Presentation on epileptic encephalopathy..

1. Epileptic encephalopathies
Dr. Surendra Kumar
SR Neurology

2. Electro-clinical Syndrome
• Group of clinical entities that are reliably
identified by a cluster of electro-clinical and
developmental characteristics
• Largely genetic in origin
• Tend to have a strong relationship to
developmental aspects of brain
2
ILAE Commission 2009

3. Concept of Epileptic Syndromes
• Factors taken into consideration include
– Seizure type(s)
– Age of Onset
– Precipitating factors
– Severity, Chronicity
– Diurnal/circadian cycling
– Etiology: genetics, structural pathology
– Associated neurological problems
– Interictal EEG
3

4. Advantages of a syndromic
diagnosis
Provide information about
– Age of onset
– Etiology
– Seizure type
– Precipitating factors
– Chronicity
– Prognosis
– Choice of treatment
4

5. Epileptic Encephalopathy
• Electro-clinical syndrome associated with a
very high probability of encephalopathic
features that present or worsen after the onset
of epilepsy
• Pharmaco-resistant
5

6. Neonatal Epileptic syndromes
• Early Myoclonic encephalopathy
• Ohtahara syndrome
6

7. 7
Early Myoclonic Encephalopathy
(Aicardi et al 1978)
• Onset: first weeks of life
• Erratic, focal, rarely generalized myoclonic and tonic
seizures
• High incidence of consanguinity
• Sometimes IEMs:- (NKHG)
• EEG: Burst- Suppression Pattern, persists for months;
awake & sleep
• Intractable to therapy - seizure pattern may change over
time
• Severe disability; early death

8. Etiology
• Inborn errors of metabolism – most common
• Non ketotic hyperglycinemia, propionic
aciduria, Methylmalonic acidemia, D glyceric
acidemia, sulfite & xanthine oxidase
deficiency, Menkes disease
• Some cases- AR inheritance
• Cases with Early Myoclonic encephalopathy
with suppression burst pattern- responds to
pyridoxine
8

9. 9

10. Investigations & Prognosis
• MRI Brain shows periventricular/ cortical
atrophy/ asymmetrical ventricular
enlargement
• Metabolic screening- serum levels of amino
acids-glycine & glycerol metabolites, organic
acids & amino acids in CSF
• More than ½ die within weeks/months
• Those who survive develop severe mental
deficits
10

11. 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
11

12. 12
Ohtahara syndrome (Ohtahara 1976)
• Onset in the first weeks of life
• 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

13. 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
13

14. 14
Fp1-F3
F3 –C3
C3 – P3
P3 – O1
Fp2 F4
F4 – C4
C4 – P4
P4 – O2
Fp1 –F7
F7 – T3
T3 – T5
T5 – O1
Fp2 F8
F8 – T4
T4 – T6
T6 – O2
EKG

15. Ohtahara syndrome Early myoclonic encephalopathy
• Tonic spasms
• Malformation of
Cortical development
• Suppression burst both
sleep and awake-
shorter lifespan
• Bursts longer
• Suppression shorter
• Transformation to WS
RULE
• Erratic myoclonus, focal
seizures, cluster spasms
• Genetic and metabolic
• Accentuated by sleep-
longer lifespan
• Shorter
• Longer
• Common but transient
15

16. Treatment
• No effective treatment
• ACTH and AED are generally not effective
• Case reports show response to zonisamide &
vigabatrin
• Neurosurgery- MCD
16

17. Electro-clinical syndromes of Infancy
• West syndrome
• Febrile seizures plus
• Dravet syndrome
• Migrating partial seizures of infancy
• Myoclonic epilepsy in infancy
• Myoclonic encephalopathy in nonprogressive
disorders
17

18. WEST SYNDROME : INFANTILE
(EPILEPTIC) SPASMS
• Myoclonic < Spasms < Tonic
• Flexor , Extensor, Flexor-extensor
• Subtle spasm
• Asymmetrical spasm in symptomatic
• Onset 3-12 m (4 months); till 2 yrs
• Occipital lesions---- early onset
Frontal lesions -----later onset
18

19. Description of IS by West
• …these bobbings … they come on whether
sitting or lying; just before they come on he is
all alive and in motion … and then all of a
sudden down goes his head and upwards his
knees; he then appears frightened and
screams out.
W. J. West (1841)
19

20. 20

21. West Syndrome
• Symptomatic , Cryptogenic, Idiopathic
• Symptomatic- cortical malformations, HIE,
tuberous sclerosis,infections, genetic and
chromosomal abnormalities etc
• Focal lesions ++
• Autistic regression / visual agnosia
• Evolution into LGS / partial seizures
21

22. Reversible causes for epileptic
spasms
• Drugs - theophylline or histamine H1
antagonists ,ketotifen -epileptic spasms and
hypsarrhythmia- reversible upon drug
withdrawal.
• Pyridoxine dependency
22

23. Pathophysiology
• very early age-related epileptic
encephalopathy -epileptiform abnormalities
may contribute to progressive dysfunction
• cortical hyperexcitability-over-expression or
excessive activation of glutamate and
particularly N-methyl-D-aspartate (NMDA)
receptors
23

24. Other hypotheses
• impaired serotonergic transmission
• alteration of the brain–adrenal axis hormones
elevated levels of corticotropin-releasing
hormone - epileptic spasms & psychomotor
deterioration of the patients
• brain stem dysfunction and abnormal cortical–
subcortical interactions
• immunological mechanisms.
24

25. Investigation
• clinical neurodevelopmental assessment
ophthalmological ultraviolet skin examination -
tuberous sclerosis and Aicardi syndrome.
• electrolyte, metabolic
• Infections- CSF
• infants with frequent vomiting, lethargy, failure to
thrive, peculiar odours & unexplained neurological
findings, urine & serum amino acid screening, serum
ammonia, organic acid, lactate, pyruvate and liver
function tests should be performed.
25

26. • CT brain/ MRI brain
• PET- Focal cortical abnormalities
• Bilateral temporal lobe hypometabolism is bad
prognostic signs
• Some cases- Chromosomal analysis
26

27. 27
Awake
Inter-ictal Hypsarrthymmia (50-60%): Chaotic background with high
amplitude delta,asynchronous multifocal spikes, polyspikes and
electrodecremental activity

28. Hypsarrhythmia with focal slowing
(Left temporo-occipital FCD )
28

29. Spasms & hypsarrhythmia resolve by 2y Evolve to focal
seizures (R occipital lesion)
29

30. Treatment options
• Hormonal therapy, corticotropin (ACTH)
• Antiepileptic vigabatrin
• Pyridoxine
30

31. Mechanism of action of ACTH
31
ACTH
CRH ACTH Adrenal gland
normal or
suppressed
Steroids
Dec Seiz
threshold

32. • Recommended as first-line treatment
• In five RCT of ACTH therapy for IS- cessation
of spasms occurred in 42-87 percent of infants,
• Time from initiation of treatment to cessation
of spasms was 7 to 12 days
• Response to ACTH was greater for infants
with cryptogenic IS than for with symptomatic
IS.
• Relapse rates ranged from 15 to 33 percent.
32

33. • Two randomized trials - response to low-dose
therapy (20 units/day) was comparable to
higher doses and resulted in fewer side effects
• 50 patients with recently diagnosed IS were
randomly assigned high-dose ACTH (150
U/m2 per day for three weeks, 80 U/m2 per day
for two weeks, 80 U/m2 every other day for
three weeks, 50 U/m2 per day every other day
for one week, and taper to zero over three
weeks) 33

34. • low-dose ACTH (20 to 30 U/day for two to six
weeks, then taper to zero over one week)
• The groups were similar in response to
treatment (cessation of spasms and
disappearance of hypsarrhythmia) (50 versus
58 percent) and rate of relapse.
• Hypertension occurred more often in the high-
dose group (31 versus 4 percent); other side
effects were similar between groups
34

35. Corticosteroids
• Less costly, easy to administer
• Uncontrolled studies with prednisone,
prednisolone, MP, Dexa control spasms
• RCT s prefer ACTH over Steroids
• Prednisone-who have not responded to initial
therapy with ACTH.
• use prednisone (2 mg/kg per day PO) for a six-
week course is based on clinical experience;
35

36. • The 2012 American Academy of Neurology
(AAN) practice parameter, the 2008 Cochrane
systemic review, and the 2010 United States
consensus report did not find sufficient
evidence to support a recommendation for use
of prednisone or prednisolone
36

37. Vigabatrin
• effective as initial treatment for IS
• Approved by FDA in 2009
• time from onset of treatment to cessation of
spasms ranged from 12 to 35 days.
• time to EEG response ranged from 7 to 35
days, and
• 11 to 83 percent of children had resolution of
hypsarrhythmia. Randomized open label,
retrospective case series, dose, duration
37

38. Other AEDS
• Valproic acid
• Zonisamide
• Topiramate
• Sulthiame
• Pyridoxine
• Lamotrigine, felbamate
• Benzodiazepines
• Ketogenic diet
38

39. Prognosis
• Mortality declined in developed countries-5%
• Death mostly due to underlying cause or treatment
with corticosteroid/ACTH
• 60% develop other seizures refractory to treatment
• Half patients- permanent motor disabilities & two-
thirds have severe cognitive & psychological
impairment
• Autistic behaviour, hyperkinetic syndrome and
psychiatric disorders
39
Only 5–12% of patients have normal
mental and motor development.

40. WHEN FEBRILE SEIZURES ARE NOT
FEBRILE SEIZURES
• GEFS + (Gen. Epilepsy febrile seizures plus)
– Common under-recognised disorder
– Autosomal dominant with high penetrance
– Typical FS, FS + lasting longer, Afebrile GTCs most
common
– Occasionally absence, myoclonic, atonic
– Focal seizures of frontal or temporal lobe in origin
– Dravet’s syndrome overlap
– Remits in adolescence 80%
– Sodium channelopathy
40

41. Dravet’s syndrome (SMEI)
• 1st year febrile / afebrile unilateral / GTCs;
status epilepticus
• Later myoclonus, atypical absence, complex
focal
• Resistant to AEDs
• Cognitive regression, ataxia 2nd year
• FH + 25-30%
41

42. • EEGs normal ; later generalized
epileptic photosensitivity
• Consider this syndrome when febrile /
illness provoked seizures start in
infancy and EEG is persistently
NORMAL
42

43. 43
GEFS +
SCN1A mutations
EM-AS
DRAVETs SIGEI

44. Treatment
• Seizures are intractable
• AEDs may reduce them but do not control
them and it is doubtful if they can affect the
outcome
• valproate, diazepines, melatonin,
phenobarbitone convulsive seizures)
ethosuximide absence & myoclonic
seizures) is partially & temporary beneficial.
44

45. • Other drugs – Topiramate, stiripentol,
zonisamide, bromides, levetirecetam
• Levetirecetam is the most efficacious
• Phenytoin, lamotrigine & carbamazepine are
contraindicated
• Infection & hyperthermia to be controlled.
45
Ketogenic diet -start at the earliest possible
stage to obtain good results

46. • Seizure deterioration ,mental & neurological
decline is relentless
• progression of symptoms halt at age of 11–12
years - seizures improve but do not cease
• patients may die -during seizure or from
concomitant diseases- 15%
• Severe impairment of cognitive functioning at
age b/w- 2-6 yrs & then becomes stable
46
Amongst 56 patients of Dravet only six
acquired communicative skills only one
was able to attend school.
All 37 patients older than 10 years were
dependent or institutionalised.
Half had an intelligence quotient lower
than 50.

47. Malignant migrating partial epilepsy of
Infancy
• Epileptic encephalopathy
• Mean age 3 months
• Continuous multifocal seizures arising
independently from multiple regions
• Psychomotor deterioration
• Seizure control is exceptional
47

48. Migrating seizures of infantile
48
Malignant migrating partial epilepsy of infancy

49. Migrating seizures of infantile
49

50. Childhood epilepsy syndromes
50
Epileptic encephalopathy with CSWS
Landau-Kleffner syndrome
Lennox-Gastaut syndrome

51. Epileptic Encephalopathy of Late Childhood
A spectrum of diseases
1. Landau- Kleffner syndrome
2. CSWS Syndrome
• Gradual cognitive/behavior
deterioration
• Acquired language impairment
• Seizures
• Dramatic activation of epileptiform
abnormalities in slow wave sleep
LKS CSWS

52. Landau Kleffner Syndrome
• Our son was normal in every way until the age of 2
years. At first he seemed to be losing his hearing but
not for environmental sounds. We thought that he
was going deaf, but the hearing test was normal…
When he was 3 years old he didn’t say anything for
over a month. He improved for a few months and
then he had a minor seizure
» From the internet description by a mother
52

53. LKS Vs Epilepsy with CSWS
» LKS
• CSWS 80%
• Spikes Temporal
• Seizures 75%
• Symptomatic rare
• Verbal auditory agnosia
• Behavioural deficit common
• 50% reach near normal life
Epilepsy with CSWS
• CSWS 100%
• Frontal spikes
• Seizures -100%
• One third symptomatic
• Expressive aphasia
• Nearly all
• One-quarter reach
normal
53

54. 54
POSTERIOR temporal lobe foci of sharp slow wave complexes-
multifocal bisynchronous, facilitated by NREM sleep

55. 55
Fp1-F3
F3 –C3
C3 – P3
P3 – O1
Fp2 F4
F4 – C4
C4 – P4
P4 – O2
Fp1 –F7
F7 – T3
T3 – T5
T5 – O1
Fp2 F8
F8 – T4
T4 – T6
T6 – O2
EKG

56. Treatment
• Seizure are easily controlled with AED
• Target is to reduce epileptiform discharges
• AED- Valproate, ethosuximide, Clobazam,
clonazepam, levetirecetam alone or in
combination
• If AED fails then steroids/ACTH
• IVIG tried successfully in some cases
• Neurosurgery- intracortical transections
56

57. Lennox Gastaut Syndrome
• Polymorphic seizures
Tonic Seizures - Commonest
Atypical absences – 2/3rd of patients
Atonic seizures (Drop attacks)
Myoclonic jerks
• Cognitive and behavioural abnormalities
• EEG Slow spike and wave,
Paroxysms of fast activity
57

58. Lennox-Gastaut Syndrome
• Peak age 3-5 years
• Symptomatic form most common
• One third idiopathic
• No genetic predisposition
• Half of the West syndrome and others progress
to LGS
• Poor prognosis
58

59. 59
Slow spike and wave activity between arrows

60. 60

61. Management
• My 13-year-old daughter has Lennox–Gastaut
syndrome. She is on Sabril, Lamictal and
Frisium. It seems multiple drug therapies work
best for these children. I have found the best
control is when the drug level or types are
changed. The initial control is good usually
reducing the seizures for a month or so, but
they then start up again. Hence, we are always
juggling the doses up and down.
• From an Internet description by a mother 61

62. Antiepileptic drugs
• Valproate- Drug of choice- with risk of liver
• Clonazepam- myoclonic, tonic
• Phenytoin- tonic, tonic status
• Phenobarb, carbamazepine, primidone- Avoid
• Ethosuximide- myoclonic & atonic
• Gabapentine- contraindicated
• Lamotrigine- atonic & absence
• Topiramate, zonisamide
62

63. EVOLUTION OF SYNDROMES
63
OHTAHARA SYNDROME
WEST SYNDROME
LENNOX GASTAUT SYNDROME

64. 64
D 15 infant refractory tonic / partial seizures; BH N
MRI N / Metabolic N
EE with suppression – burst (OHTAHARA’s )

65. 65
Epileptic spasms a few months later
HYPSARRYTHMIA MODIFIED BY SLEEP

66. 66
2.5 y; MR, Tonic seizures in sleep; Drop attacks with
injuries; Episodes of atypical absence status & regression
SLOW SPIKE WAVE-LGS

67. Epilepsy with Myoclonic-Astatic Seizures(
Doose Syndrome)
• Normal development prior to the onset
• Onset peaks at 2-4 years
• Two-thirds of children have febrile and
afebrile GTCS to begin with
• Myoclonic astatic seizures (post myoclonic
atonia)
• Normal background EEG with 2-3 Hz GSWD
67

68. Management
• Dictated by seizure type
• Valproate- m a a
• Lamotrigine
• Topiramate, levetirecetam
• Resistant cases- ketogenic diet, ACTH
• Phenytoin, carbamazepine, vigabatrin – C/I
68

69. Diagnosis of epileptic syndromes-Problems
• Exact diagnosis may not be possible on first
contact
• Needs periodic follow up
• Evolution of syndrome
eg: West syndrome LGS
• Overlapping features
69

70. 70
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