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CFERV 2019 Hausman-Kedem


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GRIN-related epileptic encephalopathy can present early in life with intellectual disability, continuous spike-and-wave during sleep syndrome (CSWS), or epilepsy-aphasia spectrum phenotypes such as in Landau-Kleffner syndrome. Efficacy of IVIG treatment was recently reported in a patient with LKS related to GRIN2A mutation.

We describe our experience with IVIG therapy in 5 patients (4 males, age range 6 months-13 years) with confirmed GRIN-related epileptic encephalopathy (4 with GRIN2A mutations presenting with epilepsy-aphasia spectrum/epileptic encephalopathy with CSWS and verbal, communicative and
behavioural regression, and one patient with GRIN2D mutation who presented with early infantile developmental-epileptic encephalopathy). All patients had global developmental delay/ intellectual disability in various degrees and were resistant to anticonvulsants. None of the patients had clinical seizures as a hallmark. All patients received monthly infusion of IVIG 2 g/ kg for 6 months; 2 patients were also treated with high-dose corticosteroids. No seizures were observed during the treatment
period in any of these patients. Marked electrographical improvement was noted in 4/5 patients, with complete normalization of the EEG in 2 patients. Expressive and receptive verbal abilities, communication skills and behaviour (hyperactivity, impulsivity and attention disorders) improved. However, visuospatial perceptual/spatial abilities, as well as executive functions and attention span remained significantly impaired.

Conclusion: IVIG should be considered in the treatment of GRIN-related epileptic encephalopathy and may lead to EEG normalization. Early treatment is advocated to rescue developmental milestones and improve developmental potential. Autoimmune mechanism in GRIN-related diseases should be further investigated.

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CFERV 2019 Hausman-Kedem

  1. 1. Moran Hausman-Kedem, MD Pediatric Neurology Institute Tel Aviv Sourasky Medical Center, Tel Aviv University, Israel CFERV Conference, Atlanta September 2019 © Moran Hausman-Kedem
  2. 2. I have no disclosures *Patients photos and names are with permission © Moran Hausman-Kedem
  3. 3. ▪ Frequent interictal epileptogenic activity can result in cognitive slowing/regression ▪ May lead to long-term neurocognitive impairment ▪ Clinical seizures are not always present ▪ Various aetiologies - genetic, structural, metabolic ▪ Suppressing the epileptiform activity may improve the developmental consequences ▪ Mechanisms underlying epilepsy and neurodevelopmental regression are incompletely understood ▪ Many of the genetic disorders may also have direct developmental consequences ▪ Developmental and epileptic encephalopathies Scheffer et al. 2017, Gardella et al. 2018, Helbig et al. 2018 Olson et al. 2018, Pons et al. 2018 © Moran Hausman-Kedem
  4. 4. When the patient is experiencing cognitive/ neurological regression, a treatment should be administer ASAP ▪ goals of treatment: ▪ to eliminate the EEG abnormality ▪ to prevent loss of neurologic function ▪ Ideally, but rarely- to restore the lost function Geva-Dayan et al, Pediatr Neurol. 2012 Abeer et al, Semin Ped.Neurol 2016 Treatment options: • Anti-seizure medications • High dose diazepam • Steroids /IVIG treatment • Epilepsy surgery Emerging therapies based on underlying pathophysiology © Moran Hausman-Kedem
  5. 5. • NMDARs are essential for neuronal development and synaptic plasticity • wide spectrum of neurodevelopmental disorders GRIN2A various types of epilepsy (benign→ severe) ▪ Benign epilepsy with centrotemporal spikes (BECTS) ▪ Epilepsy-aphasia spectrum (Landau-Kleffner syndrome (LKS) ▪ Epileptic encephalopathy with continuous spike and waves during slow-wave sleep (CSWS) ▪ Developmental-epileptic encephalopathy GRIN2D ▪ severe developmental and epileptic encephalopathies ▪ severe developmental delay, ID and refractory epilepsy ▪ muscular hypotonia ▪ movement disorders- common Lemke et al, Nature Genetics, 2013 Li et al. Am J Hum Genet. 2016 Tsuchida et al , 2018 XiangWei et al, Brain, 2019 Poot. Mol Syndromol 2019 severity of epilepsy syndrome higher mutations frequency
  6. 6. Nonspecific treatment - conventional anti-seizure drugs, hormonal, IVIG specific treatments- based on functional outcome of the pathogenic variant gain of function mutations- NMDAR antagonists- memantine, magnesium, ketamine and dextrometrophan may be beneficial. loss of the channel function - positive allosteric NMDAR modulators unknown whether these treatments can modify disease trajectory Zhu et al. Curr Opin Pharmacol 2015. Addis et al. Sci Rep 2017 Pierson Ann Clin Transl Neurol. 2014 © Moran Hausman-Kedem
  7. 7. To report the efficacy of Immunotherapy for GRIN-related epileptic encephalopathy © Moran Hausman-Kedem
  8. 8. ▪ Five consecutive patients (2017-2018) ▪ 4 males, age range 2-13.5 years ▪ All had global developmental delay/ intellectual disability ▪ All patients had normal perinatal history ▪ Extensive workup- metabolic and MRI- normal ▪ Molecularly-confirmed diagnosis of GRIN pathogenic variants (WES, confirmed by Sanger sequencing) © Moran Hausman-Kedem
  9. 9. ▪ Monthly infusion of IVIG 2 g/kg for 6 months ▪ Two patients were also treated with high-dose corticosteroids (pulse steroids, gradual weaning off ▪ Stable dosage of other concomitant antiseizure medications ▪ Monthly Neurological evaluation ▪ Sleep EEG- prior to immunotherapy and every 2 months during treatment period. SWI was calculated. ▪ Neuropsychological assessment- WPPSI™- III or Bayley Scale of Infant and Toddler Development prior to and at the end of treatment ▪ Cell-based assay for detection of serum NMDAR Abs prior to IVIG treatment © Moran Hausman-Kedem
  10. 10. Patient 1 2 3 4 5 Gender Male male female male male Age (years) 10 7 5 2.5 13.5 GRIN gene GRIN2A GRIN2A GRIN2A GRIN2D GRIN2A Variant specifier c.2041C>T p.Arg681*. c.2041C>T p.Arg681*. c.2041C>Tp.Arg681* c.1999G>A p.(Val667Ile) c.1639_1641del, p.Ser547del Inheritance pattern Familial familial familial de-novo de-novo Mutation effect loss of function loss of function loss of function gain of function loss of function Epileptic syndrome CSWS/ LKS CSWS/ LKS CSWS/ LKS IDEE CSWS Seizures Yes yes, infrequent yes, infrequent no yes, infrequent Age at seizure onset (months) 36 42 48 18 54 Seizure semiology focal onset non-motor with impaired awareness, Myoclonic focal onset non motor seizures with impaired awareness focal onset, motor, clonic electrographic seizures, no clinical seizures focal onset, non- motor with impaired awareness Spike wave index (SWI) 80% 80% 80% __ 70% Anti-seizure medication used sodium valproate, zonisamide, sulthiame, levetiracetam, perampanel high-dose diazepam, corticosteroids sodium Valproate, Sulthiame, Clobazam sulthiame sodium valproate, vigabatrin sodium valproate, levetiracetam clobazam Cognitive level prior to IVIG treatment moderate ID normal-Borderline ID moderate GDD DQ 48 moderate GDD DQ 40 moderate ID (IQ-40) Autism Spectrum Disorder (ASD) yes no yes no no Developmental regression yes (age 3) yes (age 5) yes (age 3) no Yes (age 4) Age at IVIG treatment 10 6 years 4.5 years 20 months 13.5 years Pulse methylprednisolone No yes no yes no © Moran Hausman-Kedem
  11. 11. Three siblings with GRIN2A - related epilepsy-aphasia spectrum *with permission © Moran Hausman-Kedem
  12. 12. Family history Epilepsy NF1 EpilepsyEpilepsy Epilepsy GRIN2A, c.2041C>T p.Arg681* 10.5 YO GRIN2A c.2041C>T p.Arg681* 7.5 YO GRIN2A c.2041C>T p.Arg681* 4.5 YO GRIN2A c.2041C>T p.Arg681* NF1 frame shift, truncating variant causing an early stop codon All had normal perinatal history and developmental history until ~ age 3Y Lemke et al, Eur. J. Neurosci.2011 Yuan et al, Mol. Pharm.2015 13 YO © Moran Hausman-Kedem
  13. 13. Present illness: Referred at 3 years with ▪ Seizures (eye rolling, myoclonic jerks, head drops) ▪ Developmental regression in verbal, communication, fine motor skills FIQ-65 (VIQ-75, PIQ-59) (at 3.8 years) ▪ EEG: Bilateral centro-parieto-temporal spike-and-slow wave discharges. Spike-wave index- 70% during slow wave sleep ▪ Treated with sodium valproate, zonisamide At 4.5 years seizures recurred. Further deterioration of cognitive, linguistic, communication, adaptive skills ▪ Verbal agnosia, lost language skills, developed autistic features -> diagnosed with autism spectrum disorder (severity level 3) ▪ EEG showed exacerbation -SWI of 80%-90% © Moran Hausman-Kedem
  14. 14. ▪ AT 5 years- cognitive level - mild ID range (IQ-61) ▪ Treated with numerous anticonvulsants, high dose diazepam, pulse steroids- minor clinical or EEG improvement. ▪ EEG remained stable for 3 years, with SWI of 50-60% ▪ At 9 years: further regression. moderate to severe ID ▪ Not toilet-trained; able to produce simple phrases, mainly scripted speech and echolalia, and to follow simple commands ▪ Severe attention difficulties with distractibility –started Aderall. ▪ EEG- frequent nocturnal spike and wave discharges. SWI-80%. ▪ IVIG was then initiated © Moran Hausman-Kedem
  15. 15. Following IVIG verbal abilities- mildly improved. more fluent speech, impaired picture naming, verbal reasoning and acquired knowledge, IQ<50
  16. 16. S.O.- Day 1 ▪ Present illness: Referred at 4 years with speech regression and gait instability ▪ At 3.5 years expressive and receptive speech regression appeared ▪ At 4.5 years onset of episodes of ataxia and focal non- motor seizures with impaired awareness ▪ EEG revealed multifocal parietal, centro-temporal and right frontal epileptiform discharges, accentuated by sleep. SWI- 70% ▪ Treated with sodium valproate, sulthiame and clobazam- marked clinical improvement, less prominent EEG improvement © Moran Hausman-Kedem
  17. 17. ▪ At 6 years: functional regression in all domains: ▪ unstable gait, became averbal, minimal eye contact, no danger awareness, tended to orally investigate objects. ▪ severe distractibility and psychomotor agitation with marked verbal perseveration. IQ - 43 (moderate ID) ▪ EEG - recurrence of nocturnal bilateral fronto-centro- temporal epileptic discharges. SWI of 80%. ▪ Treatment with IVIG and pulse steroids was initiated © Moran Hausman-Kedem
  18. 18. Prior to immunotherapy EEG- normalized • regained expressive language and communication skills • less marked improvement in visual-perceptual, executive functions and attention span IQ – 58 (mild ID) Following the 6th dose of IVIG © Moran Hausman-Kedem
  19. 19. ▪ Present illness: Referred at 3.5 years for speech regression ▪ At 3 years - episode of ataxia and unsteady gait, developmental stagnation. ▪ Regression in gross and fine motor, as well as verbal skills, behavioural problems, marked attention difficulties and unawareness to danger. IQ-60 (3.5 years) ▪ EEG showed multifocal interictal epileptic activity, accentuated in slow wave sleep, SWI- up to 60%. ▪ Started treatment with sulthiame- marked gait improvement and EEG improvement ▪ Risperidone for behavioural difficulties. © Moran Hausman-Kedem
  20. 20. ▪ At 4.5 years -worsening fine motor difficulties, language and communication regression, severe attention problems and distractibility. IQ-48. ▪ EEG - multifocal interictal spike and wave epileptic discharges, accentuated by slow wave sleep with maximal SWI of 80%, suggestive of CSWS ▪ Treatment with IVIG was then initiated © Moran Hausman-Kedem
  21. 21. Normal sleep recording, 3 months after treatment initiation sleep EEG prior to IVIG- multifocal interictal spike and wave epileptic discharges EEG normalized -regained expressive language & communication skills -less marked improvement in visual-perceptual, executive functions, attention span. IQ-43 © Moran Hausman-Kedem
  22. 22. A 3-year-old male GRIN2D-related early-infantile developmental epileptic encephalopathy *with permission de novo GRIN2D Gain-of-function variant (c.1999G>A, p.(Val667Ile) Li et al. Am J Hum Genet. 2016 © Moran Hausman-Kedem
  23. 23. ▪ Presentation: 3 months. developmental delay- lack of eye tracking, social smile and head control ▪ Perinatal history and family history: normal ▪ Neurological evaluation: normal head circumference, poor head control, minimal visual tracking, hypotonia, normal DTRs, lack of motor coordination, dyskinesia, choreiform movements, motor apraxia ▪ Development: severe global developmental delay At 9 months- DQ-50 ▪ At 12 months - episodes of opisthotonos and tremor Video EEG - interictal bi-central epileptic activity Treated with sodium valproate followed with memantine, Magnesium *with permission
  24. 24. ▪ EEG monitoring (18 months) ▪ diffusely slow and disorganized high-voltage background activity, with multifocal and generalized spike and slow wave discharges. ▪ electrographic seizures. No clinical seizures ▪ Treated with vigabatrin without electrographic improvement EEG at 20 months DQ =30 pulse steroids and monthly IVIG were provided © Moran Hausman-Kedem
  25. 25. At 29 months EEG normalized At 22 months multifocal & generalized epileptic activity © Moran Hausman-Kedem
  26. 26. ▪ Epilepsy: No clinical seizures, EEG normalized ▪ Development: Slowly progressive (no regression) ▪ Gross motor: sits without support at 2 years does not crawl, standing in a gait trainer ▪ Fine motor: Grasp objects and transfer, motor apraxia ▪ Language: Syllables, no words, language comprehension - 6-10m ▪ Cognitive level: more alert and focus, understands familiar situations, can choose between two pictures, DQ=30 ▪ Social communication: Displays good social interaction *with permission © Moran Hausman-Kedem
  27. 27. 14YO GRIN2A, c.1639_1641del, p.Ser547del Epilepsy GRIN2A-related CSWS (continuous spike wave in slow wave sleep)/ electrical status epilepticus in sleep (ESES) *with permission © Moran Hausman-Kedem
  28. 28. ▪ Presentation: Referred at 4.5 years due to focal seizures, speech and cognitive regression ▪ Development: delayed speech ▪ Physical examination: head circumference- 25th percentile, high arch palate, elongate face, body weight -4SD, height -2SD, BMI-12 ▪ Neurological evaluation: Opercular syndrome: weakness of facial, masticatory and tongue muscles, difficulties chewing, drooling, motor clumsiness & motor dyspraxia *with permission © Moran Hausman-Kedem
  29. 29. ▪ 4.5 years: focal motor seizures with impaired awareness ▪ EEG –multifocal/generalized epileptiform activity. treated with valproic acid. ▪ 9 years: focal clonic status epilepticus and speech arrest ▪ EEG – electrical status epilepticus in sleep (ESES/CSWS) ▪ 10.5 years - IV pulse corticosteroids / oral prednisone and IVIG ▪ EEG - normalized ▪ 12.5 years - EEG - ESES/CSWS ▪ Ospolot, Keppra – no improvement in EEG ▪ IVIG was started ▪ Mild clinical improvement-attention span ▪ EEG - no improvement after 3 months ▪ Currently on Briviact, Frisium, Attent © Moran Hausman-Kedem
  30. 30. patient Age at evaluation (years) Verbal abilities Perceptual, visuospatial abilities General cognitive level SWI/ EEG findings Prior to IVIG followin g IVIG Prior to IVIG following IVIG Prior to IVIG Followin g IVIG Prior to IVIG Following IVIG Prior to IVIG following IVIG 1 9 9.8 Expressive- simple phrases, mainly scripted speech and echolalia. Receptive- does not follow simple commands Expressive- nearly fluent speech Receptive- Follows simple commands. Severe deficit Severe deficit Mod. to severe ID, ASD. Mod. to severe ID, ASD. 80% 40% 2 6.3 6.10 VIQ – 55 Verbal IQ- 63 PIQ- 47 PIQ-50 Mod. ID FIQ- 43 mild ID FIQ- 58 80% Normal EEG 3 3.5 5.5 Expressive- single words only Receptive marked comprehension difficulties VIQ-55 Expressive- Simple phrases, echolalia. Receptive- Follows simple and complex commands VIQ- 55 PIQ- 51 PIQ- 42 Mod. ID, ASD FIQ- 48 Mod. ID, ASD FIQ- 43 80% Normal EEG 4 18m 30m None none severe deficits in visual tracking severe deficits in visual tracking GDD DQ- 30 GDD DQ=30 Encephalopa thic, electrographi c seizures Normal background activity 5 13.5 -- 52 -- 56 -- 50 -- 80% 80%
  31. 31. © Moran Hausman-Kedem
  32. 32. ▪ Clinical course of GRIN2A-related disease - periods of sudden developmental regression ▪ Abundant (up to 90%) epileptic activity in sleep was evident on EEG ▪ However, clinical seizures were not the prominent manifestation ▪ Four patients had electrographical improvement and various degrees of improvement in developmental trajectories ▪ Normalization of the EEG in 3 patients ▪ All patients had persistent cognitive deficits ▪ Visuospatial and executive functions remained severely impaired ▪ Earlier treatment age- better response? ▪ The electrographic beneficial effect lasted 6-12 months after cessation of IVIG © Moran Hausman-Kedem
  33. 33. Role of immune system in epileptogenesis Neurogenic neuroinflamation Indirect mechanism of seizures DIRECT link between NMDARs and Glutamate and the immune system Elevated inflammatory markers are found in genetic epilepsy syndromes loss-of-function GluN2A Redox state Autoimmune mechanism may play a role in GRIN-related EE Viviani. J Neurosci. 2003, Pacheco J. Immunol.2006 HIrch, Epilepsy res. 2006, Ganor Y. Glutamate in the Immune System 2012 ,Kahlfuß et al. Mol Cell Biol. 2014
  34. 34. ▪ Immunotherapy may be effective in GRIN-related epilepsy, should be considered as a therapeutic option, particularly with evidence of developmental regression, and may lead to EEG normalization and improve developmental potential. ▪ Further research is needed to investigate autoimmune mechanisms in GRIN-related diseases especially in the context of functional assay ▪ Personalized novel and directed therapies in GRIN- related disorders is the goal © Moran Hausman-Kedem
  35. 35. Aviva Fattal Valevski Pediatric Neurology Institute, Dana- Dwek Children's Hospital, Tel Aviv Medical Center Shay Ben-Shachar Pediatric Genetics, The Genetics Institute, Tel Aviv Sourasky Medical Center, Tel Aviv Shay Menascu Multiple Sclerosis Center Sheba Medical Center, Ramat Gan Yoram Greenstein, PhD Seminar Hakibutzim, Tel Aviv & Zefat College, Zefat With permission © Moran Hausman-Kedem