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British Journal of Psychiatry (1994), 164, 528â€”532

Dow n's syndrome is a comm on cau se o f m en ta lhand icap , w ith an inci dence o f approx ima te ly onein 700 registered births (Department of MedicalGenet ics,Q ueen's Univers i ty , Bel fast) . Epi lepsy isa s ig nific an t c au se o f s ec onda ry handic ap in th ement al ly hand icapped popu la tion and, i n spi te o fprevious reports to the contrary, is now beingrecognise d as an im portan t cause of m orb idity inDow n's sy nd rome.The early l it e ra tu re on Down 's syndromedoesnot

re fe r to e pile ps y a t a ll. E pile ps y w as n ot in clu de d inL an gd on D ow n's d esc rip tio n o f th e s yn drome o ve r100 years ago (Langdon D ow n, 1866). M ajortextbooks a quarter of a century ago stated thatepileptic seizures were not observed in Down'ssyndrom e (Slater & Roth, 1969). Studies of thep re va lence of ep ilepsy in D ow n's syndrom e haverep orted ra tes va rying from 1Â °oo 14% (K irm an,1951;yeah , 1974;R omano eta l , 1990;Pueschele ta l ,1991). MacG il li vr ay (1967) repo rted a p revalence rateof 8% in a hospital population of 111 Down'ss yn drome p atie nts , o ve r a te n-y ea r p erio d. S ig nifica ntly, M acG illivra y questioned the tra ditionalc on ce pt o f th e ra rity o f e pile ps y in D ow n's s yn dromea nd c la im ed th at th e n otio n th at D ow n's s yn dromeactual ly p ro te cted aga in st ep ile p sy was e rr oneous.These s tudi es , howeve r, we re based on sel ec ted andthe re fo re b iased populat ion samp les (MacG il li vr ay ,1967;Veal l, 1974;Tangye , 1979;Romano eta l , 1990;

P ue sch el c i a !, 1 99 1).Veall (1974) in his study of 1654 patients w ith

D ow n's s yn drome s howed a n in cre as ed p re va le nc eo f e pile ps y w ith in cre as in g a ge (1 .9% und er 2 0 y ea rsand 12.2% over 55 years). Veall a lso suggested a

b im od al d is trib utio n in th e a ge o f o ns et o f s eizu re s.These find ings were made possible due to theincreased life expectancy of people w ith D ow n'ss yn drome. C arte r & J an ca r (1 98 3) d emons tra te d a nin cr ease in lif e e xpec tancy o f 40 yea rs ove r the pe ri od1930â€”80.

A fu rth er c on se qu en ce o f th e in cre as ed lo ng ev ityhas been the increasing number of reports ofA lz he ime r's d is ea se i n p atie nts w ith Down's s yn

drome. S ince the early work of Jervis (1948),nume rous s tu die s hav e re po rte d th e a ss oc ia tio nbetweenDown 's syndromeand A lzhe imer 's d isease

(Olson & Shaw , 1969; W isniewski ci a!, 1985;O liv er & H olla nd , 1 98 6; Z igma n c i a !, 1 98 7; C ork ,

1990 ; E venhuis, 1 990). In a n e xtensive survey ofautopsy data for adults w ith Dow n's syndrom e,S chwebe r (1 98 9) fo un d th at b ra in n eu ro pa th olo gyo f A lz he im er's d is ea se w as u nive rs al in th ose a ge d37 and ove r. Seve ra lwo rker s have not ed tha t epile p syo f la te o ns et w as a sso cia te d w ith th e n eu ro pa th ological chan ges o f A lzheim er's disease (O lson &Shaw, 1 96 9;M in is ze k, 1 98 3;O liv er & H olla nd , 1 98 6;Lai & W illiams, 1 989; Ev enhu is , 1 990).The a im o f t he p resen t st udy was to es tab lish t he

prevalenceand the associatedfeaturesof epi lepsyinpersonsw i th a d iagnos iso f Down 's syndrome, aged19 years and over, residing within (com munityr es id en ts ) o r o rig in a tin g f rom ( hosp ita l i n- pa ti en ts )the Be lfas tca tchmentarea of the Eastern Hea lth and

Soc ia l Serv icesBoard , Northern I re land .

Method

T he selectio n c rite ria w ere a s fo llo ws:

52 8

Prevalence and Associated Features of Epilepsy in

Adults with Down's SyndromeR. W . M cVIC KER, 0. E. P. SHAN KS and A. J. M cC LELLAND

T he aim of this study w as to establish the prevalence of epilepsy in persons w ith D ow n'ssy nd rome ag ed 19 y ears a nd o ver. A to tal o f 1 91 a dults w ith D ow n's sy nd rome w ere id entifie d,giving a prevalence of 0.76/1000(95% Cl 0.75 to 0.77). Of these, 18 had epilepsy, givinga prevalence of 9.4% (95% Cl 5.3% to 13.5% ). The prevalence of epilepsy increased withage, reaching 46% in those over 50. T he neurophysiological (E EG ) findings of the epilepsygroup were compared with those of a control group of Down's syndrome adults w ithoutepilepsy. Paroxysm al abnorm alities consistent w ith a diagnosis o f epilepsy w ere found in 80%o f th e e pilep sy g ro up , comp ared w ith o nly 13% o f co ntro ls (P 'z O.OO l). E pilep sy o f late o ns etw as associated w ith diffuse E EG abnorm alities and clinical evidence of dem entia. T he aged is tr ib uti on a nd EEG fin din gs s ug ge st tw o in de pe nd en t p ro ce ss es i n t h e c au sa ti on o f e pi le ps y:late-onset epilepsy associated w ith clinical evidence of dem entia, and early-onset epilepsyin the absence of dementia.



52 9PILEPSYIN ADULTSWITH DOWN'SSYNDROME

5.3â€”l3.5Â°lo).hosewithepileps yereon aver age year so ld er t ha n t ho se w it ho ut ( P<0.OO l). Th e p re va le nc e o fe pi le ps y among t ho se l iv in g in t he c ommun it y was 6Â° lo ,comparedwith26%forthosein hospital(P<0.001). Theagedistributionftheepil epsyroup(n= 18,mean age44years) w as signific antly skew ed in com parison w ith that ofthenon-epilepsyroup(n= 173,mean age 35 years)(P< 0.001 )(Fi g.).Intho seund er50,theprevalen cefep ilep sy w as 7%, comp ared w ith 4 6% in th ose a ged 5 0 y ea rsand older(P<0.OOl ).

C lin ic al c ha ra cte ristic s o f e pile ps y

The reportedseizuretypewas generalisedtonic-clonicin17patients.wo in-patientsadanaveragefoneseizureper month, five had less than one seizure per month andtwo were seizure-free.hree of thoselivingn thecommunityhad lessthan one seizureper month,and sixwereseizure-free.nticonvulsantherapyasprescribedfor 15patients,14of whomwereon monotherapy.Sodiumvalp roate w as p rescrib ed for eigh t p atien ts an d w ascombinedwithphenytoinin one patient.Carbamazepinewas prescribedfor six patients.Regularmonitoringof serumantiÃ§onvulsantevelsas carriedutinmost patient s.

A ge of onset

I n two ( 11%) pat ie nt s e pi le ps y b eg an b ef or e 1 9 y ea rs o fage(childhoodpilepsy);neight45%)onsetasbetween20 and 29 years (youngadultonse t) , i n one at 36 years,in threebetween40 and49 years,in threebetween50 and59 yearsand in one at 63 years( late-onsetepilepsy).

Developmental regression

In thes ix adultswithepi lepsyundertheage of 35 years ,no developmentalregressionwas noted.Of the 12 adultswithepilepsyoverthea geof 35 years,eight(67%)showedclinical evidence of developm ental regression. The high

I

(a)diagnosisf Down's syndrome(thisas a clinic al d ia gnos is , a s i t w as not pos si ble t o c on firm th ed ia gno si s by chromosome analys is i n a ll c as es )

(b)age19yearsndo ver,.e.heageofcommencemen to f a tt endanc e a t adul t t ra in ing c en tr es

( c) r es iden ts f rom the Be lf as t c at chment a rea, w i th ane st ima ted adul t popu la ti on o f o ve r 250 000 .

In-pa tientsof MuckamoreAbbey Hospital , whosehomea dd re ss es w er e w it hin th e B elf as t c at chme nt a re a, w er e a ls oincluded. M uckam ore A bbey is the specialist m entalhandica phosp italervinghepopulatio nf theEast ernH ealth and S ocial S ervice s B oard. T he m edical file w as them ain source of the clinical and dem ographic data. E pilepsywas basedon clinicalvidencend was diagnos edfoneor more sei zu reshad occu rred duri ng the two yea rs p ri or

to thestudy,or ifthesubjectad been on regulara ntico nv ulsa nt th era py fo r se iz ures oc cu rrin g e arlie r.Electroencephalographic(EEG) evidence was sought in allcases to assist in the classification of seizures, using theInternational League Agains t Epi lepsy classi fica t ion of

seizureype(198 1).EGs werealsoeval uatedna groupo f 15 cont ro l subj ec tsw i thout epi lepsy , ma tched for age.

The mean ageoftheepilepsyroupatthetimeoftheEEGinvestigationas 40 years(range0â€ ”59),omparedwitha mean ageof43ye arsra nge1-65 )o rthecontrolroup.

Screening

Screenin gonsiste df identify ingdult swithDown'ssyndromettendingdultrainingentresithinhedefmedcatc hmen trea, nd usin gtheSocialervicesegisteroidentifyhosed ultsithDown'ssyndromenotattendingadulttrainingentres.ne oftheresearcheam(RMc V)reco rdedn a form theage,sex,placeof resi denc e,nddetails of the diagnosis of epilepsy: age at onset, type andfrequency of seizures, anti-epileptic drugs and EEGin ves tig atio ns . D ev elo pm en ta l reg res sio n w as n oted to b e

p re se nt if sig nif ic an t d ete rio ra tio n in th e su bje ct's c og nitiv eand behavioural skills had been observed during the tw oyears before the tim e of the study.

Results

Prevale ncef Down's syndrom e

The number of adults w ith a diagnosis of Down's syndromeinthepopulat iontudiedtotalumbe rof adul tsnthecatchme ntrea, 50000:see(c),b ove)was 191,givinga p re va le nc e r at e o f 0 .7 6 p er 1 00 0 ( 95 tVoC I 0 .7 5â € ”0 .7 7) :3 7Â ° loo ft he popu la ti on w it h Down 's s yn dr omewe re be tw e en l 9and29ye ars;33%werebetween30an d3 9years ;22%wereb etwee n40and49 yearsnd8% over50years.hereweresignificantdifferencesbetweentheage distributionof thesam pleliving in the community (n = 157, m ean age 33.5 years) and

t he h os pi ta l s ampl e (n = 3 4, m ea n a ge 5 4.5 y ea rs ) ( P< 0.OO l).

P re va le nc e o f e pi le ps y I n Down's s yn drom e

70

60

50

40

30

20

10

018â€”29 30â€”39 40-49 50â€”59 60-69

Age:years

E ig hte en a du lts w it h D own' s s yn dr om e s at is fie d th e c ri te riafor epilepsy, giving a prevalence rate of 9.4010 (95% C I

F ig . I Numbe rs o f Down 's s yn dr ome sub je ct sw i th and w it houte pile psy (@ n o e pile psy , â €¢ ¿pilepsy).



53 0 McV ICKER ET AL

prevalence of epilepsy in the 50 + age group has alreadybeen noted. Of the 15 adults over the age of 50,developm ental regression w as reported in all seven w ithepilepsy and in only one w ithout epilepsy (P=0.06).

N eu ro ph ys io lo gic al fin din gs

I nt eri ct al EEGs wer e o b ta in ed in 1 5 of t he 1 8 p at ie nts w it hepilepsy. T wo pa tients w ere uncoopera tiv e and one w as toofr ail to h av e a n E EG p er fo rm ed . P aro xy sm al a bn orma litie sconsistent with a diagnosis of epilepsy were noted in 12(80%)patientswithepilepsycomparedwithonlytwo(l3Â°bo)controls (sensitivity of 80Â°boand specificity of 87Sbo,P<0.O Ol). O f the 12 adults in the epilepsy group w ithp ar ox ysm al a bn orm alitie s, six sh ow ed a temp or al lo be f oc usand three showed a parietal lobe focus.

O f the 10 adults in the epilepsy group over 35 years, eight( 80 Â° lo )h ad d iff use a bn orm alitie s c on siste nt w ith a c lin ic ald ia gn os is o f d em en tia . S ix (7 5Â °b o) f th ese sh ow ed c lin ic alevidence of developm ental regression (P= 0.06). Of the 11adults in the control group over 35 years, only one (9% )s ho we d d iffu se a bn orm alitie s. N o su ch E EG a bn orma litie swere evident in those under 35 years in either the epilepsyorthecontrolroup.

Classification

A s reg ar ds cla ssific atio n o f s eizu re ty pe, th e clin ica l a ndE EG e vid en ce w as c on siste nt w ith p ar tia l se iz ure s e vo lv in gto se co nd ary g en er alise d s eiz ur es in th e m ajo rity o f p atie nts(ILAE, 1981). The type of epilepsy in one patient whoseseizures consisted of sudden falls, in whom the EEG wasnormal,was unclass ifiableILAE,1981).

Discussion

Th is is t he fir st r epor ted p re va lence s tudy o f epil ep syin D ow n's s yn drome b ase d o n a c ommun ity s am ple .T he p re va le nc e ra te o f D ow n's s yn drome in th e a du ltp op ula tio n o f 0 .7 6 p er 1 00 0 c ompare s w ell w ith th atreported by M allon ci a! (1991) and confirm s thereliability of the screening method. A num ber offa ct or s suggest t h at th e p re va lence r at e d id app ro xima te to fu ll a sc erta inmen t. F irs t, D ow n's s yn dromeis e as ily re co gn is ed a s a c au se o f m en ta l h an dic apand this has led to a high uptake of services, sucha s a tte nd an ce a t a du lt tra in in g c en tre s. S ec on d, th eS oc ia l S erv ic es R eg is te r w as u se d to id en tify th os efew adults w ith Down's syndrom e not attendingadult tra ining centres. Th ird, the pattern andde li ve ry o f hosp it al se rv ices fo r men ta ll y hand icappedpeople in the Ea stern H ealth a nd S ocia l S ervicesB oa rd is such tha t persons w ith D ow n's syn drom efrom the Belfast catchment area who require

specialist hospital care would be adm itted toMuckamo re Abbey Hosp ita l. T he in cr eased l ongev it yin D ow n's s yn drome is d em on stra te d in th is s tu dy ,w ith a significan t pe rcen tage (30% ) o f adults n owliving beyond the age of 40.

T he p re va le nc e o f e pile ps y in a du lts w ith D ow n'ssyndrome was 9.4% , and, based on the EEGe vidence, the epilepsy w as o f partial type in m ostca se s (ILA E, 1 98 1). T his stud y sh ow s tha t theprevalence of epilepsy increased with age, beingparticularly high (46% ) in those over the age of 50years. It was also h igher (26% ) am ong hospitali n-pa ti en ts . Wh il e hosp it al i n-pa ti en ts were general lyolder than community patients, ne ither age nore pile ps y a cc ou nte d fo r th e re aso n fo r a dm iss io n toh os pita l. T wo p atie nts h ad b ee n a dm itte d fo r c le arm ed ical reasons in the previo us 12 m onths, bothw om en in their S Osw ith a dia gnosis of dem entia.T he o th er s ev en h ad b ee n in -p atie nts fo r a n a ve ra geo f 2 0 y ea rs (ra ng e 1 1â €”3 7),w hose age at the tim e ofa dm is sio n w as o n a ve ra ge 3 1 y ea rs (ra ng e 1 1â €”4 8).T he ma jo rity o f th es ew e re a dm itte d b ec au se c are rsw ere u na ble to c op e fo r v ario us re as on s, in clu din gsever e behaviour p roblems.

T he m anifestations of an epileptic seizure m ayinclu de com plex a bnorm alities of behaviour andsubjec ti ve expe ri ence (Fen ton , 1986) . The d iagnos isa nd c la ss ific atio n o f e pile ps y c an th ere fo re b e mo red iffic ult in th e m en ta lly h an dic ap pe d p op ula tio n,g iv en t he lim it ed cogni tiv e and communicat io n ski lls .A lth ou gh th e EEG was n ot in clu de d in th e d ia gn os ticc rite ria fo r e pile ps y in o ur s tu dy , th e h ig h s en sitiv ity( 80Â°o )and speci fic ity ( 87Â°o )r at es o f par oxysmala bn orma litie s s ug ge sts t ha t th e in te ric ta l E EG has ause fu l r ol e i n a ss is tin g w it h t he d iagnosis o f ep ile psy.

Thi s s tudy has a lso demonstr at ed t he impo rtan ceo f th e EEG in a ss is tin g in th e c la ss ific atio n o f s eiz urety pe . N in e (7 5% ) o f th e 1 2 p atie nts w ith p aro xy sma la bn orma litie s o n EEG showed a tempo ra l o r p arie ta llobe focus, inde penden t of age or dem en tia . Thisco ntrasts w ith the findin gs of Tan gye (197 9), w horep orted no localising features on E EG in 13 casesof epilepsy. W e have taken the EEG evidence tos up po rt a d ia gn os is o f p artia l e pile ps y in a ll 1 2 c as esw ith EEG abn orma litie s. We h av e fo un d n o e vid en ceo f p rima ry gene ra lis ed epil ep sy in t his ser ie s. Takentogethe r w ith the d is tr ib u ti on o f age o f onset â€ ”a llb uttw o w ith a du lt o ns etâ €”th e fin din gs from th e p re se ntstu dy su gg es t t ha t e pile ps y in D ow n's s yn drome iso f th e p artia l ty pe , w ith s ec on da ry g en era lis atio n.

T he s eizu re fre qu en cy o bs erv ed in o ur s am ple o fadults w ith Down's syndrome is less than thatre po rte d in th e men ta lly h an dic ap pe d p op ula tio n ing en era l. F ors gre n c i a !, in a stu dy o f th e p re va le nc eof e pilepsy in 29 9 m enta lly retarded ch ildren and

adults in a large Swedish com munity, reportedth at 3 2% had b ee n s eiz ure -fre e d urin g th e p re vio usy ea r; 3 1Â °oh ad h ad le ss th an 1 s eiz ure p er m on th ;and 27% had daily to weekly seizures (Forsgrenci a!, 1990).



53 1PILEPSYIN ADULTSWITH DOWN'SSYNDROME

Fou rte en o f t he 1 5 p at ie nts r ec ei vin g a nt i- ep il ep ti cdrugs were on monotherapy. In contrast to thecommunity group, w ho w ere treated w ith carba

mazepine in most cases , al l seven hospital in-patientson an ti-epileptic d rugs w ere receiving sodiumvalproate, know n for its greater efficacy in absencese iz ure s. G iv en th at th e m ajo rity o f o ur p atie nts h adpartial seizures, carbam azepine m ay be a m oree ffe ctiv e firs t-lin e tre atm en t (Mattso n e t a !, 1 99 2).The age d is tr ibu tion o f ons et o f epile ps y showed

an early p eak in the third decade, w ith on ly on ep atie nt w ith a n onse t o f e pile ps y in th e 3 0â €” 44g erange. A second peak in the age of onset wasobs erved in the f if th and s ix th decades . Wh il e t he sefig ur es su gg es t a b imodal d istr ib utio n, th e sma llsample size does not permit a firm conclusion to be

d rawn . In a r ec en t s tu dy o f se iz ur e d is or de r in 4 05people w it h Down 's s yndrome, age range 6 monthst o 45 years , Pues chel e ta ! ( 1991 ) found a c le ar peakin a ge o f o nset o f seizu res b etw een 2 0 a nd 30 ye arso f a ge, w hich is co nsisten t w ith o ur fm din gs. T hesame authors also reported that few seizuresdeve loped aft er theage of 1 year and before 19years .T he s tr on ge st e vid en ce fo r th e e xiste nc e o f tw o

subgroups, how ever, em erges from both the E EGfmdings and the coex is tence , or absence , o f deve lopment al r eg re ss ion w it h epil ep sy . O f the 18 pat ient sw ith ep ilep sy, eig ht sh ow ed clin ica l ev id en ce o fdement ia . The mean age o f on se t o f s eizur es i n t ho sew it h dementi awas46 years , c ompared t o a mean ageof onset of 26 years in those w ithout dementia(P= 0 .002) . S im i la rl y, o f the 15pa t ien ts wi th ep il ep syin ve stig ate d b y EEG , e ig ht sh ow ed d iffu se a bnormal it ies ,cons is tentwith a diagnosisof dementia .The

mean ag e o f o nset o f seizu res in tho se w ith d iffusea bn orm alitie s w as 4 2 y ea rs, c ompa re d to a m ea n a geof onset of 28 years in those w ithout diffusea bn orm alitie s (P = 0 .0 2). H en ce bo th c lin ic al e vid enc eo f d em en tia, a nd d iffu se ab no rm alities o n EEG ,were a ss oc ia ted w it h epileps y o f la te ons et .

S ev era l fm din gs in th e p res en t stu dy su gge sted th att he a ss oc ia tion between epil ep sy and dementi a wasn ot sp uriou s. F irst, un like th e ep ilep sy g rou p, th econ trol grou p of adu lts w ith D ow n's syn drom ew ith ou t e pile ps y d id n ot s how c lin ic al e vid en ce o fdement ia w it h i nc reas ing age . S econd , t he re was are la ti ve absence of d if fuse EEG abnormali ti es in thec on tr ol g ro up c ompar ed w ith th e e pile ps y g ro up .Third , c li ni ca l ev idence of dementi a, observed only

in th ose ov er 35 yea rs, w as muc h more lik ely to b eassociated with epilepsy of late onset. Recentp ro sp ec tiv e s tu die s h av e c on firmed th e h ig h p ercentage (80% ) of D ow n's syn drom e adu lts w ithd emen tia who d ev elo p e pile psy (L ai & William s,1 989 ; E ven hu is, 1 990 ). T his is in co ntra st to th e

l0% prevalence of epilepsy in autopsy-provenA lzheim er's disease w ithout D ow n's syndrom e(H auser et a!, 1986).

The fmdingsprovideevidence for two dist inctaet io lo gic al p ro cess es fo r e pilep sy in D ow n's s yn drome .L ate-onset epilepsy is associated w ith neuronaldegeneration consistent w ith A lzheim er's disease.Ear ly -o ns et e pile ps y is r ela te d to a no th er , a s y etun kn ow n, p hy sio lo gic al a bno rm ality asso cia te d w iththe developm ent of an epileptic focus. Furtherprospective longitudinal studies are required toe luc idate poss ib le pred ic ti ve fac tors in the deve lopment of ep il epsy, t o e stab li sh the charact er is ti cs o fth e e ar ly -o ns et a nd th e la te -o nse t g ro up s, a nd toclarify the re latio nsh ip be tw een la te -o nse t ep ile ps yand Alzheimer 's d is ease .

Acknowledgements

We areindebtedoDrsG.J .Calvert,.M.MarriottndM.GA.McGi nn it y f or p ermi ss io n to s tu dy th ei r p at ie nt s. W e wou ld l ik eto thankthe staffof the adulttrainingcentres,Belfast,the nursingstaff at M uckam ore Abbey Hospital and the staff of the ClinicalNeurophy si ol ogy Un it , Depa rtmen t o f Ment al Heal th , Be lf as t C it yH osp ita l, fo r th eir c oo per atio n. W e a re g ra tef ul to D r I. B an kh ea d,Depa rtmen t o f P sy ch ol og y, Mu ck amore Abbe y Ho sp it al , a ndDr C . Pa tt er so n, Depa rtmen t o f Publ ic Heal th , Queen' s Un iv e rs it y,Belfast , fo r advice on s ta ti st ics .We are ob liged to Mrs D. McFetr idgefor typingthe scrip t.

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5R. W . McVicker, MRCPsych, MRCGP, DRCOG, Consultant Psychiatrist; 0. E. P. Shanks, FRCPsych, MRCP,DCH, Consultant Psychiatrist, Muckamore Abbey Hospital, 1 Abbey Road, Muckamore, Antrim

B T4J 4SH ; R . J. M cC lelland, F RC Psych,M D, P hD , D IC , P rofessor of M ental H ealth, T he Q ueen's U niversityof Belfast, The Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL

*Correspondence

(F irst received November 1991, final revision May 1993, accepted June 1993)

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Br J Psychiatry 1994; p528