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Interictal epileptiform activity and autism Georges A. Ghacibeh ⁎, Cheryl Fields Comprehensive Epilepsy Center, Hackensack University Medical Center, USA Progressive Neurology, 260 Old Hook Rd, Suite 200, Westwood, NJ 07675, USA

a r t i c l e

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Article history: Received 21 January 2015 Revised 18 February 2015 Accepted 20 February 2015 Available online xxxx Keywords: Autism Interictal epileptiform discharges Spikes Cognitive impairment

a b s t r a c t Many individuals with autism have epileptiform discharges on their EEG without having definite clinical seizures. The clinical significance of epileptiform activity in patients with autism is controversial. Some consider it an epiphenomenon of the underlying condition that should be ignored, and others believe that frequent spikes may contribute to the cognitive impairment and advocate treatment. Several studies have reported variable rates of epileptiform activity and variable response to treatment. There is an urgent need to conduct controlled clinical trials to assess the true incidence of epileptiform activity in children with autism, develop a risk assessment model, and study the effectiveness of treatment. This article is part of a Special Issue entitled “Autism and Epilepsy”.

1. Introduction The association between autism and seizures has been known since the first described cases [1]. However, the exact prevalence of seizures in children with autism is unknown, with estimates ranging from 5 [2] to 46% [3]. Estimating the prevalence of epilepsy in patients with autism faces several challenges. First, after the diagnosis of autism is made, seizures can start at any point, making the estimation of lifetime risk for seizures difficult, unless patients are followed up for many years. Second, the identification of clinical seizures is not always easy. Children with autism frequently have behaviors that are similar to complex partial seizures, such as staring, repetitive motor activity, and abrupt changes in mood and behavior. Without continuous video-EEG monitoring, it is sometimes difficult to determine if such behaviors result from seizures. Finally, many children with autism who were studied with prolonged EEGs were found to have epileptiform activity without definite clinical seizures. Many authors have concluded that a high percentage of children with autism may have interictal epileptiform activity without clinical seizures [3–6]. However, most clinicians consider the presence of frank interictal epileptiform discharges (IEDs) a strong diagnostic indicator of epilepsy. For example, if a patient without autism presents with recurrent episodes of unresponsiveness, staring, and stereotypical repetitive motor activity, and the EEG reveals frank IEDs, the diagnosis of epilepsy is usually made, and the episodes are assumed to be seizures. However, in some cases, a patient with autism having similar symptoms and EEG findings may not be diagnosed with epilepsy, unless the reported episodes are confirmed to be seizures on video⁎ Corresponding author. E-mail address: [email protected] (G.A. Ghacibeh).

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EEG, despite the presence of frank epileptiform activity. The question of whether a patient with autism has clinical seizures does not always have a simple answer. Many observational studies suggest that a large percentage of children with autism may have IEDs on their EEG and never have clinical seizures [3–6]. As discussed below, most of these studies have limitations, and the conclusion is not necessarily true. Many of the patients reported in various series may either have infrequent seizures that were not recognized by their parents or are likely to develop seizures at some point in the future. This raises an important question about treatment. Practitioners disagree on this point [7,8], with some advocating aggressive therapy to reduce or eliminate IEDs and others arguing that treatment should only be initiated if clinical seizures are confirmed. Again, this is a situation that is rather unusual. There are only a few clinical scenarios where the presence of IEDs does not necessarily lead to treatment, such as some children with benign rolandic epilepsy and siblings of patients with primary generalized epilepsy. In most other instances, the presence of definite IEDs in the EEG leads to a diagnosis of epilepsy which typically requires treatment. It is quite unusual for the medical community to argue against treatment when a diagnostic test shows definite and sometimes severe abnormalities. The principle of “treat the patient, not the test” may be somewhat misguided here. First, as mentioned earlier, the presence or absence of clinical seizures is not always evident. Second, patients with autism have neurological and cognitive deficits. While many of these patients may not have overt clinical seizures, their neurological function is by no means normal. Therefore, the presence of abnormalities on a diagnostic test that measures the integrity and stability of cortical networks in a patient with impaired cognitive function should be taken seriously. However, the question of causality remains unanswered, i.e., is there a causal relationship between IEDs

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and the symptoms of autism, or are they both epiphenomena of the underlying pathophysiological process? There may not be a simple answer to this question, and the distinction may not be very clear. The two possibilities are not necessarily mutually exclusive.

its development. Despite the presence of some animal models of severe epileptic encephalopathies [27], understanding the causal relationship between frequent epileptiform activity and cognitive dysfunction remains challenging [28].

2. Epileptic encephalopathy 3. Epileptiform discharges in autism Many patients with epilepsy develop some degree of cognitive or behavioral difficulties [9,10]; however, in some cases when epilepsy is severe, the degree of psychomotor deterioration cannot be entirely explained by the underlying etiology or neurological comorbidities [11]. In such cases, the condition is referred to as epileptic encephalopathy [12,13], and the cognitive impairment is believed to be due primarily to the seizures or interictal epileptiform activity [12]. The concept of epileptic encephalopathy stems from the idea that frequent seizures or epileptiform discharges can interfere with normal neuronal physiology and cause disruption of various cognitive processes, such as plasticity, memory encoding, and language processing. There are many recognized syndromes characterized by frequent IEDs, especially nocturnal, with infrequent or no clinical seizures, and various degrees of cognitive and behavioral disturbances [14]. In most of these syndromes, the causal relationship between IEDs and the cognitive dysfunction has not been established. Benign childhood epilepsy with centrotemporal spikes (BCECTS) is frequently associated with some degree of learning or cognitive impairment, such as central auditory processing disorder, or behavioral problems, including attention deficit. In one study, the severity of academic problems correlated with the frequency of interictal epileptiform discharges [15]. Other studies revealed that normalization of the EEG after treatment resulted in significant improvement in attention [16] and auditory processing [17]. Conditions typically referred to as epileptic encephalopathies are characterized by severe developmental delay or regression, with very frequent seizures, excessive amounts of IEDs on the EEG, or both [11]. Aggressive medical or surgical treatment frequently results in improved cognitive and neurological development, suggesting that the seizures and IEDs were probably interfering with the normal development of the brain [18–20]. It is possible to demonstrate the impact of a single epileptiform discharge on a cognitive process, and in fact, several studies have shown a one-to-one relationship between the occurrence of epileptiform discharges and a brief disruption of cognitive processes, such as reaction time or memory encoding, supporting the concept of transient cognitive impairment due to the presence of epileptiform discharges [21–25]. However, the question at play here is quite more complicated. The fact that a single spike can cause a transient disruption of a cognitive process does not necessarily mean that frequent epileptiform discharges will cause a more global cognitive decline. Landau–Kleffner syndrome (LKS) is the quintessential condition that specifically addresses this question. Landau–Kleffner syndrome is a syndrome characterized by severe language regression in a normally developing child, associated with severe EEG abnormality in deep sleep. Clinical improvement typically correlates with improvement in the EEG, providing support to the concept that cognitive deficits may be due to epileptiform activity. The key point in LKS is that epileptiform activity occurs only or primarily during sleep, with either rare or absent IEDs during wakefulness. Therefore, the concept of a direct one-to-one disruption of a cognitive process by an epileptiform discharge hardly applies here. In this condition, if we accept the causal relationship between epileptiform activity and language regression, we must then assume that frequent disruptions of normal cognitive processes over a prolonged period of time can lead to persistent disturbance of important functions, such as plasticity and memory encoding, that outlasts the occurrence of the IEDs. In other terms, the deleterious effect of IEDs causes a virtual or physiological “injury” to the networks, preventing them from performing their normal function. Recent animal studies lend support to this hypothesis [26]. This also raises the elusive question regarding the role of sleep in cognitive function and

Several series have reported the presence of abnormalities in the EEG of individuals with autism. Reported abnormalities included generalized and focal slowing, epileptiform activity, and seizures. Epileptiform abnormalities are more common than nonepileptiform abnormalities [5,29–33]. Generalized, multifocal, and focal epileptiform discharges have been reported. Focal discharges were reported in many different regions [3,4,30,34–36], with some studies suggesting more common temporal discharges [4,37] but others not supporting this finding [32,33]. The frequency of discharges is also variable [3,33,38], and the reported rate of electrical status epilepticus in sleep (ESES) is very low [33,37,39]. There is no information regarding the frequency of discharges based on the location or type. In the author's experience (unpublished data), generalized discharges tend to be infrequent, and centrotemporal spikes tend to be more frequent, sometimes reaching a very high spike index during sleep. In general, IEDs are common among patients with epilepsy but are rare (1 to 4%) in healthy individuals [40,41]. Conversely, in patients with autism, there is a high rate of IEDs even in the absence of definite clinical seizures. Reported rates are variable ranging from 6.7 to 61% [4,6,32,35,42–44], with many studies reporting rates in the 30% range [29,31,37] and others reporting much lower rates [30,34,36,39]. Some studies attempted to correlate EEG abnormalities with different subsets of individuals with autism. In one study [33], a significantly lower rate of IEDs was found in individuals with Asperger's syndrome compared to those with more severe forms of autism. In addition, the same study found a higher incidence of epileptiform activity in children with aggressive behavior. Developmental regression was also addressed in many reports with mixed results. Some studies reported a high incidence of epileptiform abnormalities in regressive autism, from 33 to 68% [45,46], and other studies found higher rates of IEDs in individuals with regression compared to those without regression [37,43], raising the potential similarity with LKS. In fact, some clinicians consider autistic regression an indication to obtain an EEG [47]. However, other studies failed to replicate this finding and found no difference in the rate of epileptiform activity between regressive and nonregressive autism [4,6,38,42,43]. A few studies evaluated the prevalence of IEDs based on intellectual function. Some reports found a high correlation between the presence of IEDs and lower IQ [43,48], but other studies failed to replicate this finding [6,31,37]. In terms of the correlation between behavior and IEDs, studies revealed no difference in behavioral problems based on the presence [49] or severity of IEDs [50]. The more important question regarding an anatomical–functional correlation between the location of spikes and the presence of specific cognitive or behavioral problems has not been properly addressed. For example, nearly all patients with autism have impairment in social skills. Several studies have revealed specific deficits in social cognition in patients with various forms of epilepsy [51–53]. Unfortunately, most studies suffer from major limitations, and the variability in the reported rates is probably due to methodological differences. The most obvious problem is that the majority of studies relied on retrospective chart review. The authors frequently had no access to the raw EEG data and relied on reports that were generated for clinical purposes. Therefore, very important information is usually missing, most importantly a standardized measure of spike frequency. If we consider that IEDs may have a causal effect on cognitive dysfunction, then the frequency of IEDs is of the utmost importance. For example, a clinician might find it easy to consider rare bursts of brief generalized discharges as

Please cite this article as: Ghacibeh GA, Fields C, Interictal epileptiform activity and autism, Epilepsy Behav (2015), http://dx.doi.org/10.1016/ j.yebeh.2015.02.025

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epiphenomena of the underlying syndrome but may find it hard to ignore very frequent unilateral or bilateral centrotemporal spikes. Furthermore, unless EEGs are obtained systematically on all patients with autism, referral bias can play an important role with a major potential influence by the clinical practice of various clinicians. Finally, the type of EEG, such as duration or the presence of a sleep sample, is another very important variable that can influence the results. When more prolonged EEGs were recorded, higher rates of IEDs were reported. Studies that used routine EEGs [36,39] revealed lower rates than studies using inpatient video-EEG [32,33] or ambulatory EEG [4]. In one study, routine EEGs and prolonged sleep EEGs were obtained from the same patients and revealed a much higher yield for abnormalities in prolonged EEGs [31]. Finally, magnetoencephalography was found to be even more sensitive than simultaneous EEG or prolonged EEG monitoring in identifying epileptiform activity [45]. 4. The question of treatment In conditions such as LKS and continuous spikes and waves during sleep (CSWS), cognitive improvement correlates with EEG improvement, lending support to the concept that frequent epileptiform activity has a deleterious effect on cortical function [11]. However, similar results have not been reliably shown in individuals with autism. This may be due to several factors. Autism is not a single condition. It is a syndrome, a constellation of symptoms, presenting with heterogeneous clinical characteristics. There have not been any successful attempts to classify patients with autism into various phenotypic categories. At this point, classification relies primarily on the severity of symptoms, mostly on speech and language functions. However, patients with autism can present with different cognitive deficits. Careful observation may lead in the future to a classification system that relies on the pattern of cognitive impairment, in a fashion similar to the classification of frontotemporal dementias [54]. In addition, patients are not typically classified into categories based on abnormal neurological or metabolic findings, such as hypotonia [55,56], MRI abnormalities [57], metabolic disturbances [58], or abnormal EEG findings and diagnosis of epilepsy. This makes the design of clinical trials, which aim to determine the effectiveness of treatment in general, difficult. Furthermore, as was mentioned above, the EEG characteristics of individuals with autism are not well defined, with most series relying on retrospective and frequently incomplete data. Treatment of epilepsy in children with autism should follow the same principles of treatment of any patients with epilepsy. However, the decision to treat abnormal EEG findings remains very controversial. If we accept the finding that many individuals with autism with epileptiform abnormalities truly never have clinical seizures, then the justification to treat IEDs would rely on two assumptions. First, epileptiform activity might have a direct or short-lasting effect on cognitive processes; therefore, treating it may improve the symptoms of autism. Second, epileptiform discharges may actually alter cortical networks and have long-term consequences on seizure susceptibility and learning abilities [59]. In other words, reducing or eliminating IEDs may actually prevent the development of epilepsy [4] and allow the brain to develop more effective mechanisms for learning and regulating behavior. Several studies and case reports suggest that suppressing IEDs leads to clinical improvement using various treatment modalities. Some studies found that the use of antiepileptic drugs (AEDs) [4,60–62] resulted in decreased epileptiform activity or improved cognitive and behavioral functions. In one study [4], treatment with valproate of 176 patients with autism with no history of clinical seizures, but with definite epileptiform activity on EEG, resulted in normalization (45%) or improvement (17%) of the EEG with no mention of cognitive function. In another study [60], the use of valproate in 14 patients with autism resulted in improvement in various behavioral symptoms with no mention of improvement in the EEG. In fact, valproate has been reported in studies of other epilepsy syndromes associated with frequent nocturnal spikes

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[63]. Some studies reported the use of corticosteroids in regressive autism without definite epileptiform abnormalities, which resulted in cognitive improvement [64–66]. Two studies reported the use of a ketogenic diet to treat patients with autism. In one study [67], a series of children who tolerated the diet showed improvement in learning abilities and social skills, but there was no mention of epilepsy or epileptiform activity. The other study [68] is a case report of a patient with autism and epilepsy who was treated with a ketogenic diet and showed marked cognitive improvement associated with reduced seizure frequency and decreased epileptiform activity on the EEG. The authors reported a case [80] of a child with autism and IEDs, without definite clinical seizures, who was treated with the modified Atkins diet and had complete suppression of his spikes, associated with improved speech and decreased hyperactivity. Finally, epilepsy surgery was also reported to cause variable cognitive and behavioral improvements in individuals with autistic regression either with [69–71] or without [45] intractable epilepsy. Unfortunately, there are no controlled clinical trials investigating the effect of treating epileptiform activity specifically in patients with autism. Most of the reports have significant limitations, consisting either of case studies or small series lacking a control arm. Furthermore, these studies did not follow a standardized protocol to quantify epileptiform activity and measure neurophysiologic and behavioral/cognitive outcomes. However, there are several studies with better methodology that report favorable cognitive outcomes in children with various epilepsy syndromes associated with high nocturnal spiking. In one open label study, transition to levetiracetam from carbamazepine or oxcarbazepine improved central auditory processing in children with BCECTS [17]. In another open label trial of children with attention and learning difficulties who had subclinical spikes without evidence of seizures [72], treatment with levetiracetam resulted in decreased spike frequency and improved memory and learning. A controlled trial of lamotrigine in patients with generalized drug-resistant epilepsy resulted in improved behavior and decreased spike frequency [73], and a controlled trial of valproate in patients with epilepsy, who had psychosocial and educational problems [74], revealed decreased spike frequency and improved social behavior. Although this study did not include patients diagnosed with autism, children with autism frequently suffer impairment in social skills. The downfall of the last two studies is that patients also had improved seizure control, in addition to decreased spike frequency, raising the possibility that improved behaviors might have been due to improved seizure control. However, another controlled trial of lamotrigine in children with well controlled seizures [75] revealed that behavioral improvement correlated with decrease in spike burden, without changes in seizure frequency, lending further support to the hypothesis that frequent IEDs may cause cognitive and behavioral deficits. In a controlled crossover study [76], levetiracetam was found to significantly decrease spike density in patients with ESES. On the other hand, a controlled valproate trial revealed opposite results with worsening of cognitive and behavioral symptoms in the treatment group [77]. The lack of controlled studies makes it difficult for clinicians to make appropriate clinical decisions regarding both the investigation and treatment of epileptiform activity in patients with autism. There is increasing awareness among parents about the high incidence of seizures and epileptiform activity in children with autism, and many parents request that EEG studies be performed to assess the presence of such abnormalities. The question of treatment remains controversial among clinicians. However, the same question is less debatable in patients without autism who have frequent epileptiform activity associated with cognitive impairment. In a large survey of epilepsy-trained neurologists [78], the majority (81%) considered that prominent sleep-potentiated spiking warranted treatment, and most of them also reported that patients improved cognitively when epileptiform activity is effectively treated. In the same survey, the treatments of choice were high doses of benzodiazepines, mostly diazepam, valproate, and corticosteroids.

Please cite this article as: Ghacibeh GA, Fields C, Interictal epileptiform activity and autism, Epilepsy Behav (2015), http://dx.doi.org/10.1016/ j.yebeh.2015.02.025

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5. Conclusion There is obviously an urgent need for systematic studies to determine the incidence of epileptiform discharges in patients with autism, define their characteristics, and correlate them with various cognitive and behavioral impairments. In addition, there is an even more urgent need for controlled trials to assess the effectiveness of treating epileptiform activity in patients with autism. For clinical trials to yield optimal information, a standardized method of assessing epileptiform discharges that will serve as a reliable measure of spike burden, such as the spike index [79], needs to be agreed upon. This will allow quantification of EEG improvement and proper correlation with cognitive and behavioral improvements. In the absence of such trials and clear guidelines, clinical practice will vary, and the debate and controversy will linger. The high prevalence of epileptiform activity in children with autism needs to be taken seriously and investigated further. Considering this finding a mere epiphenomenon of the underlying pathophysiological process is inappropriate without proper studies to prove or disprove the effectiveness of treatment. Conflict of interest The authors declare that there are no conflicts of interest. References [1] Kanner L. Autistic disturbances of affective contact. Acta Paedopsychiatr 1968;35(4): 100–36. [2] Bryson SE, Clark BS, Smith IM. First report of a Canadian epidemiological study of autistic syndromes. J Child Psychol Psychiatry 1988;29(4):433–45. [3] Hughes JR, Melyn M. EEG and seizures in autistic children and adolescents: further findings with therapeutic implications. Clin EEG Neurosci 2005;36(1):15–20. [4] Chez MG, Chang M, Krasne V, Coughlan C, Kominsky M, Schwartz A. Frequency of epileptiform EEG abnormalities in a sequential screening of autistic patients with no known clinical epilepsy from 1996 to 2005. Epilepsy Behav 2006;8(1):267–71. [5] McVicar KA, Ballaban-Gil K, Rapin I, Moshe SL, Shinnar S. Epileptiform EEG abnormalities in children with language regression. Neurology 2005;65(1):129–31. [6] Rossi PG, Parmeggiani A, Bach V, Santucci M, Visconti P. EEG features and epilepsy in patients with autism. Brain Dev 1995;17(3):169–74. [7] Kanner AM. Commentary: the treatment of seizure disorders and EEG abnormalities in children with autistic spectrum disorders: are we getting ahead of ourselves? J Autism Dev Disord 2000;30(5):491–5. [8] Tuchman R. Treatment of seizure disorders and EEG abnormalities in children with autism spectrum disorders. J Autism Dev Disord 2000;30(5):485–9. [9] Rathouz PJ, Zhao Q, Jones JE, Jackson DC, Hsu DA, Stafstrom CE, et al. Cognitive development in children with new onset epilepsy. Dev Med Child Neurol 2014;56(7): 635–41. [10] Zhao Q, Rathouz PJ, Jones JE, Jackson DC, Hsu DA, Stafstrom CE, et al. Longitudinal trajectories of behavior problems and social competence in children with new onset epilepsy. Dev Med Child Neurol 2015;57(1):37–44. [11] Holmes GL, Lenck-Santini PP. Role of interictal epileptiform abnormalities in cognitive impairment. Epilepsy Behav 2006;8(3):504–15. [12] Nabbout R, Dulac O. Epileptic encephalopathies: a brief overview. J Clin Neurophysiol 2003;20(6):393–7. [13] Shields WD. Catastrophic epilepsy in childhood. Epilepsia 2000;41(Suppl. 2):S2–6. [14] Besag FM. Behavioral aspects of pediatric epilepsy syndromes. Epilepsy Behav 2004; 5(Suppl. 1):S3–S13. [15] Piccinelli P, Borgatti R, Aldini A, Bindelli D, Ferri M, Perna S, et al. Academic performance in children with rolandic epilepsy. Dev Med Child Neurol 2008;50(5):353–6. [16] Kavros PM, Clarke T, Strug LJ, Halperin JM, Dorta NJ, Pal DK. Attention impairment in rolandic epilepsy: systematic review. Epilepsia 2008;49(9):1570–80. [17] Kossoff EH, Los JG, Boatman DF. A pilot study transitioning children onto levetiracetam monotherapy to improve language dysfunction associated with benign rolandic epilepsy. Epilepsy Behav 2007;11(4):514–7. [18] Asarnow RF, LoPresti C, Guthrie D, Elliott T, Cynn V, Shields WD, et al. Developmental outcomes in children receiving resection surgery for medically intractable infantile spasms. Dev Med Child Neurol 1997;39(7):430–40. [19] Matsuzaka T, Baba H, Matsuo A, Tsuru A, Moriuchi H, Tanaka S, et al. Developmental assessment-based surgical intervention for intractable epilepsies in infants and young children. Epilepsia 2001;42(Suppl. 6):9–12. [20] Zupanc ML. Infantile spasms. Expert Opin Pharmacother 2003;4(11):2039–48. [21] Aarts JH, Binnie CD, Smit AM, Wilkins AJ. Selective cognitive impairment during focal and generalized epileptiform EEG activity. Brain 1984;107(Pt 1):293–308. [22] Binnie CD. Cognitive impairment during epileptiform discharges: is it ever justifiable to treat the EEG? Lancet Neurol 2003;2(12):725–30. [23] Shewmon DA, Erwin RJ. The effect of focal interictal spikes on perception and reaction time. I. General considerations. Electroencephalogr Clin Neurophysiol 1988; 69(4):319–37.

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Please cite this article as: Ghacibeh GA, Fields C, Interictal epileptiform activity and autism, Epilepsy Behav (2015), http://dx.doi.org/10.1016/ j.yebeh.2015.02.025

Interictal epileptiform activity and autism.

Many individuals with autism have epileptiform discharges on their EEG without having definite clinical seizures. The clinical significance of epilept...
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