Psychiatric treatment of children with Autistic Spectrum Disorder and Epilepsy

1. Psychiatric treatment of children with Autistic Spectrum Disorder and Epilepsy Dr. Florina Rad, Dr. Ilinca Mihailescu, Dr. Cristina Anghel, Dr. Alexandra Buica, Prof. Dr. Iuliana Dobrescu

2. Prevalenta Tulburarilor de Spectru Autist la nivel mondial 1975 - 2009 (Autism Speaks, 2010)

5. Epilepsy in autism • The prevalence of epilepsy among all children is estimated at 2–3%, compared with 5 – 38.3% in autism1 • Outcomes for children with ASD are dependent on factors such as2 : • autism severity • cognitive functioning • language development, • additional psychopathology, • medical disorders (e.g. epilepsy) • access to intervention programs and services. 1. Tuchman & Rapin 2002; 2. Levy & Perry 2011

6. Epilepsy in autism • bimodal age distribution of seizures in autism (one peak before age 5 and another one during adolescence)3 • increased prevalence of early onset seizures - the majority of seizures • occurring during the first 2 years of life 4,5 • risk factors for epilepsy in autism: severity of the cognitive deficit, the presence of cerebral palsy or other overt motor deficits and severe deficits in receptive language3 3. Tuchman et al 2010; 4. Danielsson 2005; 5. Wong 1993

7. Epilepsy in autism • types of seizures in ASD: All seizure types can be associated with autism Theprevalence of epilepsy and the types of seizures varywith the population studied1: • complex partial, atypicalabsence, myoclonic, and tonic-clonic seizures (Swedish study, 34 ASD children) • generalised tonic-clonic and atypicalabsence seizures (American cohort, 302 ASD clihdren) • centrotemporal spikes typical of benign epilepsy of childhood (106 autistic patients) • infantile spasm (Finnish study, 24 ASD children) 1. Tuchman & Rapin 2002

8. EEG abnormalities in ASD EEG studies in ASD: • standard EEG • computer-analyzed EEG (C-EEG) • magnetoencephalography (MEG) • multimodal recordings (EEG with structural/functional imaging studies) Detection of isolated epileptiform discharges Investigating functional and structural brain connectivity

9. Isolated epileptiform discharges (IED) in autism • the presence of epileptiform discharges, in the absence of seizures (IED), might contribute to the symptom presentation of ASD • many different localization patterns, instead of onelocus • IEDs may be reflective of some degree of cortical hyperexcitability • Canitano & Zappella, 2006, suggested the term AutisticEpileptiform Regression for non epileptic autistic children with epileptiform EEGs

10. Isolated epileptiform discharges (IED) in autism • 21 studies from 1975 to 2015 identified IEDs among non-epileptic ASD children Selected studies

12. Isolated epileptiform discharges (IED) in autism Chez et al., 2006 15– one of the largest studies examining the rate and nature of EEG abnormalities in children with autistic symptoms who had no seizures or identifiable genetic problems • 1,268 children with ASD examined between 1996 and 2005, they excluded children with identified genetic disorders, tuberous sclerosis, or history of seizures. • 889 remaining children with no prior evidence of epilepsy -> EEG abnormalities in 60.7% (16-channel ambulatory sleep EEGs) • the right temporal site was the most common locus right hemisphere, involved in social deficits -> site of dysfunction in ASD

13. Chez et al, 2006 15- localization of IEDs among autistic children

14. Clinical implications • The presence of epileptiform abnormalities was associated with a higher incidence ofmotor stereotypies(61% vs. 36% without epileptiform abnormalities) and aggressive behavior • Epileptiform abnormalities were more likely to be seen in children with autism with lower IQ or with more severe forms of ASD (autism and PDD in contrast to Asperger's). • Children with severe EEG abnormalities have been found to have more problems with behavior, sleep, and attention than those with less persistent EEG abnormalities Mulligan & Trauner, 2014; Yasuhara eta al., 2010; Lee et al., 2011

15. Treatment of children with ASD • The comprehensive treatment of children with ASD is based on a combination of therapeutic psychosocial interventions (behavior therapy) in combination with pharmacological agents • Pharmacological interventions for children with ASD are primarily used to treat the co-existing affective and behavioral disorders or to target specific symptoms such as inattention, hyperactivity, impulsivity, repetitive behaviors, aggressiveness or irritability • Pharmacological agents have not been effective at treating the core symptoms of ASD Tuchman, 2010

16. Treatment of children with autism and epilepsy • Pharmacological treatment of children with autism and epilepsy is guided by the principles of treating childhood epilepsy • Factors such as available formulations (liquid vs. tablets vs. capsules), dosing schedules, need for blood monitoring, and, most importantly, behavioral side effects must be considered • It is important to note that treating epilepsy does not usually have a major impact on the autism symptomatology but some children may show improvements in cognition, communication, or behavior Spence & Schneider, 2009

17. Antiepileptic drugs • Carbamazepine not uncommonly causes behavioral disinhibition • Gabapentin has been associated with a worsening of hyperactivity in some cases • Valproic acid appears to be associated with fewer behavioral side effects; have mood-stabilizing effects, as well as beneficial effects on agitation and aggression • Levetiracetam - a variety of behavioral side effects including aggression as well as changed mood states such as depression, agitation, hostility, irritability and hyperexcitability (Metaanalysis showed a statistically significant relative risk of 2.18 for the total number of behavioral side-effects for levetiracetam versus placebo) Halma, 2014

18. ASD pharmacological treatment • There are presently no medications approved for the treatment of social communication deficits or restricted/repetitive behaviors in ASD. • However, medications are used to target associated emotional and behavioral disturbances in affected individuals • Two atypical antipsychotics (Aripiprazole and Risperidone) have evidence of their effectiveness for irritability/disruptive behavior in autism (Ghanizadeh et al., 2014; Marcus et al., 2011; Owen et al., 2009; Rupp et al., 2002; Sharma and Shaw, 2012; Shea et al., 2004). • Stimulant and nonstimulant medications are effective in ASD for inattentive and hyperactive symptoms if co-morbid Attention Deficit Hyperactive Disorder has also been diagnosed (Cortese et al., 2012; Posey et al., 2007; Quintana et al., 1995). • Other existing psychotropic medications (e.g., antidepressants, anticonvulsants) are employed on a case-by-case basis when behavioral interventions have failed, or when comorbid psychiatric conditions are identified and in need of treatment Brian, 2016

19. APD in patients with epilepsy • Okazaki et al (2014) - investigate whether addition of antipsychotic drugs (APD) would increase seizure frequency in epilepsy patients who were already treated with anti-epileptic drugs (AED), • They compared a one-year seizure control outcome in 150 epilepsy patients with APD treatment for psychiatric conditions and 309 epilepsy patients without APD treatment matched for ages at epilepsy onset and the baseline evaluation and types of epilepsy • In epilepsy patients who are already treated with AED, APD treatment seems safe in seizure control outcome for treatment of psychiatric conditions. • Therewasnosignificant differenceintheseizureoutcomeaccordingtothe types ofAPDorthepsychiatricconditions • Second Generation Antipsychotic (except Clozapine) seem to be generally safe in people with epilepsy but careful clinical monitoring is always advised Okazaki et al, 2014; Mula, 2016; Gimenez at al, 2010

20. Treating epileptiforme discharges in autistic children? • Could treatment of the epileptiform discharges alter theclinical symptoms? • The concept of “treating the EEG” is based on the hypothesis that discharges may have some causal relationship to the behavioral, language, or cognitive disturbance • No large-scale controlled studies have been conducted to date to determine whether such interventions have a positive effect on the ASD outcome • Studies using anticonvulsants to treat behavioural symtoms in ASD showed improvement of aggression (VPA), irritability (VPA), emotional lability (Levetiracetam) • Chez et al., 2006 treated 176 patients with autism with abnormal EEGs with valproic acid. The EEGs normalized in almost one-half of those treated, and most of the remaining had improvements noted on repeat EEG testing. No cognitive or behavioral testing was performed, however, so clinical correlations were not possible. Hollander et al., 2001; Hollander et al., 2010; Rugino et al., 2002; Spence & Schenider, 2009; Mannion & Leader, 2014, Chez, 2006

21. Clinical cases • 1. Patient, diagnosed with ASD at the age of 3, included in behavioral therapy programes, acquires constant progresses. • EEG – epileptiform abnormalities • At the age of 5– mental regress, worsening in mental and visual discontact • EEG – epileptiform discharges- absence seizures • 2. At the age of 5 – single epileptic event - EEG abnormalities - treatment with Valproat – digestive side effects • - antiepileptic treatment modification – treatment with Levetiracetam – intense psychomotor agitation – psychiatric examination, ADOS testing – ASD

22. Conclusions • The heterogeneity of clinical symptoms in children with ASD and epilepsy highlights the importance of a comprehensive assessment that includes • investigation of underlying biological etiologies as well • assessment of cognitive, language, affective, social and behavioral function prior to initiating treatment and throughout the intervention process • ! Monitoring of side effects • The decision to screen for early subclinical EEG abnormalities is still controversial; screening and specific medication may be neuroprotective prospectively Tuchman, 2010

23. Thank You!