The Treatment of Epilepsy in Autism

8/8/2019 The Treatment of Epilepsy in Autism

1/17

Journal of Au tism and Developmental Disorders, VoL 21, No. L 1991

T h e T r e a t m e n t o f E p i l e p s y i n A u t i s m 1

Christopher GillbergUniversity o f GOtebor& Sweden

A u tis m is associated with epilepsy. On e third o f the pop ulation o f peo ple withau tism hav e developed seizures in early adu lt l ife. In spite o f this w ell-knownassociation, l it tle is kn ow n ab out the treatment o f epilepsy in autism. Thispaper reviews the sparse literature and reports a systematic case-record studyo f the treatmen t o f epilepsy in autism. So m e practical guidelines fo r cliniciansare provided. Research in the fiel d o f epilepsy in au tism is highly warranted.

O n e o f t h e f i r s t c h i l d r e n , e v e r d i a g n o s e d a s s u f f e r i n g f r o m e a r l y i n f a n t i l ea u t i s m h a d e p i le p s y ( K a n n e r, 1 9 43 ). A n o t h e r o n e o f K a n n e r ' s o r i g in a lg r o u p o f 11 ( = a l t o g e t h e r 1 8 % ) h a d d e v e l o p e d s e i z u r e s i n e a r l y a d u l t l i f e( K a n n e r, 1 9 7 1 ) . A f t e r K a n n e r, a l m o s t a l l a u t h o r s i n t h e f i e l d h a v e n o t e dt h a t a n a s s o c i a t i o n e x i s t s b e t w e e n a u t i s m a n d e p i l e p s y ( B o h m a n , B o h m a n ,B j 6 r c k , & S j 6 h o l m , 1 9 8 3 ; B r y s o n , C l a r k , & S m i t h , 1 9 8 8 ; C i a l d e l l a &

M a m e l l e , 1 9 89 ; D e y k i n & M a c M a h o n , 1 97 9; F i s h & R i tv o , 1 97 9; G i l lb e rg ,1984 ; Lo t te r, 1967 ; Orn i t z , 1973 ; Rut te r, 1970 ; Scha in & Yanne t , 1960 ;Sh i ra tak i e t a l. , 1982 ; S te ffen bu rg & G i l lbe rg , 1986; T an ou e , O da , A san o ,& K a w a s h i m a , 1 98 8; W i n g & G o u l d , 1 9 79 ). O f R u t t e r ' s ( 1 9 70 ) g r o u p o fc l i n i c a l r e f e r r a l c a s e s w i t h a u t i s m , 2 8 % d e v e l o p e d e p i l e p s y i n a d o l e s c e n c e( a d d i n g t o t h o s e w h o h a d h a d o n s e t o f s e iz u r es i n ea r ly c h i l d h o o d ) . D e y k i na n d M a c M a h o n ( 1 97 9 ) in a l a rg e g r o u p o f r e f e r r a l c a s e s w i t h a u t i s ms h o w e d t h a t t h e c u m u l a t i v e r i s k o f d e v e l o p i n g e p i l e p s y b e f o r e 1 8 y e a r s w a sa b o u t 2 3 % . K n o b l o c h , R i d e r , H a r p e r , a n d P a s a m a n i c k ( 1 9 5 6 ) , Ta f t a n d

C o h e n ( 19 7 1) , a n d R i i k o n e n a n d A m n e l l (1 9 81 ) a m o n g o t h e r s h a v e d r a w na t t e n t i o n t o t h e f a c t t h a t i n f a n t i l e s p a s m s a r e o f t e n a c c o m p a n i e d b y a u t i s t i c

1 T hi s s t u d y h a s b e e n s u p p o r t e d b y a g r a n t f r o m T h e C o m m i s si o n f o r S o ci al R e s e a r c h , S w e d e n ,No. E 88/170:2.

61

0162-3257/91/0300-0061506.50O 1991 Plenum PublishingCorporation


2/17

62 Giilberg

behav io r. O l s son , S te ffenburg , and Gi l lbe rg (1988) pub l i shed a sys t emat i cs t u d y o f th e v a r i o u s k i nd s o f e p il e p sy e n c o u n t e r e d in a u t i sm a n d s h o w e d

tha t in a popu la t ion -based g roup wi th na r rowly de f ined au t i sm (Amer icanPsychia t r ic Asso cia t ion , 1980; Col em an & Gi l lberg , 1985), infant i le spasm sh a d b e e n d i a g n o s e d i n 3 % a n d c o m p l e x p a r ti al e p i le p s y o f t h e p s y c h o m o t o rva r i an t in ano the r 14%. Ot he r types o f ep i l epsy (gene ra l ized ton ic -c lon ics e i z u r e s a n d j u v e n i l e m y o c l o n i c e p i l e p s y ) w e r e a l s o r e p r e s e n t e d i n t h eOlsson e t a l. se r ie s . A g roup o f ch ild ren w i th au t i st i cl ike con d i t io ns -w i ths imi la r degrees o f cogn i tive ha nd icap - -ha d even h ighe r r a te s o f ep i l epsy(41% of the who le g roup) . Ep i l epsy in th i s g roup was conf ined to g i r l s ,wh ich was no t the case in the g roup wi th c la s si ca l au t ism wh ere the boy :g ir lra t io in the epi lept ic subgroup was 2 .5 :1 .

A g e o f o n s e t i n e p i le p s y t y p e s o t h e r t h a n i n f a n ti l e s p a s m s i s o f t e nr e p o r t e d t o b e in t h e a d o l e s c e n t a g e p e r i o d ( D e y k i n & M a c M a h o n ,1 9 79 ; G i l lb e rg & S t e f f e n b u rg , 1 9 87 ; R u t t e r, 1 9 7 0 ), b u t t w o r e c e n t s t u d i e ss u g g e s t t h a t m o s t c a s e s h a v e a n o n s e t i n e a r l y c h i l d h o o d ( O l s s o n e t a l . ,1 9 88 ; Vo l k m a r & N e l s o n , 1 9 90 ). T h e p o s s i b i li t y o f a d i s c re t e p e a k o fo n s e t i n a d o l e s c e n c e h a s l e d t o s p e c u l a t i o n t h a t t h e l i n k b e t w e e n a u t i s ma n d e p i l e p s y m i gh t b e s p e c if i c a n d n o t m e d i a t e d s o l e ly b y t h e o f t e n c o n -c o m i t a n t m e n t a l r e t a r d a t i o n ( s e e C o l e m a n & G i ll b e rg , 1 9 8 5) . H o w e v e r,t h e r e a r e i n d i c at i o n s ( O ' D o n o h u e , 1 9 8 8) t h a t e p i l e p s y in m e n t a l r e t a r -d a t i o n a l so p e a k s a t a d o l e s c e n c e . A l s o , in c h i ld r e n w i t h e p il e p s y ing e n e r a l t h e s e i z u r e f r e q u e n c y i n c r e a s e s a r o u n d t h e t i m e o f p u b e r t y, a tl eas t i n cases wi th gene ra l i zed ton ic -c lon ic se i zu res (Ni i j ima & W al lace ,1 9 8 9 ). T h e s e f i n d in g s , i n c o m b i n a t i o n w i t h t h e r e c e n t r e p o r t o f hi g hr a t e s o f e p i l ep s y e v e n i n v e r y y o u n g c h i l d r en w i t h a u t i s m m a k e s f u r t h e rs t u d y o f t h e p o s s i b l e s p e c i fi c it y o f a d o l e s c e n t o n s e t o f e p i l e p s y i n a u t i s mn e c e s s a r y.

Th e ma jo r i ty o f cases wi th au t ism w ho have ep i l epsy a l so have m en ta lr e t a rda t ion (Co rbe t t , 1982; Dey k in & M acM aho n , 1979; Gi llbe rg & S te f -fenburg , 1987; Rut ter, 1970) , but i t i s in no way except ional for a chi ldwi th normal in te l l igence and aut i sm to have epi lepsy a lso (Gi l lberg & Stef -fenburg , 1987) . For ins tance , in the Olsson e t a l . (1988) s tudy, 7 (20%)ou t o f 35 p repube r t a l ch i ld ren w i th au t i sm had ep il epsy, and 2 ou t o f theseh a d t e s t e d I Q s e x c e e d i n g 8 5 . T h e s e f i n d i n g s s u g g e s t t h a t e p i l e p s y i n"b r igh te r " and "d u l l e r" ch i ld ren wi th au t ism m igh t be equa l ly com m on. I fone looks a t t he f ind ings r epor t ed f rom Rut t e r ' s 1970 se r i e s , i n wh ich 18

o u t o f 6 4 y o u n g a d u l t s w i th a u t i s m a n d a u t is t ic l ik e c o n d i t i o n s h a ddeve loped f i t s i n ado lescence o r ea r ly adu l t l i f e , i t appea r s tha t 17% ofthe b r igh te r g roup and 3 1% of the du l l e r g roup w ere a ffec ted ( calcu lat ionsm a d e b y t h e p r e s e n t a u t h o r ) .


3/17

Trea tm en t o f E p i l ep sy i n Au t i s m 63

The seizures in autism most likely derive from the same brain dys-function/processes that underlie the autistic symptoms and the develop-

mental retardation (Coleman & Gillberg, 1985). Seizures in autism areone of the signals of a poor prognosis (Gillberg & Steffenburg, 1987;Rutter, 1970). Deterioration at puberty may be another such signal(Gillberg, 1989) and the concurrence of adolescent onset epilepsy anddeterioration, particularly in cases with severe mental retardation, pos-sibly indicates important relationships with adolescent neurohormonalchanges as well as a particularly poor outcome. However, the fact thatepilepsy in the general populat ion does not of ten have its onset in adoles-cence (Hauser & Kurland, 1975) indicates that adolescence and its hor-

monal changes per se cannot be the cause of the neurophysiological andclinical changes seen in autism (and possibly in some other developmen-tal disorders).

Thus, there can be no doubt that autism is associated with epilepsy.Also it appears that at least some variants of epilepsy may be associatedwith autism. Roughly one third of people with autism have developedseizures in adult life. This observation, taken with the evidence from recentstudies (Bryson et al., 1988; Gillberg, Steffenburg, & Jakobsson, 1991) thatautism affects at least 1 of 1,000 children and that therefore the epilepsy-

autism combination is not such a rare phenomenon, makes you want toknow what is the empirical basis for the treatment of seizures in autism.Unfortunately, the literature in this field is limited. This paper sums upthe bits and pieces of empirical evidence and suggests some practicalguidelines for the management of epilepsy in autism. It should be noted,however, that the state of the art is nowhere near acceptable and researchinto the area is sorely needed. The recommendations generally rely moreon clinical experience than on hard scientific fact. This must be kept inmind by anybody wanting to incorporate the guidelines into their own treat-ment repertoire.

A SURVEY OF 66 CASES WITH THE COMBINATION OFAUTISM/AUTISTICLIKE CONDITIONS AND EPILEPSY

Because of the lack of systematic study in the field of epilepsy inautism treatment, I conducted a survey of all cases under age 25 years seenin my own practice and followed personally for at least 2 years who hadthe combination of autism/autisticlike conditions and epilepsy. The resultsof this survey are presented here to provide a reasonable clinical basis forsuggesting treatment approaches.


4/17

64 Gillberg

M AT E R IA L A N D M E T H O D S

Subjects

O ver the l a st 16 yea r s , du r ing the cou rse o f va r ious pop u la t ion -baseds tudies a nd in my own c l in ica l prac t ice , I have fo l lo w ed a t leas t 104 pa t ien tswi th au t i sm/au t is t ic l ike p rob lem s and ep i l epsy (a t t he t ime o f r epor t ing theda ta p re sen te d he re ) . The 66 pa t i en t s r epo r t ed h e re a re a ll t he pa t i en t su n d e r a g e 2 5 y e a r s w i th a d i a g n o s is o f a u t is t ic d i s o r d e r ( D S M - I I I - R ;A m erica n Psy chia t r ic Asso cia t ion , 1987) or au t i s tic l ike condi t ion s (Steffen -

burg & Gi l lberg , 1986) wh o had a t l eas t two no nfebr i l e convu l sive ep i sod esi n c h il d h o o d o r a d o l e s c e n c e a n d w h o w e r e t r e a t e d a n d f o l l o w e d b y t h eau tho r fo r a min imum of 2 yea r s. A ma jo r i ty o f the pa t i en t s w ere t r ea tedin col labora t ion w i th child neurolog is ts spec ia l iz ing in the f ie ld of chi ld ho odep i lepsy. Som e o f these pa t i en ts , cons t i tu ting to t a l popu la t ion samples w i ththe com bina t ion o f au t i sm and ep i lepsy, have bee n rep or t ed on in Ols sonet a l. (1988) and sum mari ly in Gi l lberg (1984) . Th e m ajor i ty, how ever, w erec l in ical re fer ra l cases , and no c la ims for general izabi li ty of t rea tm ent e ffec tsto the who le au t i sm-ep i l epsy popu la t ion can be made . Never the le s s , t he

26 pa t ien ts wi th aut ism/aut i s t ic l ike co ndi t ions a nd ep i lepsy w ho con s t i tu tedto ta l popu la t ion samples ( a l l i nc luded in the p resen t s tudy) d id no t d i ff e rs ignif icant ly wi th regard to samp le charac ter is t ics or t rea tm en t s t ra tegies /ef-f ec t s f rom those 40 pa t i en t s who cons t i tu t ed the c lin ical r e fe r ra l g roups .Th ere fo re , t h e re i s no obv iou s r eason to su ppo se tha t the sub jec t s and ove r-a ll f indings are a typica l. The charac ter i s tics o f the s tudy grou ps are b r ief lys u m m a r i z e d b e l o w :

Autistic Disorder (AD).Fifty cases (37 boys and 13 gir ls ; boy:gir l rat io2 .8 :1 ) fu l f i l l ed DSM-I I I -R-c r i t e r i a fo r au t i s t i c d i so rde r. A l l bu t th ree o f

these a lso f i t ted the c l in ica l descr ip t ions in the DSM-II I and the def in i t ions e t o u t b y R u t t e r ( 19 7 8) .

Autisticlike Conditions (ALC).Sixteen cases (5 boys, 11 gir ls ; boy:gir lra t io 0 .5 :1) a lmost fu l f i l led the cr i te r ia for AD, but showed a typica l t ra i t so f som e k ind . Th i s g roup inc luded s om e cases wi th on se t o f c lin ical ly ap -pa ren t sym ptom s a f t e r the age o f 30 -36 mo nths . A few f i t t he c lin ical p i c-t u r e o f c h i l d h o o d d i s in t e g r a ti v e d i s o r d e r ( W o r l d H e a l t h O rg a n i z a t io n ,1 9 88 ). O t h e r s h a d a c le a r o n s e t o f p r o b l e m s d o c u m e n t e d b e f o r e a g e 30months bu t showed some h igh ly a typ ica l t r a i t s bo th be fo re and a f t e r onse tof the d isorde r (e .g ., ex t reme ly c linging behav ior, ex t rem es of hyperac t iv i ty) ,such tha t an unequ ivo ca l d iagnos is o f A D cou ld no t be m ade . N ever the le s s,behav io ra l s imi la r it ie s r a the r than d i ff e rences p reva i l ed when com par i sonsw e r e m a d e w i t h t h e A D g r o u p .


5/17

Tr e a t m e n t o f E p i l e p s y i n A u t i s m 6 5

Tab le 1 . Type o f Se izu re Di so rde r Accord ing to Assoc ia t ed Background cha rac t e r i s t i c s i nA u t i s t ic D i s o r d e r ( A D ) a n d A u t i s ti c li k e C o n d i t i o n s ( A L C )

AD (n = 50 )a n d A L C(n = 16)s u b g r o u p s

Type of epi lepsy*

n C P S G T C J M E I S C B E C A E

Id iopa th i cc a s e s

Boys 20

Gir ls 15

Tu b e r o u ssclerosis

Boys

Gir ls 3Fragi le X

s y n d r o m eBoys 7

Re t ts y n d r o m e

Gir ls

IQ < 50 AD 8(2 ) 5 (1 ) 4 (0) 2 (0 )ALC 1(0) 1(0)

IQ 50-70 A D 2(1) 1(0)A L C 1 ( I )

I Q > 7 0 A D 5 (4 ) 1 (0 )ALC 1(1 )

I Q < 5 0 A D 4(2) 1(1) 1(0) 1(0)A L C 3 ( 1 ) 2 (O ) 1 (0 )

IQ 50-70 AD l (1 )AL C 4(3) 1(0)

IQ > 7 0 AL C 2(1 ) 1 (0 ) 1 (0 )

6 IQ < 5 0 A D 3(0 ) 3 (0) 1 (0 )IQ 50-70 AD 1( I)IQ > 70 AD 2(2 )I Q < 5 0 A D 3 (I )

I Q < 5 0 A D 2 (2 ) l ( l )IQ 50-70 A D 2(2) I (1)I Q l 7 0 A D 1 (1 )

4 I Q < 5 0 A D 2 (1 ) 2 (1 )ALC 1(1 )

M a r k e rc h r o m o s o m e

Boys 2 IQ < 50 A D 2(0) 2(0)Encepha l i t i s

B o y 1 I Q < 5 0 A L C 1 (1 )G i rl I I Q < 5 0 A L C 1 (1 )progress ive

e n c e p h a l o p a t h yB o y I I Q < 5 0 A L C 1(1)

N e u r o -f ib romatos i s

Gir l 1 IQ 50-70 AD 1(0)D o w n

s y n d r o m eB o y 1 I Q < 5 0 A D 1 (1 )

X Y Ys y n d r o m e

Boy 1 IQ 50-70 A D 1(1)In fan t i l e

h y d r o c e p h a l u sB o y 1 I Q < 5 0 A D 1 (1 )

H y p o t h y r o i d i s mBoy 1 IQ < 50 AD 1(0) 1(0)

M C A - M R bB o y 1 I Q < 5 0 A D 1 (1 )

2(0)

1(0)

1(1)

*Numbers in pa ren theses r e fe r t o number o f cases wi th ju s t t h i s one type o f s e i zu res .b M C A - M R = M u l t i p le co f fg e n it al a n o m a l i e s / m e n t a l r e t a r d a t i o n s y n d r o m e .


6/17

66 Gillberg

Of the combined AD/ALC group, 58% had tested IQ below 50,24% had IQ in the 50-70 range, and 18% tested above IQ 70 (the WISC-

R, the Griffiths, and the Vineland scales were administered in all buttwo cases). There were associated medical conditions in 47% of the cases.The relation of IQ, medical condition, and epilepsy type is shown inTable I.

Type o f Epilepsy

All the cases in this study had suffered at least two nonfebrile con-

vulsive episodes or had absences and showed 3 cycle/sec bilateralsynchronous spike and wave activity. Seizure type and epileptic syndromeswere classified according to the Commission on Classification and Ter-minology, Internat ional League Against Epilepsy (1981, 1985). Two cases,one with generalized tonic-clonic seizures and the other with complex par-tial seizures showed completely normal EEG results in seizure-free inter-vals. All the others showed spike and sharp wave discharge on EEG inseizure-free intervals.

Complex Partial Seizures (CPS).This was by far the most common

seizure type, occurring in 82% of the cases. About half of the cases in thiscategory had CPS only.Generalized Tonic-Clonic Seizures (GTC).Generalized tonic-clonic

seizures (grand mal) occurred in 30% of the cases. Most of these had otherseizure types as well.

Juvenile M yoclonic Epilepsy (JM E).These seizures (excluding the in-fantile spasms variant) occurred in 24% of the cases, and the vast majorityhad other types also.

Infantile Spa sm s (IS).Infantile spasms with hypsarrhythmia had been

diagnosed in 11% of the whole group. All the children with IS later showedother kinds of seizure activity.Childhood Benign Epilepsy (CBE).One girl had benign focal epilepsy

(with Rolandic spikes on the EEG) with adolescent onset. Two years afteronset of CBE, she developed typical CPS.

Childhood Absence Epilepsy (CA E):Classic petit real with 3 cycle/secbilateral synchronous spike and wave activity and staring spells was seenin one boy.

Procedure

All the case records of the 66 patients were scrutinized using a datasheet designed particularly for use in the present study. Seizures were clas-


7/17

Tr e a t m e n t o f E p i le p s y i n A u t i s m 67

sifted according to the above categories. All treatments given were noted.All the medical records contained detailed follow-up information by the

author whenever changes in the treatment regimen had been undertaken.Positive and negative changes after treatment changes were noted. This isdone systematically in my practice.

Psychiatric positive and negative effects were noted. A psycho t rop iceffect of a drug was considered to be present when the caregiver spon-taneously reported that the child's behavior had improved in connectionwith treatment with a particular drug. An extremely negat ive behavioral s ideeffect of a drug was considered present when the caregiver reported thatthe child became somnolent and that this did not change for the betterwithin 1 month, autistic behavior increased, hyperactivity became unmalle-able, or irritability developed to such an extent that the family regarded itas a major problem.

Seizure activity was recorded in connection with changes in treat-ment. All parents except four kept a structured "seizure diary." C o m p l e t ese izure cont ro lwas considered to have been achieved if a child had lessthan one seizure every other year. A l m o s t c o m p l e t e s e i z u r e c o n t r o lwasthe category used for those who had less than one seizure every 6months. Cons ide rab ly improved se i zu re con t ro lwas considered present ifa child had his seizure activity reduced to one third of pretreatmentlevels, lncrease in se izure ac t iv i tywas considered to have occurred if achild after a change in treatment showed more seizure activity in the 3months following the change as compared with the 3 months precedingthe change.

Physical changes, such as skin rash, gingival changes, liver dysfunction,were monitored continuously. Most of the children came to the author forcheckup every 3 to 12 months. Three cases were seen only three times by

the author and were mostly followed by another doctor at the clinic. Theremaining 63 were seen on 5-20 occasions.

Drugs Used.Carbamazepine (CBZ), valproic acid (VPA), clonazepam(CLP), nitrazepam (NIP), phenytoin (PHY), phenobarbitone (PHO), andethosuximide (ETS) were the drugs used and evaluated in the presentstudy.

O t h e r Tr e a t m e n t s G i v e n .Apart from drugs, various kinds of adviceconcerning environmental changes were given. Some families triedketogenic diets, but these were not evaluated in the present study. A

few children received brain surgery because of treatment-resistantepilepsy.

Sta t is t ica l M etho ds Used.Chi-square test with Yates' correction when-ever appropriate was used for comparing group frequencies.


8/17

68 Glllber8

T a b l e If. Antiepileptic Pharmacological Treatment in Patients with Autistic Disorder andAutisticlike Conditions in Combinat ion with Epilepsy Who Have Been Followed Up for More

Than 2 Years

Drug No. treated

Seizure controlExtremely

Almost Increase negativePsychotropic Complete complete in seizure behavioral side

effect (%) (e/0) (%) rate (%) effects (e/0)

Carbamazepine 43 56 19 28 0 2Valproic acid 17 41 18 24 0 18Clonazepam 15 0 13 0 20 93Phenytoin 12 0 42 8 8 92Phenobarbitone 9 0 67 0 0 78Nitrazepam 3 0 33 0 0 67Ethosuximide I 100 100 0 0 0

R E S U LT S

Ta b l e I I s h o w s t h e o v e r a l l r e s u lt s o f t r e a t m e n t w i th v a r i o u s k i n d s o fd r u g s i n t h e w h o l e g r o u p o f 6 6 c a se s .

Carbamazepine (CBZ). T h e m a j o r i t y ( 6 5 % ) w e r e t r e a t e d w i t h C B Za t som e t ime . I t was u sua l l y t r i ed f i r s t o f a ll d rug s an d i n pa r t i cu l a r i n a l lt h o s e c a s e s w h o h a d C P S . S l ig h tl y l es s th a n h a l f o f th i s g r o u p h a d c o m p l e t eo r a l m o s t c o m p l e t e s e i z u r e c o n t r o l ( m o s t l y C P S ) . A m a j o r i t y o f t h o s e w h oh a d r e la t iv e l y g o o d s e i z u r e c o n t r o l p lu s a f e w m o r e w e r e a l so r e p o r t e d t oh a v e s h o w n a c l e a r p s y c h o t r o p i c e f fe c t . O n e b o y w i th a d i a g n o s i s o f A Da n d w e e k ly C P S r e c o v e r e d c o m p l et e ly o n a s y m p t o m - l e v el o n t r e a t m e n tw i t h C B Z o n ly. S e v e n m o r e b o y s i m p r o v e d c o n s i d e r a b l y as r e g a rd s n o t o n l ys e i z u r e a c t iv i ty b u t a l s o a u ti s ti c s y m p t o m a t o l o g y [ as j u d g e d b y a d r o p i ns c o r es o n t h e A u t i s ti c B e h a v i o r C h e c k l is t ( K r u g , A r ic k , & A l m o n d , 1 9 8 0)

o f 2 0 p o i n ts o r m o r e ] , w h e n o n C B Z t r e a tm e n t . A n o t h e r 8 b o y s i m p r o v e dc o n s i d e r a b l y a s r e g a r d s s e i z u r e a ct iv i ty, b u t e v e n t h o u g h a p s y c h o t r o p i c ef -f e c t w a s r e c o r d e d , t h e i m p r e s s io n w a s n o t o f m a j o r b e n e f it s . S o m e p a r e n t so f b o y s in th i s l a t t er g r o u p r e p o r t e d t h a t o n t h e o n e h a n d t h e c h i ld h a db e c o m e " m o r e m a l l e a b l e " b u t o n t h e o t h e r h a n d h e n o w t a l k e d o r b e h a v e di n a s li g ht ly m o r e r e p e t i t i o u s a n d s t e r e o t y p e d m a n n e r. T h e g i r ls w i t h A Da n d C P S d i d n o t s e e m t o b e n e f i t as m u c h a s t h e b o y s f r o m t r e a t m e n t w i thC B Z . N o n e o f t h e 4 gir ls w i t h A D a n d C P S a s th e o n l y s e iz u r e - t y p e w h or e c e i v e d s u c h t r e a t m e n t i m p r o v e d n o t a b l y ( s e i z u r e s o r b e h a v i o r ) . O n l y o n e

c h i l d i n t h e C B Z - t r e a t e d g r o u p h a d a s e v e r e s k i n r a s h a n d t r e a t m e n t h a dt o b e i n t e r r u p t e d . A n o t h e r c h il d ( a g ir l) s h o w e d e x t r e m e l y n e g a t iv e b e -h a v i o r al s id e e f fe c t s s u c h t h a t t r e a t m e n t h a d t o b e d i s c o n t i n u e d . N o C B Zt r e a t e d c a s e s h o w e d a n i n c r e a s e i n s e i z u r e a c t i v i t y.


9/17

Treatment of Epilepsy in Au tism 69

Table IlL T ype of M aj or Psychiatric/Behavioral Problem Associated with SpecificPharm acological Antiepileptic Treatment (Percentage o f G roup Treated)*

Increasing Hyper- Ir r i- So mno-Drug n alo ofness Conf us io n ac ti vi ty tability lence

Carbamazepine 43 0 0 0 0 2Valproic acid 17 0 0 0 6 12Clonazepam 15 73 20 (33) (50) (33)Phenytoin 12 58 0 0 25 8Phenobarbitone 9 33 22 11 0 11Nitrazepam 3 67 0 0 0 0Ethosuximide 1 0 0 0 0 0

*Numbers in parentheses indicate percentage showing deviant behavior as component ofother behavior classified as major psychiatric/behavioral problem.

Valproic Ac id (VP A).Of the whole group, 26% (28% of those withAD) were treated with VPA. VPA was given mostly when there was MEor a multitude of different seizure-types or when other drugs had beentried unsuccessfully. Thus, it is not surprising that seizure control was slight-ly less good than in the CBZ-treated group. In a few cases both CBZ andVPA were given. A psychotropic effect was noted in 41% of VPA treatedcases. Almost 20% of VPA-treated cases showed extremely negative be-

havioral side effects such that medication was discontinued in all cases butone (who had total seizure control and the behavioral side effects subsidedsomewhat in the longer term perspective).

Clonazepam (CLP).Of the whole group, 23% (24% of those withAID) were treated with CLP. This drug seem ed to be exceptionally unhelp-ful in that all but one of the cases treated with CLP showed extremelynegative behavioral side effects, some had an increase in seizure activity,and only two children had good seizure control. Clonazepam had usuallybeen tried in cases similar to those who received VPA, but the clinical

effects were both less positive and much more negative.Phenytoin (PH Y).Of the whole group, 18% (20% of those with AD)

were treated with PHY. This drug was mostly used when there was GTCwith or without CPS. Good seizure control was achieved in half the casestreated, but with regard to behavior the drug showed almost as many severeside effects as did CLP.

Phenobarbitone (PHO ).Of the whole group, 14% (16% of the ADgroup) were treated with PHO. This drug was used most often if there wasa combination of seizure types and if the child was under the age of 5years. Seizure control was good or very good, but severe behavioral sideeffects were very common.

Nitrazepam (NIP).Only 5% received NIP (only the AD group). Thisdrug was given only in cases with severe ME. The numbers were too small


10/17

7 0 G i l l b e r g

Table IV. Treatment outcome According to IntellectualLevel~

Goo d seizure Po or seizureIntellectual level control control

IQ 70 9 3

a N u m b e r s i n p a r e n t h e se s i nd i c at e n u m b e r s w h e n c a s e sr e c ei v i ng n o t r e a t m e n t h a v e b e e n i n c l u d e d .

f o r m e a n i n g f u l c o n c lu s i o ns , b u t th e b e h a v i o r a l a b n o r m a l i t i e s e n c o u n t e r e dw e r e s i m i la r t o th o s e s e e n in th e C L P - t r e a t e d g r o u p .

Ethosuximide (ETS). O n e b o y w i th C A E r e ce iv e d E T S . H e b e c a m et o t a ll y s e i z u r e - f r e e , h is E E G w a s n o r m a l i z e d c o m p l e t e l y, a n d h is a u t i st i cb e h a v i o r d i s a p p e a r e d a l t o g e t h e r ( G i l lb e r g & S c h a u m a n n , 1 98 3).

T h e t y p e o f b e h a v i o r a l s id e e f fe c t s e n c o u n t e r e d w i th t h e s e d r u g s a r es u m m a r i z e d in Ta b l e I I I . T h e r e w a s n o s t at is t ic a ll y s ig n i f ic a n t a s s o c i a t i o n

b e t w e e n d r u g e f f e c t a n d a s s o c i a te d m e d i c a l s y n d r o m e , e v e n t h o u g h t h e r ew a s a t e n d e n c y f o r t h e " i d i o p a t h i c " c a s e s t o s h o w a s li g ht ly b e t t e r s e i z u r ec o n t r o l a n d l es s o f b e h a v i o r a l s i de e f f e c ts .

A s s h o w n in Ta b l e I V, th e r e w a s a c l e a r t e n d e n c y t o w a r d s c a s e s w it hh i g h e r I Q h a v i n g b e t t e r s e i z u r e c o n tr o l t h a n t h o s e w i th s e v e r e m e n t a l r e t a r-d a t i o n . H o w e v e r, a l l d i f f e r e n c e s f e ll s l ig h t ly s h o r t o f s t a t is t i c a l s i g n i f i c a n c e .

D I S C U S S I O N

A n t i e p i l e p t i c p h a r m a c o l o g i c a l t r e a t m e n t s h o u l d a lw a y s b e w e i g h e da g a i n s t th e f r e q u e n c y ( o r r a t h e r i n f r e q u e n c y ) w i th w h i c h m o s t c h i ld r e n w i tha u t i s m a n d e p i l e p s y a c t u a ll y s u f f e r f r o m m a j o r s e i z u r e s . I t is a r g u a b l ew h e t h e r a m i ld l y m e n t a l l y r e t a r d e d c h il d w i t h a u t i s m w h o h a s s e i z u r e s o fa f e w m i n u t e s d u r a t i o n o r t w i c e a y e a r o r le s s s h o u l d r e c e i v e a n y k i n d o fp h a r m a c o l o g i c a l t r e a t m e n t . O f t h e 6 6 p a t i e n t s r e f e r r e d t o a b o v e , 5 d id n o tr e c e i v e a n y k in d o f t r e a t m e n t . I n 4 o f th e s e c a s e s t h e r e a s o n w a s t h a t t h er a t e o f s e iz u r e s w a s lo w (


11/17

Tr e a t m e n t o f E p i l e p s y in A u t i s m 71

m e n t m u s t a l w a ys b e m a d e ( Ta y l o r & M c K i n l a y, 19 84 ). F o r i n s t a n c e, o n eb o y a m o n g t h e 6 6 r e p o r t e d s u f f e re d fr o m a u t is m , s e v er e m e n t a l r e t a r d a -

t io n , a n d f r e q u e n t c o m p l e x p a r t ia l s e i z u re s , a ll b e g i n n i n g i n e a r ly c h i l d h o o d .Tu b e r o u s s c l e r o s i s h a d b e e n d i a g n o s e d a r o u n d a g e 7 y e a r s . H e h a d b e e nt r i e d o n v i r t u a l l y e v e r y a n t i e p i l e p t i c d r u g a v a i l a b l e ( a n d c o m b i n a t i o n s o fd r u g s ) a n d o n d i f f e r e n t d o s e l ev e ls , b u t a f t e r m a n y y e a r s, it b e c a m e c l e a rt h a t b o t h w i t h r e g a r d t o s e i z u re f r e q u e n c y a n d b e h a v i o r h e d i d b e s t w i t h o u ta n y k i n d o f d r u g t r e a t m e n t .

T h e t y p e o f e p il ep s y e n c o u n t e r e d i n a u t i s m - a s in o t h e r c as e s w i the p i l e p s y - m a y b e i m p o r t a n t w h e n c h o o s i n g t h e b e s t t r e a t m e n t . O b v i o u s l y,a l l t ypes o f s e i zu re s can occu r i n connec t ion wi th au t i sm. However, j udg ing

f rom the se r i e s r epo r t ed and f rom the l i t e r a tu re r ev i ew, i t appea r s t ha tcom plex pa r t ia l s e i zu re s a re r e l a ti ve ly ve ry co m m on (Co rbe t t , 1982; Gua l -t ie r i, Evans & Pa t t e r so n , 1987), a f f ec t ing a lmo s t t h r ee o f fou r o f a ll ch i ld renwi th the combina t ion o f au t i sm/ep i l epsy in a r ecen t s tudy (Ol s son e t a l . ,1988), and occu r r ing s ing ly o r i n com bina t io n wi th o th e r t ypes o f fi ts . Cor-be t t (1982) po in t ed to t he r isk o f unde r rep or t in g com plex pa r t i a l s e i zu re sin au t i sm becau se o f t he d i agn os t i c d i f f icu l t ie s a r i s ing wh en the com plexs e i zu r e d i s o r d e r s a f f e c t n o n c o m m u n i c a t i v e c h i l d re n . Tu b e r o u s s c le r os is i ss o m e t i m e s t h e c a u s e o f a u t is m . C o m p l e x p a r t ia l s e i z u re s a n d i n f a n t il e

s p a s m s a r e p r o b a b l y t h e m o s t c o m m o n s e i z u r e t y p e s i n s u c h c a s e s . T h ec o m b i n a t i o n o f a u t i s m a n d i n f a n t i l e s p a s m s w i t h o u t u n d e r l y i n g t u b e r o u ssc l e ros i s i s some t imes seen too ( e .g . , i n ca ses w i th neu ro f ib roma tos i s , PKU,a n d h y d r o c e p h a l u s ) ( C o l e m a n & G i l l b e rg , 1 9 8 5 ) . G e n e r a l i z e d t o n i c - c l o n i cse izures a re a l so common in au t i sm (Corbe t t , 1982; Olsson e t a l . , 1988) .P e t i t m a l v a r i a n t s ( G i l l b e rg & S c h a u m a n n ( 1 9 8 3 ) , m i n o r m o t o r s e i z u r e s( G i l l b e rg , Wi n n e rg ~ r d , & Wa h l s t r 6 m , 1 9 8 4 ) , a n d L e n n o x - G a s t a u t t y p eep i l epsy (Boye r, D esch a t r e t t e , & De lw arde , 1981) have a ll been desc r ibedin au t i sm. I t s eems tha t a comb ina t ion o f s e i zu re s is co m m on in the in -d iv idua l w i th au t i sm. Th us , s ix ou t o f s even ch i ld ren w i th au t i sm and ep i l ep -s y i n th e O l s so n e t a l. s tu d y h a d m o r e t h a n o n e t y p e o f s e iz u r e a n d t h r e eo f th e s ix h a d t h r e e o r m o r e t y p es . C h i l d h o o d b e n i g n e p i l ep s y w i th R o l a n -d ic sp ikes and ea r ly ado le scen t onse t has been obse rved in two cases byt h e p r e s e n t a u t h o r ( u n p u b l i s h e d d a t a a n d s e e b e l o w ) . C a r b a m a z e p i n e i so f t e n t h e " d r u g o f c h o i c e " w h e n i t c o m e s t o t h e p h a r m a c o l o g i c a l t r e a t m e n to f C P S ( O ' D o n o h u e , 1 98 8). T h e r e is n o g o o d r e a s o n t o s u p p o s e t h a t th i smigh t no t be t rue o f CPS in au t i sm too . In f ac t, t he r e su l t s o f the sys t em a t i cs tudy r epor t ed ind ica t e t ha t i t m ay indeed be the d rug o f cho ice in th i sp a t i e n t p o p u l a t i o n .

T h e t y p e o f d i s o r d e r u n d e r l y i n g a u ti s m ( a n d o f t e n u n d e r l y i n g t h ese i zu res a s we l l ) may a l so have a l so have imp l i ca t ions fo r t he managemen tof ep i lepsy. I f , for ins tance , there i s a progress ive bra in d isease ( such as


12/17

72 Gillberg

s o m e t i m e s o c c u r s i n t u b e r o u s s c l e r o s i s a n d a l w a y s i n t h e m u c o p o l y s a c -c h a r id o s e s ) t h e n it m a y b e a f r ui tl es s e n t e r p r i s e - - i n d e e d s o m e t i m e s h a r m -

f u l - t o a i m a t t o t a l s e iz u r e c o n t r o l . P u r i n e d i s o r d e r s m a y b e a s s o c i at e dw i t h s e i z u re s a n d a u t i s m ( C o l e m a n , L a n d g r e b e , & L a n d g r e b e , 1 97 4;C o le m an & Gi l lbe rg , 1985) and so sho u ld be spec i fi ca lly i nves t iga t ed ( and ,i f poss ib le , t r ea t e d ) i n ch i ld ren w i th au t i sm wh o dev e lop ep i lepsy.

I t i s no t f ea s ib l e t o r ev i ew he re a l l t he poss ib l e s ide e ff ec t s o f an -t i convu l san t s . Ho we ver, t he r e su l t s o f t he c l in i cal s tud y r epo r t ed acco r dwel l wi th ea r l ie r c la im s (e .g . Gua l t ie r i e t a l ., 1987; Riv in ius , 1982) th a t cer-t a i n d r u g s u s e d f o r s e i z u r e c o n t r o l s e e m t o h a v e p a r t i c u l a r l y d e l e t e r i o u se f f e c ts o n t h e g e n e r a l b e h a v i o r o f c h il d r e n w i th a u t i sm . T h u s , t h r e e d r u g s - -

o r g r o u p s o f d r u g s - - h a v e , f a ir ly r e g u la r ly, p r o d u c e d s e v e r e a g g r a v a t i o n o fa u t is t ic s y m p t o m a t o l o g y, c o n f u s i o n , a n d h y p e r a c ti v it y, w h i le a t t h e s a m et i m e l e a d i n g t o t o ta l , s o m e , o r n o s e i zu r e c o n t r o l ( a n d s o m e t i m e s , a l t h o u g hra re ly, t o an inc reased f r equ enc y o f fi ts ) . Th e th ree d rug g rou ps a re ( a )t h e b e n z o d i a z e p i n e s , ( b) p h e n y t o i n , a n d ( c) t h e b a r b i tu r a t e s . A m o n g t h e s e ,c l o n a z e p a m i n p a r t i c u l a r s e e m s t o b r i n g a b o u t s e v e r e b e h a v i o r a l d e t e r i o r a -t i on in a subs t an t i a l nu m ber o f ca ses.

O n t h e o t h e r h a n d , c a r b a m a z e p i n e a n d v a l p r o i c a c i d c a n o f t e n b eu s e d w i t h o u t a n y m a j o r s id e e f f e c t s f r o m t h e b e h a v i o r a l p o i n t o f v ie w. C a r -

b a m a z e p i n e t r e a t m e n t c a n l e a d t o m e m o r y i m p a i r m e n t , a l t h o u g h p r o b a b l yno t t o t he sam e deg ree a s w i th phe ny to in (Evan s & Gu a l t i e r i , 1985), andi t was n o t c li n ica lly ev iden t i n t he p re sen t m a te r i a l . B o th va lp ro i c ac id an dca rb am azep ine can cause hype rac t iv i ty, i r ri tab i li ty and in som nia (Ev ans &Gu al t ie r i , 1985; Riv in ius , 1982). Such s ide e ffec ts a re of ten d os e- re la teda n d o n l y r a r e l y w a r r a n t w i t h d r a w a l o f t h e d r u g . S e d a t i o n c a n o c c u r b o t hwi th va lp ro ic ac id and ca rb am azep ine bu t u sua l ly on ly in the in it ia l s tageso f t r e a t m e n t a n d t o a m u c h l es s er e x te n t t h a n w i t h th e t h r e e g r o u p s o fd rugs l i s t ed above .

Many pa ren t s c l a im tha t t he i r ch i ld w i th au t i sm and ep i l epsy i s do ingb e s t w h e n t h e c h i ld h a s j u s t h a d a m a j o r s e iz u r e . F o r d a y s , a n d e v e nmonths , mood , i n pa r t i cu l a r, i s s a id t o be pos i t i ve ly a ff ec t ed . In o the r i n -s t ances , w i thd rawa l , i r r i t ab i l i t y, and t an t rums a re r epo r t ed to s igna l t heeven t (w i th in days o r weeks ) o f a m a jo r convu l s ion o r a s e r ie s o f m inorse i zu res , wh ich migh t t hen be fo l lowed by much more pos i t i ve behav io r.T h e s e a r e t h i n g s t h a t a r e o f t e n s a i d g e n e r a l l y a b o u t p e o p l e w i t h e p i l e p s yand i t i s d i ff icu l t to assess the i r impor tance . In the present s tudy, low leve lso f au t i st i c sym ptom ato log y were obse rved in a t l ea st 5 o f t he 66 pa t i en t sdu r ing the 3 weeks fo l lowing a ma jo r convu l s ion ( these w ere cases w i th as e iz u r e f r e q u e n c y o f 4 o r le ss p e r y e a r) . T h e n o t i o n t h a t - a t l ea s t in so m ec a s e s - - t h e r e m i g h t b e a r e l at i o n s h ip b e t w e e n e x t r e m e s o f g o o d s e iz u r e c o n -t r o l a n d e x t r e m e s o f au t is ti c s y m p t o m a t o l o g y ( a n d t h a t s o m e t i m e s t h e c o n -


13/17

Tr e a t m e n t o f E p i l e p s y i n A u t i s m 73

v u l s i o n p e r s e s e e m s t o h a v e a p o s it i v e e ff e c t o n t h e c h i l d 's b e h a v i o rg e n e r a l l y ) w a r r a n t s e m p i r i c a l t e st in g .

O n t h e o t h e r h a n d , t h e r e a r e c a s e s i n w h i c h t o t a l s e i z u r e c o n t r o l h a sl e d t o r e s o l u t i o n o f a u t i s ti c s y m p t o m s ( G i l l b e r g & S c h a u m a n n , 1 9 8 3) ,T h e r e f o r e , a n a t t e m p t a t o b t a in i n g f u ll s e i z u re c o n t r o l s h o u ld b e m a d e inm o s t c a s e s w i t h e p i l e p s y b e f o r e o n e d e c i d e s t h a t i t is n o t w o r t h w h i l e .

F o r t h e p r e s e n t , b a s e d o n t h e s t u d y r e p o r t e d i n t h is p a p e r, t h e l i te r a -t u r e r e v ie w, a n d i n f e r e n c e f r o m f in d i n g s o b t a i n e d i n n e i g h b o r i n g f ie l ds , i ts e e m s r e a s o n a b l e t o s u g g e s t t h a t c a r b a m a z e p i n e a n d v a l p r o i c a c i d b e c o n -s i d e r e d d r u g s o f f ir s t c h o i c e in t h e t r e a t m e n t o f e p i le p s y i n a u ti s m i n am a j o r i t y o f t h e c as e s . C a r b a m a z e p i n e u s u a ll y ha s g o o d p o t e n t i a l in t h e

t r e a t m e n t o f c o m p l e x p a r ti a l s e i z u r es , a n d c a n s o m e t i m e s b e e f f e c t i v e int h e t r e a t m e n t o f g e n e r a l i z e d t o n i c - c l o n i c s e i zu r e s t o o . S i d e e f f e c t s - a p a r tf r o m s k i n r a s h e s , a l l e rg y, a n d d r o w s i n e s s d u r i n g t h e f i r s t d a y s o f t r e a t -m e n t - a r e r e la t iv e l y f ew. A t e n d e n c y f o r s o m e c h i l d r en w i th a u t is m a n de p i l e p s y to b e c o m e m o r e r e p e t i t i o u s a n d s t e r e o t y p e d w h i l e o n c a r-b a m a z e p i n e s h o u l d b e a c k n o w l e d g e d . A f e w c h i l d re n o n c a r b a m a z e p i n eh a v e b e e n r e p o r t e d t o d e v e l o p a g it a te d b e h a v i o r a n d ti cs e v e n w h e n t h e r eis a lo w d r u g b l o o d l e ve l ( E v a n s & G u a l t i e r i , 1 9 8 5 ). Va l p r o i c a c i d - o c -c a s io n a l ly p r o d u c i n g a n o r e x ia , v o m it in g , a n d a g g r e s s i o n - - s o m e t i m e s is a

v e r y h e l p f u l d r u g i n t h e t r e a t m e n t o f v a r i o u s k i n d s o f e p i l e p s y in a u t i sm .E s p e c i a l l y w h e n t h e r e is a m i x t u r e o f d i f f e r e n t t y p e s o f e p il e p s y, w h i c h iso f t en t he ca se , va lp ro i c ac id i s o f t e n e f f ec t i ve . T he re is , o f cou r s e t he r isko f l iv e r d a m a g e , w h i c h a l t h o u g h r a r e ( i n 4 8 c a se s o n v a l p r o i c a c id f o l l o w e dc l o se l y b y t h e a u t h o r t h is h a s n o t y e t o c c u r r e d ) , c a n n o t b e o v e r l o o k e d .H o w e v e r, t h e p o s s i b le p o s i t i v e e f fe c t s o f v a l p r o i c a c id m u s t b e w e i g h e da g a i n s t t h e s m a l l r is k o f li v er n e c r o s is , a n d t h e n a t u r e a n d t h e d e g r e e o ft h e c h i l d 's b a s ic h a n d i c a p s m u s t b e t a k e n i n t o a c c o u n t . T o t h e b e s t o f t h ea u t h o r ' s k n o w l e d g e , n o s t u d y h a s b e e n p u b l i s h e d in w h ic h l i ve r n e c r o s i s

c o u l d b e p r e d i c t e d b y p r e n e c r o s i s b l o o d t e st s o f li ve r e n z y m e s . R e p e a t e db l o o d t e s t s i n a u t i s m c a n c a u s e s o m a n y p r a c t i c a l p r o b l e m s t h a t t h e y m a yn o t b e w o r t h w h i l e , w h e n t h e r e is n o g o o d p r o o f t h a t t h e y ca n l e a d t o e a r l yd e t e c t i o n o f s e v e r e d r u g s id e e f f e ct s .

I t h a s b e e n m y e x p e r i e n c e t h a t d r u g s u s e d f o r s ei z u re c o n t r o l i na u ti sm c a n o f te n b e g iv e n at r e c o m m e n d e d o r l o w e r t h a n r e c o m m e n d e dd o s e s . A c a r e f u l e v a l u a t i o n o f t y p e o f b e h a v i o r, o t h e r p s y c h i c s y m p t o m s ,s e i z u r e c o n t r o l , a n d d r u g d o s e s m u s t a l w a y s b e m a d e i n e a c h i n d i v i d u a lc a s e. I n d i c a t i o n s f o r c o n t r o l o f s e r u m l ev e ls o f d r u g s v a r y c o n s i d e r a b l y f r o mo n e c o u n t r y to a n o t h e r. I n m y o p i n i o n , m o n i t o r i n g o f s e r u m l ev e ls s h o u l db e p e r f o r m e d w h e n d o s e i n c r e m e n t h a s n o t l e d t o o p t i m a l s e i z u r e c o n t r o l .O t h e r w i s e , a s e r u m l e v el m a y b e u s e fu l a t a n a p p r o x i m a t e r a t e o f o n c ep e r y e a r o r w h e n t h e r e is a su s p ic i o n t h a t o v e r d o s a g e m i g h t b e p r e s e n t


14/17

74 Gillberg

( s u c h a s w h e n t h e p e r s o n w i t h a u ti s m s h o w s p s y ch i c d e t e r i o r a t i o n , c o n -f u s i o n , o r i n c r e a s i n g l e v e l s o f a l o o f n e s s , a g g r e s s i o n , s e l f - i n ju r i o u s b e h a v i o r,

h y p e r a c t i v it y, a ta x i a, o r s e i z u r e a c t iv i ty ) . T h e r o u t i n e v e n i p u n c t u r e s f o rs e r u m l ev e ls e v e r y 3 m o n t h s p e r f o r m e d i n s o m e c e n t e r s m a y n o t b e w a r -r a n t e d . I t is n o t c l e a r t h a t s u c h m o n i t o r i n g w i ll a f f e c t c l in i ca l t h e r a p y a n dv e n i p u n c t u r e s c a n b e v e r y u p s e tt i n g f o r a f ew p e o p l e w i t h a u t i sm .

H a i o p e r i d o l is o f t e n r e c o m m e n d e d a s a n a d j u n c t in t h e t r e a t m e n t o fb e h a v i o r p r o b l e m s i n a u t i s m ( C a m p b e l l e t al., 1 9 8 7) . A l l n e u r o l e p t i c d r u g ss h a r e t h e c a p a c i t y t o r e d u c e s e i z u r e t h r e s h o l d l ev e ls . T h i s is n o t t o s a y t h a ts u c h d r u g s s h o u l d t h e r e f o r e n o t b e u s e d in a u ti s m , b u t t h a t s u c h p o t e n t i a ld r u g e f f e c ts m u s t b e t a k e n i n to a c c o u n t w h e n p l a n n i n g t r e a t m e n t . M u c h

t h e s a m e h o l d s f o r f e n f l u r a m i n e w h ic h s e e m e d t o p r o v o k e e p i le p t i c s ei z u re si n o n e c a s e i n a p l a c e b o - c o n t r o l l e d s t u d y o f 2 0 S w e d i s h c h i l d r e n w i th a u t i s mf r o m o u r c e n t e r ( E k m a n , M i r a n d a - L i n n 6 , G i l lb e r g , G a r l e , & W e t t e r b e r g ,1 9 8 9 ). Va r i o u s k i n d s o f B v i ta m i n s ( fo l ic ac id a n d p y r i d o x i n e , f o r i n s t a n c e )a r e s o m e t i m e s p r e s c r i b e d in c a s es w i t h a u t is m ( w i th o r w i t h o u t t h e f r a g i leX s y n d r o m e ) a n d c o ul d a l s o - a t l ea st t h e o r e t i c a l l y - i n cr e as e th e ris k o fs e i z u r e a c t iv i ty. A s a l w a y s , p o t e n t i a l h a z a r d s a n d b e n e f i t s m u s t b e c o n -s i d e r e d b e f o r e a d e c i s io n f o r o r a g ai n s t s u c h d r u g t r e a t m e n t is m a d e . F r o mt h e c li n ic a l p o i n t o f v ie w, p r o v o c a t i o n o f s e iz u r e s w i t h n e u r o l e p t i c s o r

v i t a m i n s s e e m s t o b e r a r e . S e v e r a l d o z e n o f t h e p a t i e n t s w h o h a v e t r i e dv i t a m i n B 6 ( p y r i d o x i n e ) i n o u r c e n t e r ( 3 0 0 - 9 0 0 m g / d a y ) a n d t h e 2 0 p a t i e n t sw h o h a v e t a k e n f o l i c a c id ( 0 . 5 - 1 . 0 m g / k g p e r d a y ) h a v e n o t s h o w n p r o v o c a -t i on o r i nc r ea se o f s e i zu re ac t iv i ty.

Va r i o u s e n v i r o n m e n t a l f a c t o r s , s u c h a s l o u d n o i s e , s t r e s s , c h a o t i cs i t u a t i o n s a n d s l e e p d e p r i v a t i o n , c a n c o n t r i b u t e t o t h e p r o d u c t i o n o fs e i z u r e s in a u ti s m . O n e c a n n o t s tr e s s e n o u g h t h e i m p o r t a n c e o f a c a l m ,w e l l - s tr u c t u r ed e n v i r o n m e n t f o r p e o p l e w i t h a u ti s m w h e n it c o m e s t o r e d u c -i n g s e iz u r e a c ti v it y. S u c h a s p e c t s o f ep i l e p s y in a u t i s m a r e o f t e n o v e r l o o k e d

c o m p l e t e l y in t r e a t m e n t p r o g r a m s . F r o m t i m e to ti m e m e a s u r e s t a k e n i no r d e r to r e m e d y su c h e n v i r o n m e n t a l p r o b l e m s c a n b e m u c h m o r e f o r c e f u lt h a n t h e i n t r o d u c t i o n o f a n e w o r e x t r a a n t i e p i le p t i c d r u g .

N e u r o s u r g e r y h a s p r o v e d a s u c c es s fu l t r e a t m e n t o p t i o n in m a n yc h i l d r e n w i th c o m p l e x p a r t ia l s e i z u r e s w i th a d i s t in c t f o c u s o n t h e E E G . Am a j o r i t y o f t h e c a s es r e p o r t e d b y O u n s t e d , L i n d s a y, a n d R i c h a r d s ( 1 9 8 8 )a ls o e x h i b i t e d s e v e r e b e h a v i o r p r o b l e m s s u c h a s r ag e , t a n t r u m s , v a r i o u s k i n d so f soc i al im pa i rm en t ( i nc lud ing w i thd raw a l ) , and hype rac t i v i ty. A f t e r su rge ry,b o t h t h e s e i z u r e d i s o r d e r a n d t h e d i s r u p t i v e b e h a v i o r i m p r o v e d d r a m a t i c a l l yi n m a n y c a s e s . W h e t h e r o r n o t a u t i s t i c - t y p e b e h a v i o r m i g h t i m p r o v e a f t e rb ra in su rge ry i n ch i l d r en w i th au t i sm and ( foca l ) ep i l epsy r ema in s op en t os p e c u l a t i o n . T h e r e a r e n o s y s t e m a t i c r e p o r t s r e l a t i n g t o t h i s p o p u l a t i o n i nt h e l i te r a t u r e . F u r t h e r m o r e , i t s e e m s t h a t " c h i l d h o o d p s y c h o si s " a n d


15/17

Tr e a tm en t o f Ep i l ep s y i n A u t i s m 75

" a u t is m " i n s o m e s e r ie s o f p a t i e n t s w e r e e x c l u d e d f r o m o p t i n g f o r s u r g ic a lt r e a t m e n t ( O u n s t e d e t a l . , 1 9 8 8 ) .

C O N C L U S I O N S

A t h o r o u g h s e ar c h o f th e l it er a tu r e f ro m 1 9 6 6 - 1 9 9 0 h a s n o t b e e n a b l et o id e n t i f y a s i n g le p a p e r t h a t h a s s y s te m a t i c a l ly e x a m i n e d t h e u s e o f a n -t i e p il e p t ic t r e a t m e n t r e g i m e s i n a u t is m . T h e g u i d e l i n e s p r e s e n t e d in t h ef o r e g o i n g h a v e t o b e v i e w e d in th i s p e r s p e c t iv e . T h e w h o l e f ie l d o f e p i l e p s yi n a u t i s m i s i n d i r e n e e d o f i n t e n s i f i e d r e s e a r c h i n t h e n e a r f u t u r e .

R E F E R E N C E S

American Psychiatric Association. (1980).Diagnost ic and s ta t is tical ma nu al of m enta l d isorders(3rd ed) . Washington DC: Author.

Am erican Psychia t ric Associa t ion. (1987) .Diagnost ic and s ta t is tical m an ual of m enta l d isorders(3rd ed. , rev. ) . Washington DC: Author.

Boy er, J .-P., De scha trette, A ., & D elw arde , M. (1981). A utism e convulsif?.Pddiatrie, 5.353-368.Bo hm an, M., Boh ma n, I . L. , Bj/3rck, P. O., & Sjfh olm , E. (1983). Ch ildho od psychosis in a

nor thern Swedish county: Som e prel iminary f indings f rom an epidem iological survey. InM. H. Schmidt & H. Remschmidt (Eds . ) ,Epidemiological approaches in child p~ychiaoy(Vol. 2, pp. 164-173). Stuttgart: Thieme.

Bryson, S. E. , Clark, B. S. , & Sm ith, I . M. (1988). First repo rt o f a Cana dian epide mio logic als tudy of aut is t ic syndromes.Journa l o f ChiM P~ychology and Psychiaoy, 29,433-445.

Cam pbel l , M. (1987). Drug t rea tmen t of infant i le aut ism. In H. Y. Mel tzer (Ed.) ,P~ychophar-macology: Th e thh'd generation o f progress,(pp. 1225-1231) New York: Raven Press.

Cam pbell , M ., Perry, R ., & G reen , W. H. (1984). The use of l i thium in children an d adoles-cents. Psychosomatics, 25,95-106.

Cialdel la , P., & M amel le , N. (1989) . A n epidemiological s tudy of infant i le aut ism in a Frenchdepar tmen t (Rh6ne) : A resea rch no te .Journal of Child Psychology and P~ychiao), , 30,165-175.

Colem an, M. & Gil lberg , C. (1985).The Biology o f the Aut is t ic Syndromes.New York: Praeger.Co lem an, M . , La ndg rebe , M. , & Landg rebe, A. (1974) . Prog ress ive se izures wi th hyper-

ur icosur ia reversed by a l lopur inol .Archives of Neurology, 31,238-242.Com mission on Class i fica tion and T ermin ology of the Internat ional Leagu e Agains t Epi lepsy.

(1981). P roposal for revised clinical and e lectro enc eph alog raph ic classification of epilepticseizures. Epilepsia, 22,489-501.

Commission on Class i f ica t ion and Terminology of the Internat ional League Agains t Epi lepsy.(1985). P ropo sal for classification of epilepsies and e pilep tic syndrom es.Epilepsia, 26,268-278.

Co rbett , J . (1982). Ep ilepsy and th e electroe nce pha logr am in early childh ood psychoses. InJ . K. Wing & L. Wing (Eds . ) ,Handbook ofp~ych ia t ry.(Vol. 3, pp. 198-202). London:Cam bridge Univers i ty Press.

Craft , M., lsmail , I . A., Krishnamurti , D., Mathews, J . , Regan, A., Seth, R., & North, P. M.(1987) . Li th ium in the t rea tm ent of aggress ion in men tal ly handica pped pat ients . Adouble-blind tr ial .British Journal of Psychiatry, 150,685-689.

Deykin, E. Y. , & M acM ahon, G. (1979) . The incidence of se izure , am ong chi ldren wi th aut ist icsymptoms.American Journal of P~ychiat ry, 136,1310-1312.


16/17

76 Gi l lbe rg

Ekman, G. , Miranda-Linn~, F. , Oi l lberg , C. , Gar le , M. , & Wetterberg, L. (1989) . Fenf luraminetreatment of twenty aut is t ic chi ldren.Journal of Au tism an d Developmental Disorders, 19,511-532.

Evans , R. W . , & Gual t ier i , C. T. (1985). C arbam azepine: A neuropsychological and psychia tr icprofile. Clinical Neuropharmacology, 83,221-241.

Fenwick , P. (1985) . The EEG. In M. Rut t e r & L . Hersov (Eds . ) ,Child and adolescentpsychiatry: M od em approaches(pp. 382-399). Oxford: Blackwell Scientific.

Fish, B., & Ritvo , E. (1979). P sychoses of childh ood . In V. Nosh pitz (Ed .) ,Basic handbookof child psychiatry(Vol. 2, pp. 249-303). New York: Basic Books.

Gillberg, C. (1984). Infanti le autism and other childhood psychoses in a Swedish urban region.Epidemiological aspects.Journal of Child Psychology and Psychiatry, 25,35-43.

Gi l lberg , C. (1989). Aut ism . Specif ic problem s of adolescence. In C. G i l lberg (Ed.) ,Diagnosisand treatment of autism. New York: Plenum Press .

Gi l lberg , C. , & Schaum ann, H. (1983). Epi lepsy present ing as infant ile aut ism? Tw o casestudies. Neuropaediatrics, 14,206-212.

Gillberg, C., & Steffenburg, S. (1987). Outcome and prognostic factors in infanti le autismand s imilar condi t ions . A popula t ion-based s tudy of 46 cases fol lowed through puber ty.Journal of Au tism and Developmental Disorders, 17,271-285.

Gi l lberg , C. , W innerg~rd, I ., & Wahls t r6m, J . (1984). The sex ch ro m os om es -O ne key toau t i sm? An XYY case o f in fan t i l e au t i sm.Applied Research in Mental Retardation, 5,353-360.

Gi l lberg , C., Steffenburg, S . , & Jakobsson, G . (1991) . Is aut ism mo re com m on now than 10years ago?British Journal o f P~ychiatry,(in press).

Gillberg, C., Steffenburg, S. , Wahlstri im, J . , Sjfstedt, A., & Eeg-Olofson, O. (1991). Autismassoc ia ted wi th marker ch romosome.Journa l o f the Amer ican Academy of Chi ld andAdolescent Psychiaoy,(in press).

Gua l t ier i , T. , Evans , R. W. , & Pat terson, D. R. (1987). T he medical t rea tm ent of autis t icpeople . P roblem s and s ide effects . In E. Schop ler & G. M esibov (Eds . ) ,Neurobiologicalissues in autism.New York: Plenum Press .

Ha rris, R. (1972). E E G aspects of unclassified me ntal retard ation. In .1. B. Ca vanag h (E d.) ,The brain in unclassified me nta l retardation. Stud y group No. 3.L o n d o n : C h u r c h i l lLivingstone.

Hau ser, W . A. , & Kurland, L. T. (1975) . The epidem iology of epilepsy in Roch ester, M in-nesota, 1935-1967.Epilepsia, 16, 1-66.

Ka nner, L. (1943). A utist ic disturban ces o f effcctivc contact .Nervous Child,Z 217-250.Ka nner, L. (1971). Follo w-u p study of 11 autist ic children originally report ed in 1943.Joufllal

o f Au tism a nd C hildhood Sch&ophrenia, I ,119-145.Kn obloc h, H., Rid er, R., Ha rper, P. , & Pasamanick, B. (1956). Ncuro psyc hiatric seq uela e of

prematur i ty.Journal of the Am erican Medical Association, 16 1,581-585.Kolvin, I . , Ounsted, C., & Roth, M. (1971). Studies in the childhood psychoses: V. Cerebral

dysfunction and childhood psychoses.British Journal o f P~ ychiatry, 118 ,407-414.Krug, D . A. , Arick, J. , & A lmon d, P. (1980) . Aut ism Behav ior Checkl ist for ident ify ing severely

hand icapp ed individuals with high levels of autist ic behavior.Journal of ChiM P~ycholo~,and Psychiatry, 21,21-229.

Niij ima, S-I. , & Wallace, S. J . (1989). Effects of puberty on seizure frequency.DevelopmentalMedicine and Child Neurology, 31,174-180.

Lot ter, V. (1967). Epidem iology of autis t ic condi t ions in young chi ldren. I1. Som e charac-ter is t ics of the parents and chi ldren.Social P~ychiaoy, 1,163-173.

O 'Donohue , N . V. (1985) .Epilepsies of childhood(2nd ed) . London, But terworths .Olsson, I . , Steffenburg, S. , & Gillberg, C. (1988). Epilepsy in autism and autist ic-l ike condi-

t ions: a population-based study.Archives of Neurology, 45,666-668.Orn itz, E. M. (1973). C hildh ood autism: a review of the clinical and ex perim ental l i terature.

California Medicine, 118,21-47.Ounsted, C., Lindsay, J . , & Richards, P. (1987).Tempo ral lobe epilepsy. A biograph& al study

1948-1986 (Clinic. ,; in D evelop me ntal M edicine No. 103) . Oxford: Mac Kei th Press.


17/17

Tr e a t m e n t o f E p i l e p s y i n A u t i s m 7 7

Riikonen, R. , & Amnel l , G. (1981) . Psychia t r ic d isorders in chi ldren wi th ear l ier infant i lespasms. Developmental Medicine and Chi ld Neurology, 23,747-760.

Rivinius , T. M . (1982). Psychia t r ic effects of the ant iconvulsant regimens.Journal of Cl inicalPsychopharmacology, 2,165-192.

Ru t ter, M. (1970) . A ut is t ic chi ldren. Infancy to adul thood.Seminars in Psychiatry, 2,435-450.Ru t ter, M . (1978) . D iagnosis and d ef ini t ion. In M. R ut te r & E. Schopler (Eds . ) ,A u t i s m . A

reappraisal of concepts and t reatment(pp. 1-25). New York: Plenum Press.Schain , R. , & Ya nnet , H. (1960). Infant i le aut ism: an analys is of 50 cases and a considera t io n

of cer ta in re levant neuropsychological concepts .Journal of Pediatrics, 57,560-567.Shira taki , S . , Kuromaru, S . , Hanada, M. , Sugiura , Y. , Yamada, T. , Ushjda , S . , & Shimada, S .

(1982, July).Longterm fol low-up s tudy of 13 aut is t ic chi ldren.Paper p resen ted a t theInternat ional Conference on Chi ld Psychia t ry, Dubl in , I re land.

Steffenburg, S . , & Gil lberg , C. (1986) . Aut ism and aut is t ic l ike condi t ions in Swedish rura land urban areas: a population study.British Journal of Psychiatry, 149,81-87.

Taft , L. T. , & Cohe n, H . J . (1971). H ypsarrh ythm ia and child hoo d autism: a clinical re port .Journ al o f Au t ism and C hi ldhood Schizophrenia, 1 ,327-336.

Ta nou e, Y ., Od a, S. , Asan o, F. , & Kawashima, K. (1988). Ep idem iolog y of infanti le autismin southern Ibaraki, Japan : Differenc es in prevalence ra tes in b i r th cohor ts .Journal oJ"Aut i sm and Deve lopmenta l Disorders , 18 ,155-166.

Ta ylor, D., & M cKinlay , 1. (1984). W hen n ot to treat ep ilepsy with drugs.D e v e l o p m e n t a lMed&ine and ChiM Neuro logy, 26 ,822-827.

Volkmar, F. R., & Nelson, D. S. (1990). Seizure disorders in autism.Journa l o f the Amer icanAcademy of Chi ld and Adolescen t Psych ia t ry, 29 ,127-129.

Wor ld Hea l th Organ iza t ion (1987) .ICD 10 . Dra f t o f Chap te r V. Menta l , Behav ioura l andDevelopmental Disorders .Geneva : Author.

Wing, L. (1976).Early childhood autism(2nd ed. ) . Oxford: Pergamon.W ing, L. , & G ould , J . (1979). Severe imp airm ents of social interaction and associated abn or-

malit ies in children : E pide m iolog y and classification.J o u r n a l o f A u t is m a n d D e v e l o p m e n t a lDisorders, 9, 11-29.

Documents

The Treatment of Epilepsy in Autism