MASTER ABA di I e II livello: Applied Behavior Analysis. Epilessia ed autismo incluse le manifestazioni non epilettiche

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1 MASTER ABA di I e II livello: Applied Behavior Analysis Epilessia ed autismo incluse le manifestazioni non epilettiche Prof. Federico Vigevano Dipartimento di Neuroscienze, Ospedale Pediatrico Bambino Gesù Consorzio Universitario Humanitas - tutti i diritti riservati, è vietata la riproduzione e/o l utilizzo non autorizzato

2 613 children enrolled with newly diagnosed epilepsy and followed a median of 10.5 years: Global cognitive function: Normal = 451 (73,6%) Borderline. = 31 ( 5,1%) Mild MR = 21 ( 3,4%) Severe MR = 45 (7,3%) Devastated = 29 (4,7%) NFC = 36 (5.9%) Variable associated to subnormal global cognitive function: Age at onset < 5 years Symptomatic etiology Epileptic encephalopathy Remission status Current AED treatment

3 Intellectual deterioration in childhood epilepsy Apparent delay in cognitive development performance against age-related norms appears to drop Real due to concomitant degenerative neurological disease of which epilepsy is also a symptom consequence of one or more of a number of other factors Brown S., Epilepsia 2006

4 AEDs reduce neuronal irritability but also reduce neuronal excitability and, so, may impair cognition

5 The risk of side effects increases with : - higher drug load - higher doses and serum levels - polytherapy - speed of uptitration

6 Epileptic encephalopathy - Definitions Condition in which the epileptiform abnormalities are believed to contribute to progressive disturbance in cerebral function. (Engel, 2001) Evidence suggests or supports the notion that there is an epilepsy-dependent neurodevelopmental or neurodegenerative process involved in the evolution of the syndrome (as opposed to an underlying metabolic, degenerative, or encephalitic process), (Engel, 2006) Epileptic encephalopathy embodies the notion that the epileptic activity itself may contribute to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone (e.g., cortical malformation), and that these can worsen over time...and. may potentially occur in association with any form of epilepsy. (Berg et al. 2010).. the term epileptic encephalopathy refers to conditions characterized by epilepsy associated with psychomotor impairment, the latter being potentially reversible once epileptic activity is controlled

7 Condition in which the epileptiform abnormalities are believed to contribute to progressive disturbance in cerebral function. (Engel, 2001) Epileptic Encephalopathies ETIOLOGIES - Brain malformations - Chromosomal or genetic abnormalities - Neurocutaneous diseases - Hypoxic ischemic injuries - Postnatal causes (vascular or infectious insults) 1- Seizures control THERAPEUTIC GOALS 2- Decrease or resolution of EEG abnormalities 3- Developmental outcome

8 West syndrome Lennox-Gastaut syndrome Epilepsy with continuous spike-waves during slow-wave sleep (CSWS) Etiologies are variable. Peculiar evolution of epilepsy towards a syndrome specific electro-clinical picture. Quantifiable cognitive and motor regression, characterized by an evident worsening of the neuropsychological profile when compared to pre-onset neurodevelopmental phenotype. Variable evolution, ranging from complete remission to very severe conditions, such as drug resistant epilepsy and severe mental retardation.

9 West Syndrome Severe epileptic encephalopathy characterized by: epileptic spasms hypsarrhythmic EEG pattern developmental delay

10 Syndrome Etiology Prognosis - Cryptogenic - Malformation - Genetic - Hypoxic-ischemic - Metabolic West Syndrome, Infantile Spasms - Seizure-free -Drug-resistance -Cognitive decline Fusco L.

11 After 4 weeks of treatment Before ACTH

12 Lennox-Gastaut Syndrome: Epidemiology and Etiology 1-10% of childhood epilepsies 7% of children with ID ( 55% LGS IQ <50) Prevalence: 4% of childhood epilepsies incidence in new onset epilepsy : 0,6% ( Trevathan et al, 1997; Camfield et al, 1996) Onset: 2-8yrs ( most commonly 3-5yrs); very rare late onset ( Down s syndrome) Persist through adolescence and on into adulthood Males have 5.3 relative risk vs female De Novo : 10% (? ) Prior West Syndrome: 30-65% Preceding history other than West syndrome: 70-80%

13 Lennox-Gastaut Syndrome: Epidemiology and Etiology Cryptogenic 33% Symptomatic 66%: - Brain malformation ( LIS1, DCX,GPR56) - Infection - Tumor - TSC (TSC1, TSC2) - HHE - Gene mutations ( CHD2 FOXG1 )

14 LGS Characteristic EEG: Slow Spike and Wave Paroxysmal Fast Activity American Epilepsy Society 2015

15 Epilepsy with continuous spikes and waves during slow sleep Focal seizures, negative myoclonus and drop attacks ESES Cognitive decline, attention deficit, behavioral problems

16 ML, 7 yrs onset, awake ML, 9 yrs outcome Epilepsy Onset of rolandic seizures After 6 months new focal motor seizures without impairment of counsciousness Drop attacks and abcences Cognitive and attention deficits CLB and LEV ineffective Video-EEG: multiple myoclonic seizures, CSWS ML, 8 yrs, Myoclonic Seizure M.L., 9 yrs, F Epilepsy ACTH (20 IU) disappearance of CSWS, recovery ML, 8 yrs, Sleep Rolandic Epilepsy

17 Normal/abnormal development Epilepsy Epileptic encephalopathy is a dynamic condition not depending from the etiology that may persist over time causing increasingly severe functional effects It may improve and remit, either spontaneously or with treatment which suppresses the proposed causative epileptic activity Suppress EEG Abnormalities + Seizures Improvement of Cognitive deterioration RESOLUTION OF EPILEPTIC ENCEPAHOPATHY

18 Delta power Associated pattern. Although spikes caused a cortical activation pattern similar to that in focal epilepsies, slow wave activity produced a hypsarrhythmia-specific activation in cortex and subcortical structures such as brainstem, thalamus, and putamen.

19 FULL-LENGTH ORIGINAL RESEARCH Epilepsia, 52(4): , 2011 doi: /j x EEG-fMRI reveals activation of brainstem and thalamus in patients with Lennox-Gastaut syndrome *Michael Siniatchkin, *Diana Coropceanu, *Friederike Moeller, yrainer Boor, and *yulrich Stephani *Department of Neuropediatrics, Christian-Albrechts-University, Kiel, Germany; and ynorthern German Epilepsy Center, Raisdorf, Germany Even if etiologies of Lennox-Gastaut syndrome (LGS) are diverse, the multiple causes converge into a final common pathway that results in this specific epilepsy phenotype. Figure 2. Results of the group analysis in patients with LGS (p < 0.001, noncorrected). Epilepsia ILAE Significant activation of brainstem and thalamus (especially centromedian and anterior thalamus) associated with epileptiform discharges in patients with LGS.

20 doi: /brain/awq183 Brain 2010: 133; BRAIN A JOURNAL OF NEUROLOGY Neuronal networks in children with continuous spikes and waves during slow sleep Michael Siniatchkin, 1 Kristina Groening, 1 Jan Moehring, 1 Friederike Moeller, 1 Rainer Boor, 2 Verena Brodbeck, 3 Christoph M. Michel, 3 Roman Rodionov, 4 Louis Lemieux 4 and Ulrich Stephani 1 The spike-related deactivations were found in structures of the default mode network (precuneus, parietal cortex and medial frontal cortex)in all patients and in caudate nucleus in four. Despite aetiological heterogeneity, patients with CSWS were characterized by activation of the similar neuronal network: perisylvian region, insula and cingulate gyrus. The deactivations in structures of the default mode network are consistent with the concept of epileptiform activity impacting on normal brain function by inducing repetitive interruptions of neurophysiological function.

21 CSWS West syndrome Deactivation in the Default mode network Lennox-Gastaut Absence seizures Multiple causes may activate a syndrome specific neuronal network Courtesy of Siniatchkin

22 ESES Duration 13 months 18 months The duration of ESES was months (range 2 60 months), with no significant difference between the different etiologies N=30 Kramer et al., 2009, Epilepsia

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24 Dravet syndrome v v Epileptic encephalopathy Onset: 1 st year of life Febrile and afebrile seizures Febrile and afebrile status epilepticus Myoclonic seizures Absences Focal seizures Early photosensitivity Cognitive Delay

25 Epilepsy & Behavior 31 (2014) Contents lists available at ScienceDirect Epilepsy & Behavior journal homepage: Cognitive and adaptive evaluation of 21 consecutive patients with Dravet syndrome Nathalie Villeneuve a,b,c, Virginie Laguitton a, Marine Viellard b, Anne Lépine a,c, Brigitte Chabrol c, Charlotte Dravet d, Mathieu Milh c,e, u SCN1A was mutated in 19 out of 21 patients u After the age of 6 years, none of the DS patients had a normal intelligence quotient (IQ):mean total IQ = 47 ± 3 u They did not find any significant correlation between the IQ or developmental quotient assessed between 6 and 10 years of age and the quantitative and qualitative parameters of epilepsy during the first two years of life in this small group of patients. 25

26 Encephalopathy in children with Dravet syndrome is not a pure consequence of epilepsy Patients with severe delay and neurological features in the mutated group - Lack of psychomotor deterioration - No correlation between the severity of the epilepsy and the severity of the cognitive delay - Main troubles in visual motor integration and visual perception - Additional direct role for SCN1A mutation? N Chemaly

27 Dravet syndrome u Epileptic encephalopathy due to a single etiological factor (SCN1A interneuron abnormalities). u It is characterized by a constant electro-clinical pattern, evolving only in terms of intensity and severity, without any possibility of complete resolution. u It may be considered as a real disease and a specific nosographic entity.

28 Developmental and epileptic encephalopathies Developmental encephalopathy where there is just developmental impair- ment without frequent epileptic activity associated with regression or further slowing of development; Epileptic encephalopathy where there is no preexisting developmental delay and the genetic mutation is not thought to cause slowing in its own right; Developmental and epileptic encephalopathy where both factors play a role Where a genetic mutation is identified, the well recognized developmental and epileptic encephalopathies can be called by their gene name together with the word encephalopathy : KCNK2 Encephalopathy. Scheffer et al., 2017

29 How common is epilepsy in patients with autism? 30% of patients with Autism have epilepsy. 30% of patients with epilepsy have Autism. Highest risk for Autism is seen in those whose seizures that start in the 1 st year of life. Risk for epilepsy in children with Autism is higher in those with greater intellectual disability, symptomatic vs. unknown cause, and history of regression 35-65% of patients with Autism have EEG abnormalities Epilepsy in autism confers increased mortality

30 Difficulty in Diagnosing Epilepsy in Children with Autism Difficulty in distinguishing a behavioral episodes (staring, repetitive movement) from an epileptic seizure. EEG may be abnormal in patients who do not have epileptic seizures.

31 Do seizures cause autism? Does autism lead to seizures? Atypical neuronal networks - Phases of synaptogenesis in human brain ü ü ü During the first three years of life, an excess of cell/synaptic growth rate and inhibitory currents could increase the risk of ASD. Mutations within the mtor/pi3k pathway lead to an excess of synaptic/cell growth. Mutations within the NRXN NLGN SHANK pathway lead to abnormal synaptogenesis and excess of inhibitory currents. Bourgeon, 2009

32 Altered genes in ASD with epilepsy Gene Locus Type of mutation Transmission Molecular abnormalities SCN1A 2q24 Point mutation De novo Na-channel SCN2A 2q23 q24.3 Deletion De novo Na-channel KCNMA1 10q22 Point mutation Dominant inheritance K-channel NLGN4X Xp22.31 Point mutation Inherited Synapse formation NRXN1 2p16.3 Deletion Recessive inheritance Synapse formation Point mutation De novo CNTNAP2 7q35 Deletion Recessive inheritance Synapse formation Point mutation De novo SYNGAP1 6p21.3 Point mutation De Novo Synapse RasGAP ARX Xp22.13 Duplication Inherited De novo Aristaless-related homeobox protein Modified from Amiet 2013 and Betancur 2011

33 Disorders of synaptic plasticity Genetic conditions causing disrupted synaptic plasticity, abnormal Inhibition/Excitation Abnormal plasticity ü genetic conditions ü seizures during early post-natal development may alter synaptic plasticity and contribute to ASD ASD Early life seizures Abnormalities in synaptic plasticity ü alterations in receptors ü signaling molecules ü neurotrophins Brooks-Kayal, 2010