic EEG. Dravet syndrome begins with prolonged febrile

1. Epileptic Encephalopathies
in infancy
Dr. Arghya Deb
DM (Neurology)Resident
Bangur Institute of Neurosciences, Kolkata

2. Definition
• Epileptic encephalopathies are severe brain
disorders in which the epileptic electrical
discharges may contribute to progressive
psychomotor dysfunction.
• Onset- early age and manifest with electrographic
EEG paroxysmal activity that is often aggressive
• Seizures- commonly multiform and intractable
• Cognitive, behavioural and neurological deficits
may be relentless sometimes early death.

3. • This age-related epileptogenic reaction is
peculiar to the immature brain and varies
significantly in accordance with the stage of
brain maturity at the time that this occurs.
• Thus, EEG demonstrates
– Primarily burst-suppression patterns in the
neonatal period,
– Hypsarrhythmia in infancy
– Slow generalised spike–wave discharges
(GSWD) in early childhood.
Concept

4. Classification
• The following are syndromes of epileptic
encephalopathies with onset in the neonatal
period and infancy-
1. Early myoclonic encephalopathy (EME)
2. Ohtahara syndrome (EIEE)
3. West syndrome
4. Dravet syndrome (SMEI)

5. Early Myoclonic Encephalopathy
Early myoclonic encephalopathy (EME) is a
dreadful but fortunately rare epileptic
encephalopathy of the first days and weeks
of life p/w frequent myoclonias and partial
seizures, and burst-suppression in the EEG.

6. Demographic data
• EME usually starts in the first days of life,
sometimes immediately after birth.
• More than 60% start before 10 days of age
and rarely after the second month.
• Boys and girls are affected equally.

7. Clinical manifestations
• The syndrome manifests with a triad of
intractable seizures.
1. Erratic myoclonus
2. Simple focal seizures
3. Tonic epileptic (infantile) spasms.

8. Erratic myoclonus
• Erratic or fragmentary myoclonus is the defining
seizure type that may sometimes appear
immediately after birth.
• The term ‘erratic’ is because the myoclonias shift
typically from one part of the body to another in a
random and asynchronous fashion.
• 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.

9. Other seizure types
• Simple focal seizures, often clinically
inconspicuous, manifest with eye deviation or
autonomic symptoms such as flushing of the face
or apnoea.
• Tonic seizures occur frequently and usually
appear in the first month of life. They manifest
with truncal tonic contraction, which usually also
involves the limbs. They occur during wakefulness
and sleep.
• Genuine tonic epileptic spasms are rare and
generally appear later.

10. Psychomotor development
• Psychomotor development may be abnormal
from the onset of seizures or arrests and
deteriorates rapidly afterwards.
• There may be marked truncal hypotonia, limb
hypertonia, disconjugate eye movements,
dyspnoea, or opisthotonic or decerebrate
posturing.
• All patients have bilateral pyramidal signs.
• Patients are unable to follow moving objects with
their eyes.

11. Aetiology
• High incidence of familial cases.
• In some there is an AR inheritance.
• Inborn errors of metabolism are the M/C causes,
which also explains the high incidence of siblings
with this disorder.
• These inborn errors of metabolism include non-
ketotic hyperglycinaemia, propionic aciduria,
methyl malonic acidaemia, Menkes’ disease and
Zellweger syndrome, molybdenum co-factor
deficiency etc.

12. Diagnostic Procedures
• Brain imaging is usually normal at the onset of
the disease but progressive cortical and
periventricular atrophy often develop.
• Malformations of cortical development are very
rare.
• A thorough metabolic screening is mandatory.
• This should include serum levels of amino acids
and particularly glycine & glycerol metabolites,
organic acids and amino acids in the
cerebrospinal fluid.

13. Electroencephalography
• Inter-ictal EEG consists of a repetitive burst
suppression pattern without physiological
rhythms.
• The bursts of high-amplitude spikes and
sharp-and-slow waves last for 1–5 s and
alternate with periods of a flat or almost flat
EEG, lasting 3–10 s.
• In most cases the burst-suppression pattern
becomes more apparent during deep sleep
and may not occur in the EEG of wakefulness.

14. Awake EEG showing Mutifocal spikes in the disorganized
background activity (EME)

15. Sleep EEG showing burst-suppression pattern (EME)

16. DDx, Prognosis, & Rx
• Main differential dx is Ohtahara syndrome
• More than half the patients die within weeks or
months of onset and the others develop
permanent severe mental and neurological
deficits.
• ACTH therapy and AEDs are of no benefit.
• Patients with non-ketotic hyperglycinaemia may
benefit from a reduction in dietary protein and
administration of sodium benzoate 120 mg/kg
daily, although the outcome is commonly very
poor.
• A trial with pyridoxine is justifiable.

17. Ohtahara Syndrome
Synonym: Early Infantile Epileptic
Encephalopathy with Suppression Burst
(EIEE-SB)

18. Clinical manifestations
• Onset is mainly around the first 10 days of life,
sometimes within the uterus or up to 3 months
after birth.
• Tonic spasms usually consist of a forward tonic
flexion lasting 1–10 s, which is singular or in long
clusters 10–300 times every 24 h.
• They may be generalised and symmetrical or
lateralised.
• They occur in both the awake and sleep stages.
• Less often, a third of the neonates may have
erratic focal motor clonic seizures or
hemiconvulsions.
• Erratic myoclonias are not featured.

19. Aetiology & Diagnostics
• M/C cause is malformations of cerebral
development s/a hemimegalencephaly,
porencephaly, focal cortical dysplasia etc.
• Brain imaging usually shows severe
abnormalities and malformations of cortical
development.
• Metabolic screening is mandatory if brain
imaging is normal.

20. Electroencephalography
• The EEG burst-suppression pattern has a
pseudorhythmic periodicity, is continuous
during wakefulness and sleep, appears at the
onset of the disease and disappears within the
first 6 months of life.
• The bursts consist of high-amplitude slow waves
mixed with spikes lasting for 2–6 s.
• The suppression period of a flat or almost-flat
EEG lasts for 3–5 s.
• The interval between the onsets of two
successive bursts is in the range of 5–10 s.

21. Awake EEG: Burst-suppression pattern with
Pseudorhythmic periodicity

22. Sleep EEG: Continuous & consistent S-B pattern
with pseudorhythmic periodicity

23. Differentials
“Tonic seizures during the awake & sleep stages in the early
days or weeks of life are almost pathognomic of Otahara
syndrome”

24. Prognosis & Management
• 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.
• ACTH therapy and any type of AEDs are of no
benefit.
• Neurosurgery in focal cerebral dysplasia is
sometimes beneficial

25. West Syndrome

26. Definition
• It is characterised by a unique type of seizure
called epileptic (infantile) spasms and gross
EEG abnormalities of hypsarrhythmia.
• West syndrome is commonly used
synonymously with infantile spasms. However,
infantile spasms refer to a type of seizures
(preferably called ‘epileptic spasms’), which
are common but not exclusive for West
syndrome.

27. Clinical features
• Onset is between 3 and 12 months (peak at 5
months) in 90% of cases.
• Males (60–70%) predominate.
• Usually starts insidiously with mild epileptic
spasms occurring 2 or 3 times in succession.
• The full-blown features develop in a few
weeks with spasms typically occurring in
clusters of 1–30 per day, with each cluster
having 20–150 attacks.

28. Description of spasms
• The epileptic spasms are clusters of sudden, brief
(0.2–2 s), bilateral tonic contractions of the axial
and limb muscles.
• They are slower than myoclonic jerks and faster
than tonic seizures.
• They may involve widespread muscle groups or
be fragmented, involving flexion of the neck only
(bobbing of the head), abdomen (mild bending)
or just the shoulders (a shrug-like movement).
• The force is usually violent, but it may also be
mild or intermediate.

29. Cont.
• The spasm is often followed by motion-
lessness and diminished responsiveness
lasting up to 90 s.
• On rare occasions this ‘arrest’ effect
constitutes the entire seizure.
• Alteration and pauses of respiration during
the spasms are common (60%), whereas
changes in heart rate are rare.
• A cry or laughter often follows the end of the
attacks.

30. Types of spasm
• Each infant has more than one type of spasm,
which may also be influenced by body
positions.
1. Flexor spasms (aka ‘salaam spasms’) are
common (≈ 40% of all)
– There is abrupt flexion of the neck and the trunk,
– the arms raise forwards or sideways sometimes
with flexion at the elbows, and
– the legs are elevated with flexion at the hips and
knees.

31. Cont.
2. Extensor spasms are less frequent (≈20%),
– Sudden backwards movements of the head
– Hyperextension of the body, and
– Extension and abduction of the limbs similar to
the Moro reflex.
3. Flexor–extensor spasms are the most common
spasms (≈ 50%), and combine
– Sudden contraction of both flexor and extensor
muscles with flexion of the neck, trunk and arms,
but extension of the legs.

32. Salient points
• Epileptic spasms are usually symmetrical, although
1–30% may have lateralising features with the head
or eyes turned to one side or one limb consistently
moving more vigorously.
• However, asymmetrical, lateralised or unilateral
spasms are highly correlated with contralateral
cerebral lesions of symptomatic West syndrome.
• The epileptic spasms predominantly occur on
arousal and in alert states, less often during NREM
sleep (3%) and exceptionally during REM sleep.
• Sudden loud noises or tactile stimulation, but not
photic stimulation, may precipitate spasms.

33. Psychomotor development
• Developmental delay, mild or severe,
predates the onset of spasms in 2/3rd of
cases. In the other third, the infants are
normal before the onset of epileptic spasms.
• Deterioration of psychomotor development
usually occurs with the onset of epileptic
spasms and affects head control, reaching for
objects and eye tracking.

34. Classification
1. Symptomatic West syndrome (80%) due to
discernible organic insults. It is by far the M/C.
2. Probably symptomatic (Cryptogenic) West
syndrome (10–15%). With improved technology,
their prevalence is declining as their causes are
increasingly being documented.
3. Idiopathic West syndrome (5–30%), with normal
pre-morbid development and possible hereditary
predisposition s/a a family history of epilepsy,
febrile seizures or EEG genetic patterns.

35. Main causes of Symptomatic West syndrome
• Pre-, peri- and postnatal brain ischemia are
probably the m/c cause, responsible for 20-80%
cases of SWS.
• Brain congenital anomaly in third of cases
• Half of all pts with Tuberous sclerosis may have
epileptic spasm (7-25% of SWS)
• Congenital (TORCH) or acquired infections
• Chromosomal abnormality
• Inborn errors of metabolism
• Hypothalamic hamartoma, occasionally

36. Pathophysiology
• Poorly understood- proposed hypotheses are:
1. Brainstem dysfunction: by an abnormal
functional interaction between the brainstem
(raphe nuclei) and a focal or diffuse cortical
abnormality.
2. Immunological dysfunction:
– Presence of Abs to extracts of normal brain
tissue
– increased numbers of activated B cells and T cells
in the peripheral blood
– Abnormal leukocyte antigen studies in patients
with infantile spasms compared with control
subjects

37. Cont.
3. Role of CRH: Stress or injury during early
infancy results in the release of excess
amounts of CRH, which in the presence of an
abundance of CRH receptors, produces
epileptogenic alterations in the brainstem
pathways that result in spasms.
 The therapeutic benefit of corticosteroids and
ACTH in this disorder would be secondary to
the suppression of CRH synthesis by these
hormones.

38. Diagnostic procedures
1. A thorough clinical neurodevelopment assessment
and ophthalmological and ultraviolet skin
examination.
2. Neuroimaging- CT/MRI/PET
3. Electroencephalography
4. Urine and serum amino acid screening and serum
ammonia, organic acid, lactate, pyruvate and liver
function tests.
5. TORCH screening, CSF analysis.
6. Chromosome analysis.
In unexplained
cases

39. West Syndrome- EEG
• Hypsarrhythmia (hypsos = high) is the archetypal
inter-ictal EEG pattern and occurs in 2/3rd of pts.
• This EEG pattern is a chaotic mixture of giant
abnormal, arrhythmic and asynchronous biological
brain electrical activity of slow and sharp waves,
multi-focal spikes and polyspikes.
• As a result of their high amplitude, individual
components and localisation are impossible to
detect at routine sensitivity recordings of 100μV/cm
• There are no recognisable normal rhythms.

40. Typical hypsarrhythmic pattern seen with regular EEG sensitivity

41. Same EEG sample at reduced EEG sensitivity

42. Cont.
• Asymmetrical and other patterns of modified
or atypical hypsarrhythmia occur in 1/3rd of
cases.
• REM sleep shows relative EEG normalisation.
• In NREM sleep, hypsarrhythmia becomes
fragmented and presents with discontinuous,
repetitive, high amplitude discharges of
spikes/polyspikes and slow waves, which are
more synchronous than in the awake-stage
EEG.

43. DDx
1. Exaggerated startle responses
2. ‘Colic and abdominal pain’
3. Benign myoclonus of early infancy
4. Benign neonatal sleep myoclonus
5. Sandifer syndrome of gastro-oesophageal
reflux
• Recognition of epileptic spasms is easy due
to the characteristics of the individual attacks
and mainly their clustering, often on arousal.
Singular events are rare.

44. Prognosis
• 60% pts develop other types of seizure that are
usually resistant to treatment. Lennox–Gastaut
type and complex focal seizures are the M/C.
• Half of the pts have permanent motor disabilities,
and 2/3rd have, usually severe, cognitive &
psychological impairment.
• Only about 5–12% of pts have normal mental and
motor development.
• The consensus is that idiopathic and cryptogenic
West syndrome have a significantly better
prognosis than symptomatic cases, with 15–30%
of patients achieving relative normality.

45. West Syndrome- Treatment
ACTH and less often corticosteroids or vigabatrin
(in c/o TS) are the drug of chioce, controlling the
epileptic spasms in 2/3rd of patients within days of
initiating any of these medications.
Lamotrigine, levetiracetam, nitrazepam,
pyridoxine, topiramate, valproate & zonisamide
are also used as adjunctive medications when
ACTH and vigabatrin fail.
Resective neurosurgery may be the desperate
solution in intractable cases with localised
structural lesions.

47. Approach

48. Dravet syndrome
Synonym: Severe Myoclonic Epilepsy
In Infancy (SMEI)

49. Clinical features
• Onset is always within the first year of life, with a peak
age at 5 months, affecting previously normal children.
• Twice as many boys are affected.
• Dravet syndrome is characterised by a tetrad of
seizures, which is seen in more than half of cases:
1. Early infantile febrile clonic convulsions
2. Myoclonic jerks
3. Atypical absences
4. Complex focal seizures
Convulsive, myoclonic or absence status epilepticus are
frequent.

50. Three periods of evolution in Dravet syndrome
The first period is relatively mild (the pre-seismic
period), it lasts for 2 weeks to 6 months and manifests
mainly with febrile clonic convulsions.
• These are mainly unilateral and less often generalised.
• They are usually long (10 min) progressing to CSE in
about a quarter of cases.
• In 3/4th of pts seizures are usually provoked by
hyperthermia of around 38°C, minor infections,
immunisations or hot baths.
• The remaining 1/4th of pts have non-febrile seizures.
• These seizures recur frequently within 6–8 weeks.

51. The second period is relentlessly aggressive (the
seismic period) with the emergence of other
multiple-seizure types and severe neurocognitive
deterioration.
• Various forms of febrile and non-febrile convulsive
seizures, myoclonic jerks, atypical absences and
complex focal seizures occur on a daily basis and
frequently evolve to status epilepticus.
• Cognitive and neurological deterioration is variable
but usually severe. It develops between the second
and sixth years and remains stable later.
The third period is static (the post-seismic period).
The seizures may improve, but serious mental and
neurological abnormalities are irreversible.

52. Seizure-precipitating factors
• Hyperthermia (febrile illnesses, warm
environment, hot baths) is a frequent
precipitating factor, particularly at onset of
seizures, but this may continue in adolescence
(‘febrile seizures plus’).
• Photic and pattern stimulation, movements and
eye closure precipitate GSWD, myoclonic jerks
and absence seizures.
• A quarter of patients have self-induced seizures
by hand waving or pattern stimulation.

53. Aetiology
• Dravet syndrome is mostly genetically
determined, but the mode of inheritance is
unknown.
• Approximately half of patients have a family
history of various epileptic syndromes
(including IGE) and mainly febrile seizures.
• Mutations in the voltage-gated sodium
channel gene SCN1A were found in a high
percentage (range 35–100%) of pts with
Dravet syndrome.

54. Diagnostic procedures
• There is no metabolic abnormality.
• Tissue biopsies are normal.
• Genetic testing: a severe SCN1A gene defect, if
present, is strongly supportive but not diagnostic
of Dravet syndrome.
• Brain CT and MRI scans are either normal or
show mild cerebral or cerebellar atrophy.
• Functioning brain imaging may be normal or
show focal hypoperfusion and hypometabolism,
even when the MRI is normal.

55. Electroencephalography
• The inter-ictal EEG may initially be normal, but 20% show
generalised photoparoxysmal responses.
• Within 1 year the EEG becomes very abN in 2/3rd of pts.
• The background progressively deteriorates with diffuse
theta and delta waves. Brief asymmetrical paroxysms of
poly spike/spike–slow-wave discharges (GPSWD) usually
dominate the EEG.
• Focal and mainly multi-focal abnormalities of sharp or
slow spike-waves are frequent.
• Photoparoxysmal discharges occur in 40% of patients but
persist in less than 5%.
• Eye closure and pattern stimulation may also induce
generalised discharges and myoclonic jerks.

57. Management
• Seizures are intractable. AEDs may reduce them but do
not control them.
• VPA, BZD, PB (in convulsive seizures), ETX (in absence
and myoclonic seizures) and bromides are temporarily
beneficial.
• CBZ, PHT, & LMZ are contraindicated.
• Of the newer AEDs, topiramate, stiripentol, zonisamide
and levetiracetam have been found to be useful.
• Stiripentol has been recently licensed in 2009 to use in
conjunction with CLB and VPA as adjunctive therapy for
refractory GTCS in Dravet syndrome.
• A ketogenic diet is beneficial, starting as early as
possible.

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