The neonatal presentation of genetic epilepsies

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1 The neonatal presentation of genetic epilepsies Maria Roberta Cilio, MD, PhD Professor, Neurology and Pediatrics Director of Research, UCSF Epilepsy Center Director, Neonatal Neuromonitoring and Epilepsy Program University of California San Francisco

2 I have nothing to disclose

3 Objectives Provide an apileptological approach to seizures in the neonate Improve the early recognition of neonates with genetic epilepsies Discuss personalized treatment of these disorders

4 Challenges and tools The challenge of recognition: neonates are in the NICU Collaboration with neonatologists and nurses is key The challenge of treatments: does one size fits all? Increased availability of genetic testing Increasing use of video-eeg in the NICU Implementation of brain-oriented neonatal intensive care units

5 Figure. Genes associated with epilepsy by age at presentation. Birth 1 Year 10 Years 20 Years KCNQ2 SCN2A STXBP1 CDKL5 ARX KCNT1 KCNT1 SCN8A PRRT2 SCN1A PCDH19 GRIN2A CHRNs LGI1 DEPDC5 From: Swaiman s Pediatric Neurology: Principles and Practice 6e; Ch 64, Cilio and Sands, 2016 The electroclinical presentation in the neonatal period of neonatal-onset epilepsies is not yet well defined Many patients are diagnosed later in life, and clinical and EEG findings related to the neonatal period may be scarce.

6 Age at onset Developmental course EEG Other seizure types Ini:al Seizure type Diagnosis Examina:on findings MRI findings Genes Courtesy of Ingrid Scheffer

7 The forgotten neonatal phenotype Does it matter?

8 Benign Familial Neonatal Epilepsy Age-dependent genetic epilepsy of the newborn Autosomal dominant, penetrance 85% Healthy neonates Seizure onset in the first days of life Seizure semiology: tonic phase with focal features and autonomic component often followed by a clonic phase Brief frequent seizures lasting 1 to 2 minutes Interictal EEG background is normal may have interictal epileptiform abnormalities Mean duration of clusters varies from 2 hours to 3 days Favorable outcome in regard to seizures and neurological development Two genes: KCNQ2 and KCNQ3 Ronen et al, 1993; Singh, 1998; Charlier 1998; Cilio 2004; Sands, 2016

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12 Epilepsia, 1995

13 Rapid and safe response to lowdose carbamazepine of benign neonatal epilepsy Figure 3. Treatment responses in BFNE Case 1 Case 2 LZP iv x 4 doses PB iv 20 mg/kg + PB iv 40 mg/kg CBZ po 10 mg/kg/day LEV iv 60 mg/kg/day Midazolam drip CBZ po 10 mg/kg/day Case 3 PB iv 30 mg/kg LEV iv 30 mg/kg CBZ po 10 mg/kg/day Case 4 PB iv 40 mg/kg B6 iv 100 mg Clonazepam po Diazepam iv CBZ po 10 mg/kg/day Case 5 PB iv 40 mg/kg B6 iv 100 mg Clonazepam po Diazepam iv CBZ po 10 mg/kg/day Case 6 CBZ po 10 mg/kg/day Case 7 PB iv 40 mg/kg CBZ po 10 mg/kg/day Case 8 CBZ po 10 mg/kg/day Case 9 Case 10 PB iv 20 mg/kg PB iv 20 mg/kg + PHT iv 18 mg/kg * PB po 5 mg/kg/day CBZ po 10 mg/kg/day Case 11 CBZ po 10 mg/kg/day Case 12 CBZ po 10 mg/kg/day Case 13 B6 iv 100 mg PB iv 40 mg/kg Midazolam drip CBZ po 10 mg/kg/day Case 14 PB iv (multiple loads) CBZ po 10 mg/kg/day Case 15 PB iv (multiple loads) Midazolam drip Thiopental drip Case 16 PB 20 iv mg/kg CBZ po 10 mg/kg/day Case 17 PB iv (multiple loads) LEV iv 40 mg/kg x 2 OXC po 35 mg/kg/day Case 18 CBZ po 10 mg/kg/day Case 19 CBZ po 10 mg/kg/day Sands, et al. Epilepsia, in press

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27 The neonatal phenotype The response to carbamazepine The response to carbamazepine and phenytoin

28 SCN2A-related epilepsies: Benign Familial Neonatal-Infantile Epilepsy BFNIS is a benign autosomal dominant epilepsy Family syndrome Intermediate phenotype between benign familial neonatal seizures (BFNS) and benign familial infantile seizures (BFIS). Age of onset in these BFNIS families varied from 2 days to 6 months, with spontaneous resolution in most cases before the age of 12 months. Seizures are focal and generally occur in clusters over one or a few days with often a posterior focal seizure autosomal dominant.

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30 SCN2A encephalopathy Mutations are de novo Neonatal onset Infantile onset Developmental delay EEG shows a pattern of epileptic encephalopathy with multifocal epileptiform discharges Brief, very frequent tonic seizures shifting laterality Response to sodium channel blockers Howell et al, Neurology 2015

31 Epilepsy of Infancy with Migrating Focal Seizures Multifocal intractable seizures arising independently and sequentially from both hemispheres Severe developmental delay Decline of head circumference percentile Seizures do not respond to sodium-channel blockers nor other conventional AEDs Some seizure control reported with potassium bromide and levetiracetam Coppola and Dulac, 1995; Okuda et al. 2000; Hmaimess et al. 2006, Cilio et al. 2009

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33 Sodium-activated potassium channel

34 KCNT1 The first epilepsy-associated gene identified by exome sequencing in sporadic cases Preliminary phenotyping for the identification of homogeneous cohorts A powerful approach for unraveling the genetic mechanisms underlying rare epilepsies Barcia et al, Nature Genetics 2012

35 Electrophysiological studies of MPSI-associated mutations Gain-of-function Activation of the channel Enhanced K + current Its C terminal region is involved in protein-protein interaction with several partners including FMRP (Fragile-X Mental Retardation Protein) Seizures due to the impairment of channel function Motor and cognitive delay due to the impairment of the ability to interact with developmentally relevant protei Bhattacharjee & Kaczmarek 2005; Brown MR et al. 2008; Ruffin VA, et al. 2008

36 KCNT1 gain-of-function is not affected by any conventional AEDs It is target of several cardiac drugs Antiarrhythmic drug quinidine operates as a pore blocker Annals of Neurology, 2014 Bearden et al.

37 Quinidine as targeted treatment for KCNT1- associated epilepsies Exposure to Quinidine, a drug approved for the treatment of cardiac arrhythmias, significantly reduced the gain of function in all mutation studied Milligan et al, Annals of Neurology 2014

38 Genetic neonatal-onset epilepsies Phenotype does matter One size does not fit all! Video-EEG as a diagnostic tool Collaboration is key Early diagnosis is essential for early treatment and prognosis Goal is seizure control Targeted treatment may change prognosis of severe neonatal-onset epilepsies

39 Phenotype does matter Early diagnosis is essential for early treatment Determining mutation pathogenicity and mechanisms of disease Early treatment of seizures may lead to better outcome by reducing the effects of frequent seizures in the neonatal brain Targeted treatment may drastically change prognosis

40 EPILEPSY GENETICS INITIATIVE EGI has created a data repository of clinical exome and genome sequences Data is being reanalyzed every 6 months for novel genetic changes New results will be communicated back to patients via their doctor Data will also be made available to advance epilepsy research

41 To improve is to change, to be perfect is to change often Winston Churchill UCSF NICN Nation s First NeuroIntensive Care Nursery