Epileptic encephalopathy

1. EPILEPTIC
ENCEPHALOPATHIES
DR SOORAJ PATIL
SR NEUROLOGY
IMS BHU
Moderator- Prof Deepika Joshi

2. LEARNING OBJECTIVES
• Definition of epileptic encephalopathy
• Classification according to age
• Brief overview of each epileptic encephalopathy syndromes
• EEG features and treatment

3. DEFINITION
• Epileptic Encephalopathy is defined as condition in which
Epileptiform activity itself contributes to severe
cognitive and behavior impairments and beyond what might
be expected from the underlying pathology alone ( eg. Cortical
Dysplasia )
ILAE classification of the epilepsies: Position paper of the ILAE Commission for
Classification and Terminology Ingrid E. Scheffer- 2017

4. DEFINITION
• A group of heterogeneous brain disorders occurring at a critical
period of brain development, where frequent abnormal ictal
and/or interictal EEG epileptiform activity is mainly responsible
for behavioural, cognitive and motor regression
• (1) Electrographic EEG paroxysmal activity that is often aggressive
• (2) Seizures that are usually multi-form and intractable
• (3) Cognitive, behavioural, and neurological deficits that may be
relentless, sometimes early death
EPILEPSY FOUNDATION 2017

6. Ohtahara
Syndrome
Early Myoclonic
Encephalopathy
West Syndrome
Dravet Syndrome
Myoclonic Status
In Non Progressive
Encephalopathies
Lennox -Gastaut
Syndrome
Landau -Kleffner
Syndrome
Epilepsy With
CSWS
Rassmussen
encephalitis
Neonatal Infantile Childhood

7. “Age-related” epileptic encephalopathy
Progressive maturation of the various areas of the
brain
Early and late childhood
Late-
onset
epilepti
c
spasms
in
clusters
Lennox–
Gastaut
syndrome
infancy
West
syndrom
e
neonatal period
Early epileptic
encephalopathy

8. EARLY INFANTILE EPILEPTIC
ENCEPHALOPATHY/OHTAHARA SYNDROME
• Neonatal onset 10 days to 3 months of age, some times intrauterine
seizures
• Static structural brain damage most common
• Tonic spasm > Generalized /Lateralized, tonic clonic, myoclonic, atonic,
absences, partial, gelastic, and Jacksonians
• Disorder progressively deteriorates with increasing frequency of seizures
and severe Psychomotor Retardation
Diagnosis and Management of Epileptic Encephalopathies in Children
Puneet Jain Suvasini Sharma and Manjari Tripathi- EPILEPSY REASEARCH & TREATMENT 2013

9. CAUSES
• Structural- Hemimegancephaly and Cortical Dysplasia
• Metabolic- Non ketotic Hyperglycemia, Pyridoxine Deficiency , and a variety of disorders
implicating the Mitochondrial Respiratory Chain.
• Genetic Causes -ARX, CDKL5, SLC25A22, STXBP1, SPTAN1, KCNQ2, ARHGEF9,
PCDH19, PNKP, SCN2A, PLCB1, SCN8A, S3GAL3, TBC1D24, and BRAT1.

10. EIEE
• EEG – Burst Suppression pattern with high voltage
Paroxysmal spike/ poly-spike discharges for Up to 3-6
seconds followed by prolonged periods of nearly flat tracing
for up to 2-5 seconds.
• This pattern remains unchanged during wakefulness and
sleep

11. EIEE- EEG

12. TREATMENT
• Prognosis Poor
• Variety of antiepileptic drugs-clobazam , clonazepam ,
vigabatrin , topiramate , zonisamide , Phenobarbital,
valproate, or felbamate .
• Ketogenic diet
• Most patients -Adverse Neurocognitive outcome , early
death / may progress to WEST/ LGS
• Minority specific treatment – Hemispherectomy /
Pyridoxine supplement

13. EARLY MYOCLONIC ENCEPHALOPATHY
• Neonatal period up to 3 months
• Focal myoclonia of the face or extremities with random migration from
one part to another
• IEM -Most common causes( Amino Acidopathies), NKH, Zellweger
syndrome, menkes ds, pyridoxin deficiency
• Less often – structural abnormality ( cortical dysplasia)
Review Article- Pediatric Neurol 2012
Early-Onset Epileptic Encephalopathies: Ohtahara Syndrome and Early Myoclonic Encephalopathy

14. EME
EEG – Suppression Burst Pattern
• Back ground- Suppression Burst Pattern
• Burst suppression pattern more prominent during the sleep
• The bursts last for 1–5 seconds with longer periods of
suppression (3–10 seconds)

15. EIEE- EEG

16. EIEE VS EME

17. TREATMENT
• AEDS, Pyridoxin trial
• Ketogenic Diet
• Epilepsy Surgery
• Correcting Metabolic Problem
• Many children progress to WEST /LGS

18. Epilepsy of Infancy with Migratory
Focal seizures
• First few months of life
• Focal seizures with multiple topographical origins
• Seizures are typically prolonged and often fulfill criteria for status
epilepticus
• Genetic - mostly

19. Epilepsy of Infancy with Migratory
Focal seizures
• Mostly genetic mutations- SCNA1 , SCN2A , PLCB1 , TBC1D24
• EEG- prominent slowing , disorganization and multifocal
independent epileptiform discharges
• The area of ictal onset shifts from one region to another and
from one hemisphere to the other, with occasional overlapping
of consecutive seizures

20. TREATMENT
• Usually drug refractory
• There are some reports of Stiripentol and bromides
• Ketogenic diet
• Vagal nerve stimulation
• Surgical options- FOCAL LESIONS

21. INFANTILE SPASMS (WEST SYNDROME)

22. William James West,
1841
• Dr West's original letter gives a vivid
clinical description of what was to become
known, over a century later as West's
syndrome
• This letter, that was a call for help about
his son to the medical profession,
appeared in The Lancet 180 years ago

23. Duncan. Infantile spasms: the original description of Dr West. Epileptic
Disorders. 2001;3:47-8. Article historique

24. Infantile spasms (IS)
• An epilepsy syndrome with onset usually in infancy
• Rarely an onset >2 years
• Main clinical manifestation: clinical spasms
• Clusters
• Most characteristic EEG finding is hypsarrhythmia
• Not always, not throughout
• Often associated with developmental arrest or
regression

25. West syndrome (WS)
Clustered
spasms
Hypsarrhy
-thmia on
EEG
West
syndrome

26. INFANTILE SPASMS (WEST SYNDROME)
• Spasm -Flexor / Extensor
• Individual spasm generally last between 0.5 and 1.0 seconds
and repeat every 5 to 30 seconds in clusters approximately 2 to
20 minutes

27. Infantile spasm-single spasm variant (ISSV)
ISSV=Single spasms +
hypsarrhythmia
WS= clustered spasms + hypsarrhythmia
hypsarrhythmia without IS= no spasms + hypsarrhythmia
(HWIS)

28. CAUSES
STRUCTURAL
• Pre, Peri And Post Natal Cerebral Ischemia
• Cerebral Malformations
• Neuro Infections Sequel
• Neurocutaneous Hamartoma
Metabolic- Biotidinase Deficiency , PKU, Mitochondrial Disorders , Menkes Disease ,NKH
GENETIC
• CDKL-5 , MeCP 2, ARX, STXBP-1 , SPTAN 1and PLC-B1
• Chromosomal Disorders : Down Syndrome , Ip 36 deletion and Pallister – Killan syndrome
Unknown

29. 3 clinical states and corresponding EEG types
• Clinical state 1
• Weeks to months
• Clinically silent phase
• Type 1 EEG: presents with (multi-)focal epileptic discharges <50% of
NREM EEG recording time
• Clinical state 2
• Several weeks
• Beginning mental deterioration
• Type 2 EEG: with bihemispheric epileptic discharges >50% of the non-
NREM EEG recording time within abnormal background activity
(imminent hypsarrhythmia)

30. • Clinical state 3
• Mental deterioration
• Characterized by hypsarrhythmia
Conclusions: Infants with WS could be reliably identified several weeks
before the occurrence of hypsarrhythmia by a typical EEG pattern (type
2), thereby opening the way for early intervention studies

31. Type 1 EEG (clinical state 1)
• Focal or multifocal sharp-wave activity
• Occupying <50% of the non-REM EEG recording
time
• Background activity is normal or mildly abnormal

32. Type 2 EEG (clinical state 2)
bihemispheric sharp-wave activity
Occupying 50%–90% of the non-REM EEG
Background activity is definitely abnormal.
Type 2 EEG appears ~ modified hypsarrhythmia.

33. Type 3 EEG (clinical state 3)
90%–100% non-REM EEG
Irregular bihemispheric sharp-waves
hypsarrhythmia

34. TREATMENT
• ACTH High dose, Low dose
• Corticosteroids
• AEDS - Clobazam, Clonazepam ,
Valproic Acid
• VIGABATRIN- Most effective in
Tuberous Sclerosis Complex
• Use associated with
Irreversible Visual Loss
• Resectable surgeries for focal
etiologies like cortical dysplasia

35. TREATMENT

36. TREATMENT
• Are other forms of corticosteroids as effective as ACTH for short-term treatment
of infantile spasms?
• Are low-dose ACTH regimens effective for short-term treatment of infantile
spasms?
• Is ACTH more effective than VGB for short-term treatment of infantile spasms?
• Is there a role for the ketogenic diet or for AEDs other than VGB in managing
infantile spasms?
• Does the successful short-term treatment of infantile spasms lead to long-term
improvement of neurodevelopmental outcomes or a decreased epilepsy
incidence?

37. TREATMENT
The evidence is insufficient to recommend the use of
prednisolone, dexamethasone, and methylprednisolone
as being as effective as ACTH for short-term treatment
of infantile spasms (class 3 & 4)
Class I study showed similar efficacy between low-dose
(20–30 IU) and high-dose (150 IU/m2) natural ACTH
Two Class III studies (1 from the 2004 parameter and a
later study) demonstrated that ACTH is more effective
than VGB for short-term treatment of children with
infantile spasms (excluding those with TSC)
A shorter lag time to treatment of infantile spasms with
either hormonal therapy or VGB may be considered to
improve long-term cognitive outcomes (Level C)

38. Treat for 14 days
Monitor ADR: infection, irritability, HTN
Start low-dose ACTH at 20- 30 IU/m2
Increase rapidly to max doses as rapidly
Repeat EEG after 2 weeks
EEG s/o hyps but no clinical IS
No clinical spasms and EEG resolved
Neuro-developmental
follow-up
Continue Rx for 2-4 weeks

39. SEVERE MYOCLONIC EPILEPSY OF
INFANCY/DRAVET SYNDROME
• Early infantile febrile clonic seizures (before 1 yr of age )
• Myoclonic jerks, tonic- clonic, atypical absences, focal aware /
impaired awareness
• Vaccine seizures
• Low grade fever, hot bath , warm environment
• Cognitive and neurological detioration
Retracing the natural history of Dravet syndrome: Report and review of literature
Sachin Sureshbabu, Ivy Sebastian- Neurol india 2018

40. Age 4 -8
months(Feb
rile stage)
• Febrile
Seizures
• EEG normal
Age 1- 4 yrs
(worsening
stage)
• Other seizure
types appear,
regression of
mile stones
• EEG abnormal
Age 5+
stabilizatio
n stage
• Seizures may
become less
frequent
• Cognitive
problems
plateau
Dravet Life Timeline

41. EEG
Progressive increase of Paroxysmal Abnormalities
• During wakefulness background activity remains normal in 50 % of the cases
/ Remaining background activity becomes slow and poorly organized.
• Generalized Fast Spike – wave or Poly – spike appears in bursts or in isolation
, sometimes with unilateral predominance/ induced by Eye Closure and
intermittent Photic stimulation.
• Focal and multi focal abnormalities such as Fast Spikes or poly – spikes
involving Asynchronously the Fronto- Central or Centro-Temporal areas.

43. TREATMENT
• Limited success AEDS-
Levetiracetam, Clobazam,
Clonazepam , Topiramate,
,Valproic Acid
• Ketogenic Diet
• Vagal Nerve Stimulation
• Surgical Options
• Cannabidiol –some patients
• Avoid Na Channel
Blockers

44. LENNOX- GASTAUT SYNDROME
• LGS - triad of multiple drug-resistant seizure types, a specific
interictal electroencephalographic (EEG) pattern showing bursts
of slow spike-wave (SSW) complexes or generalized paroxysmal
fast activity (GPFA) and intellectual disability (ID)
• Multiple seizure types - Atypical absence , Tonic seizures (most
common) and Drop seizures , NCSE in 2/3rd
Asadi-Pooya AA. Lennox-Gastaut syndrome: a comprehensive review. Neurol Sci.
2018 Mar

45. LGS
• Causes are genetic, structural in 60-70 %
• 20 % may have west syndrome in past
• LGS is considered as secondary epilepsy

46. EEG
• The EEG background activity is probably never normal in LGS and shows a
diffuse increase in slow waves
• Characteristic EEG feature in LGS is slow (< 2.5 Hz) spike-and-wave
complexes with an abnormally slow background activity
• Hyperventilation may facilitate GSWD and Atypical Absences

48. EEG
• Bursts of diffuse or bilateral fast (10–25 Hz) rhythm patterns, also called
GPFA, are usually recorded during slow wave sleep

50. TREATMENT
• Drop seizures most difficult to control
• Topiramate/ Valproic acid / Felbamate / Lamotrigine, Benzodiazepines
• Clobazam and Rufinamide to combat Drop Seizures.
• Ketogenic diet in early age ~50% reduction in seizures, ~ 20% seizure
free
• Corpus callosotomy, VNS in refractory seizures
Asadi-Pooya AA. Lennox-Gastaut syndrome: a comprehensive review. Neurol Sci.
2018 Mar

51. MYOCLONIC – ASTATIC SEIZURES
(DOOSE SYNDROME)
• Normal development, Male predominant in 70-90 %
• Onset of Myoclonic , Myoclonic Atonic or Atonic seizures between the
age group of 1 and 6 yrs
• Part of GEFS +
• No tonic seizures
• Normal EEG background with generalized spike / Poly spike
discharges at 3- 7Hz with Photosensitivity

52. EMAS
• Initial seizures can be Febrile or Afebrile Generalized Tonic
Clonic Seizures
• Followed by characteristic seizure the Myoclonic- Atonic which
combines a symmetrical Myoclonic jerk immediately followed
by an Atonic seizure causing a Drop attack
• Episodes of NCSE lasting hours / days occur in some children.

53. EMAS
• EEG- Background activity is normal at the age
• Rhythmic theta activity in the parasagittal region may be the
only significant abnormality.
• Frequent paroxysms of GSWD at 3 Hz or more appear once
patient develops drop attacks

55. Features LGS EMAS
Type of seizures Tonic, Atonic , Atypical Absences Myoclonic,Atonic and Myoclonic-
Atonic
Tonic seizures Common and characteristic,
diurnal and nocturnal
Not Seen
Developmental abnormalities
before onset of seizures
Common Exceptional if any
Etiology Symptomatic ( Most Cases) Idiopathic
Genetic Predisposition None Common
Progression from West
Syndrome
Common Incompatible
Prognosis
Commonly Bad Relatively Good
EEG Background Abnormal By Rule Usually Normal
Paroxysmal Fast Activity Common and Characteristic Not Seen
EEG GSWS Slow (< 2.5 Hz) Fast (> 3Hz)

56. LANDAU KLEFFNER SYNDROME
• Rapidly Progressive Linguistic Deterioration following seizure episode
• Onset between 2 and 8 yrs of life
• Atypical absence (50%), oral (33%), secondarily generalized tonic–clonic (SGTC)
(33%), atonic (16%), and hemiconvulsive (16%) attacks
• Diagnosis is often delayed as children are often thought to have acquired
deafness , Autistic Regression or Mutism
• Seizures ( Mostly Nocturnal ) occur in 2/3rd and easy to control
• Behavioral and Cognitive disturbances are commonly observed

57. LKS-EEG
• Background activity remains normal in most cases
• High amplitude , Epileptiform discharges are seen in Temporo
Parietal areas/ Centro Parietal areas ( spikes, sharp waves
/spike and sharp wave)
• EEG abnormality is enhanced by sleep deprivation
• ICTAL EEG – Focal seizures , Focal Ictal pattern from Temporo-
Parietal / Posterior Temporal areas

59. TREATMENT
• AEDS- BZD and VAL (does not effect language)
• High dose corticosteroids – Stabilization of Language Problems
• The prognosis is Favorable
• 17 % can have complete recovery, 63 % can develop GDD
• Poor prognosis in <4 years of age, duration > 1 years

61. CONTINUOUS SPIKE WAVE EPILEPSY
• Classical presentation is a child with around 5 years of age, typically
between age 4 and 7 years
• TRIAD consists of
1. Intractable seizures
2. Interictal Epileptiform Activity that becomes prominent during sleep ,
leading to EEG pattern of Electrical Status Epilepticus in sleep (ESES) or
CSWS
3. Neurocognitive Regression after 2-3 years of seizures

62. CONTINUOUS SPIKE WAVE EPILEPSY
• EEG abnormalities became continuous with sleep onset and
ceased to be continuous upon arousal, occupying at least 85%
of slow sleep tracing
• neurocognitive impairments are the presenting symptoms in the
absence of clinical seizures but can be seen in up to 20% of
cases

63. CSWS- EEG
Active stage
• Typical CSWS pattern appears on EEG 1-2 years after the first seizures
• Children with Frontal CSWS – Aggressiveness/ Disinhibition/ Inattention
• Children with Temporal CSWS- Expressive Aphasia with Non fluent speech
Remission stage
• After 3- 8 years of age seizures remit in all cases
• EEG gradually remit to normal state

65. CSWS LKS
Clinical
Seizures All patients 40- 70 %
Primary language
impairment
Expressive aphasia, motor,
cognitive decline
Verbal auditory agnosia
Behavioral deficit Nearly all patients 40- 50 %
EEG
CSWS 100% of patients 80% of patients
Spike location Frontal , centro –temporal Posterior temporal , centro -
parietal

66. TREATMENT
• High dose Benzodiazepines
• Corticosteroids
• AEDS= Valproate / Ethosuximide / Levetiracetam/ Lamotrigine
Continuous Spike-Wave during Slow Wave Sleep and Related Conditions
Nilika Shah Singhal* and Joseph E. Sullivan ISRN-2014

67. RASSMUSSENS ENCEPHALITIS
• Drug-resistant focal epilepsy, progressive hemiplegia, and
cognitive decline, with unihemispheric brain
• Affected brain shows inflammation on histology and
Autoimmune pathology (GLUR3 antibody).
• Age of onset between 6- 8 yrs and affected children have
previous normal cognition and development.
Rasmussen’s encephalitis: clinical features, pathobiology, and treatment advances-Lancet Neurol 2015

68. STAGES - RASSMUSSENS ENCEPHALITIS
Acute stage-
• EPC, Progressive hemiparesis , hemianopia ,
cognitive deterioration and aphasias.
• Median duration is 8- 12 months.
Residual stage-
• Permanent and stable neurological deficits and
frequent seizures , although less frequent
seizures than in acute stage
Rasmussen’s encephalitis: clinical features, pathobiology, and treatment advances-Lancet Neurol 2015

69. DIAGNOSTIC CRITERIA
Rasmussen’s encephalitis: clinical features, pathobiology, and treatment advances-Lancet Neurol 2015

70. EEG
• Background EEG may be normal. Subsequently unilateral focal theta-
delta range slowing appears , which often becomes synchronized .
• INTER –ICTAL Discharges- Multiple independent spike/ sharp –
wave discharges are seen in the affected hemisphere
• In 30 % the discharges are bilateral.
• Activation – EEG abnormalities are enhanced by sleep deprivation as
well in sleep
Rasmussen’s encephalitis: clinical features, pathobiology, and treatment advances-Lancet Neurol 2015

71. Rasmussen’s encephalitis: clinical features, pathobiology, and treatment advances-Lancet Neurol 2015

72. TREATMENT
• Steroids and other Immunomodulators are given early in the
course of disease to reduce the inflammation , seizure activity
and severity of deficit
• Refractory seizures – Hemispherectomy
• Prognosis below the age of 10 is good who are treated well.
Rasmussen’s encephalitis: clinical features, pathobiology, and treatment advances-Lancet Neurol 2015

73. Immunomodulatory therapy versus surgery
Takahashi Y et al. Immunomodulatory therapy
versus surgery for Rasmussen syndrome in early childhood. Brain Dev. 2013

74. ALGORITHM
< 3 Months <3 months – 1
year
Burst
Suppression
Pattern
Partial
Seizures/
Erratic
Myoclonus
Ohtahara
Syndrome
Early Myoclonic
Encephalopathy
Infantile
Spasm
West
Syndrome
Tonic
Spasms

75. > 1 YR
-Atypical Febrile
seizures
-EEG- Normal
background > 3
Hz Generalized
Discharges
-Myoclonic Status
- Generalized
Spike< Slow wave
Background
Slowing
-Myoclonic Asatic
Seizures
-Parasagittal
Slowing
-Fast Generalized
Spike/Polyspike
Discharges
Dravet
Syndrome
Myoclonic Status in Non
Progressive
Encephalopathy
Doose
Syndrome

76. -Drop Attacks
-GSWD, Multifocal
Discharges
-Paroxysmal Fast Activity
-Background Slowing
Partial Seizures
LGS
Auditory
Agnosia+/-
ESES on EEG
ESES on
EEG
-EPC
-Progressive
Neurological
Deficit
LKS CSWS
Rasmussen
Encephalitis
>1 yr

77. TAKE HOME MESSAGES
• Age of presentation and prior developmental status is most
important to diagnose epileptic encephalopathy syndromes
• EEG will help to early detection and differentiation of each
encephalopathies
• Proper treatment helps child to have a seizure free childhood
and normal development

78. THANK YOU