EEGs were recorded in 86 autistic patients during sleep. Epileptic discharges were observed in 37 cases (43%). Twenty-seven (73%) of these 37 cases had localized spikes, 8 had multiple spike foci, one had generalized spikes, and one had both multiple spike foci and generalized spikes. Fourty-seven epileptic discharge foci were registered in 36 cases, the exception being one with generalized spikes. Thirty-six (76.6%) of the registered 47 epileptic discharge foci were in the frontal region, one (2.1%) in the temporal region, 7 (14.1%) in the centro-parietal region, and 3 (6.4%) in the occipital region. Twenty (55.6%) of the 36 frontal spikes were at midline (11 at Fz and 9 at Cz), 8 on the left side, and 8 on the right side. The dipole of midline spikes was in the deep midline frontal region. These results suggest that frontal dysfunctions are important in the mechanism of symptoms in autism

Fukumizu, Michio

Hanaoka, Shigeru

Hashimoto, Toshiaki

Kato, Takeji

Sasaki, Masayuki

Sugai, Kenji

Tokushima University Institutional Repository

INTRODUCTIONAutism is a behavioral syndrome including prob-lems in relatedness, communication disorders, andrepetitive and stereotyped patterns of behavior. Evi-dence of neurobiological abnormalities has been ob-tained in some cases of autism (1), but in many in-stances the etiology has been unknown since Kanner’study (2). Underlying functional and organic brainabnormalities due to prenatal insults have beenrevealed by means of brain imaging studies, elec-troencephalography (EEG), neuropsychological studiesand so on (3-10). As symptoms of brain damage, abouthalf or one-third of autistic patients may have elec-troencephalographic abnormalities and epileptic sei-zures, respectively. In EEG studies on patients withautism, epileptic discharges, slowing and/or prema-turity have been observed in many studies (11-13).However, foci of EEG paroxysms in autism havebeen reported in various regions and the results ofprevious studies have been contradictory.The aim of the present study was to determinewhether there are peculiar localizations and abnor-malities of epileptic discharges on EEG in autisticpatients.SUBJECTS AND METHODSThe subjects were 86 autistic patients, rangingfrom 2 years and 3 months to 19 years and 5 monthsof age (mean +/- SD= 6 years and 3months +/- 3 yearsand 6 months), who were referred to the Departmentof Child Neurology, National Center Hospital forMental, Nervous and Muscular Disorders, NationalCenter of Neurology and Psychiatry (NCNP) betweenParoxysmal discharges on EEG in young autistic patientsare frequent in frontal regionsToshiaki Hashimoto＊, Masayuki Sasaki＊＊, Kenji Sugai＊＊, Shigeru Hanaoka＊＊,Michio Fukumizu＊＊, and Takeji Kato†.＊Department of Education for Handicapped Children, Naruto University of Education, Tokushima,Japan ; ＊＊Department of Child Neurology and †Department of Center Laboratory, National CenterHospital for Mental, Nervous and Muscular Disorders, National Center of Neurology and Psychia-try (NCNP), Kodaira, Tokyo, Japan.Abstract: EEGs were recorded in 86 autistic patients during sleep. Epileptic discharges wereobserved in 37 cases (43%). Twenty-seven (73%) of these 37 cases had localized spikes, 8 hadmultiple spike foci, one had generalized spikes, and one had both multiple spike foci andgeneralized spikes. Fourty-seven epileptic discharge foci were registered in 36 cases, theexception being one with generalized spikes. Thirty-six (76.6%) of the registered 47 epilep-tic discharge foci were in the frontal region, one (2.1%) in the temporal region, 7 (14.1%)in the centro-parietal region, and 3 (6.4%) in the occipital region. Twenty (55.6%) of the 36frontal spikes were at midline (11 at Fz and 9 at Cz), 8 on the left side, and 8 on the rightside. The dipole of midline spikes was in the deep midline frontal region. These resultssuggest that frontal dysfunctions are important in the mechanism of symptoms in autism.J. Med. Invest. 48 : 175-180, 2001Keywords : EEG, autism, epileptic discharge, dipole, mappingReceived for publication May 29, 2001 ; accepted July 27,2001.Address correspondence and reprint requests to ToshiakiHashimoto, Department of Education for Handicapped Children, NarutoUniversity of Education, 748 Nakashima, Takashima, Naruto-cho,Naruto-city, Tokushima 772-8502, Japan and Fax : +81-88 -687-6019.ORIGINALThe Journal of Medical Investigation Vol. 48 2001１７５January, 1995 to June, 1998, and had sleep EEGsrecorded. The gender ratio, male to female,was69 : 17.Their development quotients, DQ (or intelligence quo-tient, IQ), ranged from 13 to 114 (mean +/- SD=50.6 +/- 21.7). DQ or IQ was measured by meansof the Enjyoji developmental test, or Binet or WISCÅ [R, respectively. EEGs were recorded duringsleep, induced by medication such as triclofos syrup,hydrochrolide or pentobarbital, using a digital EEGmachine (Ceegraph C-32, Biologic System Co.), theelectrodes were placed according to the 10/20 inter-national system. EEGs were stored on photo-discs,and analyzed using the Brain Atlas IIIs and DipoleSource Localization (Biologic System Co.). The elec-trode sites were divided into 4 regions : frontal re-gion including Fp1, Fp2, F3, F4, F7, F8 and Cz, tempor-al region including T3, T4, T5 and T6, centro-parietalregion including C3, C4, P3, P4 and Pz, and occipitalregion including O1 and O2. The EEG assessmentwas performed blindly by two physicians (psychia-trist in the EEG laboratory and T. Hashimoto).Whenthe two physicians agreed, the EEG findings werejudged to be abnormal.The diagnosis of autismwasmade using theDSM-IVcriteria. Five patients showed regressive autism spec-trum disorders. Eighteen patients had a history ofseizures. The backgrounds of the subjects were com-pared as groups with and without spikes.The Student t test and chi square test were usedfor statistical analysis.RESULTSThere were no differences in the mean age, sexratio and percentage of regression between the groupswith and without spikes. However, the DQ (IQ) andpercentage of cases with seizures were lower andhigher, respectively, in cases with spikes than inthose without spikes (Table 1).Spike discharges were observed in 37 cases (43%),and abnormal sleep spindles, such as the scarce ap-pearance and/or alternate appearance of sleep spin-dles, were observed in 11 (12.8%) of the 86 autisticpatients. Twenty-seven (73%) of these 37 cases hadlocalized spikes, 8 had multiple spike foci, one hadgeneralized spikes, and one had both multiple spikefoci and generalized spikes (Fig. 2a, b). Thirty-six cases,the exception being one with generalized spikes,exhibited a total of 47 spike foci. Thirty-six (76.6%)of the 47 registered spike foci were in the frontalregion, one (2.1%) in the temporal region, 7 (14.1%)in the centro-parietal region, and 3 (6.4%) in theoccipital region. Twenty (55.6%) of the 36 frontalspikes were at midline (11 at Fz and 9 at Cz), 8 onthe left side, and 8 on the right side. In the centro-parietalregion, 2 were on the left side, 4 on the right side,and one at midline. In the occipital region, two wereon the left side and one on the right side. In thetemporal region, one was on the left side. The num-bers of spikes did not differ between the left andright hemispheres (13 spikes on the left side and13 spikes on the right side) (Figs. 1 and 3). The spikesat the frontal midline were analyzed for mappingand a single dipole source by means of the Brain AtlasTable 1. The backgrounds of the subjects.Cases with spikes(n=37)Cases without spikes(n=49)age (months)sex ratio (M : F)DQ (IQ)seizures (+)regression78.6 +/- 49.230 : 743.1 +/- 17.013/37 (35.1%)2/37 (5.4%)70.3 +/- 36.639 : 1056.2 +/- 23.2＊＊5/49 (10.2%)＊3/49 (6.1%)＊＊ : p<0.005 (Student t test), ＊ : p<0.05 (chi-square test)Fig. 1 The frequencies and localization of epileptic discharges in autism.＊One case had both mutifocal spikes and generalized epileptic discharges.T. Hashimoto et al. EEG in autism１７６IIIs and Dipole Source Localization. Fig. 4a, b and cshow a typical case with a frontal midline spike focus(Fz). Mapping of spikes at Fz was also performed.Spikes extended from Fz to F4 and Fp2. The dipoleof these midline frontal spikes was in the deep fron-tal region at the midline and directed to the upperright anterior region.DISCUSSIONIn autism, EEG studies have revealed a high rateof epileptic EEG abnormalities. Small (14) documenteda relationship between EEG and IQ, in that the in-cidence of mental retardation was higher in the groupwith EEG abnormalities. Kawasaki et al. (7) reportedthat there was a significant relationship betweenthe presence of epilepsy and the occurrence of spikes.The backgrouds of the subjects in the present studywere consistent with those of previously reportedstudy subjects.Although the focus of spike discharges has beenreported to be the centro-temporal (8), temporal(15, 16), or frontal (7) region, there has been noconsensus. Kawasaki et al . reported that spike dis-charges on EEG became focused to the frontal re-gion with increasing age (7). The prevalence of thisEEG abnormality became increasingly greater withthe number of EEG recordings. In the present studyabnormal spike discharges were observed in 43%of 86 cases with autism. This result was consistentwith those previously reported (17.6 - 60.8%) (7, 17).In the present study, a normal control study was notperformed. However, the incidence of epileptiformabnormalities observed on EEG in children withoutepilepsy has been reported to be 3.5-4.0% (18, 19).In comparison, 43% had spike discharges in thepresent study.The focus of spike discharges was mostly in thefrontal region, especially at midline (Fz and Cz). Thedipole of midline spike discharges present in thedeep frontal midline region may represent thecingulate gyrus. The frontal dominance of spikes isconsistent with the findings of Kawasaki et al . (7).It is important to note that 22/37 cases (59.5%) anda bFig. 2 Epileptic discharges observed in autism. a, 6-year-old girl. She has autism with mental retardation. Her EEG shows multifocalspikes at both Fz and Pz. b, 2-year-old boy. He has autism with mental retardation. His EEG shows focal spikes at Cz. Calibration, 3´cm/sec. and 50E V/5 mm.Fig. 3 Locations of the 47 registered epileptiform discharges.One ring shows one epileptic discharge focus. There are manyfoci at Cz and Fz in the midline region. There was no differencein the number of spike foci between the two hemispheres.１７７The Journal of Medical Investigation Vol. 48 200136/47 total registered spike foci (76.6%) showed afrontal spike focus. The frontal region is related tothe theory of mind and executive function (9, 20).Baron-Cohen et al. hypothesed that in autistic patientsthe theory of mind is deficient (21). Happe et al. (9)found in a PET study that normal controls exhib-ited an increase in metabolism in the left medialfrontal region (BA 8 and 9) during the theory of mindtest, while Aspergar syndrome patients exhibited anincrease in metabolism in the left frontal region(BA 10) in front of one of the controls. Haznedar etal. found, in studies involving MRI and PET, thatautism exhibited decreased glucose metabolism activityand a volume loss in the cingulate gyrus (Broadmanarea 24’) (22). In a PET study, Chugani et al. (6)found decreased serotonin synthesis in the left fron-tal cortex and thalamus in 5 of 7 boys, and in the rightfrontal cortex and thalamus in the remaining 2 autis-tic boys. In a neuropathological study of autisticbrains, Bauman and Kemper observed an increasedcell-packing density and reduced nerve cell size inthe anterior cingulate gyrus, which comprises a majorportion of the limbic system of the brain (3).In an EEG study, Dawson et al. (23) found thatcompared with normally developing children, autis-tic children exhibited reduced EEG power in the fron-tal and temporal regions, but not in the parietalregion, and that the differences were more promi-nent in the left than the right hemisphere. Harrisonet al. (24) presented an adult autistic patient withresults suggestive of left anterior deactivation andright frontal activation. His quantitative EEG findingsrevealed relative activation of the right frontal regioncorresponding to deactivation of homologous zonesof the left frontal region.In the present study, frontal epileptic paroxysmswere highly frequent. Beun et al. (25) observed fron-tal sharp wave activity during drowsiness and/or lightsleep in 41 of 60 healthy adult volunteers. We didnot judge the sharp waves, which are shown in Figs. 1and 2 of their publication, to be abnormal waves.Their subjects were adult in comparison to the chil-dren in the present study. On the other hand, a pro-pensity for frontal propagation of paroxysmal dischargesa cFig. 4. EEG analysis in autism (9-year-old boy) with typi-cal frontal midline spikes. a, EEG shows polyspikes at Fz,denoted by open squares. b, mapping of spikes at Fz.Spikes extend from Fz to F4 and Fp2. c, dipole source.There is a single dipole in the deep anterior frontal re-gion at the midline that is directed to the upper, right andoral sites.bT. Hashimoto et al. EEG in autism１７８during sleep has also been mentioned in relation toepileptic discharges (26). However, the present findingssuggested that the spike discharges observed in thefrontal region in autism represent a dysfunction of thefrontal region, because autistic patients have some fron-tal lesion signs and/or symptoms such as perseveration,disturbances of creativity and executive function,attention disorders, and so on.Although the focus of spike discharges has beenreported to be the centro-parieto-temporal (8) andtemporal (15, 16), in the present study there werefew centro-temporal spike foci. Moreover, Lewine et al.(27) observed epileptic activity in the intra-perisylvianregion using magnetoencephalography in childrenwith regressive autism spectrum disorders. Althoughthe reason for this discrepancy is unknown, sever-al factors may contribute to it. One factor may havebeen that all chidren in the present study had beensedated with medication. The second factor is the dif-ference in the recording methods. We included F7,F8 and Cz in the frontal region. Cz is anatomicallyin the posterior frontal region and so was includedin the frontal region. Olsson et al. (16) reported EEGabnormalities in the temporal lobes of autistic chil-dren with epilepsy. However, only one case showedspikes at F8 in the present study, and this did nothave an affect on our conclusion that F8 should beincluded in the temporal region. The third factor isthe difference in subjects. In the present study, therewere only a few patients with regression of symp-toms. The final factor is that the brain dysfunctionsin autismoccur at several levels, including the brainstem,cerebellum, limbic system (especially amygdala andhippocampus) and association cortex (especially fron-tal lobe). The present cases may be a subgroup withfrontal lesions. Anatomical studies of the autisticbrain have shown deep medial temporal lesions in-cluding those in the hippocampus and amygdala.Although the reasons for the few temporal epilepticdischarges are unknown, deep medial temporal le-sions may be one reason. In future studies the useof sphenoidal electrodes may be needed.REFERENCES1. Gillberg C, Coleman M, eds : The biology of theautistic syndromes. 2nd ed. Mac Keith Press,Oxford, 1992.2. Kanner L : Autistic disturbances of affective con-tact. Nervous Child 2 : 217-250, 1943.3. Bauman M, Kemper TL : Histoanatomic obser-vations of the brain in early infantile autism.Neurology 35 : 866-874, 1985.4. Courchesne E, Yeung-Courchesne R, Press GA,Hesselink JR, Jernigan TL : Hypoplasia of cer-ebellar vermal lobules VI and VII in autism. NewEngl J Med 318 : 1349-1354, 1988.5. Hashimoto T, Tayama M, MurakawaK, YoshimotoT, Miyazaki M, Harada M, Kuroda Y : Devel-opment of the brainstem and cerebellum in autis-tic patients. J Aut Dev Disord 25 : 1-18, 1995.6. Chugani DC, Muzik O, Rothermel R, BehenM, Chakraborty P, Mangner T, da Silva EA,Chugani HT : Altered serotonin synthesis in thedentatothalamocortical pathway in autistic boys.Ann Neurol 42 : 666-669, 1997.7. Kawasaki Y, Yokota K, Shinomiya M, ShimizuY, Niwa S : Brief report : electroencephalographicparoxysmal activities in the frontal area emergedin middle childhood and during adolescence ina follow-up study of autism. J Aut Dev Disord27 : 605-620, 1997.8. Rossi PG, Parmeggiani A, Bach V, Santucci M,Visconti P : EEG features and epilepsy in patientswith autism. Brain Dev 17 : 169-174, 1995.9. 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Paroxysmal discharges on EEG in young autistic patients are frequent in frontal regions

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Paroxysmal discharges on EEG in young autistic patients are frequent in frontal regions

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