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- 1. Epileptic encephalopathies Dr. SurendraKumar SR Neurology
- 2. Electro-clinical Syndrome • Groupof 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 EpilepticSyndromes • 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 asyndromic diagnosis Provide information about – Age of onset – Etiology – Seizure type – Precipitating factors – Chronicity – Prognosis – Choice of treatment 4
- 5. Epileptic Encephalopathy • Electro-clinicalsyndrome 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 (Aicardiet 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 errorsof 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.
- 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 effectivetreatment • 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 (Ohtahara1976) • 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 ofcortical 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 Earlymyoclonic 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 effectivetreatment • ACTH and AED are generally not effective • Case reports show response to zonisamide & vigabatrin • Neurosurgery- MCD 16
- 17. Electro-clinical syndromes ofInfancy • 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 ISby 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.
- 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 forepileptic spasms • Drugs - theophylline or histamine H1 antagonists ,ketotifen -epileptic spasms and hypsarrhythmia- reversible upon drug withdrawal. • Pyridoxine dependency 22
- 23. Pathophysiology • very earlyage-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 • impairedserotonergic 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 neurodevelopmentalassessment 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 focalslowing (Left temporo-occipital FCD ) 28
- 29. Spasms & hypsarrhythmiaresolve by 2y Evolve to focal seizures (R occipital lesion) 29
- 30. Treatment options • Hormonaltherapy, corticotropin (ACTH) • Antiepileptic vigabatrin • Pyridoxine 30
- 31. Mechanism of actionof ACTH 31 ACTH CRH ACTH Adrenal gland normal or suppressed Steroids Dec Seiz threshold
- 32. • Recommended asfirst-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 randomizedtrials - 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 2012American 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 asinitial 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 • Valproicacid • Zonisamide • Topiramate • Sulthiame • Pyridoxine • Lamotrigine, felbamate • Benzodiazepines • Ketogenic diet 38
- 39. Prognosis • Mortality declinedin 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 SEIZURESARE 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.
- 44. Treatment • Seizures areintractable • 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 partialepilepsy 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 ofinfantile 48 Malignant migrating partial epilepsy of infancy
- 49. Migrating seizures ofinfantile 49
- 50. Childhood epilepsy syndromes 50 Epilepticencephalopathy with CSWS Landau-Kleffner syndrome Lennox-Gastaut syndrome
- 51. Epileptic Encephalopathy ofLate 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 Epilepsywith 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 lobefoci 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 areeasily 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 • Peakage 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 andwave activity between arrows
- 60.
- 61. Management • My 13-year-olddaughter 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 OHTAHARASYNDROME WEST SYNDROME LENNOX GASTAUT SYNDROME
- 64. 64 D 15 infantrefractory tonic / partial seizures; BH N MRI N / Metabolic N EE with suppression – burst (OHTAHARA’s )
- 65. 65 Epileptic spasms afew 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-AstaticSeizures( 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 byseizure type • Valproate- m a a • Lamotrigine • Topiramate, levetirecetam • Resistant cases- ketogenic diet, ACTH • Phenytoin, carbamazepine, vigabatrin – C/I 68
- 69. Diagnosis of epilepticsyndromes-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.