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Definition and natural history of Lennox Gastaut syndrome

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  • IQ classification not defined. Also subgroups included IS, LGS and patients with IS and LGS. Of 25 pts with LGS 11 had IS + LGS.

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  • 1. Definition and Natural Historyof Lennox Gastaut SyndromeDr. Pramod K.11/05/2012
  • 2. Scheme of presentation Introduction History Definition Epidemiology Etiology Clinical characteristics EEG features Treatment Evolution and Outcome Conclusion
  • 3. Introduction Lennox Gastaut Syndrome (LGS) is one of the most severe childhood epilepsies. It has precise well-defined clinical and neurophysiological characteristics and is a fairly homogenous, but uncommon entity. However, its pathophysiological mechanisms remain poorly understood. Its definition has varied over time resulting in misclassification and over-diagnosis in the past.
  • 4. Historical perspective andEvolution of the Definition
  • 5. Historical perspective Gibbs (1938) described the characteristic diffuse 2-2.5 Hz slow spike and wave discharges in EEG. He called this ‘petit mal variant’. Lennox (1945), and Lennox and Davis (1950) described the triad of mental deficiency, polymorphic seizures and diffuse slow spike and wave discharges in EEG. Margaret Buchtal-Lennox proposed the name LGS in tribute to the work of Lennox and the Marseille School headed by Gastaut.
  • 6. ILAE Definition, 2001 Onset during childhood Coexistence of multiple seizure types: Common- atypical absence, axial tonic and atonic seizures. Presence of tonic seizures in sleep is a constant feature. Infrequent- are myoclonic, GTCS, focal. EEG: Diffuse slow spikes and waves and bursts of fast rhythms at 10-12 Hz during sleep. Permanent psychological disturbances with psychomotor delay, personality disorders, or both.
  • 7. Definitions of LGS Group Onset in MR Multiple Tonic Sz Diffuse GPFA in childhood Sz types in sleep SSW sleepILAE Yes Yes Yes Yes Yes Yes2001Genton Yes Yes Yes - Yes Yeset al, 2000Goldsmith Yes - Yes Yes Yes -et al, 1999Lennox - Yes Yes - Yes -et al, 1950Trevathan Yes - Yes - Yes -et al, 1997French - Yes Yes - Yes -et al, 2004Not all patients have all of the core seizure types, especially at onset. Arzimanoglou et al., 2009.When the complete criteria is applied, LGS is a rare disorder.
  • 8. Classification LGS is classified among the symptomatic or cryptogenic generalized epilepsies. In the 2001 proposal of ILAE, it is classified as an epileptic encephalopathy, a concept formally endorsed in 2006 by ILAE and further emphasized in 2010 (Berg et al., 2010). International Classification of Epilepsies and Epileptic Syndromes
  • 9. Classification1. Cryptogenic (25%): onset between 1-8 years of age, in a previously normal child, due to an undetected but suspected cause. (Abandoning this term has been suggested). Engel 20012. Symptomatic (75%): onset between 1-15 years of age, in a child with prior signs of brain damage. Hancock and Cross, 2009; Borggraefe and Noachtar, 2010
  • 10. Epidemiology
  • 11. Epidemiology Accounts for 1- 5% of all epilepsies and 3- 10% of childhood epilepsies. Trevathan et al., 1997; Hancock & Cross, 2009. No ethnic or geographic predilection. Boys are slightly more affected than girls. Markand O, 1977 In the Nova Scotia study, only 4 patients had LGS at the time of epilepsy diagnosis; 20 years later the number was 17, with most of the new cases evolving from West syndrome. Camfield & Camfield, 2007.
  • 12. Incidence of LGS Author Area N Definition IncidenceHeiskala H Finland 1-14 yrs of age Gastaut 1.9-2.1 /100,000et al, 1997 children/yrRantala H et Finland < 15 yrs of age Gastaut 1.93/100,000 children/al, 1999 yrCamfield Nova Scotia 1m- 16yrs of age ? 0.6% of all new onset1996 epilepsies (46/100,000/yr). Prevalence of LGSCamfield Nova scotia 1m- 16 yrs of age ? 4% of symptomatic1996 generalised epilepsyTrevathan Atlanta < 10 yrs of age Gastaut Lifetime prevalence atet al, 1997 10 yrs of age was 0.26/1000. 4% of childhood epilepsies
  • 13. Etiological Factors
  • 14. Etiologies in symptomatic LGS (n= 107). Goldsmith I.L. et al. Epilepsia 2000; 41: 395- 99.
  • 15. Etiology in children with LGS Etiology LGS (n= 15)Cryptogenic 8Progressive encephalopathy 3Chromosomal abnormality 2Angelman syndrome 1Stroke 1 Rantala H. Epilepsia 1999; 40: 286- 89.
  • 16. Pathogenesis of LGS Blume WT. Epileptic Disorders 2001; 3: 183- 96
  • 17. LGS and Infantile spasm Author N h/o Infantile spasm CommentRantala H 25 40% 10/37 patients with ISet al, (27%) evolved to LGSLombrosos CT, - - 23% of children with ISet al, 1983 evolved to LGSRiikonen. 192 20- 36%1982Ohtahara S - 36% 54% of IS evolved toet al, 1980 LGSGoldsmith IL 107 13.1 % h/o IS more commonet al, 2000 in symptomatic LGSMean time from the beginning of IS to beginning of LGS was 2.8 years(0.4-8.8 years). Rantala H et al. Epilepsia 1999; 40: 286-89.
  • 18. History of Infantile spasms (IS) and other seizures in LGS. Goldsmith I.L. et al. Epilepsia 2000; 41: 395- 99.
  • 19. LGS and Infantile spasms (IS) LGS evolved from other seizure types in 54.2% cases. In 29.0% there was no history of seizures or epilepsy. IS was more in the symptomatic subgroup (p= 0.05). Patients with cryptogenic/ indeterminate LGS were more likely to develop LGS without a h/o seizures. Late onset LGS rarely had a h/o IS (6.3%) or seizures (12.5%) compared to early-onset LGS (p= 0.05). Goldsmith I.L. et al. Epilepsia 2000; 41: 395- 99.
  • 20. LGS and West syndrome Author N h/o West syndromeHeiskala H 75 (1-14 yrs of age) 28 %et al, 1997Weinmann 174 17.8 %et al, 1988Yagi 102 22 %et al, 1996Oguni H 72 33 %Et al, 2010Camfield 692 children with epilepsy 65 %et al, 200740 % of children who developed LGS from West syndrome had h/oanoxic episodes early in life. Blume 2001
  • 21. Clinical Features
  • 22. Cognitive dysfunction LGS has profound deleterious effects on intellectual and psychosocial function. Camfield & Camfield, 2008; Arzimanoglou et al., 2009. Cognitive impairments are clinically apparent in 20– 60% of patients at the time of diagnosis of LGS. Arzimanoglou et al., 2009. The cognitive impairment becomes more apparent over time, and within 5 years of onset, serious intellectual problems is noted in 75–95% of patients. Beaumanoir & Blume, 2005; Hancock & Cross, 2009.
  • 23. Behavioural problems Many patients with LGS develop behavioral and psychiatric disorders. Glauser, 2004 Attentional problems, aggression, and autistic features can be very prominent in LGS and represent enormous challenges for the family.
  • 24. Tonic seizures Tonic seizures are the most important seizures associated with LGS and is required for diagnosis. May not always be present at onset of LGS. Arzimanoglou et al, 2009 Presentation: brief tonic upgaze, change in respiration, facial tightening, neck flexion, brief vocalization, involve axial muscles, or entire body. Dulac & N’Guyen, 1993. The frequency is easily underestimated because they occur most often during sleep and are often subtle.
  • 25. Atypical absence It is the second most common seizure type in LGS. It is not easily defined, and often being subtle, they are not easily recognized. Manifests as a brief lapse in consciousness, although some awareness may be preserved. Arzimanoglou et al., 2009. Onset and termination are not always apparent; patients seem to fade in and out of consciousness. EEG: slow and often irregular spike waves (2.5 Hz) that may be indistinguishable from interictal bursts. Dulac & N’Guyen, 1993.
  • 26. Sudden tonic or atonic falls At least 50% of LGS patients have ‘‘drop attacks.’’ Often preceded by a single generalized myoclonic jerk followed by a tonic contraction of axial muscles or axial atony or a combination that leads to falls. Prevention of facial injuries requires use of a helmet and full face mask, which is highly stigmatizing and often impractical. Camfield & Camfield, 2002; Arzimanoglou et al., 2009.
  • 27. Nonconvulsive status epilepticus Occurs in 2/3rd of LGS patients and consists of continuous/nearly continuous atypical absences lasting minutes to hours that cause varying levels of diminished consciousness. Hancock and Cross, 2009. Major contributor to intellectual impairment Superimposed brief tonic seizures may occur. EEG: nearly continuous slow spike-and-wave pattern occasionally interrupted by brief bursts of generalized polyspikes. Dulac & N’Guyen, 1993.
  • 28. Other seizure types Most patients have myoclonic seizures that may be subtle or severe enough to cause falls. Myoclonia are not required for the diagnosis of LGS. Camfield & Camfield, 2002; Arzimanoglou et al., 2009. Other seizure types: GTCS, unilateral clonic, focal clonic with or without secondary generalization. These occur mostly in the later stages of LGS. If very frequent, the diagnosis may be obscured. Arzimanoglou et al., 2009.
  • 29. EEG Features
  • 30. EEG features Slow (2.5 Hz) spike-and-wave bursts with abnormal background activity is the hallmark. Bursts may be irregular without a clear onset/ offset. The average age of onset of slow spike wave is 8.2 years, with a mean duration of 8.6 years. The distinction between ictal and interictal discharges is often challenging. Clinically apparent atypical absence seizures always have an associated slow spike-wave burst. Arzimanoglou et al., 2009.
  • 31. Diffuse slow- spike and wave discharges over a slow background
  • 32. Diffuse slow- spike and wave discharges over a slow background
  • 33. Bursts of generalized fast polyspikes (10–20 Hz), especially in sleep,also define the EEG of LGS. Donat, 1992; Blume, 2001; Arzimanoglou et al., 2009.
  • 34. EEG features The slow spike-and-wave EEG pattern is transient, and focal discharges are frequently seen with time. Average age of onset of the classic, slow spike-wave EEG patterns was 8.2 yrs (1– 35 yrs). Average duration of the pattern was 8.6 yrs (1– 36 yrs). After the slow spike-wave pattern disappeared, 95% of patients had focal discharges and 95% had diffuse slowing. Hughes JR et al. Clin Electroencephalogr 2002;33:1–7.
  • 35. EEG in tonic seizures Sudden onset of generalized, rapid (10–13 Hz), low- amplitude spikes predominantly in the vertex and anterior head regions, and may increase progressively in amplitude and decrease in frequency. Duration: few seconds to minutes (typically 5–10 s). Post-ictal: abrupt return to background rhythms or a short epoch of generalized, high-amplitude delta. EEG does not show generalized suppression that is more typical of other tonic seizures. Dulac & N’Guyen, 1993.
  • 36. Tonic seizures- ictal onset
  • 37. Tonic seizures- offset followed by post-ictal diffuse slowing.
  • 38. Differential diagnosis Focal epilepsies with secondary bilateral synchrony, Doose syndrome, Dravet syndrome, West syndrome. Oguni, 2010. Tonic seizures occur prominently in West syndrome, frontal lobe epilepsies. Dulac& N’Guyen, 1993. Drop attacks, may occur in many other syndromes. One study reported misdiagnosis in 38/103 patients referred with a diagnosis of LGS. Beaumanoir, 1982.
  • 39. Pseudo-Lennox/atypical benignpartial epilepsy (ABPE) Clusters of seizures are typical and there may be striking periods with few or no seizures. Arzimanoglou et al., 2009. It may represent BECTS that is modified by medication toxicity or illness. Donat, 1992. Unlike LGS, EEG does not show bursts of generalized paroxysmal fast activity, and there are no tonic seizures. Arzimanoglou et al., 2009.
  • 40. Evolution and outcomes
  • 41. Evolution of LGS and Outcome The long-term outcome for LGS patients is very poor, and complete seizure freedom is unusual.Dulac & N’Guyen, 1993; Goldsmith et al., 2000; Beaumanoir & Blume, 2005; Arzimanoglou et al., 2009; Hancock & Cross, 2009. In a recent study on the outcome of severe epileptic encephalopathies, a new syndrome, the “severe epilepsy with multiple independent spike foci” has been suggested as the final evolution of LGS. Yamatogi et al, 2006.
  • 42. Seizure Outcomes
  • 43. Evolution and outcome The Nova Scotia population-based study investigated long-term outcomes in 17 cases of LGS Length of follow-up: 20 ± 6.5 years. 59% of patients had their first seizures in infancy. At the end of follow-up, 94% of LGS cases had intractable epilepsy, significantly more than other SGE syndromes (p < 0.001). Camfield & Camfield, 2007. Of 9 patients with LGS included in the final analysis: 6 had poor and 3 had moderate social outcome. Camfield and Camfield, 2008.
  • 44.  102 patients of LGS > 15 yrs of age. Mean age at time of survey: 28.6 yrs (15- 60 yrs). Mean age at epilepsy onset: 4.3 yrs (2m to 18 yrs). Average length of follow-up: 16.3 yrs (10- 20 yrs) 82/102 required multiple hospitalisations. The typical clinical and EEG features of LGS continued in 1/3rd of cases during the study period. No patient evolved to any LRE during the study. Yagi K et al. Epilepsia 1996; 37:48- 51
  • 45. Evolution of LGS: etiology and outcomeIn the 22 patients who evolved from West syndrome, 15 evolvedimperceptibly into LGS, while 7 had a mean interval of > 6 monthsbetween end of West syndrome and beginning of LGS. Yagi K et al. Epilepsia 1996; 37:48- 51
  • 46. Seizure type at study end in 102 patientsGeneralized tonic seizures were the most resistant to therapyand persisted for years in nearly all patients.Eight patients were seizure free for > 1 year. Yagi K et al. Epilepsia 1996; 37:48- 51
  • 47.  72 patients (M:F= 46:26) Prenatal, perinatal, and postnatal factors were considered to have been etiologic factors in 30, 14, and seven patients, respectively. Motor deficits were noted prior to epilepsy onset in 21 patients. Mean age at epilepsy onset: 2 years 4 months. Oguni H et al. Epilepsia 1996; 37: 44-47
  • 48. Comparison of types of LGS Cryptogenic LGS Symptomatic LGSNumber 21 51Mean age (in yrs) 21± 5 23± 5Follow-up period (in yrs) 17± 4 17± 5Mean age at 1st visit (in yrs) 6± 3 3± 3Average age at LGS 6± 3 (2- 10) 6± 3 (2- 15)diagnosis Oguni H et al. Epilepsia 1996; 37: 44-47
  • 49. Age at diagnosis of LGS: Sympt West(+), Symptomatic LGS with a h/oWest syndrome; Sympt West(-), symptomatic LGS without a h/o Westsyndrome; Crypt, cryptogenic LGS. Oguni H et al. Epilepsia 1996; 37: 44-47
  • 50. Age at appearance of drop attacks: Sympt West(+), Symptomatic LGSwith a h/o West syndrome; Sympt West(-), symptomatic LGS withouta h/o West syndrome; Crypt, cryptogenic LGS.61% had onset at older than 10 years. Oguni H et al. Epilepsia 1996; 37: 44-47
  • 51. Seizure types during the clinical course Seizure type NumberTonic seizures 100 %Myoclonic seizures 51 %Atypical absence seizures 50 %Atonic seizures 46 %Astatic seizures 32 %GTCS 28 %Periodic spasms 15 %Status epilepticus/ tonic status 15 %Complex partial seizures 14 %Focal motor seizures 3% Oguni H et al. Epilepsia 1996; 37: 44-47
  • 52. Epilepsy outcome at final examination LGS MISF SGE LRE NCrypto (n= 21) 14 (67%) 0 5 1 1Sympto (n= 51) 23 (45%) 8 14 4 2 West (-) 11 4 7 4 1 West (+) 12 4 7 0 1Total 37 8 19 5 3 More than two thirds of the patients had daily/ weekly seizures, of which tonic seizures were the most frequent. No difference in seizure outcome between the cryptogenic and symptomatic groups. Six (8%) patients were either seizure free (3), or had only a few attacks annually (3). Oguni H et al. Epilepsia 1996; 37: 44-47
  • 53.  Retrospective chart review of 107 patients. Median age of LGS onset: 4 yrs (6m- 29 yrs). M:F= 1.49: 1.0 Late-onset LGS (age > 8 yrs) in 17/107 patients. 74 had follow-up of > 3 yrs: Cryptogenic (12), indeterminate (29) and symptomatic (33) groups. Mean duration of follow up: 12.8 yrs Goldsmith I.L. et al. Epilepsia 2000; 41: 395- 99.
  • 54. Seizure outcome No significant difference in outcome between the 3 subgroups with regard to seizures and cognition. Classification on the basis of the presence or absence of partial seizures at LGS onset did not result in a significant difference in seizure or cognitive outcome. Symptomatic patients had more atonic and atypical absences at the end of study versus frequent tonic and myoclonic seizures in the cryptogenic group. Goldsmith I.L. et al. Epilepsia 2000; 41: 395- 99.
  • 55. Long-term follow-up (> 3 yrs) of patients with LGS. Goldsmith I.L. et al. Epilepsia 2000; 41: 395- 99.
  • 56. Seizure outcome No significant difference in seizure frequency between the cryptogenic (54%) and symptomatic (63%) subgroups, although patients in the symptomatic subgroup had more types of seizures. Tonic, atypical absence, and GTCS were the most common seizure types seen at end of follow-up. Only 3 (4.6%) patients were seizure free, and all were part of the indeterminate subgroup. Goldsmith I.L. et al. Epilepsia 2000; 41: 395- 99.
  • 57. Seizure types in patients with LGS. Goldsmith I.L. et al. Epilepsia 2000; 41: 395- 99.
  • 58.  25 children with LGS (M:F= 14:11). Mean age at onset: 4 yrs (1.2- 9.0) Mean follow-up: 10.2 yrs (5.3- 15.6) Mean age at last F/U: 13 yrs (6.6- 17.9) 1/16 (6%) children with symptomatic LGS and 2/8 (25%) children with cryptogenic LGS recovered from their epilepsy. Rantala H et al. Epilepsia 1999; 40: 286- 89.
  • 59. Evolution of EEG features
  • 60. Evolution of epileptiform discharges in LGS Yagi K et al. Epilepsia 1996; 37:48- 51
  • 61. Evolution of epileptiform dischargesin sleep Slow spike-and-wave complexes during waking disappeared first. Multiple spike-and-wave complexes in repetition or burst or fast rhythms or both during ‘sleep’ remained for several years. Finally, solitary spike-and-wave complex during sleep were seen before epileptic discharges disappeared. This evolution was characteristic of patients whose seizures improved. Yagi K et al. Epilepsia 1996; 37:48- 51
  • 62. Intellectual outcomes
  • 63. Mental retardation in LGS subtypes Goldsmith I.L. et al. Epilepsia 2000; 41: 395- 99.
  • 64. Mental retardation in LGS patients with normal cognition at LGS diagnosis Goldsmith I.L. et al. Epilepsia 2000; 41: 395- 99.
  • 65. Intellectual outcome 33% of cryptogenic cases were normal, compared to indeterminate (3%) and symptomatic cases (3%) (p≤ 0.01). When patients with MR at onset were excluded, 33% of the cryptogenic patients were normal, compared to indeterminate (17%) and symptomatic (20%) groups. No significant difference was seen in terms of seizure frequency or types, EEG findings, or antiepileptic medications. Goldsmith I.L. et al. Epilepsia 2000; 41: 395- 99.
  • 66. Intellectual outcome At end of study 8.1% of the patients were cognitively normal. The 6 patients with a good cognitive outcome had a median age of LGS onset of 9.5 years compared with 4.5 years for those who were initially normal but eventually had a poor cognitive outcome (p≤ 0.01). It is likely the brain of such patients has already gone through certain critical developmental stages such as apoptosis and synaptogenesis. Goldsmith I.L. et al. Epilepsia 2000; 41: 395- 99.
  • 67. Intellectual Outcome in LGS IQ Cryptogenic Symptomatic Total LGS First/Last visit First/Last visit First/last visitNormal (> 70) 7/1 17/0 24/1Mild MR (55- 70) 5/2 7/2 12/4Moderate MR (35- 55) 5/9 11/10 16/19Severe MR (20- 35) 4/4 21/13 25/17Profound MR (< 20) 0/5 0/26 0/31 Oguni H et al. Epilepsia 1996; 37: 44-47
  • 68. Intellectual outcome in LGS Severe or profound MR was diagnosed in 9 (43%) patients in the cryptogenic and 39 (76%) patients in the symptomatic group. IQ scores below the moderate levels composed 86% of the cryptogenic and 96% of the symptomatic group. IQ score decrease of ≥15 points was seen in 9/11 (82%) patients with cryptogenic LGS and in 7/9 (78%) patients with symptomatic LGS. Oguni H et al. Epilepsia 1996; 37: 44-47
  • 69. Intellectual outcome in LGS at mean follow- up of 10 yrs Cognitive status LGS (n= 14)Normal 2Subnormal 2Mild retardation 2Moderate retardation 5Severe retardation 1Profound retardation 2No child with symptomatic LGS was mentally and neurologicallynormal at follow-up compared with 2/8 children with cryptogenicLGS, but the difference was not statistically significant. Rantala H. Epilepsia 1999; 40: 286- 89.
  • 70. Persistence of Seizures and MR in LGS patients Study N Duration of Seizure MR F/U (yrs) persistence persistence (% of pts) (% of pts)Kurokawa 123 >5 66 93et al, 1980Ohtsuka 89 >5 76 91et al, 1990Yagi 102 > 10 92 75et al, 1996Oguni 72 > 10 92 99et al, 1996Goldsmith IL 74 >3 95 92et al, 2000 Glauser TA. Epilepsia 2004; 45: 23- 26.
  • 71. Other outcome measures
  • 72. Functional outcome of LGS patientsNormal occupational status 12Working part time 7Housewife 1Vocational training at work/training centres 29Students at special school for handicapped 5Institutionalised for care 21Custodial care at home 19Hospitalised for care 6Death (details not provided) 2Total 102 Yagi K et al. Epilepsia 1996; 37:48- 51
  • 73. Other outcome measures Variable gait disturbances, preexisting and acquired, developed in 22/74 patients by the end of follow-up. Some became wheelchair bound, due to gait disturbance and also due worsening of the violent drop attacks in those who were ambulant. Deficits at end of follow-up (but not at onset) and developmental delay correlated significantly with severity of epilepsy. Oguni H et al. Epilepsia 1996; 37: 44-47
  • 74. Neurologic findings in LGS after mean follow-up of 10.2 years Deficit LGS (n= 14)Normal 2Clumsiness 4Muscular hypotonia 0Ataxia 4Spastic hemiplegia 1Spastic tetraplegia 1Flaccid paraparesis due to meningomyelocele 0Pure cognitive disability 2 Rantala H et al. Epilepsia 1999; 40: 286-89
  • 75. Mortality in LGS The mortality rate is high. Varies from about 3%–7%, mostly related to accidents (Glauser 2004), to 25% due to underlying neurological conditions Camfield and Camfield 2007. The incidence of SUDEP is higher in these patients. Markand ON, J Clin Neurol 2003. 2/102 patients with LGS were death by the end of the follow-up period. Yagi K et al. Epilepsia 1996; 37:48- 51
  • 76.  80% of children with LGS continue to experience seizures, severe cognitive, psychiatric, and behavioral deficits. Camfield & Camfield, 2008; van Rijckevorsel, 2008. It has a devastating impact on patients’ quality of life and inflicts a considerable burden on their caregivers. Gallop et al., 2009. A defined strategy for transitioning patients from pediatric to adult care should be an essential component of the long-term management plan. Jurasek et al., 2010.
  • 77. Outcome of LGS Author N F/U ResultOhtsuka 89 > 5 yrs 31 (34.8%) had features of LGS.et al, 1990 28 (31%) of those who had lost the features of LGS had progressed to severe epilepsy with MISF.Beaumanoir 103 10 yrs 48/103 (46.6%) had features of LGS.et al, 1982Oller- Daurella 235 > 5 yrs 50% retained features of LGS.et al, 1987Oguni H 72 17 yrs LGS features disappeared in 33% ofet al, 1996 cryptogenic and 55% of symptomatic cases.
  • 78. SCTIMST experience 56 patients with follow-up of > 2 yrs. Idiopathic (11), symptomatic (33), indeterminate (6). Median age at onset of LGS: 24 months. No late onset (after 8 years) LGS. First unprovoked seizures and LGS in the symptomatic group was before 2 years of age, which was statistically significant. 2 patients (1 each in symptomatic and indeterminate group) were seizure free at the end of follow up. Mini S et al. (unpublished)
  • 79. SCTIMST experience Cognitive decline was progressive and 96% patients had intellectual disability at final follow-up. 50% of patients had physical disability or behavioural problems (ADHD, autistic features). Quality of life of the patient was rated as poor. Idiopathic and symptomatic LGS were similar in terms of final seizure and intellectual outcome. Absence of preceding West syndrome did not predict a better prognosis. Mini S et al. (unpublished)
  • 80. Treatment
  • 81. Treatment of LGS Chronic medical treatment remains disappointing. Only 6 randomized double-blind controlled trials. Treatment: broad spectrum AEDs/ polypharmacy. AEDs effective for one seizure type may worsen another or provoke SE. No specific experimental model for LGS. Treatment of comorbidities may aggravate seizures. Disease may fluctuate independent of treatment.
  • 82. Comparison of double blind randomized placebo controlled trials in LGS Van Rijckervorsel K. Neuropsychiatric disease and treatment 2008; 4: 1001-19
  • 83. Treatment strategy for LGSVan Rijckervorsel K. Neuropsychiatric disease and treatment 2008; 4: 1001-19
  • 84. Drug Benefit Disadvantages/ worsening of seizuresVPA Drug of choice Risk of hepatotoxicity/ pancreatitis with polytherapy.FBM All Sz types Aplastic anemia/ hepatic failure.LTG All Sz types Drug interaction with VPA, skin rashes.TPM All Sz types Interaction with VPA, cognitive side-effects.RUF All Sz types Headache, sedation, tremor.LEV Myoclonus Behavioural side effectsZSN >50% seizure Cognitive slowing, ataxia, sedation. reductionCLB Drop attacks Tonic seizures, tonic status epilepticus, behavioural problems, sedation, tolerance.CZP Myoclonus Same as above. In addition, ataxia, significant drug interactions.CBZ/OXC Tonic- clonic, Atypical absences, myoclonus. tonic, focalPHT Tonic- clonic, Atypical absences, myoclonus. tonicPB/PRM Tonic- clonic, Sedation, cognitive and behavioural worsening.
  • 85. Drug Benefit Disadvantages/ worsening of seizuresNZP Sedation.STM Myoclonus, Acute psychotic episodes in predisposed individuals. focal seizuresTGB NCS, focal Narrow spectrum, may worsen atypical absences.VGB Mised results Frequent worsening of seizures, especially myoclonus. Anecdotal reports/ uncommon AEDsGabapentin AllopurinolPregabalin AcetazolamideFlunarizine BromideThyrotropin releasing hormone Pyrodoxine Newer AEDsCarisbamate Valrocemide/ Di-isopropyl acetamideFluoro- felbamate StiripentolGanaxolone RemacemideBrivaracetam/ Seletracetam
  • 86. Immunotherapy in LGSPrednisolone Prednisone 1 mg/kg/day for 12 weeks (6 weeks daily and 6Sinclair weeks alternate therapy) in addition to their regular AEDs.et al, 2003 The follow-up period was for 1 to 5 years. 7/10 children with LGS became seizure free. Side effects: were uncommon; weight gain, aggression.Verhelst 32 children with intractable epilepsy (excluding Westet al, 2005 syndrome). In 47% there was a decrease in seizure frequency. 25% became seizure free. 11% had a seizure reduction of >50% 11% had a seizure reduction of <50%.IVIG Anecdotal and case series suggest benefit in LGS.
  • 87. ACTH in LGSN= 45 23 (51.1%) became "seizure free" for over 10 days. 10/23 relapsed within 6 months. 13/23 cases were seizure free for > 6 months. 8/13 patients had relapse from 9 months to 7 years later. 5/13 cases did not have relapse.Factors Age at ACTH treatment: up to 4 years oldaffecting Early initiation of ACTH: (within 1 year, preferably within 3response mth). Idiopathic/ cryptogenic cases. No cognitive defects at onset. Absence of tonic seizures. EEG findings: absence of asymmetry.Note Continue ACTH as long as possible, till disappearance of seizure discharges, or at least the disappearance of diffuse seizure discharges. Yamatogi Y, et al. Brain Dev 1979; 4: 267- 76
  • 88. Prognostic factors Normal neurologic examination. Cryptogenic LGS. Normal cognitive status at onset. Older age of onset. EEG changes, seizure frequency, seizure type, family history of epilepsy does not affect outcome. Furune S et al. Brain dysfunction 1988; 1: 146- 53. Oguni H et al. Epilepsia 1996; 37: 44- 47.
  • 89. Conclusion Long-term outcome in terms of seizure control and intellectual development are disappointing and can be extraordinarily stressful for families. Cognitive problems are greatest with earlier onset suggesting a profound effect on brain maturation at a critical stage of development. Seizure control is only one of the important goals in attempting to improve the lives of these patients.
  • 90. Thank you