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Epilepsy in adolescents and young adults with autistic disorder
Brain & Development 22 (2000) 102±106
Original article
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Epilepsy in adolescents and young adults with autistic disorder Paola Giovanardi Rossi*, Annio Posar, Antonia Parmeggiani Department of Child Neurology and Psychiatry, Neurological Institute, University of Bologna, via Ugo Foscolo 7, 40123 Bologna, Italy Received 7 May 1999; received in revised form 25 October 1999; accepted 25 October 1999
Abstract Since the ®rst description by Kanner (1943) the association between autistic disorder (AD) and epilepsy has been observed in 4±42% of patients. Some authors reported that seizures prevailed in adolescence but a systematic investigation has never been undertaken. We examined retrospectively 60 patients divided into two groups (with and without epilepsy and EEG paroxysmal abnormalities) with AD unrelated to a congenital or acquired encephalopathy (mean age 17 years 2 months). The aim was to investigate epilepsy, EEG paroxysmal abnormalities and possible etiological factors. The prevalence of epilepsy was 38.3%, much higher than that in a normal population of a similar age (6.6½). The prevalence of EEG paroxysmal abnormalities without epilepsy was 6.7%, higher than that in a population of adolescents and adults with psychiatric pathologies (2.6%). Seizure onset was after age 12 years in 66.7% of cases. The most common type of epilepsy was partial in 65.2% and four patients (17.4%) had a benign childhood epilepsy with centro-temporal spikes. At the last observation 44.4% of patients had been seizure-free for 2 years or more. There were no organic factors in¯uencing the development of epilepsy but familial and personal antecedents, mental retardation and CT scan/MRI data may suggest an early brain dysfunction responsible for AD and epilepsy. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Epilepsy; Adolescence; Autistic disorder; Pervasive developmental disorders; Mental retardation; EEG paroxysmal abnormalities
1. Introduction Autistic disorder (AD) is characterized, according to DSM-IV [1] criteria, by qualitative impairment in social interaction and communication; restricted, repetitive and stereotyped patterns of behavior, interests, and activities, and onset before 3 years of age. Since the ®rst description by Kanner (1943) [2] many reports have described the association between AD and epilepsy [3±18]. We previously studied 106 patients with AD aged from 3 years 1 month to 31 years 3 months, ®nding a 23.6% prevalence of epilepsy and/or febrile convulsions (FC) and 18.9% EEG paroxysmal abnormalities (PA) without epilepsy [15]. The mean age at onset of seizures was 10 years 1 month and 45% of subjects had seizure onset after 10 years. These data are compatible with those of the literature where the prevalence of epilepsy in patients with AD ranges from 4 to 42%, higher than in the normal population of children and adolescents [15,19,20]. Some authors noted that seizures frequently arose in adolescence [5,9,11,13,15] when EEG PA without epilepsy recurred from 14.3 to 82.9% [19,21±23]. * Corresponding author. Tel.: 139-051-644-2282; fax: 139-051-333725. E-mail address: [email protected] (P. Giovanardi Rossi)
A systematic investigation following speci®c international diagnostic criteria for AD and epilepsy has never been undertaken in adolescent and young adult patients. We therefore investigated epilepsies and EEG PA: prevalence, genetic and organic predisposing factors, type and evolution in a similar aged sample of patients with AD, not correlated with a congenital or acquired encephalopathy.
2. Material The retrospective study included 60 inpatients with AD, 53 males and seven females aged from 12 years to 29 years 9 months (mean age 17 years 2 months). The mean follow-up from the ®rst to the last observation was 3 years (range 1 month to 10 years 7 months). We excluded patients with autistic syndromes secondary to a congenital or acquired encephalopathy, but we included those with mild aspeci®c cerebral lesions of unknown etiology [15]. In all subjects the diagnosis was made according to DSM-III-R [24] and DSM-IV [1]. Epilepsy features were detected according to the Revised Classi®cation of Epilepsies and Epileptic Syndromes [25].
0387-7604/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S03 87-7604(99)0012 4-2
P. Giovanardi Rossi et al. / Brain & Development 22 (2000) 102±106
3. Method We divided the 60 patients into two groups: Group A, subjects with epilepsy including FC (seizures appearing within 5 years triggered by fever) and/or PA; Group B, subjects without epileptic seizures or PA. For every patient a protocol was utilized [26] to collect information on familial history for epilepsy and/or FC and other neurologic and psychiatric diseases; personal organic pre-peri-postnatal antecedents; neurological examination; IQ assessment according to intelligence tests (StanfordBinet scale, WPPSI, WISC-R, WAIS) and clinical observation; language disorders; CT scan and/or MRI ®ndings; and medications for AD. In particular, serial EEG recordings during wakefulness and sleep were performed in every patient at the ®rst observation and during the follow-up, focusing on background activity, aspeci®c abnormalities such as fast activity, theta activity, delta activity, excluding drug induced manifestations, and PA (spikes, spike-waves, polyspikes, polyspikewaves, multifocal, diffuse and generalized). Epilepsy features were investigated considering seizure type and frequency, age at onset, antiepileptic treatment and evolution. The statistical evaluation of data was made by the Fisher exact test.
4. Results Group A included 27 subjects (24 males, three females) (45.0%), 23 with epilepsy (mean age at last observation 17 years 9 months; range 12 years 9 months to 29 years 9 months) and four with EEG PA without epileptic seizures (mean age at last observation 15 years; range 13 years 3 months to 17 years 8 months). Group B included 33 patients without epileptic seizures or EEG PA (55.0%) (29 males, four females); mean age at last observation was 17 years 2 months (range 12 years to 26 years 11 months). Epilepsy recurred in 38.3% of the whole sample; EEG PA without epileptic seizures in 6.7%. A familial history for neuropsychiatric diseases, including epilepsy and/or FC, was present in 31/60 patients (51.7%), only epilepsy and/or FC in 11/60 (18.3%), only neurological disorders in 15/60 (25.0%), and only psychiatric disorders in 16/60 (26.7%). Organic pre, peri and postnatal antecedents were found in 22/60 subjects (36.7%): mainly dystocic delivery in 10 (16.7%) and threatened abortions in eight (13.3%). The neurological examination showed mild non-speci®c signs in 25/60 cases (41.7%); the most frequent were hypotonia (25.0%), macrocrania (15.0%), hyperlaxity (15.0%) and clumsiness (11.7%). Mental retardation had been present in all patients (100%)
103
since the onset of AD: mild/moderate in 15 (25.0%) and severe/profound in 45 (75.0%). Language disorders were characterized by lack of development in 16 (26.7%), syntactic and semantic abnormalities in the other 44 (73.3%). CT scan and/or MRI showed mild non-speci®c abnormalities in 20/60 cases (33.3%): subcortical subatrophy in 11 (18.3%), diffuse cortical-subcortical subatrophy in three (5.0%), cerebellar vermis hypoplasia in three (5.0%), left temporal lobe hypoplasia in two (3.3%), and diffuse cortical subatrophy in one (1.7%); the others were normal. Only patients with epileptic seizures received antiepileptic treatment. Twenty-three (38.3%) patients with AD, from the ®rst observation during the follow-up, were treated with medications for their behavior (29.6% versus 45.5%, Group A versus Group B). Drugs used comprised neuroleptics, benzodiazepines, niaprazine, vitamin B6 and magnesium. No signi®cant differences between Groups A and B were found for any of the above data. 4.1. EEG and epilepsy characteristics Interictal EEG recordings during wakefulness and sleep showed normal background activity in 56/60 patients (93.3%): Group A 92.6% versus Group B 93.9%. Theta or delta activity was found in 21/60 (35.0%): Group A 44.4% versus Group B 27.3%. Fast activity at 14±22 Hz and voltage less than 20 mV was found in 7/60 subjects (11.7%): Group A 14.8% versus Group B 9.1%. The fast activity prevailed on anterior and median brain regions. No signi®cant differences between Groups A and B were found either for background activity abnormalities or presence of theta, delta and fast activity. EEG PA were present in 14/60 patients (23.3%): in Group A (27 patients) in 10/23 with epilepsy (43.5%) and in the four without epilepsy. PA were focal/multifocal in 6/27 (22.2%), diffuse/generalized in 4/27 (14.8%), focal/ multifocal 1 diffuse/generalized in 4/27 (14.8%) (Table 1). Focal and multifocal PA prevailed in the frontal, temporal and parietal regions mainly in the left hemisphere. Drowsiness and slow sleep usually increased PA frequency. PA were never continuous or subcontinuous. Different types of epilepsy and epileptic syndromes [25] were present in 23/60 patients (38.3%) also including idiopathic forms: benign idiopathic neonatal convulsions (BINC) in 1/23 (4.3%); FC in 4/23 (17.4%); FC followed Table 1 EEG paroxysmal abnormalities (PA): Group A 27 cases PA 14/27
10/23 with epilepsy
4 with only PA
%
Absent Focal/multifocal Diffuse/generalized Focal/multifocal 1 diffuse/generalized
13 3 3 4
0 3 1 0
48.1 22.2 14.8 14.8
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by partial epilepsy in 3/23 (13.0%); partial epilepsy in 12/23 (52.2%); generalized epilepsy in 3/23 (13.0%). Not complicated FC were present in 7/23 subjects (30.4%). A partial epilepsy was present in 15/23 cases (65.2%). In 4/23 patients (17.4%) the epilepsy showed the characteristics of benign childhood epilepsy with centro-temporal spikes (BCECTS). In other patients with partial epilepsy, the clinical characteristics of seizures and the EEG data suggested a diagnosis of frontal epilepsy in six patients, temporal epilepsy in three, occipital epilepsy in two. Among the patients with generalized epilepsy one showed epilepsy with generalized tonic-clonic seizures on awakening; the other two had an unclassi®ed benign generalized epilepsy. Mean age at onset of seizures, excluding BINC and FC, was 11 years 11 months (range 2 years 6 months to 19 years 6 months); the onset of seizures was before 12 years in 6/18 patients (33.3%) and after 12 years in 12/18 patients (66.7%). In the four subjects with BCECTS, mean age at onset of seizures was 5 years 3 months (range 4 years to 6 years). The type of seizure diagnosed, excluding BINC and FC, was mainly partial, in particular partial with secondary generalization in 11/18 patients (61.1%) and complex partial (CP) in 5/18 patients (27.8%). Patients could present more than one type of seizure. Table 2 shows the seizure types as percentages of the total number of seizures. At the end of follow-up seizures were controlled in the patient with BINC and in the four subjects with only FC; in the other 18 cases seizure control for at least 2 years was obtained in eight (44.4%). Seizures were not controlled in ®ve cases (27.8%) and in another ®ve patients (27.8%) the evolution was not considered due to too short follow-up or irregularity of antiepileptic treatment. Among the eight subjects with controlled seizures, four had an epilepsy with the characteristics of BCECTS. At the last observation the frequency of seizures in the other 10 patients (55.6%) was under 1 seizure/year in one (10.0%); under 1 seizure/month in ®ve (50.0%); , 1 seizure/month in two (20.0%); over 1 seizure/week in two (20.0%). No signi®cant differences were found between the eight controlled patients and the ®ve uncontrolled patients with adequate follow-up with respect to sex, familial neuropsychiatric disorders including epilepsy/FC, personal antecedents, severity of mental retardation, onset of epilepsy before or after 12 years, EEG data, CT scan and MRI pathological ®ndings. Table 2 Types of seizure (excluding benign idiopathic neonatal convulsions (BINC) and febrile convulsions (FC)) Complex partial Elementary partial Partial with secondary generalization Generalized tonic-clonic Hemiconvulsive status epilepticus
5 2 11 3 1
22.7% 9.1% 50.0% 13.6% 4.5%
A signi®cant difference (P , 0:05) was observed for neurological signs (hypotonia, macrocrania, hyperlaxity and clumsiness) present in all ®ve patients with seizure persistence and in only 2/8 patients with controlled seizures. At the last observation 16 patients (69.6%) were still taking an antiepileptic therapy, 14 as monotherapy and two as polytherapy. The anticonvulsant drugs mainly employed were carbamazepine, valproate and phenobarbital. 5. Discussion This study was performed to investigate the characteristics of epilepsy in a population of adolescents and young adults with AD. There are few data on the occurrence of epilepsy in a similar homogeneous sample of patients for age and diagnostic criteria for AD. On the other hand, literature reports on epilepsy and AD are often contradictory due to: (a) different diagnostic criteria for AD and epilepsy; (b) different ®ndings in samples studied; (c) different duration of follow-up. In agreement with literature, the prevalence of epilepsy (38.3%) in our sample of adolescents and young adults with AD not related to a congenital or acquired encephalopathy was higher than in a general population aged between 10 and 19 years (6.6½) [27]. Excluding BINC and FC, typically age-related, the mean age at onset of seizures was 11 years 11 months, but 66.7% of individuals developed epilepsy after 12 years [5,9]. In our previous sample, epilepsy had an onset after 10 years in 45.0% of patients [15]. In this study, our patients presented different types of epilepsy with a prevalence of partial forms (65.2%): four showed a clinical-EEG picture compatible with BCECTS, six had frontal epilepsies, three temporal, two occipital. When available, data in the literature also describe frontal and occipital epilepsies [23,28]. Seizures were frequently partial with secondary generalization (61.1%), which have a favorable prognosis [29], whereas literature reports more often described CP seizures in AD [12,15,17] that have generally a more unfavorable prognosis in patients with epilepsy [29]. Some authors described scant psychomotor and generalized seizures with a high recurrence in AD [13,18]. Seizure control for a period of two or more years was obtained in eight patients (44.4%). Among these there were four cases with BCECTS. We did not ®nd in the literature exhaustive data on the evolution of epilepsy in adolescents and adults with AD. A signi®cant recurrence of mild heterogeneous neurological signs was evident in the ®ve patients with uncontrolled seizures (P , 0:05) as possible cerebral involvement; this was the only factor negatively in¯uencing the prognosis. CT scan and/or MRI ®ndings did not affect the evolution of epilepsy.
P. Giovanardi Rossi et al. / Brain & Development 22 (2000) 102±106
In the present series EEG PA without epilepsy affected 6.7% of cases. This value was in the range from 1.1 to 6±8% [30] found in a general population of normal children and adolescents but was lower than the 18.9% found in the global series of children and adolescents with AD previously reported [15]; probably EEG PA are age dependent, more frequent at an early age and tend to disappear towards puberty. This seems to be con®rmed by the fact that the percentage of PA in our sample is higher than the 2.6% found in a population of adolescents and adults with psychiatric pathologies [31]. Some authors described a different trend stressing the increase in PA during puberty in particular on the frontal regions [19,23]. Even before puberty, we did not ®nd in our cases clinical and EEG ®ndings compatible with acquired epileptic aphasia or electrical status epilepticus during sleep that can overlap with `autistic regression' or `autistic-like behavior' [20,32]. Patients with AD may have different types of epilepsy including benign forms with a lower epileptogenic threshold with respect to the general population. Comparing Group A and Group B, we failed to ®nd any genetic and organic factors predisposing to epilepsy. However, a general in¯uence of genetic factors and a consistent presence of nonspeci®c organic factors in subjects with AD is suggested by familial antecedents for neuropsychiatric pathologies (including epilepsy) in 51.7% of subjects, personal antecedents in 36.7%, CT scan and/or MRI abnormalities in 33.3%, the presence of mental retardation in all patients and an abnormal neurological examination in 41.7%. This means that AD, epilepsy and mental retardation are probably the result of an early common dysfunction of the central nervous system. The high prevalence of epilepsy in our series of adolescents may be also related to age dependent biological factors correlated with puberty as reported in the general population of patients with epilepsy [33]. Acknowledgements The authors are grateful to Ms Silvia Muzzi and Ms Marina Michelessi for expert technical assistance and Ms Anne Collins for linguistic revision. References [1] American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th. edn. Washington, DC: American Psychiatric Association, 1994. [2] Kanner L. Autistic disturbances of affective contact. Nerv Child 1943;2:217±250. [3] Rutter M. Autistic children. Infancy to adulthood. Semin Psychiatry 1970;2:435±450. [4] Kanner L. Follow-up study of eleven autistic children originally reported in 1943. J Autism Child Schizophr 1971;1:119±145. [5] Deykin EY, MacMahon B. The incidence of seizures among children with autistic symptoms. Am J Psychiatry 1979;136:1310±1312.
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[6] Riikonen R, Amnell G. Psychiatric disorders in children with earlier infantile spasms. Dev Med Child Neurol 1981;23:747±760. [7] Gillberg C, Schaumann H. Epilepsy presenting as infantile autism? Two case studies. Neuropediatrics 1983;14:206±212. [8] Gillberg C. Autistic children growing up: problems during puberty and adolescence. Dev Med Child Neurol 1984;26:125±129. [9] Gillberg C, Steffenburg S. Outcome and prognostic factors in infantile autism and similar conditions: a population-based study of 46 cases followed through puberty. J Autism Dev Disord 1987;17:273± 287. [10] Olsson I, Steffenburg S, Gillberg C. Epilepsy in autism and autisticlike conditions. A population-based study. Arch Neurol 1988;45:666± 668. [11] Volkmar FR, Nelson DS. Seizure disorders in autism. J Am Acad Child Adolesc Psychiatry 1990;29:127±129. [12] Gillberg C. The treatment of epilepsy in autism. J Autism Dev Disord 1991;21:61±77. [13] Tuchman RF, Rapin I, Shinnar S. Autistic and dysphasic children. II: Epilepsy. Pediatrics 1991;88:1219±1225. [14] Wong V. Epilepsy in children with autistic spectrum disorder. J Child Neurol 1993;8:316±322. [15] Giovanardi Rossi P, Parmeggiani A, Bach V, Santucci M, Visconti P. EEG features and epilepsy in patients with autism. Brain Dev 1995;17:169±174. [16] Elia M, Musumeci SA, Ferri R, Bergonzi P. Clinical and neurophysiological aspects of epilepsy in subjects with autism and mental retardation. Am J Ment Retard 1995;100:6±16. [17] Steffenburg S, Gillberg C, Steffenburg U. Psychiatric disorders in children and adolescents with mental retardation and active epilepsy. Arch Neurol 1996;53:904±912. [18] Mouridsen SE, Rich B, Isager T. Epilepsy in disintegrative psychosis and infantile autism: a long-term validation study. Dev Med Child Neurol 1999;41:110±114. [19] Hara H, Sasaki M. Autistic syndrome and epilepsy: signi®cance of the annual electroencephalographical examination. Brain Dev 1990;12:708. [20] Rapin I, Katzman R. Neurobiology of autism. Ann Neurol 1998;43:7± 14. [21] Rutter M, Lockyer L. A ®ve to ®fteen year follow-up study of infantile psychosis. I. Description of sample. Br J Psychiatry 1967;113:1169±1182. [22] Creak M, Pampiglione G. Clinical and EEG studies on a group of 35 psychotic children. Dev Med Child Neurol 1969;11:218±227. [23] Kawasaki Y, Yokota K, Shinomiya M, Shimizu Y, Niwa S. Brief report: electroencephalographic paroxysmal activities in the frontal area emerged in middle childhood and during adolescence in a followup study of autism. J Autism Dev Disord 1997;27:605±620. [24] American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 3rd. revised edn. Washington, DC: American Psychiatric Association, 1987. [25] Commission on Classi®cation and Terminology of the International League Against Epilepsy. Proposal for revised classi®cation of epilepsies and epileptic syndromes. Epilepsia 1989;30:389±399. [26] Giovanardi Rossi P, Visconti P, Mariani Cerati D. Autismo infantile: proposta per un protocollo di ricerca eziologica. Giorn Neuropsich EtaÁ Evol 1991;11:175±192. [27] Hauser WA, Kurland LT. The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia 1975;16:1±66. [28] Nass R, Gross A, Devinsky O. Autism and autistic epileptiform regression with occipital spikes. Dev Med Child Neurol 1998;40:453±458. [29] Pazzaglia P. Le epilessie parziali sintomatiche o secondarie. In: Lega Italiana Contro l'Epilessia, editor. Manuale italiano di epilettologia, Padova: Piccin Nuova Libraria, 1992. pp. 571±585. [30] Cavazzuti GB, Cappella L, Nalin A. Longitudinal study of epileptiform EEG patterns in normal children. Epilepsia 1980;21:43±55. [31] Bridgers SL. Epileptiform abnormalities discovered on electroence-
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phalographic screening of psychiatric inpatients. Arch Neurol 1987;44:312±316. [32] Giovanardi Rossi P, Parmeggiani A, Posar A, Scaduto MC, Chiodo S, Vatti G. Landau±Kleffner syndrome (LKS): long-term follow-up and
links with electrical status epilepticus during sleep (ESES). Brain Dev 1999;21:90±98. [33] Morrell MJ. Hormones and epilepsy through the lifetime. Epilepsia 1992;33(Suppl 4):S49±S61.
Original article
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Epilepsy in adolescents and young adults with autistic disorder Paola Giovanardi Rossi*, Annio Posar, Antonia Parmeggiani Department of Child Neurology and Psychiatry, Neurological Institute, University of Bologna, via Ugo Foscolo 7, 40123 Bologna, Italy Received 7 May 1999; received in revised form 25 October 1999; accepted 25 October 1999
Abstract Since the ®rst description by Kanner (1943) the association between autistic disorder (AD) and epilepsy has been observed in 4±42% of patients. Some authors reported that seizures prevailed in adolescence but a systematic investigation has never been undertaken. We examined retrospectively 60 patients divided into two groups (with and without epilepsy and EEG paroxysmal abnormalities) with AD unrelated to a congenital or acquired encephalopathy (mean age 17 years 2 months). The aim was to investigate epilepsy, EEG paroxysmal abnormalities and possible etiological factors. The prevalence of epilepsy was 38.3%, much higher than that in a normal population of a similar age (6.6½). The prevalence of EEG paroxysmal abnormalities without epilepsy was 6.7%, higher than that in a population of adolescents and adults with psychiatric pathologies (2.6%). Seizure onset was after age 12 years in 66.7% of cases. The most common type of epilepsy was partial in 65.2% and four patients (17.4%) had a benign childhood epilepsy with centro-temporal spikes. At the last observation 44.4% of patients had been seizure-free for 2 years or more. There were no organic factors in¯uencing the development of epilepsy but familial and personal antecedents, mental retardation and CT scan/MRI data may suggest an early brain dysfunction responsible for AD and epilepsy. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Epilepsy; Adolescence; Autistic disorder; Pervasive developmental disorders; Mental retardation; EEG paroxysmal abnormalities
1. Introduction Autistic disorder (AD) is characterized, according to DSM-IV [1] criteria, by qualitative impairment in social interaction and communication; restricted, repetitive and stereotyped patterns of behavior, interests, and activities, and onset before 3 years of age. Since the ®rst description by Kanner (1943) [2] many reports have described the association between AD and epilepsy [3±18]. We previously studied 106 patients with AD aged from 3 years 1 month to 31 years 3 months, ®nding a 23.6% prevalence of epilepsy and/or febrile convulsions (FC) and 18.9% EEG paroxysmal abnormalities (PA) without epilepsy [15]. The mean age at onset of seizures was 10 years 1 month and 45% of subjects had seizure onset after 10 years. These data are compatible with those of the literature where the prevalence of epilepsy in patients with AD ranges from 4 to 42%, higher than in the normal population of children and adolescents [15,19,20]. Some authors noted that seizures frequently arose in adolescence [5,9,11,13,15] when EEG PA without epilepsy recurred from 14.3 to 82.9% [19,21±23]. * Corresponding author. Tel.: 139-051-644-2282; fax: 139-051-333725. E-mail address: [email protected] (P. Giovanardi Rossi)
A systematic investigation following speci®c international diagnostic criteria for AD and epilepsy has never been undertaken in adolescent and young adult patients. We therefore investigated epilepsies and EEG PA: prevalence, genetic and organic predisposing factors, type and evolution in a similar aged sample of patients with AD, not correlated with a congenital or acquired encephalopathy.
2. Material The retrospective study included 60 inpatients with AD, 53 males and seven females aged from 12 years to 29 years 9 months (mean age 17 years 2 months). The mean follow-up from the ®rst to the last observation was 3 years (range 1 month to 10 years 7 months). We excluded patients with autistic syndromes secondary to a congenital or acquired encephalopathy, but we included those with mild aspeci®c cerebral lesions of unknown etiology [15]. In all subjects the diagnosis was made according to DSM-III-R [24] and DSM-IV [1]. Epilepsy features were detected according to the Revised Classi®cation of Epilepsies and Epileptic Syndromes [25].
0387-7604/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S03 87-7604(99)0012 4-2
P. Giovanardi Rossi et al. / Brain & Development 22 (2000) 102±106
3. Method We divided the 60 patients into two groups: Group A, subjects with epilepsy including FC (seizures appearing within 5 years triggered by fever) and/or PA; Group B, subjects without epileptic seizures or PA. For every patient a protocol was utilized [26] to collect information on familial history for epilepsy and/or FC and other neurologic and psychiatric diseases; personal organic pre-peri-postnatal antecedents; neurological examination; IQ assessment according to intelligence tests (StanfordBinet scale, WPPSI, WISC-R, WAIS) and clinical observation; language disorders; CT scan and/or MRI ®ndings; and medications for AD. In particular, serial EEG recordings during wakefulness and sleep were performed in every patient at the ®rst observation and during the follow-up, focusing on background activity, aspeci®c abnormalities such as fast activity, theta activity, delta activity, excluding drug induced manifestations, and PA (spikes, spike-waves, polyspikes, polyspikewaves, multifocal, diffuse and generalized). Epilepsy features were investigated considering seizure type and frequency, age at onset, antiepileptic treatment and evolution. The statistical evaluation of data was made by the Fisher exact test.
4. Results Group A included 27 subjects (24 males, three females) (45.0%), 23 with epilepsy (mean age at last observation 17 years 9 months; range 12 years 9 months to 29 years 9 months) and four with EEG PA without epileptic seizures (mean age at last observation 15 years; range 13 years 3 months to 17 years 8 months). Group B included 33 patients without epileptic seizures or EEG PA (55.0%) (29 males, four females); mean age at last observation was 17 years 2 months (range 12 years to 26 years 11 months). Epilepsy recurred in 38.3% of the whole sample; EEG PA without epileptic seizures in 6.7%. A familial history for neuropsychiatric diseases, including epilepsy and/or FC, was present in 31/60 patients (51.7%), only epilepsy and/or FC in 11/60 (18.3%), only neurological disorders in 15/60 (25.0%), and only psychiatric disorders in 16/60 (26.7%). Organic pre, peri and postnatal antecedents were found in 22/60 subjects (36.7%): mainly dystocic delivery in 10 (16.7%) and threatened abortions in eight (13.3%). The neurological examination showed mild non-speci®c signs in 25/60 cases (41.7%); the most frequent were hypotonia (25.0%), macrocrania (15.0%), hyperlaxity (15.0%) and clumsiness (11.7%). Mental retardation had been present in all patients (100%)
103
since the onset of AD: mild/moderate in 15 (25.0%) and severe/profound in 45 (75.0%). Language disorders were characterized by lack of development in 16 (26.7%), syntactic and semantic abnormalities in the other 44 (73.3%). CT scan and/or MRI showed mild non-speci®c abnormalities in 20/60 cases (33.3%): subcortical subatrophy in 11 (18.3%), diffuse cortical-subcortical subatrophy in three (5.0%), cerebellar vermis hypoplasia in three (5.0%), left temporal lobe hypoplasia in two (3.3%), and diffuse cortical subatrophy in one (1.7%); the others were normal. Only patients with epileptic seizures received antiepileptic treatment. Twenty-three (38.3%) patients with AD, from the ®rst observation during the follow-up, were treated with medications for their behavior (29.6% versus 45.5%, Group A versus Group B). Drugs used comprised neuroleptics, benzodiazepines, niaprazine, vitamin B6 and magnesium. No signi®cant differences between Groups A and B were found for any of the above data. 4.1. EEG and epilepsy characteristics Interictal EEG recordings during wakefulness and sleep showed normal background activity in 56/60 patients (93.3%): Group A 92.6% versus Group B 93.9%. Theta or delta activity was found in 21/60 (35.0%): Group A 44.4% versus Group B 27.3%. Fast activity at 14±22 Hz and voltage less than 20 mV was found in 7/60 subjects (11.7%): Group A 14.8% versus Group B 9.1%. The fast activity prevailed on anterior and median brain regions. No signi®cant differences between Groups A and B were found either for background activity abnormalities or presence of theta, delta and fast activity. EEG PA were present in 14/60 patients (23.3%): in Group A (27 patients) in 10/23 with epilepsy (43.5%) and in the four without epilepsy. PA were focal/multifocal in 6/27 (22.2%), diffuse/generalized in 4/27 (14.8%), focal/ multifocal 1 diffuse/generalized in 4/27 (14.8%) (Table 1). Focal and multifocal PA prevailed in the frontal, temporal and parietal regions mainly in the left hemisphere. Drowsiness and slow sleep usually increased PA frequency. PA were never continuous or subcontinuous. Different types of epilepsy and epileptic syndromes [25] were present in 23/60 patients (38.3%) also including idiopathic forms: benign idiopathic neonatal convulsions (BINC) in 1/23 (4.3%); FC in 4/23 (17.4%); FC followed Table 1 EEG paroxysmal abnormalities (PA): Group A 27 cases PA 14/27
10/23 with epilepsy
4 with only PA
%
Absent Focal/multifocal Diffuse/generalized Focal/multifocal 1 diffuse/generalized
13 3 3 4
0 3 1 0
48.1 22.2 14.8 14.8
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by partial epilepsy in 3/23 (13.0%); partial epilepsy in 12/23 (52.2%); generalized epilepsy in 3/23 (13.0%). Not complicated FC were present in 7/23 subjects (30.4%). A partial epilepsy was present in 15/23 cases (65.2%). In 4/23 patients (17.4%) the epilepsy showed the characteristics of benign childhood epilepsy with centro-temporal spikes (BCECTS). In other patients with partial epilepsy, the clinical characteristics of seizures and the EEG data suggested a diagnosis of frontal epilepsy in six patients, temporal epilepsy in three, occipital epilepsy in two. Among the patients with generalized epilepsy one showed epilepsy with generalized tonic-clonic seizures on awakening; the other two had an unclassi®ed benign generalized epilepsy. Mean age at onset of seizures, excluding BINC and FC, was 11 years 11 months (range 2 years 6 months to 19 years 6 months); the onset of seizures was before 12 years in 6/18 patients (33.3%) and after 12 years in 12/18 patients (66.7%). In the four subjects with BCECTS, mean age at onset of seizures was 5 years 3 months (range 4 years to 6 years). The type of seizure diagnosed, excluding BINC and FC, was mainly partial, in particular partial with secondary generalization in 11/18 patients (61.1%) and complex partial (CP) in 5/18 patients (27.8%). Patients could present more than one type of seizure. Table 2 shows the seizure types as percentages of the total number of seizures. At the end of follow-up seizures were controlled in the patient with BINC and in the four subjects with only FC; in the other 18 cases seizure control for at least 2 years was obtained in eight (44.4%). Seizures were not controlled in ®ve cases (27.8%) and in another ®ve patients (27.8%) the evolution was not considered due to too short follow-up or irregularity of antiepileptic treatment. Among the eight subjects with controlled seizures, four had an epilepsy with the characteristics of BCECTS. At the last observation the frequency of seizures in the other 10 patients (55.6%) was under 1 seizure/year in one (10.0%); under 1 seizure/month in ®ve (50.0%); , 1 seizure/month in two (20.0%); over 1 seizure/week in two (20.0%). No signi®cant differences were found between the eight controlled patients and the ®ve uncontrolled patients with adequate follow-up with respect to sex, familial neuropsychiatric disorders including epilepsy/FC, personal antecedents, severity of mental retardation, onset of epilepsy before or after 12 years, EEG data, CT scan and MRI pathological ®ndings. Table 2 Types of seizure (excluding benign idiopathic neonatal convulsions (BINC) and febrile convulsions (FC)) Complex partial Elementary partial Partial with secondary generalization Generalized tonic-clonic Hemiconvulsive status epilepticus
5 2 11 3 1
22.7% 9.1% 50.0% 13.6% 4.5%
A signi®cant difference (P , 0:05) was observed for neurological signs (hypotonia, macrocrania, hyperlaxity and clumsiness) present in all ®ve patients with seizure persistence and in only 2/8 patients with controlled seizures. At the last observation 16 patients (69.6%) were still taking an antiepileptic therapy, 14 as monotherapy and two as polytherapy. The anticonvulsant drugs mainly employed were carbamazepine, valproate and phenobarbital. 5. Discussion This study was performed to investigate the characteristics of epilepsy in a population of adolescents and young adults with AD. There are few data on the occurrence of epilepsy in a similar homogeneous sample of patients for age and diagnostic criteria for AD. On the other hand, literature reports on epilepsy and AD are often contradictory due to: (a) different diagnostic criteria for AD and epilepsy; (b) different ®ndings in samples studied; (c) different duration of follow-up. In agreement with literature, the prevalence of epilepsy (38.3%) in our sample of adolescents and young adults with AD not related to a congenital or acquired encephalopathy was higher than in a general population aged between 10 and 19 years (6.6½) [27]. Excluding BINC and FC, typically age-related, the mean age at onset of seizures was 11 years 11 months, but 66.7% of individuals developed epilepsy after 12 years [5,9]. In our previous sample, epilepsy had an onset after 10 years in 45.0% of patients [15]. In this study, our patients presented different types of epilepsy with a prevalence of partial forms (65.2%): four showed a clinical-EEG picture compatible with BCECTS, six had frontal epilepsies, three temporal, two occipital. When available, data in the literature also describe frontal and occipital epilepsies [23,28]. Seizures were frequently partial with secondary generalization (61.1%), which have a favorable prognosis [29], whereas literature reports more often described CP seizures in AD [12,15,17] that have generally a more unfavorable prognosis in patients with epilepsy [29]. Some authors described scant psychomotor and generalized seizures with a high recurrence in AD [13,18]. Seizure control for a period of two or more years was obtained in eight patients (44.4%). Among these there were four cases with BCECTS. We did not ®nd in the literature exhaustive data on the evolution of epilepsy in adolescents and adults with AD. A signi®cant recurrence of mild heterogeneous neurological signs was evident in the ®ve patients with uncontrolled seizures (P , 0:05) as possible cerebral involvement; this was the only factor negatively in¯uencing the prognosis. CT scan and/or MRI ®ndings did not affect the evolution of epilepsy.
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In the present series EEG PA without epilepsy affected 6.7% of cases. This value was in the range from 1.1 to 6±8% [30] found in a general population of normal children and adolescents but was lower than the 18.9% found in the global series of children and adolescents with AD previously reported [15]; probably EEG PA are age dependent, more frequent at an early age and tend to disappear towards puberty. This seems to be con®rmed by the fact that the percentage of PA in our sample is higher than the 2.6% found in a population of adolescents and adults with psychiatric pathologies [31]. Some authors described a different trend stressing the increase in PA during puberty in particular on the frontal regions [19,23]. Even before puberty, we did not ®nd in our cases clinical and EEG ®ndings compatible with acquired epileptic aphasia or electrical status epilepticus during sleep that can overlap with `autistic regression' or `autistic-like behavior' [20,32]. Patients with AD may have different types of epilepsy including benign forms with a lower epileptogenic threshold with respect to the general population. Comparing Group A and Group B, we failed to ®nd any genetic and organic factors predisposing to epilepsy. However, a general in¯uence of genetic factors and a consistent presence of nonspeci®c organic factors in subjects with AD is suggested by familial antecedents for neuropsychiatric pathologies (including epilepsy) in 51.7% of subjects, personal antecedents in 36.7%, CT scan and/or MRI abnormalities in 33.3%, the presence of mental retardation in all patients and an abnormal neurological examination in 41.7%. This means that AD, epilepsy and mental retardation are probably the result of an early common dysfunction of the central nervous system. The high prevalence of epilepsy in our series of adolescents may be also related to age dependent biological factors correlated with puberty as reported in the general population of patients with epilepsy [33]. Acknowledgements The authors are grateful to Ms Silvia Muzzi and Ms Marina Michelessi for expert technical assistance and Ms Anne Collins for linguistic revision. References [1] American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th. edn. Washington, DC: American Psychiatric Association, 1994. [2] Kanner L. Autistic disturbances of affective contact. Nerv Child 1943;2:217±250. [3] Rutter M. Autistic children. Infancy to adulthood. Semin Psychiatry 1970;2:435±450. [4] Kanner L. Follow-up study of eleven autistic children originally reported in 1943. J Autism Child Schizophr 1971;1:119±145. [5] Deykin EY, MacMahon B. The incidence of seizures among children with autistic symptoms. Am J Psychiatry 1979;136:1310±1312.
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[6] Riikonen R, Amnell G. Psychiatric disorders in children with earlier infantile spasms. Dev Med Child Neurol 1981;23:747±760. [7] Gillberg C, Schaumann H. Epilepsy presenting as infantile autism? Two case studies. Neuropediatrics 1983;14:206±212. [8] Gillberg C. Autistic children growing up: problems during puberty and adolescence. Dev Med Child Neurol 1984;26:125±129. [9] Gillberg C, Steffenburg S. Outcome and prognostic factors in infantile autism and similar conditions: a population-based study of 46 cases followed through puberty. J Autism Dev Disord 1987;17:273± 287. [10] Olsson I, Steffenburg S, Gillberg C. Epilepsy in autism and autisticlike conditions. A population-based study. Arch Neurol 1988;45:666± 668. [11] Volkmar FR, Nelson DS. Seizure disorders in autism. J Am Acad Child Adolesc Psychiatry 1990;29:127±129. [12] Gillberg C. The treatment of epilepsy in autism. J Autism Dev Disord 1991;21:61±77. [13] Tuchman RF, Rapin I, Shinnar S. Autistic and dysphasic children. II: Epilepsy. Pediatrics 1991;88:1219±1225. [14] Wong V. Epilepsy in children with autistic spectrum disorder. J Child Neurol 1993;8:316±322. [15] Giovanardi Rossi P, Parmeggiani A, Bach V, Santucci M, Visconti P. EEG features and epilepsy in patients with autism. Brain Dev 1995;17:169±174. [16] Elia M, Musumeci SA, Ferri R, Bergonzi P. Clinical and neurophysiological aspects of epilepsy in subjects with autism and mental retardation. Am J Ment Retard 1995;100:6±16. [17] Steffenburg S, Gillberg C, Steffenburg U. Psychiatric disorders in children and adolescents with mental retardation and active epilepsy. Arch Neurol 1996;53:904±912. [18] Mouridsen SE, Rich B, Isager T. Epilepsy in disintegrative psychosis and infantile autism: a long-term validation study. Dev Med Child Neurol 1999;41:110±114. [19] Hara H, Sasaki M. Autistic syndrome and epilepsy: signi®cance of the annual electroencephalographical examination. Brain Dev 1990;12:708. [20] Rapin I, Katzman R. Neurobiology of autism. Ann Neurol 1998;43:7± 14. [21] Rutter M, Lockyer L. A ®ve to ®fteen year follow-up study of infantile psychosis. I. Description of sample. Br J Psychiatry 1967;113:1169±1182. [22] Creak M, Pampiglione G. Clinical and EEG studies on a group of 35 psychotic children. Dev Med Child Neurol 1969;11:218±227. [23] Kawasaki Y, Yokota K, Shinomiya M, Shimizu Y, Niwa S. Brief report: electroencephalographic paroxysmal activities in the frontal area emerged in middle childhood and during adolescence in a followup study of autism. J Autism Dev Disord 1997;27:605±620. [24] American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 3rd. revised edn. Washington, DC: American Psychiatric Association, 1987. [25] Commission on Classi®cation and Terminology of the International League Against Epilepsy. Proposal for revised classi®cation of epilepsies and epileptic syndromes. Epilepsia 1989;30:389±399. [26] Giovanardi Rossi P, Visconti P, Mariani Cerati D. Autismo infantile: proposta per un protocollo di ricerca eziologica. Giorn Neuropsich EtaÁ Evol 1991;11:175±192. [27] Hauser WA, Kurland LT. The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia 1975;16:1±66. [28] Nass R, Gross A, Devinsky O. Autism and autistic epileptiform regression with occipital spikes. Dev Med Child Neurol 1998;40:453±458. [29] Pazzaglia P. Le epilessie parziali sintomatiche o secondarie. In: Lega Italiana Contro l'Epilessia, editor. Manuale italiano di epilettologia, Padova: Piccin Nuova Libraria, 1992. pp. 571±585. [30] Cavazzuti GB, Cappella L, Nalin A. Longitudinal study of epileptiform EEG patterns in normal children. Epilepsia 1980;21:43±55. [31] Bridgers SL. Epileptiform abnormalities discovered on electroence-
106
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phalographic screening of psychiatric inpatients. Arch Neurol 1987;44:312±316. [32] Giovanardi Rossi P, Parmeggiani A, Posar A, Scaduto MC, Chiodo S, Vatti G. Landau±Kleffner syndrome (LKS): long-term follow-up and
links with electrical status epilepticus during sleep (ESES). Brain Dev 1999;21:90±98. [33] Morrell MJ. Hormones and epilepsy through the lifetime. Epilepsia 1992;33(Suppl 4):S49±S61.