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1. Epileptic encephalopathies
Presented by : Dr. Sachin Adukia
Moderator: Dr. Gopal Krishna Dash

2. Content
 Definition
 Shared features
 Classification
 Syndromes
 Clinical features
 EEGs
 Treatment
 Prognosis

3. Epileptic encephalopathies
 Definition:
heterogeneous group of epileptic disorders in which epileptic activity itself (ictal or
interictal) impairs cognitive and behavioral function above and beyond what is
expected from the underlying pathology alone
 Underlying assumption is that aggressive ictal (seizure) and electrical
(electrographic) epileptogenic activity during brain maturation is the main
causative factor of progressive cognitive and neuropsychological deterioration
 All epileptic encephalopathies have a tendency to abate, discontinue or even stop
in adolescence but often with serious neurocognitive residuals

4.  Common features
 start at an early age
 manifest with electrographic EEG paroxysmal activity that is often aggressive
 multiform and intractable seizures usually
 cognitive, behavioural and neurological deficits that may be relentless
 sometimes early death
 EEG changes vary as per brain maturity
 burst-suppression in neonatal
 hypsarrhythmia in infancy
 and slow generalised spike–wave discharges (GSWD) in early childhood

6. Electro-clinical syndromes by age at onset
 Neonatal period
Benign familial neonatal seizures (BFNS)
Early myoclonic encephalopathy (EME)
Ohtahara syndrome
 Infancy
Migrating partial seizures of infancy
West syndrome
LGS, epileptic encephalopathy with CSWS including LKS
Benign infantile seizures
Benign familial infantile seizures
Dravet syndrome
Myoclonic encephalopathy in nonprogressive disorders

7. Epileptic encephalopathies include
 early myoclonic encephalopathy
 Ohtahara syndrome
 West syndrome
 Dravet syndrome
 Lennox– Gastaut syndrome
 epileptic encephalopathy with CSWS including Landau–Kleffner syndrome (LKS)
 myoclonic encephalopathy in non-progressive disorders

8.  Syndromes will be discussed as under:
 Brief description
 Age of onset
 Gender
 Incidence
 causes
 Seizure phenotype and variants
 EEG
 Treatment
 Prognosis

9. Early myoclonic encephalopathy
 The syndrome manifests with a triad of intractable seizures.
 Erratic myoclonus appears first, followed by simple focal seizures and later
tonic epileptic (infantile) spasms
 Age: usually starts in the first days of life, sometimes immediately after birth
 Gender: M=F
 prevalence and incidence are unknown
 Causes
 Inborn errors of metabolism: non-ketotic hyperglycinaemia, propionic aciduria,
methyl malonic acidaemia, D-glyceric acidaemia
 Familial: autosomal recessive

10. Clinical features
 Erratic or fragmentary myoclonus is the defining seizure: erratic as it shifts
from one body part to another:- face, limb, finger, toe, eyelid, eyebrow, lips
 Simple focal seizures: eye deviation or autonomic symptoms such as flushing
of the face or apnoea
 Tonic seizures usually appear in the first month of life with truncal tonic
contraction, usually also involves limbs
 Psychomotor development may be abnormal from the onset of seizures or
arrests and deteriorates rapidly afterwards
 All patients have bilateral pyramidal signs.
 there is no trace of intelligent activity

11. EEG
 Inter-ictal EEG consists of a repetitive BSP without physiological rhythms
 BSP is probably exacerbated by sleep and does not continue in wakefulness
 BSP evolves to atypical hypsarrhythmia or multifocal spikes and sharp waves
3 or 4 months from onset of the disease
 However, atypical hypsarrhythmia is transient and returns to BSP, which
persists for a long time

12. Burst suppression

13. Investigations
 CT / MRI
 Metabolic screen
 serum levels of amino acids, glycine and glycerol metabolites
 organic acids and amino acids in CSF

15. Treatment and prognosis
 There is no effective treatment
 AED, ACTH are not effective
 50% die within weeks or months of onset
 50% develop permanent severe mental & neurological deficits

16. Ohtahara syndrome
(Early infantile epileptic encephalopathy)
 Clinico-EEG features are mainly tonic spasms and continuous BSP occurring
in the sleeping and wakeful states.
 Onset is mainly around the first 10 days of life, sometimes within the uterus or up
to 3 months after birth
 Gender: slight male predominance
 Incidence is unknown as it is a rare disorder
 Causes:
 cerebral development such as hemimegaloencephaly, porencephaly, FCD
 metabolic disorders, genetic
 Investigations: Imaging, metabolic screening
Genetic testing: STXBP1 is seen in 13 to 38% cases

17. Clinical features
 Tonic spasms consist of a forward tonic flexion lasting 1–10 sec: singular or in long
clusters 10–300 times every 24 h
 generalised and symmetrical or lateralised
 1/3rd neonates may have erratic focal motor clonic seizures or hemiconvulsions

18. EEG
 BSP has a pseudorhythmic periodicity, is continuous during wakefulness and sleep
 appears at onset of disease and disappears within first 6 months of life
 Bursts consist of high-amplitude slow waves mixed with spikes lasting 2–6 s
 Suppression period of a flat or almost-flat EEG lasts for 3–5 s
 interval between the onsets of two successive bursts is 5–10 s
 Tonic spasms of variable duration are concomitant with the burst phase

21. Treatment and prognosis
 There is no effective treatment.
 ACTH and AEDs are of no benefit
 Neurosurgery in FCD is sometimes beneficial
PROGNOSIS
 50% die within weeks or months of onset
 50% develop permanent severe mental & neurological deficits
 In survivors, the clinical and EEG patterns change to West syndrome in a few
months and then to LGS at age 2 to 3 years if they survive

23. West syndrome
 Brief description
triad of (1) epileptic spasms, (2) hypsarrhythmia, and (3) arrest or regression
of psychomotor development.
 Age of onset: between 3 and 12 months (peak at 5 months) in 90%
 Gender Males (60–70%) predominate.
 Incidence 3–5 per 10,000 live births

24. Causes
 Pre, peri and post brain ischemia
 Brain congenital anomalies
 Tuberous sclerosis
 Focal cortical dysplasia
 Chromosomal abnormalities: Down’s syndrome
 Congenital and acquired infections
 CMV, rubella, HSV, adenovirus
 Meningococci, pneumococci
 Inborn errors of metabolism
 Rarely, hypothalmic hamartoma
 Cryptogenic (10 to 15%) and idiopathic (5 to 30%)

25. Seizure phenotype and variant
 spasms typically occur in clusters of 1–30 /day, with each cluster having 20–150
spasms
 epileptic spasms are clusters of sudden, brief (0.2–2 s), bilateral tonic
contractions of the axial and limb muscles
 spasm is f/b motionlessness and diminished responsiveness lasting up to 90 s
 spasms are usually symmetrical
 Asymmetrical or unilateral spasms correlate with contralateral cerebral lesions of
symptomatic West syndrome
 Spasms are flexor extensor (50%- commonest), flexor (40%), or extensor (10 -20%)
 Focal seizures may precede or follow spasms and should suggest an underlying
focal pathology

26. Investigations
 CT/ MRI/ PET Scan
 Ophthalmological and UV skin examination – Woods lamp- for tuberous sclerosis
 Chromosomal studies
 Infectious disease including CSF
• Neurometabolic tests:
• Ammonia,
• Lactate, Pyruvate
• Urine and serum amino acid screening
• Organic acid
• LFT,
• Serum electrolytes

27. EEG
 chaotic mixture of giant abnormal, arrhythmic and asynchronous electrical
activity of slow and sharp waves, multi-focal spikes and polyspikes.
 There are no recognisable normal rhythms.
 Symmetrical in cryptogenic or idiopathic cases
 Asymmetrical in structural cases
 Progress of hypsarrhythmic EEG patterns with age:
 chaotic hypsarrhythmic pattern gradually becomes more organised, and
disappears with age.
 By age 2 and 4 years, is replaced by slow GSWD pattern of LGS
 Multi-focal independent spikes appear first, f/b gen. spike discharges from
where the slow GSWD of LGS emerges.

28. Ictal EEG patterns
 last for 0.5 s to 2 min.
 characteristic pattern in 72% consists of
(1) a high-voltage, generalised slow wave,
(2) episodic, low-amplitude fast beta activity and
(3) marked diffuse attenuation of EEG electrical activity (electro decremental ictal
EEG pattern)

34. Treatment
 First-line treatments: ACTH, prednisolone, or vigabatrin.
 Vigabatrin
 treatment of choice in tuberous sclerosis, seizure cessation s/i 95% cases
 also effective in FCD
 ACTH may have greater short-term efficacy than vigabatrin once tuberous
sclerosis is excluded- induces Sz remission in about 60 to 75% cases
 In focal cortical structural abnormalities, possible surgical therapy is indicated if
both hormonal therapy and vigabatrin fail
?? Corticotropin may have direct anticonvulsant effects, perhaps via suppression of
corticotropin-releasing hormone that may provoke convulsions in immature brain.

36. Prognosis
 idiopathic and cryptogenic have significantly better prognosis than symptomatic (54%
versus 12.5%)
 Relatively favorable symptomatic etiologies include
 Down’s syndrome,
 Neurofibromatosis type 1,
 preterm infants with periventricular leukomalacia
 neonatal hypoglycemia.
 Additional factors predictive of better outcome include
 Shorter treatment lag
 favorable response to initial therapy
 absence of other seizure types prior to spasms
 absence of atypical spasms, focal seizures, or asymmetric EEG abnormalities

37. Dravet syndrome
 severe myoclonic epilepsy in infancy.
 rare progressive epileptic encephalopathy that is genetically determined
 Affecting previously normal children
 Onset - always within first year of life, peak age at 5 months
 Gender M: F is 1:1
 Incidence 1 per 40,900 infants

38. Clinical features
 Dravet syndrome is characterized by a tetrad of seizures, s/i >50% cases:
 early infantile febrile clonic convulsions
 myoclonic jerks
 atypical absences
 complex focal seizures.
 Convulsive, myoclonic or absence status epilepticus are frequent.
 Classically, seizures switch sides, starting on the right with some and the left with others;
this alternating pattern is highly suggestive of Dravet syndrome.

39. First period: Pre-seismic period
 lasts for 2 weeks to 6 months and manifests mainly with febrile clonic convulsions
intermixed with some tonic components.
 These are mainly unilateral and less often generalised. Lasting upto 10 min
 Progress to convulsive status epilepticus in 25%

40. Second period - seismic period
 relentlessly aggressive , 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

41. Third period - Post-seismic period
 static period
 seizures may improve, but serious mental and neurological abnormalities are
irreversible

42. EEG findings in Dravet syndrome are not specific.
 background is normal at epilepsy onset, but by 1 to 2 years of age, most patients
show diffuse background theta slowing.
 Epileptiform discharges (usually generalized) are seen in 25% at epilepsy onset.
 Between age 2 -5 yrs, an increase in paroxysmal abnormalities (which can be
generalized, focal, or multifocal) is seen.
 Photic stimulation and eye closure may elicit discharges in 25%

43. Dravet syndrome

46. Investigations
 SCN1A sequencing
 No metabolic abnormailites
 Brain CT and MRI scans are either normal or show mild cerebral or cerebellar
atrophy, hippocampal sclerosis, loss of gray- white differentiation.
 Functioning brain imaging may show focal hypoperfusion and hypometabolism,
even when MRI normal

47. Treatment: extremely pharmacoresistant
 First line drugs are valproic acid or clobazam
 topiramate, levetiracetam, and possibly zonisamide may also have efficacy
 Stiripentol is often considered if firstline therapy is ineffective
 Sodium channel blocking agents are avoided , including CRBZ,
oxcarbazepine, lamotrigine, and phenytoin, as they exacerbate seizures
 ketogenic diet:
 a high fat, adequate-protein (1 gram/kg), low-carbohydrate diet that produces
metabolic changes often associated with the starvation state, but which of these
metabolic changes induces Sz reduction is not known
 prevented by early treatment of infectious diseases and hyperthermia
 avoidance of precipitating factors like ambient hot temperatures

48. Prognosis
 Cognitive and neurological deterioration is usually severe.
 It develops between the second and sixth years and remains stable later.
 Neurological deficits consist of ataxia, pyramidal symptoms and paroxysmal
movements
 worsening and progression of the symptoms usually comes to a halt at around
the age of 11 or 12 years

49. Lennox–Gastaut syndrome
 the triad of:
 polymorphic intractable seizures that are mainly tonic, atonic and atypical absence
seizures
 cognitive and behavioural abnormalities
 EEG with paroxysms of fast activity and slow (<2.5 Hz) GSWD
 Age of onset between 1 to 7 years with peak at 3 to 5 years
 Gender Male : female 3:2
 Incidence 2.8 per 10,000
 Causes of LGS are similar to West syndrome with 1/3rd being cryptogenic or idiopathic
 Investigations are similar to West syndrome but MRI/PET are almost always abnormal

50. Clinical features
 Commonest Sz are tonic fits, atypical absences and atonic seizures, in that order.
 Myoclonic jerks occur in 11–28% alone or in combination with other seizures.
 Cognitive & behavioural abnormalities are present before seizure onset in 20–60%
 50% West syndrome and other infantile epileptic encephalopathies progress to LGS

51. EEG
 EEGs of abnormal background contain paroxysms of fast rhythms characterising
tonic seizures and slow (<2.5 Hz) GSWD characterising atypical absences

52. LGS- Tonic seizure with generalized spike and fast activity with EMG changes

53. LGS- Generalized Paroxysmal Fast Activity and intermittent suppression

54. Lennox Gastaut Syndrome (LGS) – Multifocal spike and wave discharges

60. Management strategy
 include the following elements:
 Appropriate AED
 Tonic Sz- difficult to treat
 Atypical absences, myoclonic and atonic seizures are more amenable to Rx
 treatment of behavioural and cognitive problems with educational programmes
 physical therapy
 family support

64. Prognosis
 5% die
 80–90% continue having seizures in adult life
 85–92% have severely impaired cognition and behaviour
 Cognitive impairment is more likely
 in symptomatic or West syndrome-related cases,
 when the onset is before 3 years of age,
 Frequent seizures and status epilepticus occur
 constantly EEG background showing Localised and multifocal EEG
abnormalities

65. Landau–Kleffner syndrome
 LKS is a partly reversible, epileptic encephalopathy of childhood manifesting with
acquired verbal auditory agnosia and other predominantly linguistic deficits that often
occur together with other cognitive and neuropsychological behavioural abnormalities.
 Seizures are infrequent and not a prerequisite for LKS
 Onset is at age 2–8 years (peak at 5–7).
 Gender male to female ratio 2:1.
 Incidence One or two cases are seen every year in highly specialised centres
 Etiology is unknown
 MRI is often normal

66. Clinical features
 verbal auditory agnosia, occurring in an initially normal child who had
achieved developmental milestones and had already acquired age-appropriate
speech
 parents notice a gradual inability of the child to respond to their calls despite
raising their voices
 Later complete word deafness; and non linguistic sounds like door bell
 Finally may become entirely mute
 Behavioral disorders such as hyperactivity and attention deficit are common
 Seizures are mainly nocturnal and often heterogeneous
 atypical absences, atonic seizures with head drop, minor automatisms and
secondarily GTCSs are reported

67. EEG
 The EEG is characterised by mainly posterior temporal lobe foci of sharp–slow-
wave complexes that are often multi-focal and bisynchronous
 CSWS is not a pre-requiste for diagnosis

69. Right posterior Temporal predominant

70. Treatment
 valproate is the first line option, usually in combination with clobazam
 phenytoin, phenobarbital and carbamazepine may worsen the EEG discharges and
neuropsychological deficit
 ? ACTH
 ? Prednisolone
 ? Ketogenic diet
 ? multiple subpial intracortical transections in medically refractory cases

71. Prognosis
 Seizures and EEG abnormalities are age dependent and often remit by age 15 yrs
 Language and other neuropsychological improvement corresponds to
disappearance of EEG epileptiform activity
 50% can live a relatively normal life

72. Epileptic encephalopathy with CSWS
 Triad of:
 EEG CSWS
 seizures
 neuropsychological impairment
 CSW during NREM sleep is a prerequisite for diagnosis
 Onset of Sz: between 2 months and 12 years
 Onset of EEG abnormality: age 1 to 2 years, peak at 8 years
 Gender Males 62%
 Etiology- unknown
 Pathology : 1/3rd have unilateral or diffuse cortical atrophy, focal porencephaly and
malformations of cortical development as can be seen on CT / MRI / PET

73. Clinical features
 50% are normal before onset of disease.
 50% have pre- or perinatal illness, neonatal convulsions and neurological
abnormalities such as congenital hemiparesis or tetraparesis, ataxia, psychomotor
or language deficits
 acquired deterioration of cognitive function with CSWS is probably by an
alteration of maturation of one or several associative cortices, primarily involving
local interneurones and cortico-cortical associative networks
 Linguistic impairment : d/t epileptogenic foci over one or both temporal lobes
 Mental deterioration and autistic behaviour : d/t frontal lobe epileptogenic
foci
 Motor impairment such as dyspraxia and dystonia: d/t dysfunction of motor
cortex

74.  3 stages:
 First stage - before the discovery of CSWS
 hemiclonic status epilepticus: unilateral, nocturnal, >30 min
 Second stage - with CSWS
 Increased freq of Sz, new types of Sz like GTCS, absences, NCSE, atonic Sz
 Tonic Sz are incompatible with diagnosis of CSWS
 Frontal or prefrontal CSWS:
 damages cognitive skills, executive functioning, language
 Presents as hyperkinesia, agitation, disinhibition, aggressiveness,
inattention
 Temporal CSWS- linguistic disturbances: expressive aphasia rather than
verbal auditory agnosia
 Motor disturbances consist of ataxia, hemiparesis and dyspraxia
 Third stage of clinico-EEG remission starts after usually 2–7 years from onset

75. EEG
 First stage:
•Inter-ictal awake EEG shows focal or multifocal slow spikes in more than
two-thirds of patients, mainly localized in the fronto-temporal centro-temporal
and less often in the parieto-occipital electrodes
•These are activated by sleep without altering their morphology
• Second stage
•Characteristic EEG pattern in this stage occurs during sleep
•Continuous spikes and waves during NREM sleep are the defining EEG pattern
continuous or almost continuous, bilateral and bisynchronous sharp–slow
waves with a rate of 1.5 to 2 Hz
•higher amplitude in the anterior or central regions
• Third stage
•Progressive improvement is seen towards normalization, may take >15 yrs

76. CSWS - awake

77. CSWS sleep

78. Awake Sleep
100
µv
1
sec

79.  Management is similar to LKS

80. Prognosis
 Spontaneous resolution of epileptiform discharges and seizures occurs in the mid-
teens, coinciding with stabilisation or improvement of behavioural and
neuropsychological deficits
 Seizures reduce and finally remit in all, commonly by age 10–15
 Cognitive and behavioural abnormalities show a global improvement, starting
after the end of CSWS, but is partial: never return to normal functioning in
language and attention
 < 25% return to acceptable social and professional levels

82. Myoclonic encephalopathy in non-progressive
disorders
 c/b
 a fixed, non-progressive encephalopathy
 recurrent episodes of prolonged and erratic atypical myoclonic-absense status
epilepticus
 Onset is from day 1 of life to 5 years of age (peak at 12 months).
 Gender : M:F is 1:2
 Incidence is unknown
 Causes
 Angelman and 4p syndromes (50%)
 Pre- or perinatal brain hypoxia, malformations of cortical development (20%)
 Investigations: MRI, chromosomal analysis and metabolic screening

83. Clinical features
 fixed encephalopathy characterised by severe axial hypotonia, ataxia,
continuous jerky movements, tremor, and severe cognitive and learning
abnormalities
 seizure :- repetitive and long (sometimes for days) episodes of atypical and subtle
myoclonic status epilepticus, consisting of myoclonic jerks and discontinuous
absences

84. EEG
 The inter-ictal EEG is diffusely slow with frequent focal or multi-focal
abnormalities of slow waves and spikes
 The ictal EEG shows continuous or subcontinuous brief bursts of diffuse slow
spikes and waves.

85. Treatment & Prognosis
 In chromosomal abnormalities : some beneficial effect of valproate combined with
ethosuximide or clobazam, but ACTH treatment is often needed
 Prognosis is poor even for those who initially appear only hypotonic
 hypotonic state progressively deteriorates to, sometimes severe, neurocognitive
deficits

88. References
 Panayiotopoulos CP. A clinical guide to epileptic syndromes and their treatment:
Based on the new ILAE diagnostic scheme. Bladon Medical Pub; 2002.
 Wirrell E. Infantile, childhood, and adolescent epilepsies. CONTINUUM: Lifelong
Learning in Neurology. 2016 Feb 1;22(1, Epilepsy):60-93
 Hussain SA. Epileptic encephalopathies. CONTINUUM: Lifelong Learning in
Neurology. 2018 Feb 1;24(1, Child Neurology):171-85.

90. Thank You