1961 The N ew England otained t 10h ilJ be Journal of Medicine

Copyright ]961 by th e Massacbuscns Medical Society

Volume 265 lsp ital merl y Irorn

n 15

Riiexcl0cJc

OCTonER 26 1961 Number 17

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

EDWARD P RrCHARDs oN JR MmiddotDt

BOSTON e a nd

~fassa INthe course of th e regular post-mort em examina shyfi~rnj tion of the bra ins of pa tien ts com ing to a utopsy

a t the M assachusetts General H ospit al m y atten tionllrncr l

has been ca lled in recen t years to an unu sual disord er l~ tOrt

of the cerebral white matter with distinctive feat ur es iston

uniacuteamiliar to me and my col1eagues from our ow n NclV

experience al th at of others We report ed 3 such le of cases in 19581 and ca lled the condition progressive l (1 multifocal leukoen cephalopathy to em ph asize th e -I5Sltl ~ outstanding ciinicopathological features Sinc e th ese -Icn 3 cases and 3 of th e 5 others prev iously report ed nu were associa ted eithe r with lym phati c leukemia 01

in with H odgkins d isease we considcred the disorder S(p

to be a hitherto unrecognized com plica tion of th ese lit diseases al tho ugh we realiacutezed th at it might occashy

in sionally occur unde r other con ditions We were un shygi n able to offel any suggestions abou t its cause Since hial then our experience with it has been considerably22 auc broadened by the acq uisition of ne w material so that

OUl pr evious staternents now r equire sorne m odifica shynon

ork

ia shy

ec G vE REPoRTS

lit CASE 1t (M G H 0 1-72- 58 autopsy 16159 ) A 71 shy0 year-oid wom an had had chronic lym phatic leukernia for

16 yea rs Abo ut 4 months bef ore death a grad ua lly pro shyIG iacutelessive lef Hided hemiparesis ap peared followed by insidi shygc ousy deve loping disori en tation con fm ion and blindness

and te rm inal1y h em ip ar esis on the right side On repea ted ~c I lumbar punc tu res the cereb ros pin al fluid was norm al in aH

respects excep t for 25 Iymphocyt es pe r cub ic millimet er inre a samp le taken sho rtly befor e deathV Post-mor tcm exani nation confi rmed the diagn osis of

1-I ch ronic lyrnph at ic letikcm ia In the bra in therc wer e exshy

tensive dem yelinat ive lesions of the white matte r of th e cerebral h emi sph er es wh ich on the righ t ex tende d fr omI tbe occip i ta l to tb e fr ontal pole and on th e left we re con shy

j fined to th e occipi tal lobeo T he dee p struc ture s of the I brain an d the cerebe llurn and brain stem were fr ee of Jeshy

sions M icr oscopical1y lh e patholo gic p roce ss wa s characte r shyized by lhe occurrence of innum er able mi nu te foci up to

From the Charles S K ubi k Laborat o ry [o r Neuropatbology o[ lh e am c~ H omc r V rjghr P3thology Labo()lOr jcs ~la~saclHLi e[[s General l -fo s[) lt l a nd the D cpartme nt oiacute N cu ropathologymiddot1ieurology H ar van1 ~( e cl i cal School (This paper is b3sed upon a th csili su1Jmi tlcd in ap plimiddot calion iacuteo r a tlm ~sion to mem bcrship in th c American Ne urological AssoshyClatl on )

tA~ lStan t pro Iacutec i50r ncuropa tho loglgtt a nd plt J(

Ca scs 2 and 3 ~um ma ri led he le for

of neu ropathologyl H a r 8rd ldedical Scho ol associare neuroogis t JvI assac hu~us Ge ne ra l H osmiddot

ere those p revlously rep oned 1 T ile) ate b r ieAy the sak e or comp~ e (e lles 5

abo ut 1 mm in di arneter th a t coa lesced to form th e largc rnacroscoplc lesion s Within th e lesions mvelin shea ths were abs ent and there wer e nurn erous rnacrophages contai n ing the in tcn sely suda nophilic lipid dropl ets tvp ical uf mveliri breakdown Axi s cy lin der s were relatively spare d tbus th e p rocess m ay accu ra tely be eal led d em yelina tive In many of the lesions th er e were dense acc um nla tions of lvrnph ocytes in t he pe rivascula r spaces In addition to th ese find ings which are cornmon ly observe d in d cm yelin a tivc lesions the re were cer tain wh oll y unf amiliar cell ch an ges In th e first pl ace many of the astrocytes in th e lar ger lesion s were gigan tic in size wi th irregular or multipl e nuelei con ta ini ng dense masses of ch ro rnatin and occasional lv mi toses sorne of which were mu ltipo la r Secondly a l the pe rip he ry of the lesiona ther e were numerou s srnaller cels with round de nse shyly basophilic nu clei th at often co n ta ined eosinop hilic inshyclusions Yle id en tified th ese ce lls as oligodend rocv tes an d conside red th at they wer e un dergoing an alteration not pre shyvio usly desc ribe d

CASE 2 (MGH 9 1-2 1-38 aut opsy 1902 4) A 73-year shyold wo man had had chronic lym ph atic leu kernia for 5 vears Four m onths befor e -d ea th she bec ame irri ta ble and deshypr essed an d cornp lai ned of d ifficu l ty in conce ntra ti ng In th e en suing months a p rogre ssiacutevc right-sided h emiparesis and aphas ia developed fol1owed by a hom on vm ou s hemianop sia on tlie righ t side and even tua lly blind ness ancl complete de rnentia The most significan t find ing am ong the numero us labora torv investigations was a norm al ce relirospin al fluid

Post- m ortero examina tion showed widespread ch an ges ryp ical of chron ic lym ph a tic leukem ia In th e bra in the re wer e m ul tiple bila teral lesion s of th e same charac ter as in Case 1 In th e p resen t case they were par ticularlv numershyous in th e deep laver s of the cortex and the subcortica l whi te m atter T he cent ral nucJ ei of the cereb ra l hern ispheres as well as rhe b ra in stern and eerebellum conta ined many le sion s an d th er e wa s a la rge conflue nt focus (wh ere the di sshyease a ppeare d to be farlhest advance d) in the iexclefl pa rietal region Gigantic astrocytes (bu t Withou t m itoses) an d the d ist in c tive alter ation of oligodend rocytes were ab undan tly evident There we re no pe rivascula r lymphocyt ic in filtrations Alt hough th e granule-ce l layer of th e ee rebellar cortex showed poor preserva tion of cel slruclure as a result of ei ther termin al or pos t-morlem changes recent review of th e sections has shown iu this laycr a remarkable er tologic a lterashytion th at wa s firs t recogn ized in Case 8 ancl is des cribed with lhe pos t-rno rtem find ings in thal case

CASE 3sect (Emory U nivers ity H ospital Case 6 1-7uuml7U autopsy A54-155 M G H Ne u ropath L ab ac c n o X - 165 ) A 42 -yea r-old man was found to ha ve H odgk ins d isease about 10 months befo re death I n the Ja st 3 monlhs of Jife p rogressive ap has ia and righ tmiddotsided wea kncss develop ed folmiddot lowed by confusion and fin a lly coma O n pos lmiddotmorlCm exam in a tion chan ges typical of H od gkin s dj sease were found in m any organs I n lhe whi te ma lt er of bo th cereo bral he misp her es there were numero u lesions most abun shy

sectR ep r tcd thr0ugh lthe courty o iacute Dl~ Herbcrt R Ka rp lValt er H Shcid orr-an d H e jnZ Ba uer Emor-y Univcrsiiexcly Schoof 01 1I1cdici Jlc G eorgi

~bull

el oacute T HE lE ENGL~D j O U R i-L OF il ED1C INE (J I 26 1lb 1

dant In (hmiddot lef t pariet a l regi oacuten I1icro seop ie all y thc v wcrc idcu t ica l o (hose in C ases 1 an d 2 although gi an t ascror yresiacute

linIO ra rc Thc rc werc 110 pcrivasc ula r Iympho cvt ic infi lshyuraquo LJ (~ Il ~

C ~ E ~ (ll G ll 1I110PY 2 15)0) A l5-car-old rail shymiddotoa d man r arne- lO medica a u eri uon in D cr ern b cr 1~iexcl~ 5 beshylaquoausc of Iever anci uucx plain ed anemia A srcr nal-ma rro w Iiiopsy showerl chronic mvelogcnous lc ukern ia H e wa s adshymitted o n numcrcus O( casio ns to the E rnc rson H osp i tal beshycause of Iever aud anemia and was rcp ca t ed v Iound to have pnr-umonia T rca trncn t consisicd of t ransfusions anri shybiotics a n d at va rio us times busull a n r a nd pred nis one Thcre had bcen no ne urologic abnorrnal ir ies un til mi dshySep tc mber 195 8 w he n morn ing co n iacuteusion and slurring oiacute spccch wi rh asymmet ry of the Ia ce a nd wekncss of t he left a rm a n d leg su ddenlv ap p ca rcd He be came cmorio n shyl1y labi le to a n increasing d cgrce wi rh sil liness in appro shyp i i atc Iaughte r lt1nd so rne tea rfulncss a nd di ed in coma on j an uarv JI 1959

Posl-m or trm aminalion show ed in creascd re ll ula r iTV of he bon c m arrow w i lh a pred om in a n ce ol my eloi d e lem~n t s chiexclril eters tic 01 ch ron ic my elogenous lc uk emi a I n tl1C b raiacuten rn u l lipe cSiOJl5 gener a Jly 1 lo 3 mm in d ia mcier bu t with SODW larlaquoer conrJ uenl Ioe i we rc preseot in t he ubc o rtical w hite maller an d d eep cortical lay e n in th e rig ht lron topariel al regi on T he re were a [e w sim ila r le shysions in Ihe le ft cerebral hemispher( a nd in lh e rni dbrai n Microscop1call y iexclbese were 01 the same m ultifocal de m yeshylinatve ch ara cte r as in the p re vio us case s Ciant as tmshycytes however were ab sent an d a lte red oligodendroey te s w e re sca ree Per ivase u iar lym p hoc )tic infi l trat io n w ithin 01 acljacent lo iexclhe Ic sio ns was [r eq ue n t ancJ th is case wa s llni qll e in tha t many sca tte re d p la sm a cells were loca ted wi lh jo lhe lesions

CA~ E 5i ( R oy a l Penh H osp il al a utopsy -59270) A 4middot9-yea Imiddot-old m a n was seen in n eu rolog ic eonsulteacuteltlo n beshyeause of wcaknegts of t he righ t a nn of ab o u t 6 weeks d ura shytio n Sorne 2 y~ yea r s previously he had been fo un d to nave sp le nomega ly a nd wiacuted espread lymphad en op a th y biopsy oC a ce rvica l Iymph nod e diacutesclosed Iym p hosa r com a Subse shyquen lly he was given radiation the rap y wilh a n exce llent c lin ica l r eult A rela pse oc curred 6 months before iexclh e fin a l a dmission Ior which he w as t re al ed firs t w it h ni tro e n IDustard eacutelnd lhe n be eaus e oC ev id ence oC h emol yuacutes ilh p redn iso lone T here wa s a sa tisfac to ry resp oo se to 1hi~ re~ishyn len A re cunence of anemia 2 mon ths la ter was tre a t~ d it h [u n he r rad ia tion th e ra p y to iexclhe spleen and transfu shysions Shor-tly a ft e rwal d we akness of t he r igh t a lm a p shyp ea r ed On neurolo g-ic examin a rion 6 wec ks later he was vmiddotague in g ivi ng his h istory and he ve ere d lo explicablv [m m apprehensive depression lo ina pprop ri~t e j ocula ri ly middot H e waS ho we ve r full y oti ented and co-o p er a ti ve T h er e was fla tten in g of lhe righ t naso la b ial fol d a nd seve re flaecid wea kness of th e rig h t arm w i l h o ut sensory ehan(es T b e tendon leflex es were d ec rea sed in th e riacute ght a rrn but b risk elsewhe re the p lantar re flex es we re norm a l T h e ce re b roshyspinal fluid was normal in a 1l r esp eets His s tate grad uall y dere rio ratecl W i hin 3 we e ks a lter th e in itiacuteal n eurolog ic consu l tatio n lhe weakness o [ lh e r ight arro h a d become spas tie w i th exaggerated re flexeacutes R epli es 10 sem o r y ex shyamiacutenation we (e unreliable T esting sh owed d e [ee ts in m em shyo1y a nd j udgrne m an d in ea icu la li ng abitit y An e lec tro shyc nceph alog larn was d i1Tusely a lm orrn al w ith sornewha t more p ro n()uneed changes on th e le ft Dysarth ria a n d a n obvio us iphasia thCll d evc1ope d H e di ed about 3 mon ths a f ter the cnser 01 thc neurolog ic ill ness

Pos t-m o rte m exami na tion sho wed seve re ri g h l-upper- Iobe pneu mon ia T he re was li tt le g ross evidence oI Iym p hom a b u t ir was fou nd microscop jcally in the liv er sp leen p a ra shyao rt1c ly mph nod es and bone ma rrow Neuro pathulogical e x amlI1al~On dis ciosec1 m u lti pl e bil ale ra l d e myel i n aiexcli~middote le shy

~l ~~I JI IJl(hbtc J (O lile palltll ts phls~clall D I L P l-1CJ uck Co ncord ~b S ~ Kh ll Cl1 S Jm1 l h c l (c1 lCa ReCQ rd~ Oep rtltlent C rne rso tl HO I ~ l l a l COllcord ~ 111) Il-ldc h t dll1 ical nol cs ln i b l5 ca se avaiacutelabl c

I n lbe ( ~n ~ uf i1ylern ll urroughs Ve llcom e 3 11d C o mp HlY T uck shydwc Ncw 1or h

1 a rA) llldeu[u lO D r l cr cy SaJj~l rJLurnJuumlglc cons ultant lO th~

Departmell oI MedIcine VnleiSltv u Vcslcrn Aust ralia Pcn h -V i fQ I lbc cllfllcaI nd patholog1ltill findll ~gs lt l t his case as ell as g en~ngtus dSJc)nm erl of excelleacuten t 3tamcd scctlons of the bra ~ n

sions in t h e d cc p co rncal 1CImiddot ancl in ih c suh Il ica l hIte mat re1 ge ne rallv hout I ro ) nun 1 d 13nl e ln iJUI with ru many i co nfiue n t [OCI most n urnc rous ID tlw fron la l and 11 p arie ta l l ob e ~ A le w mall iesrons wcre p l~~I gtl in ih c (~I)_ iexcli ) tra l nU C C1 of ihe cerebra l nCIl1rSf he res thr rr wcre nouo in t he cercbcl lu rn brain srem O ( spin al cl)ld ivficr c scn j) callshy

1 Th I t I1f Icsions wcr e rypu a e ( l a r) CtllJitJC aliluioll 01

oliaodend rocy rcs as C~ ~lSpllUOUS man- (r tl( arrc-flecl cc lls onlallcd eosulOphl lllt in tran urle ar l1clu011S Thc-iexcl er e i req ueu t g iexclg-an t~c astro vres P ( l l a ~ ( [llar 1~middot1lIphocvt) infilr rat ions wc re alisen t lo

L CAS] 6sect ( V A H Porrla rid 0 rl - o n a lp ~ ) )() ~fiacuteG e

fIP ar c no 31 J j 70 i C E l(urop3Ih L3h acc nmiddot h X-2~7)~ A 31-year- oJd m anwas Iound in ICJ 49 ro hav e a n r~edl a S lJ nd l mass OH il rc)Ull ~le su rvev fil oiacute lhr- r hest 111

Iliop sv 01 a n en larged supracla vir ular l- mph noclc in 19)0 p l we d H od g k in s di sc ase D U J in the ncxt 1- CIo he reshy 111 ceived gr ade d rad ia rio n t ne rapv 10 mul iiplc visce ral sit es 1 B ric f courses of ni trogr-n mus tard t rca lmclIl WC I~ iven in (

April 1955 and Apri l 1956 folloyed OTl cae h laquoccasion 1middot o) a dec rcIse i n tIJe size of Ihe tumor m asscs I n M al 1956 rle h e complained o [ b lu rrccJ n ion Ex a m im11iacuteon howeciexcl h om o nymous blindncss in the riht JOW T q Ll l r1 ra ll t thill IEl ICr p ro g~cssed u nd cr oh se n a tio l1 lO a om p k c homonyshymOll S hemlan opsla on the ngh sde 1 herc was ale a l igh t-sid ed hem ip ares is mos t pronounccd in t he fate T n e III

~ la n tar re flex was bil a tcr a Jly ex tenso r lllore stroncmiddot j) on Ihe 1 Ilgh t Lumbar punelure showccl a no rmal p lC su tc md a ce re brosp inal-Dllid prolein of 22 mg pcr 100 m Al ccCshy w t1middotoeneep haJog ram d isc losecl a bilatultt occip ta l do~ - wavc T ab no rmaliacute ty Soon aIterwar d le fL-sid ed el elJCllar a l ltt~ i a 01

g ra d ualy d eve lope9 a nd he De Cante b lin cl -- wi th no rm al o p rie d isks and pupi ls t h a reacted Il ggishty LO limiddotl ] n

1uly ancl iugUS( 1956 radiatio n therapy wa gnmiddotcll to lhe occip it a r egions b ilate r a lly A pn e u m oe nce jJhalo~r arn d onc at th is tim e sho wed a su ggestion of 8 g r ea te r l-)iquestn ) Ilonna l amou n l of ai r ov er the o ~cipila l l obe~ B is condi lill dcmiddot cJined in a l r esp ects Terrn inally genelaliacuteze d n ic1cs lyp ishy

lc a l oC he rpes zosle r 8 p p eared H e c1iacutecd n l1 D ~ c nhcr 18 195 6 ti

P ost -m ortem examinati on sh owe d w iclbpl cad imolvcshy men t oI ly m ph node s and visc e ra by H o dg k in s c-alorna I n t h e brain t he re were ex te ns ive lcsi ons oC iexclOl h Cltelir l ti hemispher es espe ci a lly io the pos te1middotior paris ol1lew ha t mOre 00 th e l eiacute t h isto iogica lly of lh e same charlner as in tith e o th er cases N o g ia n t a str o cy tes were fOllnd ho wec r There we re a Ccw sca tl e red p e rivasc uJa r Jymphoctic inmiddot iexcliexcl

lil tr a tions

CA SE 7~ ( M C H 02-2 2-7 5 au to p sy 9-17f1) 11 82shyyea r -old man had b een freq u en tl y seen a t lhe ) 1assachusclts G eneral H osp ital sin ee 19 22 m a iacuten ly becal1se of h)pcr lensjon ( b loo d pressure oI 190 I 00) c h ron ic eo n gcslyp leart CaiJshyu re a n d angina p cctor is Wiacuteth limitaiexcl ion of 3ct ivi tics d igi shylalis n itlOgJy ce rin and carefu l di c ta r) rqulaiexclion he reshymained fo r ye ars r ela ti vely u n tro u b led by hi s ill ncss es a nc n worke d regula rly I r a bo u t m id- ]anuary J 940 f riends noshy 1)t ic ed lha t he b a d beeome rnentall y sIowe r th1 before and tha his sp eech was slu r re d O n thei r a d vie lle cnter(d lit hospital on F ebru a ry 2 19 1O Ex am na iexcl- ion sho wed m c1 conges ljve hear t Ia il u re Neuro log jca lly he was rcspo l1SlVC a nd co -operativc bu t speee h w as slu r rc d a n d th er e was somc slighiexcl wca k ne ss I iexclhe Id i side of Ih e b( c un d tong-lle T e nd o n re flexes we re re la ti vel y more a~ t l ve III Ihe lefl arm Ih an els ewhe re bu i no o th e r a bno1nu l neurulogic findi n(s J Vere d ese riexclb ed R o n till e a dmission b loo d ex a m ina I ivm ga e n ormal re su l is He SOOll be earne frIacuteJrile his ~cn Cral slale wors ene d a nd h e d ied on February 15

Po s t~ mon en 1 exanUumlIl aUuml QrJ sllowe d seve-e CO I0nll) a lheroshysde rosis Vi th aeu te rhrombosis and hcalcd myor ardla in shy[arc rion to ge the r wi iexclh Elcu tC bronchop nc u m on ia and hcaed apical p ulm on ar- ll1berfu losJ~ lhelc V l- n rjt h l n l~ to sug -

SI a m lndcfJllu tQ DI J J I JHS middotlJtjn D ] I ~ I O tl (Ir C I I l p l)IIICJr

uacute ty o[ Orcgoll fvcd iCeacutell School D r J ~nH ~ t r Losij chimiddotf oiacute L lhuriexclwnshyScnmiddotlce i c llt ra Jb Altl ~U u l1~ ([llonmiddot HopitL Pn-tbl ld O ng l ll l[c1 Colollel F ra nk ~I T Ovnscncl dr cctor and Dr Veob fiexclyJT1 l kfr lt- h ld Teurop athol ogy Sec lion Ar rncd F orces In( llIIC o[ P~l t h vl () gy Wbl un gshyton D C icJ p c r m issiorl t O pub ljh this CI~ C lI H fm cl ill iexclr tl 1I0 1lS and palho loglcal m aacutetCriaJ genc1Qusly p l ac~ cl nt 1lI) di -I H1 sa l ~Th i ~ casr J-llch liad beco ciasifiexcltd c O lliexcl ~ -hl Jiri- (pe ulHJcll l shy

ntlll(d was rCCllJtlydiscovcrcd by ch a llCt i n t n v i o f (lllll J)llLtQshy

~~upJctl ma lcna l 111 the D epa n UHn f fiexcllt~

- s111__IIL middot

el oacute T HE lE ENGL~D j O U R i-L OF il ED1C INE (J I 26 1lb 1

dant In (hmiddot lef t pariet a l regi oacuten I1icro seop ie all y thc v wcrc idcu t ica l o (hose in C ases 1 an d 2 although gi an t ascror yresiacute

linIO ra rc Thc rc werc 110 pcrivasc ula r Iympho cvt ic infi lshyuraquo LJ (~ Il ~

C ~ E ~ (ll G ll 1I110PY 2 15)0) A l5-car-old rail shymiddotoa d man r arne- lO medica a u eri uon in D cr ern b cr 1~iexcl~ 5 beshylaquoausc of Iever anci uucx plain ed anemia A srcr nal-ma rro w Iiiopsy showerl chronic mvelogcnous lc ukern ia H e wa s adshymitted o n numcrcus O( casio ns to the E rnc rson H osp i tal beshycause of Iever aud anemia and was rcp ca t ed v Iound to have pnr-umonia T rca trncn t consisicd of t ransfusions anri shybiotics a n d at va rio us times busull a n r a nd pred nis one Thcre had bcen no ne urologic abnorrnal ir ies un til mi dshySep tc mber 195 8 w he n morn ing co n iacuteusion and slurring oiacute spccch wi rh asymmet ry of the Ia ce a nd wekncss of t he left a rm a n d leg su ddenlv ap p ca rcd He be came cmorio n shyl1y labi le to a n increasing d cgrce wi rh sil liness in appro shyp i i atc Iaughte r lt1nd so rne tea rfulncss a nd di ed in coma on j an uarv JI 1959

Posl-m or trm aminalion show ed in creascd re ll ula r iTV of he bon c m arrow w i lh a pred om in a n ce ol my eloi d e lem~n t s chiexclril eters tic 01 ch ron ic my elogenous lc uk emi a I n tl1C b raiacuten rn u l lipe cSiOJl5 gener a Jly 1 lo 3 mm in d ia mcier bu t with SODW larlaquoer conrJ uenl Ioe i we rc preseot in t he ubc o rtical w hite maller an d d eep cortical lay e n in th e rig ht lron topariel al regi on T he re were a [e w sim ila r le shysions in Ihe le ft cerebral hemispher( a nd in lh e rni dbrai n Microscop1call y iexclbese were 01 the same m ultifocal de m yeshylinatve ch ara cte r as in the p re vio us case s Ciant as tmshycytes however were ab sent an d a lte red oligodendroey te s w e re sca ree Per ivase u iar lym p hoc )tic infi l trat io n w ithin 01 acljacent lo iexclhe Ic sio ns was [r eq ue n t ancJ th is case wa s llni qll e in tha t many sca tte re d p la sm a cells were loca ted wi lh jo lhe lesions

CA~ E 5i ( R oy a l Penh H osp il al a utopsy -59270) A 4middot9-yea Imiddot-old m a n was seen in n eu rolog ic eonsulteacuteltlo n beshyeause of wcaknegts of t he righ t a nn of ab o u t 6 weeks d ura shytio n Sorne 2 y~ yea r s previously he had been fo un d to nave sp le nomega ly a nd wiacuted espread lymphad en op a th y biopsy oC a ce rvica l Iymph nod e diacutesclosed Iym p hosa r com a Subse shyquen lly he was given radiation the rap y wilh a n exce llent c lin ica l r eult A rela pse oc curred 6 months before iexclh e fin a l a dmission Ior which he w as t re al ed firs t w it h ni tro e n IDustard eacutelnd lhe n be eaus e oC ev id ence oC h emol yuacutes ilh p redn iso lone T here wa s a sa tisfac to ry resp oo se to 1hi~ re~ishyn len A re cunence of anemia 2 mon ths la ter was tre a t~ d it h [u n he r rad ia tion th e ra p y to iexclhe spleen and transfu shysions Shor-tly a ft e rwal d we akness of t he r igh t a lm a p shyp ea r ed On neurolo g-ic examin a rion 6 wec ks later he was vmiddotague in g ivi ng his h istory and he ve ere d lo explicablv [m m apprehensive depression lo ina pprop ri~t e j ocula ri ly middot H e waS ho we ve r full y oti ented and co-o p er a ti ve T h er e was fla tten in g of lhe righ t naso la b ial fol d a nd seve re flaecid wea kness of th e rig h t arm w i l h o ut sensory ehan(es T b e tendon leflex es were d ec rea sed in th e riacute ght a rrn but b risk elsewhe re the p lantar re flex es we re norm a l T h e ce re b roshyspinal fluid was normal in a 1l r esp eets His s tate grad uall y dere rio ratecl W i hin 3 we e ks a lter th e in itiacuteal n eurolog ic consu l tatio n lhe weakness o [ lh e r ight arro h a d become spas tie w i th exaggerated re flexeacutes R epli es 10 sem o r y ex shyamiacutenation we (e unreliable T esting sh owed d e [ee ts in m em shyo1y a nd j udgrne m an d in ea icu la li ng abitit y An e lec tro shyc nceph alog larn was d i1Tusely a lm orrn al w ith sornewha t more p ro n()uneed changes on th e le ft Dysarth ria a n d a n obvio us iphasia thCll d evc1ope d H e di ed about 3 mon ths a f ter the cnser 01 thc neurolog ic ill ness

Pos t-m o rte m exami na tion sho wed seve re ri g h l-upper- Iobe pneu mon ia T he re was li tt le g ross evidence oI Iym p hom a b u t ir was fou nd microscop jcally in the liv er sp leen p a ra shyao rt1c ly mph nod es and bone ma rrow Neuro pathulogical e x amlI1al~On dis ciosec1 m u lti pl e bil ale ra l d e myel i n aiexcli~middote le shy

~l ~~I JI IJl(hbtc J (O lile palltll ts phls~clall D I L P l-1CJ uck Co ncord ~b S ~ Kh ll Cl1 S Jm1 l h c l (c1 lCa ReCQ rd~ Oep rtltlent C rne rso tl HO I ~ l l a l COllcord ~ 111) Il-ldc h t dll1 ical nol cs ln i b l5 ca se avaiacutelabl c

I n lbe ( ~n ~ uf i1ylern ll urroughs Ve llcom e 3 11d C o mp HlY T uck shydwc Ncw 1or h

1 a rA) llldeu[u lO D r l cr cy SaJj~l rJLurnJuumlglc cons ultant lO th~

Departmell oI MedIcine VnleiSltv u Vcslcrn Aust ralia Pcn h -V i fQ I lbc cllfllcaI nd patholog1ltill findll ~gs lt l t his case as ell as g en~ngtus dSJc)nm erl of excelleacuten t 3tamcd scctlons of the bra ~ n

sions in t h e d cc p co rncal 1CImiddot ancl in ih c suh Il ica l hIte mat re1 ge ne rallv hout I ro ) nun 1 d 13nl e ln iJUI with ru many i co nfiue n t [OCI most n urnc rous ID tlw fron la l and 11 p arie ta l l ob e ~ A le w mall iesrons wcre p l~~I gtl in ih c (~I)_ iexcli ) tra l nU C C1 of ihe cerebra l nCIl1rSf he res thr rr wcre nouo in t he cercbcl lu rn brain srem O ( spin al cl)ld ivficr c scn j) callshy

1 Th I t I1f Icsions wcr e rypu a e ( l a r) CtllJitJC aliluioll 01

oliaodend rocy rcs as C~ ~lSpllUOUS man- (r tl( arrc-flecl cc lls onlallcd eosulOphl lllt in tran urle ar l1clu011S Thc-iexcl er e i req ueu t g iexclg-an t~c astro vres P ( l l a ~ ( [llar 1~middot1lIphocvt) infilr rat ions wc re alisen t lo

L CAS] 6sect ( V A H Porrla rid 0 rl - o n a lp ~ ) )() ~fiacuteG e

fIP ar c no 31 J j 70 i C E l(urop3Ih L3h acc nmiddot h X-2~7)~ A 31-year- oJd m anwas Iound in ICJ 49 ro hav e a n r~edl a S lJ nd l mass OH il rc)Ull ~le su rvev fil oiacute lhr- r hest 111

Iliop sv 01 a n en larged supracla vir ular l- mph noclc in 19)0 p l we d H od g k in s di sc ase D U J in the ncxt 1- CIo he reshy 111 ceived gr ade d rad ia rio n t ne rapv 10 mul iiplc visce ral sit es 1 B ric f courses of ni trogr-n mus tard t rca lmclIl WC I~ iven in (

April 1955 and Apri l 1956 folloyed OTl cae h laquoccasion 1middot o) a dec rcIse i n tIJe size of Ihe tumor m asscs I n M al 1956 rle h e complained o [ b lu rrccJ n ion Ex a m im11iacuteon howeciexcl h om o nymous blindncss in the riht JOW T q Ll l r1 ra ll t thill IEl ICr p ro g~cssed u nd cr oh se n a tio l1 lO a om p k c homonyshymOll S hemlan opsla on the ngh sde 1 herc was ale a l igh t-sid ed hem ip ares is mos t pronounccd in t he fate T n e III

~ la n tar re flex was bil a tcr a Jly ex tenso r lllore stroncmiddot j) on Ihe 1 Ilgh t Lumbar punelure showccl a no rmal p lC su tc md a ce re brosp inal-Dllid prolein of 22 mg pcr 100 m Al ccCshy w t1middotoeneep haJog ram d isc losecl a bilatultt occip ta l do~ - wavc T ab no rmaliacute ty Soon aIterwar d le fL-sid ed el elJCllar a l ltt~ i a 01

g ra d ualy d eve lope9 a nd he De Cante b lin cl -- wi th no rm al o p rie d isks and pupi ls t h a reacted Il ggishty LO limiddotl ] n

1uly ancl iugUS( 1956 radiatio n therapy wa gnmiddotcll to lhe occip it a r egions b ilate r a lly A pn e u m oe nce jJhalo~r arn d onc at th is tim e sho wed a su ggestion of 8 g r ea te r l-)iquestn ) Ilonna l amou n l of ai r ov er the o ~cipila l l obe~ B is condi lill dcmiddot cJined in a l r esp ects Terrn inally genelaliacuteze d n ic1cs lyp ishy

lc a l oC he rpes zosle r 8 p p eared H e c1iacutecd n l1 D ~ c nhcr 18 195 6 ti

P ost -m ortem examinati on sh owe d w iclbpl cad imolvcshy men t oI ly m ph node s and visc e ra by H o dg k in s c-alorna I n t h e brain t he re were ex te ns ive lcsi ons oC iexclOl h Cltelir l ti hemispher es espe ci a lly io the pos te1middotior paris ol1lew ha t mOre 00 th e l eiacute t h isto iogica lly of lh e same charlner as in tith e o th er cases N o g ia n t a str o cy tes were fOllnd ho wec r There we re a Ccw sca tl e red p e rivasc uJa r Jymphoctic inmiddot iexcliexcl

lil tr a tions

CA SE 7~ ( M C H 02-2 2-7 5 au to p sy 9-17f1) 11 82shyyea r -old man had b een freq u en tl y seen a t lhe ) 1assachusclts G eneral H osp ital sin ee 19 22 m a iacuten ly becal1se of h)pcr lensjon ( b loo d pressure oI 190 I 00) c h ron ic eo n gcslyp leart CaiJshyu re a n d angina p cctor is Wiacuteth limitaiexcl ion of 3ct ivi tics d igi shylalis n itlOgJy ce rin and carefu l di c ta r) rqulaiexclion he reshymained fo r ye ars r ela ti vely u n tro u b led by hi s ill ncss es a nc n worke d regula rly I r a bo u t m id- ]anuary J 940 f riends noshy 1)t ic ed lha t he b a d beeome rnentall y sIowe r th1 before and tha his sp eech was slu r re d O n thei r a d vie lle cnter(d lit hospital on F ebru a ry 2 19 1O Ex am na iexcl- ion sho wed m c1 conges ljve hear t Ia il u re Neuro log jca lly he was rcspo l1SlVC a nd co -operativc bu t speee h w as slu r rc d a n d th er e was somc slighiexcl wca k ne ss I iexclhe Id i side of Ih e b( c un d tong-lle T e nd o n re flexes we re re la ti vel y more a~ t l ve III Ihe lefl arm Ih an els ewhe re bu i no o th e r a bno1nu l neurulogic findi n(s J Vere d ese riexclb ed R o n till e a dmission b loo d ex a m ina I ivm ga e n ormal re su l is He SOOll be earne frIacuteJrile his ~cn Cral slale wors ene d a nd h e d ied on February 15

Po s t~ mon en 1 exanUumlIl aUuml QrJ sllowe d seve-e CO I0nll) a lheroshysde rosis Vi th aeu te rhrombosis and hcalcd myor ardla in shy[arc rion to ge the r wi iexclh Elcu tC bronchop nc u m on ia and hcaed apical p ulm on ar- ll1berfu losJ~ lhelc V l- n rjt h l n l~ to sug -

SI a m lndcfJllu tQ DI J J I JHS middotlJtjn D ] I ~ I O tl (Ir C I I l p l)IIICJr

uacute ty o[ Orcgoll fvcd iCeacutell School D r J ~nH ~ t r Losij chimiddotf oiacute L lhuriexclwnshyScnmiddotlce i c llt ra Jb Altl ~U u l1~ ([llonmiddot HopitL Pn-tbl ld O ng l ll l[c1 Colollel F ra nk ~I T Ovnscncl dr cctor and Dr Veob fiexclyJT1 l kfr lt- h ld Teurop athol ogy Sec lion Ar rncd F orces In( llIIC o[ P~l t h vl () gy Wbl un gshyton D C icJ p c r m issiorl t O pub ljh this CI~ C lI H fm cl ill iexclr tl 1I0 1lS and palho loglcal m aacutetCriaJ genc1Qusly p l ac~ cl nt 1lI) di -I H1 sa l ~Th i ~ casr J-llch liad beco ciasifiexcltd c O lliexcl ~ -hl Jiri- (pe ulHJcll l shy

ntlll(d was rCCllJtlydiscovcrcd by ch a llCt i n t n v i o f (lllll J)llLtQshy

~~upJctl ma lcna l 111 the D epa n UHn f fiexcllt~

- s111__IIL middot

817 PROGR ES S IVE LEUKOENC EPHAL OPATHY - R I CHARD SONVoL 265 No J7

cest leuk~llla Iymphorna or a granu lomato us inAammatory d isese T h e brain was u n remarkab le to nakcd -eve exam shyinar ion Microscopicallv there were nu rne rous focal dernveshyIina iive lesions in the cerebral hern isph eres cerebelJum and brain slem Ciant as trocy tes we re Irequent and a m ultiposhylar mi lolc ficure was Io und in one of thern Ther e we re man y rvpi r all v altered olig odenclrocvtes Perivascula r lyrn shyphocyiic infiJtration was unusua llv pronou nced

CAS 8 (St M ar ys Hospi tal Waterbury Conn aushytopsv A-16-58 AFIP acc no 92731 6 M C n Ne uropath Lab acc no X- 2511 ) A 42 -yea r-ol d man Jived about 2 vean afte r the diagnosis of chron ic g ran ulocytiacutec le ukem ia had bec n established For mos t oiacute the l sr year be was treatcd wiexclth b usu lfan Beca use of Ia ilu re of resp onse durshying the 2d yea r tr e a trne n l was changed lo 6-mercaptoshypurine and p rednisone I n addition he received nume rous blood t rans fus ions D esp i te his illn ess he wa s ab le to work unril ahou t 3 weeks before dca th wh en he beca n havi ng vertigo wi th a teride ncy to al to the left This w as Iolshylowcd by apa thy and repetitious sp eech Seve ra l da ys before death a lcft -sided hernipa res is ap peared

Post -rnor tern examina tion showed findings tvp ie al of chronic laquoJanulocytic Ieukernia L esion s oi th e type en shyCOllnter ed in the orhe r cases were present in both ce rebra l hemispheres more on (he righ t and in the cerebe llal whi te mal te Mi croscopicaHy the lesions showed characteris lic oliodendrod ia l and astlocyti c changes wi th no p erivasshycu[a r Iy m ph o cy tic in fil tration In th e cereh d lum tbcre were lr sions no t prev iously seen in an y case of tbis series Tbcse consis ted of foei of destluc t ion of the granu le ceUs of tbe cerebella r cOltex vary ing from rnicroscop i-al size lo 05 to l O mm in d iameter Sorne were contin uous with typical demyelin a tive lesions in the ce rebe lla r whi te matter i thin and a [ th e manaacutens o r th ese cere bella r cor tica l leshysions were numer OUS r o~nd or sligh t1y ova l cell nu cle i wit h abundan t ch lom at in granules but withou t stain ab le cytoshyplasrn even in fields where the processes oI ast rocyt es were visual ~ed by the Cajal-gold -sub limate rne thod t Thlse nushyelei occuned in g roup s or clust ers in a manner suggesti ng the normal cytoarchitec ture of the granu1e-ce ll layer of the cerebe llar co rtex They wer e how ever lar gel th an the granule ceHs The largest with a d iame ter abo u t twice tha t of a no rmal granu le cel wer e loca ted in the m or e censhytral parts of th e lesions More pe rip he ra lly th ey resemb led more an d more closely the nOlm al g ra nule ce lis wi th which they were in telmin gled un til at last in the in tac t p ort ions of the gran u le-ce ll iexclayer no mor e co uld be Iecognized Alshythough abso lute iden tifica tion oE th e ~e eells was not possible th er ap pearance an d d ist ribution suggested th at th ey rnight be alt er ed gra nu le n eu rons oI the celebellar cor tex

CASE 9l (Presby terian-St Luk es Ho~pila l Ch icago 6 1608 au topsy A58 - ISD M GH N euro path Lab acc no X-272 ) A 68-year-old woman ente red th e hospit al on M ay 12 1958 eompla ining oE dys ph agia di zziness and n au sea of 5 days dUla tion T wen ty-t wo m onths p reviou sly a rad ical rnastectorny h ad been perfonned for ca rcinoma of the righ t breltcst C ar cinoma was found in SOO1e of th e excised lymph nodes Two weeks before the fina l adm ission she began having occasional n ausea and di zziness D ysphagia and dipl op ia on la teral gaiexcle then develop ed On exa mination iexclhe on ly significant physical finding was nystagm us on la te ral gaze La ter she h ad count e rcJock wise ver tigo tog ether wi th left -lower -facial -muscle weak ness iacuternp ai rrnent in rapid alrernaling movemen ts of the righ t h and and foot an d ataxia of th e right a rm o Treatment consiacutes ted of predn isone and gene ra l supporti vc me asu res About 1 month befor e deaLh an int race rebral injec tion of a nitr ogen mustard arrashylague was give n wi tho ut effeet on che neurologic abnorshy

- J am indcb tcd lo Dr Marcus E Cox director Departmen l 01 ~ ZIb() r1 l 0 ric) S to Mlryls Hospital) Wa teTbury C onnect Jcut ~nd tu CoJonci Fra nk M T o wnS(ld direc tor md D r ~ cbb H aymcuuml c r ch icf 0 ( l be NeuroparhoJogy Se Ctl On Armcd For ce- I UH it ure oI Pa thology ashjngton D C ( ho kindly furnished clinica l noles and pathologlcal mJ Leria l) for permission to publish liacuteUumli case

t 6 considerable nll rnber of 11lsw logic me thods were used in an al ~cmpt tI demOllSlriexclllC the shape Or cy toplasrn1c feat ures oI these ce lls and aH faiexclJcd lo do so T h cytopiasm oC I he cerebe llar granu le cells as sinll lar-Iy unHuined by aH these proccdures

M Ll teri al froro this ciexcl)se and permision for its publica tio n were ge ntr Dusly dona lcd by Dr Raymond A CIasen Dcpartment oiacute Pa tholshyog y PresbyteriLl n-S t Luke s H ospital Chicago I l1in o is lO whom 1 arn grea ll y lndeb ted

rnalitics H er condition grad ual lv wors en ed and she d ied en J uly 17

Post-rnort em examinat ion showed tbe immediatc cause of dea th lO be bronchopneumoniacutea T here were rnu l tir-Ie foci of me ras tatic carcinoma in the lungs and mediastinal Iym ph nod es I n th is case the most ex te nsive brain lesions were in th e cere be llar white rna t rer an d mi dd le cerebellar ped u n rle bila teral T he cere bral hernisp heres we re spa red exccp t Ior a small cluster of lesions in the left pa r ieta l re gion Abn orrn a l ol igo dendrocytcs of tvplcal appearance were nushymerous bu t gian t astrocvtes wcre rare o Therc wer e no periva scu lar lvm p hocv tic infil tr a tions I n rhis case as in Case J and as found Ia ter in Case 2 there we re scattered Ioci of nerve-cel l loss in the granulc-ce ll la yer in the cere shybellar co rt cx an d these coritained u n u su al nu cle i suggesti ng en larged gr a nu le neurons

CASE 10sect ( VAH o S t L ou is M isso u ri a u topsy A54 1 AF IP acc no 339069 M G H Neuropath Lab acc no X-259 ) Gencral ized Ivmpha denoparhy deve lop ecl in th is 35-yea r-old man in 1949 and Iacuteyrnphosarc oma was foun d Vith rad i at ion th er a py nitrogen m us tard and co rtisone at various times he rernained generally wel On June 26 1956 he en tered the hospita l cornplaining of irnpaired

m ernorv of 1 rnonths d u ra tion O n examination there wa s genera lized lymp had enop a lhy and enlargement oiacute the liver and spleen H e had difficuacute lty in using wor ds and was slow in answering (juestions bu l the re wer e no other neu rologic fibnotma lities L UJnbar p u n cturc showed n ornl al cc rcbro~

spinal-flu id finrlings Thereaf tcr progressively in cr easing ap hasi a and right-sided hemjp ar csis d evelop ed un inHue nc ed by radi a tion therapy to th e sku ll and nitrogen m usta rd H e became unable lo swa llow an d grad ua lly went iexcln to coma dyi ng on Sep ternber 5

Post -mo r tem examinatiacuteon showed widesp read invo 1veshyment of Iym ph nod es and rnany orga ns by Iymp hocytic Iymp homa middot In the br a in the re were di iexclruse white-m a tt er lesions in bo th cerebral h ernisph eres mor e ex tensive on t-he left wi th scattered small de my elina tive Ioci in th e brain stem M icroscopically lhe lesions were of the sa me charac shyter as in the p revious cases Gi an t astrocy tes were freq uen t an d ma ny of the abn ormal oligodendrocyte nuclei contained eosi nop hi lic in clu sions

DISCUSSIO N

Ten cases h ave been prese n ted o l a p rog r e SSlve centra l-n ervous-system di so rder of r e la ti v e ly rap id

cours e occurring in nearly each o ne o n a b a ck ground

of a p re -exist iacuteng ch ron ic d isea se I n a Jl th e le sio ns

h a v e b een typic al ol what h as p r evio u sly been d eshy

scribed as prog ressive mult ifocal leukoe ncephalopshyathy

To th ese 10 cases m a y n ow b e a d ded 12 that h a v e

been st u d ie d by o th er w or kers and ei ther h a v e a lshy

re ady b een r eported or h a v e been prep a r ed fo l publishyca tian T h rough th e kin d n ess ol the in ves tig a to r s

concerned 1 h a v e b ee n priv ileged to exam i ne a pproshy

priate ne u r o p a th ol a gic a l sectio ns lram 9 o l t h e 12 a n d th us h a ve been a b le to assu r e m yself t h at the

neu r o pathologic p rocess i n each is the same a s th at

seen in th e cases d escr ib ed aboye I n t h e 3 rema inin g cases 3 th e published descrip t ions a nd ill us t ra lio n s o l

th e brain lesion s le a ve n o d o u b t ol t h ei r b e lo n g ing in his group arr d they are so iderrt ified b y th e a uthors

T h e entire grou p of 22 cases is su m marized in T a b le 1

sect[ am i~b l ( cI to D r Ho ward L R ichardson ch lef oiacute L (i borarorymiddot SCI iceiexcl V e te rans Adm nistrat ion H ospitat S to LOUlS JvIisso uri an d to Colone Fra nk M Townsend director Dr Webb HaynallteT ~Je[ 01 lhc Neuror athology 5ectiCln and D r Richard L Da is Ar med f orces l ns tiru lc ofmiddot-Patholosy V a~h i ll gt on D C 10r pe miss-ion to pu bhsh (his c ase anuuml for c1irllca l notes ancl pathologicaJ ma terial

shy

818 T H Emiddot NEW E--JG L ND j OLR NAL UF M ED ICI N E --

C l iacuteni ca l A spects encephalop aihy m ust be viewed as a complicalion of As shown in Ta ble 1 progrcssi e m ul u foca l leulo shy a number o f d isea scs othcr 1han H odg Lin s clislCasc o)

encephalopathy is a d isease that ltl ff ects adu lts of chronic lyrnpharic lcukeruia If Hoclg linlt discac both scxcs T he oungesl pa tien l clied al thirty-one lyruphosa rcoma and th e arious iexclO ITI I o f ieuL(l nia

S O l ReF OP DmiddotTmiddot Srx O U1 o t - fl L- r N fU IWI 11 [OLucrr

f r ll I)JII

1J1tl ()[dl~ (1 93~ ) CJC 1 (] B 1 1-1 ~ J Jl l l r y tubvrc u lc s rs U I I ~(CI(I gait d vsa r rhr-ia de - ~ l i J ~ (l y dic ) It l ll ui e l 1thrd le

IH IIfI (l ll ln amp IfDd )1llt nt )iexcl tfI)tlrIU visio n I U - vious JlIuuml l ~ lmiddot l l )l 0l e minallv g ene ru lizec iexclmiddotig-ic1lt) rior -lv ruuiv ~Ill l-tro

cvrcs CISL 2 rFG ) 71 r D cm c ur ic gcucrahaecl ch orci- G mo Lcciou mor e lth- truruc e lblll

Io r m muveiuc n es tc rrn in a l 1 m C nsc J ~~ raquol l IL( IJlltIiexcl~ loshyap hasin c0lt~d In ((lltl tl amp Iacute1 t p ~1

rcgronv S rh d gII ~tIL(lI SCu u -rcd foci )11 pon amp ccn I H[~~U ~ [Iiexcl lt 111L(k r no

lcsrou- rrr [1lln[ ~ u i-d m tl) -Cl)(l l tJlO v tt-s IJ1 c rl we r than iu CIC l

Winkcl u i an amp 44 fa rno IjU I l ~ l h C(Tv lc J1 rad ic uop- (Q raquo ro c )( ( ~ Il ~ j c lej Oll~ ( 1)( 11 11 M oo rc - ( 1941 ) a rhy thouuhr rlue ro Iocal In righ t ccrcbrn t htnl ishy

involvemc n t by lvrnphe- spher-c rvpici l c vll t h 11( qr-anul o rnafous masses

Tc rm in a llv stupor lef r-sidcd lt J ITl O

be m iparcs is lnlater-al pvrnmidal-trac t signs

ll a lf ll W(J el al e 43 Progr essivc visua l i mpa ir men t 2 100 Diffusc occipi tnl ltIOll lt 1 ~ p (I 9middotij ) d c nrcu tra cly-u-th ria p a rusis ical cell (hiexcll Jl~ middot)

of light a r-m r i ~h ( ex tensor pl an ta r rc fi x

Christcns cn amp- Fv g1 )9 Agra phia ale- ja amp apha sia jo rno E tc nSIVC icsions PilrIJy cavshy( 1955) - visu a l impairmen t p ro grcssin c ita ted 11i posteri or lultlt a l

j o blin dn ess left- Fa cia l- tm rscl c both CCr c1Ueacute hc nusphcrcs wcak ncss demcntia finaliv manv giant dgtl fnnt(O S stupor

C ava nagh el aL2 ( 1919) Case iexcl j bull M H odgkin s discas e j Yl Dc rnen tia rnild le lt-siclcd plusmn 2 mo M os t SCvCr ~ lcsicns in l H~ iexcll l

he rniparesis Iro nt al lobc multip lc snrrl l Ioci b i l ~ttC tmiddotB ]fy

CaSE 2 66 M Ch rOllic lvm ph a tic 311 yr Lelt-sidcd ho monymn us h em i- Gmo M osr scvcrc iuvolvemc nt iu lcu kcmia au opsia p rogressive leIr-sicled right OCCIpI ta l louc gtll (

h crn ipa rusis ap a th y amp COn middot bilateral Ioc r fusion o

LJoyd amp UlichJ Ji F Lymphosarcc ma Bmo H ca d aches ef t-sidod se nsory I 1110 ~r tllt ipl c 5nJall lcsi(m j ll Clll shy( 199 ) impa irmcn l irnpaircd vis io n tex SHbcorlitlI tl1lY m~l tt(l

amp pons Flshcr ct al g 54 M Ca rcinomatosis m uJ ~ J lh yr (Chro nic periphe rlil ncurop- OY2 YT Chronic pcri ph(l id llcwmiddotopaLh

( 196 1) tiple organs pyi - alhy visual impairmcn t j mo widemrcad bJbtral i ~ iexcl o nl ma rv sou rce un- terminaly riacuteght-sidcd mOH middotcjltmiddotnsivc i n ldt dete~mincd h cm lp leg ia wi th 3 J hasia certhraJ hcmiltp L C rc lUdl

foci in iplrLal C()rc Hall crvold eo amp 47 F Sarcoiciosis 2 yr PnjgTcssivc ln~ leltJd i nc s 01 4 mo T pical ks ioll~ 8 ull cIJa l1 g~

Hoelsc hertJ gai t irnpainnenf 01 v)sic n ( 196 1 )

Siacuteblev amp W eis- 5i M Ch ro nie J)m pha lic 6 )1 L~ r l - id (u hOmOD Vt1l 0u hernshy 7 Jo be gcrO (1 961 ) eukcm lt anops ia p rogresslve l cJ t~s i(l e cl

hemi parcs-is hem ihypesthcs)a D obuan amp Caj lnsl1 Jl M Hocl ~k i n s d iser1e 1 j T D e rncn tia dysar thria j left-sidccl M ulliacutepk ~lTMl1 [Dei III fnH1l t

(1 96) h ()mo nymou ~ h cm ia no JJS1ltl lobes amp iJll(rll ~ ~J ~8 pllks1

lef l-facial-m llsclc eak n es~ largc ucslrnc lll IC)IOns iLl ldf -siccd palatal wcakness rlg h paoacute cud amp Id r oc shyamp JcIt~sid e d ataxia ler mishy cipita l lobcs amp nmiddotnmiddotbcJl l ~

I naHy dy-s phagia left- idcu middothicc marLer iexcl middot ~middot ]l l ca l cc H Daccilt1 h l~ mijJa r ( s i$ amp righ Lshy cha nges ioch)(JlP~ 1l111l1n shyltidcc ipastic h cmjpan~~~ oiexcls gia nl tl i1fl)( I l ~ ) l iexcl) ~

ith nIllO~e)

-- -- - - - - - - - - _ _- - - - shy

a n d th e olelest at cigh ty-two years of age Th e average are consiclcred l O be neopiastic d iseases 17 o[ th e 22 age a t the time 01 elea th was fi 1 tY -seven M en ~ ere wiacuteth iexclhe 2 cases of carcinoma tosis VerC asoriatcc affect ed tw ice as oft en as lo men ( 15 t o 7J) nu t in wi th neopla sms T h ree o f lhe ) rema in ing Hle ca ses

iacuteew of the rela tiveuroly srnall number of case iexclnI-oh eel of gra nuJomat ous inAal1lma tion (2 o[ sarcoidosis J

it ca n llO[ be tated lba l l h is cli1erence is sign ificltt n l o f miliar ) tu berculosis ) Orle oiacute the 2 add i lional pashytients (Case 7) hae coronar) liean e isca-e (he o lhcrl t has already been pointed out l na t the neurologic ( C3-e 2 ol H a Ilcrvord en ) hacl no known preccclingd iorde r regular]y OC CUfS on Lh e bacLglOu nd of a pre shyilJness Both iexcl5i icnt5 were of adV2LrlCcd- age-reiglUacuteYshye-iacutesting chronic disease T he arious associated sta tes tVo a ncl se en t~-on e years respecLAacute ely ~

a le show n in T a ble 2 T ht calt repon c oiuuml ains no record cf pOSI-rn(l)(Cm illlcllllgS ( l h C

As iacute now appar enl progrcsme lIlultiiocal leuko- lh8n lh(iexcl~( 11 lhe cep t r~d neniacutelllS sySLCrfl

amp

I

Vol 265 No iexcl 7 PR OGRESSrVE LEUKOENCEPHALOPATTIY - - RI CHARD SON Bl 9

Although the pre -existing disease was freq uentIy whi ch the record s are sufficien tly complete on th ese of many years du ra tion as iacutendic ated III Table 1 the aspec ts ncurologic illness was re lativ ely bri cf On an averag e T he neurologic sym ptoms and slgns 111 mos t cases le ra n a cou rse from onset lo dea th of th rce to Iour were th ose of a di fiacuteuse but asymmet rica l disease of

TBtE 1 (Con du ded)

Prcscnt report

Ciexclse ) 1

Case 3

Cose 5

Casp 6

Case 7

Case O

Ca se 9

A GE

j-r

71

73

42

55

49

31

82

68

35

A SS OClATID D l S EASZ

Dl ACN O S IS D U RA nON

F C hronic lvrnpha tic 16 yr lcukem ia

F Chro uic lvrnpha tic 5 yr lc u kcm ia

M H odgki n s di sease 10 mo

M C b ron ic rnyc log eno us 2Y~ v r le u ke rn ia

M Lymphosarcorna 2Yl yr

M Hodgkins d iscasc i )T

Coron ary -ar terv plusmn15 yr disease healed a pical tubercushylosis

M Cbro nie myelogen ou s 2 vr Ic ukem la

F CarCllomalosis (pri- 2 yr ma ry 50l1 rce blteast )

M LYUlphosa rcom a 7 yr ( lym rhocY iic Jymp Hgtma )

N EUROlOG IC D l S0 RDIn

l IU N CI PAL MiexclN IF L s nnONS

Pro grc ssive lciacutet -sided hern ipare shysis clcrne nt in visual im shypa irmc nt pro gressmg to ulind uess d ysa rthria

rrrilability amp dcprcs sion headshyac h e anhas ia r-ight -sided hcm ipare sis r igh t-sided hoshymo n ymous hem iancpsia lcad ing ro b lin d ness

Aphasia r-igh t-sided hcmiparcshys iso

Lef t-sid cd h em ipa rcsis - dvsar shyt h r-ia em o tio na l labilit v

R ight -sided he mipa resis intclshylec tual imp a irment la ter aphasia

Ri gh t- sidcd h cmorrym ou s h CIDlshyanops ia amp h emipares is Icf t shysided cere bellar a taxia Ia ter b lind ness

Mental slow ness dysarthria mi n ima l lef t-sid ed h emishypare sis

V er t igo with Ialling to lef t d cmc ntia ter-mi nali v lcf tshysided hernipa re s is

Ver liacutego dysphagia leH-fac ial shymuscle weakness a t altla oC righ t Jimbo nYltagmus

Progressive aphasia amp rish tshysidc d hcmi parcsis dy~ -ph ag ia j rclmiddotminiquestlIl YI coIna

4 mo

middot1 mo

2 mo

ruacuteo

3 roo

7 mo

1 mo

3middotwk

2 mo

3 ~ fil a

O U r ST I N DJK G N E LlRor l H OLOG1C

FF_T lru s

Ri gh r occip ital rcgion most seve rcl y affec- rcd carly Icshysions in le iacute t o ccipi l-a l reshygio n man y gia n t asn-oshyc vtc s sorn e wit h mi toses

WidesprcJcl bilateral iesions most extensivo in IeIt p a r-rcto-ooci p itnl r cgion i ma n y lesio ns in b ra in s tr-rn amp r-e reh c-H a r whi te m at te r pecu lia r ce ll cha nges in cc reb e llcr g ran ~ ll iexcl r Iayer c f Cases 3 amp 9 )

Mulii ple srnall Ioc i mos r abuuda n t in IcUacute pa r ie tal rc gicn gia n t as rrc cv res rareo

Ra thcr aparsc lcsions hi la tcrshya l1y b u r ehie Ay rig h r I rontoparietal no gia nt astroc v tes p lasma cel ls in lcsic ns

M ult ipl c bilateral lcsio ns t yp ical cell chauges

Se ver e lesione b ila re raflv most cx te nsi ve po s te ri o r-Iy amp in left cereb ral h emishysphc re ~ le iacuter ccre bcllar whi te ma t rer sevcre ly affecleu right less so no gia nt as troshye vt es

Sca rtc rcd srnall lcsions in ce re bral h e rrrisp h e r-es ano br ai n stcm many giant a SA trocyres 1 with m itosis

Wjdcsprcad lesic ns m ore exshyt ensivc in rizh r ce r cbr a l hemi sp here uuusual lcsions in granular layer oCcerebclshylar cort egt with rema rkabte cell changes

Lcsions mosl ext ensive iexclu se r ebcll um amp brain stcm fe in c erehra l hemispheres peculiar changes in ce reshyhenar cortex as in Cases 2 amp 8

Extensive ks ions iacuten both cereshybra l hemip hen~ s m Ore o n leh typicaI c cll c han gcs

months HaJlervoIden s first case in which neurologic sym ptoms began one year before death is excep tiona1

TAll L E 2 Pathologicll Sta fes Assoeiated wilh Plogressive M ult ifocal Le ukoencephalojJathy

OJ SEASl

H oclgl in IS di scase ChronIacutec Iym phatic lcukem i Lymphosarcoma Chroni c mtel ogen 0t15 leukemia Sarco idosis C) lCinomalosis wIJlilttry lubc-rcul o5is Coronar) hCltl T t ulscas U nk nown (old age )

TOl a l

No Of CASF$

6 ~

3 2 2 2

22

the cerebral hemispheIes H emiparesis) spastic oI f1 accid was fr equ ent occurring in 17 of lhe 22 cases (9 Idt and 8 right) Bilateral hemiparesis often ocshycurre d in th e terminal phases of the illness bu t was neveI an ea rly sign o In the case rep orted by Dolman and Cairns hemiparesis eventua lly bila teral was prec eded by unila teral ataxia of the limbs and hom oshyla teral lower-cr ania l-ne rve pal sies Some degree of men tal change con sistin g o[ impair ment o[ a war eness 01 orientat ion decline in in lel1ectual abil ities and (in sorne cases) abnorrnal emotional responses occurrec1 sooner oI la teI in nearl y every case

Viuacuteon was irnpai red in a large propor tion iquestf cases Seveiexclr--patients had eeneralizerl visual loss froro the first and 5 had a homonymous hemianopsia Four of the s~12 pa tients becam e totally blind aJthough the pupifi con tinued to react to light T he changes in

In 4 cases the du ra tion oE the neurologic ilne ss Nas one month 01 less The onset wa s gradua l or insidious anc th e COLme relcnt lessly p rogressie in a l cases in

~-

820 T HE NE W ENGLAND

VISlOll mal be ascribed in eac h case to lesions in the visual -projection fibers oiacute the occipi ta l lobes O ther

F IG U R G l I 0 w - P oul e1 P h o t o m ic rogr a iacuterh 0 1 t h e C ereb ra l Cort es an d White M al ler in Case 5 Sh ounng M u tti ple D em Yelin a iw L esion s o] Va ry in g S iee ( L ay a Al et h od [or

Myelin X 3)

FIG UR E 3 Photo m icrograb i 01 a Gian A strocyt e unt h Mul tiple H yp erchrom atic Iuele in C ase Hem at ox y lm

an d E osin S ta in X 900)

ocular a bnonna lities were considerabl y less I req uent Para lysis of con j ugate gaze to the pare tic sicle in ihe pr csen cc of a hemi paresis was occasionall y rccorded (2 cases) nyslagmu s was rnen t io ned in 2 T he on ly c lear isola ted extraocu la r-rnusc le pa lsy was a la teral rectus weakness in Case 2 In the case p resen ted by Fi shcr el a 18 a t ransitory optic neu ri tis preceding the gen eral ized neurolog iacutec illness was associated with

~ Pos t - mo r t cm c-cam ina rio u of the opt ic n er~~ sho wcd no lcvion s

JO URNAL QF MEDICIN E O L 26 1961 ( unila tera l pallor of the opt ic d isk and in tb t I llaquo~ d T h a oDa ternan -gtqUl res an annbau scr- i he Iciacute t d isk Cl

al

h( L di b( 11middot

~ (l(

li

1(

d 1

l i 11

F IG URE 2 Phot om icrograpli in Ca se 5 S h ounne En lareeaacute D e n se iy B aso p iulic Olig o d end ro cytc N ucle i ioit li L o( 01

N uclear Detail ( Hemato s vlin and EOJin Slllin Xf50) Oligoden d roc y te n uclei of no rmal size Ole h own ampy t h e

arro ios a (

1]

e

iexcl

e

11 e

F IG UR E 4 P hotom icrograph in Ca se 5 S h ounn g 1lt00 En shyIarged Ot ig od endroc yt e N uclei Coru ainin g E osm ophilic JIshy

clusto n s ( H em at ox yli n and E osin S tain X 900 ) A n oligo den dr ocy t e ll u ce lLJ 01 norma l siz e iacute iexclIOiexclmiddot n th r

loioer le]t co m er

vas d cscribed a s a trophi c I n al ihc ot licr cases ihe optic disks either we re sta ted to be norma l 0 1 el e

not spccifically men tioned in none was thei e papii- led erna

T h irt een patien ts had ab norrnal iti es 01 spcech I n 7 the a bnormal ify VI as an aphasia gene ra ny wi th both expressive an do receptive cornp oncnt s tha r co uld

E

11

Vol 265 No 17 PROCRESSI VE LE UK OE NC EPHAL OPATHY -- RI CHARD SO N 82 1

be rel aterl to ex tensivo lesions in th e dominant (left ) cerebra l hemiacutesphe re In the 6 orher s it was a dysshy

arthria Sensory im pa irme n t in volving one side of th e bod y

as recorded in 4 cases This was associa ted with a hcmi pa resis on th e same side in 3 In th e case of L loyd and Ur ich th e onl y evide nce of a unila teral disord er was numbncss down th e left side of th e boc1y wi th im pa ir ed sensat ion and d irn ini sh ed vibrashytion sense below the left knee

Im pa irrnen t in swa llowing ( dysphagia ) pro ba bly occurred in many of th e pa tien ts as th e end neared ir was speci fica IJy recorded how ever in on ly 4

In 2 pa Lients (Cases 8 a nd 9 ) the pri ncipal ncushyrologic sym ptorns a nd signs were referable to lesions in the cerebe llum and brain stem These consisted of vershyt igo a tende ncy to Iall to one side (Case 8 ) nystagshymus (Case 9) dysph agia (C ase 9) unilateral a taxia (presen t a lso in Case 6 ) and in Case 9 crossed signs (left -facia l-m usce wea kn ess right-sided a taxia)

Unsteadiness oiacute gai t not further specified w as reshycorde d in 2 cases In a sing le case (Case 2 of Halshylervord en ) th ere was a mavement disarder of a type associa ted with basal-gangion disease ~ that is gene ra lized choreiform mo vemen ts

H eadach es were inf requ ent They were m ention ed as a pr ominent symp tom in on ly 2 cases and were eit her absen t or minimal in th e o ther s None of the pashytient s had convu lsive seizures

i Cerebrospinal-Fluid Findings

A consistent and significan t Iearure of the en tire group of cases was th e minimal degr ee of abnormality in the cereb rospina l fluid T hus of the 11 cases in which th e cerebros pina l fluid was exa mined th e findmiddot ings were en tire ly normal in 6 In 2 the onl y abnorshymalit y was a sligh t elevat ion of pressur e (275 mm and 200 mm la) A sligbt in crease in ce Jls was recordshyed in 2 ~ 25 lymphocytes per cu bic millimeter (C ase 1) and 6 white blood celis per cubic mitlimeter ll the cell cou n t was normal or not mentioned in th e others In 2 cases there were minimal eleva tions of to ta l protein a s light rise 7 and 50 mg per 100 ml l1

respecti vely

Electroencephalographic Findings

Electroencephalograpby was a bno rmal in every case in wh ich it was done (7 of the 22 ) The re ports were kindly reviewed by D r J ohn A Abbott who summ ashyr iacutezed the findings as f01l0s D iffuse sow-wave (delta 0 1 th eta ) actiacutevi ty of a sort in no way distin ctive of this disorder with normal activity pe rsisting 01

obliterat ed a nd wirh asym me tr ies correspon ding wit h the structura l abnorrnali ties in 1 case (Case 1) flatshy

The ca~e oC Fisher e l al8 (who kindly allolcd me ~o see their unp ubliexclshed ma nusc riacutept ) is no t indudcd In thiacutes the pIOtcin was elevated (43j mg per l OO mL ) on a single cX3mina tion clone whi le t-h e pa rient was under obse latjon rOl chro nic periph era l neuropltHhy bdorc evi middot cltn cc oC cerebra l d lsease had appearecl

tenin g and sharp waves were noted on tb e side of greater struc tu ral a bnorrnali ty

Radio logic Findings

Plain films of the skul l whenever taken inva r iabl y were nor mal In a ll 3 cases in wh ich pn eu moenc ephashylography was performed (Case 6 a nd those of C hrisshytensen and Fog and Bat ern an et al ) the findings exc lude d a space-occupying lesiono In the on ly case in which cereb ral angiog raphy was done tbi s showed a normal va scular pattern

A Iocalization study using a radioac tive iso tope (As ) wa s don e in on ly 1 ca se (Case 2 ) with normal find ings

PathologicaJ Aspects

Alt hough the lesions in the cen tral nervou s syst em were of the same character in a l 22 cases th ey varie d considerably from case to ea se in location and cx tc rrt A s a rule thc y w cro JT10St n un ic rous in the cere bral hernispheres bu iacute oiacuteten the brain stern and cere be tlum were severely affcc ted The spina I cord when exarnined was normal or at m ost showed minishymal changes In the pre vious publication evidence was give n for considering progr essive mutifocaJ leukoshyencepha lopathy to be a dist inct neuropathologic en tiacutety that cannot be classified with hitherto recognized diseases of the cen tra l nervous system The com binashytion of multiple demyelin ative lesions of a l po ssiacuteble gra da tions in size an d stage of evolu tion (F ig 1) with remar kable cha nges in oligodendroey tes (F ig 2) and oft en in astrocytes (F ig 3 ) does not occur in any othe r disease known to me The appe a rance of th e lesions suggests th at prog ression of th e c1in ica disorde r result s from th e enJargeme n t and confluen ce oI sma lI lesions and th e con tin uous ad ditions oI new ones The ea rlier d escription 1 placed conside rable emphasis on th e hyperplasia of ast rocy tes iexclnto bizarre gian t Ior ms whiacutech resembled neopl astic ce lIs It is now a pparent however th at the astrocytes do not unde rgo this altera bo n in al cases On th e o ther hand en la rgemen t oI oligode ndrocyte nuclei with dense basophiJia an d loss of nuclear det ail Iacutes inshyvaria bly presen t Eosinophilic intranuclear inclusions have been seen within th ese ab normal oligo de ndroshycytes in nearly every case (F ig 4 ) but mal no t always be found (lor exam ple in C ase 4 and in the case oI Dolman and Ca irnsl1

) Exp elience with the ad di tiona l cases here repor ted has sugge sted sti ll ano the r fonn of ce llu lar hypert rophy unkn own to us from previous expel ience In Cases 2 8 and 9 th erc were in esions in th e gra nule -ce ll layer of the cer eshybellar cortex Iarge nucl ei wh ich [rom th eir form loca tion -_and a rrangernen t have been tentati vely iden tified as altered cere belIar gra nule neurons (F igmiddot 5 ) Althoug h the identity of these cels ha s not been established beyond all doubt thi s ce ll- change seemS

r

=- -

822 THE -EW ENG LA N D

to be of suflicient int erest to wai rant a pre liminary note

Frcun s 5 Ph otonn crogr ap ]i o i lp e C ereb ellar C ortes in Case 8 Shoioing Llnus uai Nu elei m th e Granular L ay er ( H emashy

tox y lin arul E osin S ta in X250 )

Near ilie t op [u st be ncatn the sp artely ce llu lar molecular laye r al e norm al granule neu aniexcl lJelow th eJe simii arl) grOllped m io clu sters m e lal ger n u clei bel onging lO eell r

Iha l may be path ologrcall y en lar ged gran ule n eu l on s

The earlier im prcssion tha t lh e lesions ha middotc a pre shydom ina ndy pe rivascular dis tri bution 1 h as DOt been borne O L1L b y th e p e~ en t stu di es Exa mina tiacuteon 01 ser ia l SCltlions gen er ally cliscoses at Jeast one m in u te esse ith in e en smal l e~ions bu t in view o f the Iarg e n um bers of such esse ls nonnally pre~en t in the braiacuten iL canno l be sta tccl lh a( lhis r ela tion iacutes a significa n t on e T his conelusion is in agreernen t wi lh iexclhe find ings of F isber e t aLs On t1w ol her hand

JOUR NA L OF MED IC Il E 0 l ~6 1961

ihe add itional case materia l does con firrn lhe pr C iou findi ng th a i infl amma tio n in the Iorrn ol pe ivascu l a~ lymphocyuc in filtra tions is with rarc l cepl ions mi n imal or absen t

T he par hologic changes in orga ns oihei i han the cen tral ncrvous system were in cach l l Se lypieal of n the pa rticular d isea se pr esent T herc wns no e iden ce

P iha t th e cases o iacute ch ro n ic d isease a ssocia ted wit h pro shygrcs s i v~ mu ltifoc a l lcukoe ricepha lopa thy di lfcred [rOI11 ot hc rs o f the same di sease in which chis n eurolooic disorder was p resent A h hough in m ost cases J1e underly ing d isease was such tha t in i tself it would ha e b ccn cxpect ed u lt im a tely to han been fa tal iexcln an y of (he pa t ien ts a p pa re ntly d ied a s a rewiexcl of Che de vastating efTects of the lesions in thc brain 1t seern s rc asonable to su ppose that if th e cerebr a l disease cou ld ha vc bee n pre ven ied 0 1 eflecrivelv

[( (

tr eated m a ny of the patien ts wo uld h ave SHVi ed ur

tilonger th an they di d

Etiologi c Consid erations

The cause and p athogenesis o f progressive muln shyfoca l leu koen cephalop athy rem ain uul now n H owshy

I eve r it occu rs with cond i tions in wh ich iacutemmu noshylogic h ypo re a c tivi ty has b cen de rno nsn-atcd (Iym shy Il

reph om asV leu kem ia13 sarcoidosisUl ca rcinornato shy (

S i S ~ a nd o ld age9) and thcrcforc decrea sed resisishy

ance to inf ection s m ight be expected Thc ch anges in o ligoclen d rocy tic an d as tr ocyt ic nuclei c1 escri bed a boye are consisten t with th e cyto pa tho logic effects a l a virus w hich in th e p resen ce of impaired iin shymu no logic respon ses could result in a typical lesions I t is hopecl that in the Iutu re cases of thi s sort wi ll be recognizecl so th al ap propria te investigat ions may be underta ken duri ng life and stu dies ca rr iecl out on fres h tissues ob taine d at au to psy

SUMMARY AND CONCLUSIONS

T en cases of progr essive multifocal leuk oen ccphalop shya thy a n un usual ce ntr al -ne rvous-systern d isease with

j

distin ctive neu ro pathologic fea tur es occu rring la te in L

the co u rse of severa] forros of chronic illn css ar e presented 10 these are aclded 12 cases stud ied by others g iving a to tal of 22 13

Th e ou tsra nd ing cliacuten ica Iea tures of th is con dition a re t hose uf a rapid ly p rogressi e focal or aS)l11me tric d isord cr of ihc bra in unaccompa ni ed by increascd fl in tracrania l p reSSllre 0 1 sign ifican l cereb rospina I-fluid i

changes Ir has mos t fr cgu en tly been asociatcd w ith ma lign a nt lym phoma or leuktm ia bu l may oCCl r ilh sa rcoidosis carcinom al osis m iliar) tuhcrcdoSis 01 rare acl ancccl age with0u t neoplaslic nI ~ a n u shy

Irloma lous d isease Ei den cc iacutes ci ted that lhe on e bctor CUl11 111 0n l() bull

a 11 the ch ro n icdi seases me l VI iexclth in iexcllis series is lhe p reence o relat ie imm 1l101ogie u nn pont ellemiddot T he cam e nf l og nsi e m uli roca l JeukcHncepbalop shya thy rc m ltl ins Bntildel~no n hu thE sugg eslion i ~ made

e

Vo] 2G5 N o 17 EF FECT O f C H LO R PRO PAM ID E - SIN GER ET AL 82 )

t hat the nervous-system lesions are cons isten t wi th an atypical form of virus infecti on

Further progress in un de rstanding th is cond it ion will depencl upon the stu cly of ca ses during life a nd of Iresh tissue samples For these purp oses recogshynition of cases during Iife which shoul d now be possib le is u rgecl

T wo a dd itiona l cas es both asso ciatc d with long stand ing chr onic lvrnph a tic leukernia have kiridl v bcen b rough t to mv altcn tio n a nd I have been permit ted to exami ne ne uro shypatho louica l ser tion s fr om both The first fra m DI Ell iott L M an call D ep artme nt oi Neuro loav J efferson Med ica Co llege Ph iladelphia Psnn svlvani a an d to be repo rte d by him is thar of a iacuteort v-on e-vear -old man in wh om the on ly ncu roloc ic abnorrna li iy consisted oiacute gene ralized convulsions five d avs before dea th T he secon d fro m D I C L Do lman Dep ar tment of Pa thologv V an co uver Ge ne ral H osp ita l V ancouver B C occu rred in a fift v-eizht-vear- old ma n with a very o rief terminal neuro logic illness who ha d had gen era liacutezed convu lsive seizu res for Iour years referab le to a n olisndend rogiiorna di scovered p ost rnortern as an incishyd ent a l findi ng

Drs R aymon d D Adams Ben jamin Castl em an C h arles S K ub ik Byron r-L W alcsma n an d Ba rry Amasan oC the M a ssach use t t Gener laquo1 Ho pilal P rofessor Jliu H all er shyvorden Max-Planck-In stiwt [uumlr Hirn forschung Giessen Vestern Ge rm any an d D I John F E nders havc given me friendl y help md encollra gcme n t fo r which 1 am inshyd eed gra te iu l r am grea tly indebted to D r W aksman ior im m uno loic advic c and for sULges ting how viral in Iec rioll could ac count fQr th e ne uro patholo gic Jesions in th is series oC cases

R EFERENCES

lo Astro m K middot E Ma nca ll E L and Richardson E P Jr Promiddot grcssive muJtrocal leuko -cncephalopathy h ithc rto u nlccosnized comp Jication oI chronic lymphat ic leukacm ia Qnd Hodgkrns d~scase Drain 81 93- 111 1958

2 Cavanash ] n G rcenba um D Matshal f l H b a nd R ub iacuten shysrc in L J Cerebral d e mve h na uo n assoc iaied with dis or de rs of re ticulocndor hc lia l system L ance 2 524-)iquest9 1959

3 Llovrl O C a nd Urich H Acu re d issemi ua ted dem ycli ua rion 01 hra in associa red wi th lymphosarcoma L ancet 2)29 1959

4 H all e r vor d cn J E igenar t ige und m ch t rubria iacutecrbarc Prcz essc In H a ndb ucti d er C ciSl eskrrwkheiacutet cn V ol 11 (pan 7) D ie A nfit o mie der P SCe OfeTl Edi tccl by O Bum ke 1136 pp Ber lin Spr ingcr 1930 Pp 1063middot1 107

5 W in kelma n N V an d Moorc 11 T Lv m phogra n ulo ma tosis ( Hod ~k i n~ d isease ) of ncrv o us systc m A rch Nc ur ol amp Psvc hi at 45 304-318 1941

6 Batcrnan O ] J- Squ ircs G a nd T hann ha use- S J H odg shyki ns d isease associa tecl with Sch ilders discase An n l n t Al eJ 22 426-431 1945

7 Ch ristcns en E an d Fog M Case of Schilders d iscase in ad ult wi th re ma rks 0 0 e t iolo g-y a nd pa t hog eocs is Acta Jsch iat el neuro iacute S cand inau 30 14 1-154 19] 5

8 F ishcr C 11 Vil1ianls H W a nd Ving E S Ir Co rnbincd cncephalopa t hy an d nc uropa thy wi th carcinoma ] Nc uropo th amp Ex per JVcUoL (i n p rcss

9 H a ller vorden J Personal com mu nica tion 10 Siblcv W A xnd We isb rg er A S Dem yelinat ing d iscase of

bra in in chronic lym nha ttc le ukemia OCCll1TCncc e l c ase in hosba nd of pat ien t with m ili tiple sclero sis A rch N eurol S 3UumlO-3Uumli 1961

11 Dol man C L bull an d Cairns A R M Le ukoc ncephalopathv assoshyciat ed -i th H orlgkins d isease N eu roiacuteo gy 1) 349~353 1961

12 Schi cr 7 W C uta neous ane rgy a n d H odgktrr s discasc N ew E ng ] M cd 250 353-361 19j 4

13 Epste in V L I nd uc tion o iacute allerg ic con tac t de rma titis in patlcnts w ilh 1)JOphOlna 4 Icukcmia co mple xo ] f rtUes1 D erma 30 39 195U

14 K eJly W D Lamb D -L Vareo R L an d Goa d R A_ Inveacutestiga tion oC H odgkin d iampease wl th respe ct to prohkm 01 ho rno h-iexclnp llJ) la tion 1 7111 N nc Y o rk Acad S e B7 IB7-2uuml2 1960

15 Fr lOu G J S tlldy of Cll la neOlS r eaciexcljons to oid io myciacuten tri choph)shytino and mump s skin te)t ant is cns in patic n ts w it h sarc uiJ mio Yal ] Biot amp M ed 24 533-539 1952

16 Ep s te ln W L and M a yo ck R L [ nJ lc t)OO oC a l h rs~c c on lac t c1 erm~iexcl i ti s_ in pa l ien ll ifu arcoidos Proc Soco Fx per Biol amp Med 95 186 1957

17 Logan J Ddayltd typc o [ alergic leadjon in cancer ate rcd respo ltse t O hJbcrcu li n a ncl m llmps vi ros N cw Zealand M 55 4)amp-41O 19) 6

18 Sou tham C M aud M oore A_ E I ndn ced im mu ni y to ca nce r 19~~ h omo grafts in man o An Tt N ew Y o rk A cad S e 73 635-653

19 Ca ndti~ G LaUergie f ub erc rJeuJe che z lhomme Coll ecti on di llnJf i( u l P aJteur 338 pp Pari$ FJammario n 1946 Pp -4042 and 61

CHLORPROPAMIDE IN PATIENTS ON HIGH IN SULIN DOSAGE

DAVID L SINGE R M D t R OBERT C S T EW ART MD t AN D D AVID HURWlT Z lvLD sect

BOST ON

A RE CEN T review of patien ts [r om w e D iabe tes C lin ic of the Boston C ity H ospita l r eveal ed a

substa n tia l num be r do ing well OIl ch lorpropamidell hose insu lin requir em en t had exceeded 50 uIlits Because it has bec(Piexclne a lm ost ax iomatic tha t th ese palien ts sho uld not be expecte d to do well on t he sulfonylu rea type of agen t the subject was pursuecl furthe r Adcli tiona l p a tien ts reeciving 50 un its of in shysul in 0 1 more a day we re transferred to chlorp ro p ashy

--Frorn thc D Labeles Clinic and the T hornJike 11cmor ial Labora tory Sccon d and Fou rth (H arvard) M cJ icat Se rvjecs Bostoll City H ospital and lhe De par tme nt of M edicine H a rva rd M edical School

Aidcd b y a gran l (2Amiddot5060) (om lhe U ni ted Staacutet cs Public H ea lth Se-rvic~

tRt s e~rch fe llow in medicin e l H arvard M edicaiacute St-hool rt 5carch fellow T hornd lkc M emorial L abora to ry

t Assislan t in medicin e H arvard M ed ica l School iexcl lt~ss1 s t i ng phy~ i dan llm ton Ci ty H ospi tal

Sit an t cJinca l p rofesso r o) m ed ici ne H a rvar d M edl cal 5chool chieL D iabe tes CJin ic aDd vislt ing physlc iall Sccond an d Fourlh (Har shyvar J ~ M edical Servic ~o Bost on Ciry H osp ita l c1uef lfed ical Ser vice 1ount Aub urn HO-5 p i m l ~ Cambridge Massach u~e t ts

~KlDd l y supp hed as D ~ b i n e se b Chltirlcs Pfiu r Jld C O J(Ip a Tl) Tncorporat ed Brool d yn New Y OImiddotk

m ide ancl their response ta bu lated T he resu l ts In

28 pa tie n ts constitu te th e basis 01 thi s report

METHODS AlD M AT ERI ALS

Crileria for inclu sion in the stu d y wer e a s follows th e d iabe tes was of th e m a turity -on set type an d reshyq ui red 50 units of ins ul in or m ore per day al the tim e of transfer to chlorp ropam idej pa tients wit h a hi sto ry of diabe tic acidos is we re excJu ded (ca rbon d iox icl e beJow 15 m illiequiv per lite r ) an d all pn shytients m ust have been main tai n ed on chl orp rop am ide long enough to m alee a cJea r eva luation o f con trol If a goocl r espo nse wa s ob tai ne d a placebo triaJ las giacuteven in ac cordance wiacuteth th e sing le-b lin d cl esign al lhe study a s ou tline cl below The charts of a ll pashytien ts=receiving ch lorpropam id e belore - J une 1960 were -exam ined an d al those ful filliacuteng the cri teria statecL-bo ve were ind udd I n ad cJ iiion a ll pa tien ls seen ircthe clin iacutec between Jul y 1959 a nd J une

amp

818 T H Emiddot NEW E--JG L ND j OLR NAL UF M ED ICI N E --

C l iacuteni ca l A spects encephalop aihy m ust be viewed as a complicalion of As shown in Ta ble 1 progrcssi e m ul u foca l leulo shy a number o f d isea scs othcr 1han H odg Lin s clislCasc o)

encephalopathy is a d isease that ltl ff ects adu lts of chronic lyrnpharic lcukeruia If Hoclg linlt discac both scxcs T he oungesl pa tien l clied al thirty-one lyruphosa rcoma and th e arious iexclO ITI I o f ieuL(l nia

S O l ReF OP DmiddotTmiddot Srx O U1 o t - fl L- r N fU IWI 11 [OLucrr

f r ll I)JII

1J1tl ()[dl~ (1 93~ ) CJC 1 (] B 1 1-1 ~ J Jl l l r y tubvrc u lc s rs U I I ~(CI(I gait d vsa r rhr-ia de - ~ l i J ~ (l y dic ) It l ll ui e l 1thrd le

IH IIfI (l ll ln amp IfDd )1llt nt )iexcl tfI)tlrIU visio n I U - vious JlIuuml l ~ lmiddot l l )l 0l e minallv g ene ru lizec iexclmiddotig-ic1lt) rior -lv ruuiv ~Ill l-tro

cvrcs CISL 2 rFG ) 71 r D cm c ur ic gcucrahaecl ch orci- G mo Lcciou mor e lth- truruc e lblll

Io r m muveiuc n es tc rrn in a l 1 m C nsc J ~~ raquol l IL( IJlltIiexcl~ loshyap hasin c0lt~d In ((lltl tl amp Iacute1 t p ~1

rcgronv S rh d gII ~tIL(lI SCu u -rcd foci )11 pon amp ccn I H[~~U ~ [Iiexcl lt 111L(k r no

lcsrou- rrr [1lln[ ~ u i-d m tl) -Cl)(l l tJlO v tt-s IJ1 c rl we r than iu CIC l

Winkcl u i an amp 44 fa rno IjU I l ~ l h C(Tv lc J1 rad ic uop- (Q raquo ro c )( ( ~ Il ~ j c lej Oll~ ( 1)( 11 11 M oo rc - ( 1941 ) a rhy thouuhr rlue ro Iocal In righ t ccrcbrn t htnl ishy

involvemc n t by lvrnphe- spher-c rvpici l c vll t h 11( qr-anul o rnafous masses

Tc rm in a llv stupor lef r-sidcd lt J ITl O

be m iparcs is lnlater-al pvrnmidal-trac t signs

ll a lf ll W(J el al e 43 Progr essivc visua l i mpa ir men t 2 100 Diffusc occipi tnl ltIOll lt 1 ~ p (I 9middotij ) d c nrcu tra cly-u-th ria p a rusis ical cell (hiexcll Jl~ middot)

of light a r-m r i ~h ( ex tensor pl an ta r rc fi x

Christcns cn amp- Fv g1 )9 Agra phia ale- ja amp apha sia jo rno E tc nSIVC icsions PilrIJy cavshy( 1955) - visu a l impairmen t p ro grcssin c ita ted 11i posteri or lultlt a l

j o blin dn ess left- Fa cia l- tm rscl c both CCr c1Ueacute hc nusphcrcs wcak ncss demcntia finaliv manv giant dgtl fnnt(O S stupor

C ava nagh el aL2 ( 1919) Case iexcl j bull M H odgkin s discas e j Yl Dc rnen tia rnild le lt-siclcd plusmn 2 mo M os t SCvCr ~ lcsicns in l H~ iexcll l

he rniparesis Iro nt al lobc multip lc snrrl l Ioci b i l ~ttC tmiddotB ]fy

CaSE 2 66 M Ch rOllic lvm ph a tic 311 yr Lelt-sidcd ho monymn us h em i- Gmo M osr scvcrc iuvolvemc nt iu lcu kcmia au opsia p rogressive leIr-sicled right OCCIpI ta l louc gtll (

h crn ipa rusis ap a th y amp COn middot bilateral Ioc r fusion o

LJoyd amp UlichJ Ji F Lymphosarcc ma Bmo H ca d aches ef t-sidod se nsory I 1110 ~r tllt ipl c 5nJall lcsi(m j ll Clll shy( 199 ) impa irmcn l irnpaircd vis io n tex SHbcorlitlI tl1lY m~l tt(l

amp pons Flshcr ct al g 54 M Ca rcinomatosis m uJ ~ J lh yr (Chro nic periphe rlil ncurop- OY2 YT Chronic pcri ph(l id llcwmiddotopaLh

( 196 1) tiple organs pyi - alhy visual impairmcn t j mo widemrcad bJbtral i ~ iexcl o nl ma rv sou rce un- terminaly riacuteght-sidcd mOH middotcjltmiddotnsivc i n ldt dete~mincd h cm lp leg ia wi th 3 J hasia certhraJ hcmiltp L C rc lUdl

foci in iplrLal C()rc Hall crvold eo amp 47 F Sarcoiciosis 2 yr PnjgTcssivc ln~ leltJd i nc s 01 4 mo T pical ks ioll~ 8 ull cIJa l1 g~

Hoelsc hertJ gai t irnpainnenf 01 v)sic n ( 196 1 )

Siacuteblev amp W eis- 5i M Ch ro nie J)m pha lic 6 )1 L~ r l - id (u hOmOD Vt1l 0u hernshy 7 Jo be gcrO (1 961 ) eukcm lt anops ia p rogresslve l cJ t~s i(l e cl

hemi parcs-is hem ihypesthcs)a D obuan amp Caj lnsl1 Jl M Hocl ~k i n s d iser1e 1 j T D e rncn tia dysar thria j left-sidccl M ulliacutepk ~lTMl1 [Dei III fnH1l t

(1 96) h ()mo nymou ~ h cm ia no JJS1ltl lobes amp iJll(rll ~ ~J ~8 pllks1

lef l-facial-m llsclc eak n es~ largc ucslrnc lll IC)IOns iLl ldf -siccd palatal wcakness rlg h paoacute cud amp Id r oc shyamp JcIt~sid e d ataxia ler mishy cipita l lobcs amp nmiddotnmiddotbcJl l ~

I naHy dy-s phagia left- idcu middothicc marLer iexcl middot ~middot ]l l ca l cc H Daccilt1 h l~ mijJa r ( s i$ amp righ Lshy cha nges ioch)(JlP~ 1l111l1n shyltidcc ipastic h cmjpan~~~ oiexcls gia nl tl i1fl)( I l ~ ) l iexcl) ~

ith nIllO~e)

-- -- - - - - - - - - _ _- - - - shy

a n d th e olelest at cigh ty-two years of age Th e average are consiclcred l O be neopiastic d iseases 17 o[ th e 22 age a t the time 01 elea th was fi 1 tY -seven M en ~ ere wiacuteth iexclhe 2 cases of carcinoma tosis VerC asoriatcc affect ed tw ice as oft en as lo men ( 15 t o 7J) nu t in wi th neopla sms T h ree o f lhe ) rema in ing Hle ca ses

iacuteew of the rela tiveuroly srnall number of case iexclnI-oh eel of gra nuJomat ous inAal1lma tion (2 o[ sarcoidosis J

it ca n llO[ be tated lba l l h is cli1erence is sign ificltt n l o f miliar ) tu berculosis ) Orle oiacute the 2 add i lional pashytients (Case 7) hae coronar) liean e isca-e (he o lhcrl t has already been pointed out l na t the neurologic ( C3-e 2 ol H a Ilcrvord en ) hacl no known preccclingd iorde r regular]y OC CUfS on Lh e bacLglOu nd of a pre shyilJness Both iexcl5i icnt5 were of adV2LrlCcd- age-reiglUacuteYshye-iacutesting chronic disease T he arious associated sta tes tVo a ncl se en t~-on e years respecLAacute ely ~

a le show n in T a ble 2 T ht calt repon c oiuuml ains no record cf pOSI-rn(l)(Cm illlcllllgS ( l h C

As iacute now appar enl progrcsme lIlultiiocal leuko- lh8n lh(iexcl~( 11 lhe cep t r~d neniacutelllS sySLCrfl

amp

I

Vol 265 No iexcl 7 PR OGRESSrVE LEUKOENCEPHALOPATTIY - - RI CHARD SON Bl 9

Although the pre -existing disease was freq uentIy whi ch the record s are sufficien tly complete on th ese of many years du ra tion as iacutendic ated III Table 1 the aspec ts ncurologic illness was re lativ ely bri cf On an averag e T he neurologic sym ptoms and slgns 111 mos t cases le ra n a cou rse from onset lo dea th of th rce to Iour were th ose of a di fiacuteuse but asymmet rica l disease of

TBtE 1 (Con du ded)

Prcscnt report

Ciexclse ) 1

Case 3

Cose 5

Casp 6

Case 7

Case O

Ca se 9

A GE

j-r

71

73

42

55

49

31

82

68

35

A SS OClATID D l S EASZ

Dl ACN O S IS D U RA nON

F C hronic lvrnpha tic 16 yr lcukem ia

F Chro uic lvrnpha tic 5 yr lc u kcm ia

M H odgki n s di sease 10 mo

M C b ron ic rnyc log eno us 2Y~ v r le u ke rn ia

M Lymphosarcorna 2Yl yr

M Hodgkins d iscasc i )T

Coron ary -ar terv plusmn15 yr disease healed a pical tubercushylosis

M Cbro nie myelogen ou s 2 vr Ic ukem la

F CarCllomalosis (pri- 2 yr ma ry 50l1 rce blteast )

M LYUlphosa rcom a 7 yr ( lym rhocY iic Jymp Hgtma )

N EUROlOG IC D l S0 RDIn

l IU N CI PAL MiexclN IF L s nnONS

Pro grc ssive lciacutet -sided hern ipare shysis clcrne nt in visual im shypa irmc nt pro gressmg to ulind uess d ysa rthria

rrrilability amp dcprcs sion headshyac h e anhas ia r-ight -sided hcm ipare sis r igh t-sided hoshymo n ymous hem iancpsia lcad ing ro b lin d ness

Aphasia r-igh t-sided hcmiparcshys iso

Lef t-sid cd h em ipa rcsis - dvsar shyt h r-ia em o tio na l labilit v

R ight -sided he mipa resis intclshylec tual imp a irment la ter aphasia

Ri gh t- sidcd h cmorrym ou s h CIDlshyanops ia amp h emipares is Icf t shysided cere bellar a taxia Ia ter b lind ness

Mental slow ness dysarthria mi n ima l lef t-sid ed h emishypare sis

V er t igo with Ialling to lef t d cmc ntia ter-mi nali v lcf tshysided hernipa re s is

Ver liacutego dysphagia leH-fac ial shymuscle weakness a t altla oC righ t Jimbo nYltagmus

Progressive aphasia amp rish tshysidc d hcmi parcsis dy~ -ph ag ia j rclmiddotminiquestlIl YI coIna

4 mo

middot1 mo

2 mo

ruacuteo

3 roo

7 mo

1 mo

3middotwk

2 mo

3 ~ fil a

O U r ST I N DJK G N E LlRor l H OLOG1C

FF_T lru s

Ri gh r occip ital rcgion most seve rcl y affec- rcd carly Icshysions in le iacute t o ccipi l-a l reshygio n man y gia n t asn-oshyc vtc s sorn e wit h mi toses

WidesprcJcl bilateral iesions most extensivo in IeIt p a r-rcto-ooci p itnl r cgion i ma n y lesio ns in b ra in s tr-rn amp r-e reh c-H a r whi te m at te r pecu lia r ce ll cha nges in cc reb e llcr g ran ~ ll iexcl r Iayer c f Cases 3 amp 9 )

Mulii ple srnall Ioc i mos r abuuda n t in IcUacute pa r ie tal rc gicn gia n t as rrc cv res rareo

Ra thcr aparsc lcsions hi la tcrshya l1y b u r ehie Ay rig h r I rontoparietal no gia nt astroc v tes p lasma cel ls in lcsic ns

M ult ipl c bilateral lcsio ns t yp ical cell chauges

Se ver e lesione b ila re raflv most cx te nsi ve po s te ri o r-Iy amp in left cereb ral h emishysphc re ~ le iacuter ccre bcllar whi te ma t rer sevcre ly affecleu right less so no gia nt as troshye vt es

Sca rtc rcd srnall lcsions in ce re bral h e rrrisp h e r-es ano br ai n stcm many giant a SA trocyres 1 with m itosis

Wjdcsprcad lesic ns m ore exshyt ensivc in rizh r ce r cbr a l hemi sp here uuusual lcsions in granular layer oCcerebclshylar cort egt with rema rkabte cell changes

Lcsions mosl ext ensive iexclu se r ebcll um amp brain stcm fe in c erehra l hemispheres peculiar changes in ce reshyhenar cortex as in Cases 2 amp 8

Extensive ks ions iacuten both cereshybra l hemip hen~ s m Ore o n leh typicaI c cll c han gcs

months HaJlervoIden s first case in which neurologic sym ptoms began one year before death is excep tiona1

TAll L E 2 Pathologicll Sta fes Assoeiated wilh Plogressive M ult ifocal Le ukoencephalojJathy

OJ SEASl

H oclgl in IS di scase ChronIacutec Iym phatic lcukem i Lymphosarcoma Chroni c mtel ogen 0t15 leukemia Sarco idosis C) lCinomalosis wIJlilttry lubc-rcul o5is Coronar) hCltl T t ulscas U nk nown (old age )

TOl a l

No Of CASF$

6 ~

3 2 2 2

22

the cerebral hemispheIes H emiparesis) spastic oI f1 accid was fr equ ent occurring in 17 of lhe 22 cases (9 Idt and 8 right) Bilateral hemiparesis often ocshycurre d in th e terminal phases of the illness bu t was neveI an ea rly sign o In the case rep orted by Dolman and Cairns hemiparesis eventua lly bila teral was prec eded by unila teral ataxia of the limbs and hom oshyla teral lower-cr ania l-ne rve pal sies Some degree of men tal change con sistin g o[ impair ment o[ a war eness 01 orientat ion decline in in lel1ectual abil ities and (in sorne cases) abnorrnal emotional responses occurrec1 sooner oI la teI in nearl y every case

Viuacuteon was irnpai red in a large propor tion iquestf cases Seveiexclr--patients had eeneralizerl visual loss froro the first and 5 had a homonymous hemianopsia Four of the s~12 pa tients becam e totally blind aJthough the pupifi con tinued to react to light T he changes in

In 4 cases the du ra tion oE the neurologic ilne ss Nas one month 01 less The onset wa s gradua l or insidious anc th e COLme relcnt lessly p rogressie in a l cases in

~-

820 T HE NE W ENGLAND

VISlOll mal be ascribed in eac h case to lesions in the visual -projection fibers oiacute the occipi ta l lobes O ther

F IG U R G l I 0 w - P oul e1 P h o t o m ic rogr a iacuterh 0 1 t h e C ereb ra l Cort es an d White M al ler in Case 5 Sh ounng M u tti ple D em Yelin a iw L esion s o] Va ry in g S iee ( L ay a Al et h od [or

Myelin X 3)

FIG UR E 3 Photo m icrograb i 01 a Gian A strocyt e unt h Mul tiple H yp erchrom atic Iuele in C ase Hem at ox y lm

an d E osin S ta in X 900)

ocular a bnonna lities were considerabl y less I req uent Para lysis of con j ugate gaze to the pare tic sicle in ihe pr csen cc of a hemi paresis was occasionall y rccorded (2 cases) nyslagmu s was rnen t io ned in 2 T he on ly c lear isola ted extraocu la r-rnusc le pa lsy was a la teral rectus weakness in Case 2 In the case p resen ted by Fi shcr el a 18 a t ransitory optic neu ri tis preceding the gen eral ized neurolog iacutec illness was associated with

~ Pos t - mo r t cm c-cam ina rio u of the opt ic n er~~ sho wcd no lcvion s

JO URNAL QF MEDICIN E O L 26 1961 ( unila tera l pallor of the opt ic d isk and in tb t I llaquo~ d T h a oDa ternan -gtqUl res an annbau scr- i he Iciacute t d isk Cl

al

h( L di b( 11middot

~ (l(

li

1(

d 1

l i 11

F IG URE 2 Phot om icrograpli in Ca se 5 S h ounne En lareeaacute D e n se iy B aso p iulic Olig o d end ro cytc N ucle i ioit li L o( 01

N uclear Detail ( Hemato s vlin and EOJin Slllin Xf50) Oligoden d roc y te n uclei of no rmal size Ole h own ampy t h e

arro ios a (

1]

e

iexcl

e

11 e

F IG UR E 4 P hotom icrograph in Ca se 5 S h ounn g 1lt00 En shyIarged Ot ig od endroc yt e N uclei Coru ainin g E osm ophilic JIshy

clusto n s ( H em at ox yli n and E osin S tain X 900 ) A n oligo den dr ocy t e ll u ce lLJ 01 norma l siz e iacute iexclIOiexclmiddot n th r

loioer le]t co m er

vas d cscribed a s a trophi c I n al ihc ot licr cases ihe optic disks either we re sta ted to be norma l 0 1 el e

not spccifically men tioned in none was thei e papii- led erna

T h irt een patien ts had ab norrnal iti es 01 spcech I n 7 the a bnormal ify VI as an aphasia gene ra ny wi th both expressive an do receptive cornp oncnt s tha r co uld

E

11

Vol 265 No 17 PROCRESSI VE LE UK OE NC EPHAL OPATHY -- RI CHARD SO N 82 1

be rel aterl to ex tensivo lesions in th e dominant (left ) cerebra l hemiacutesphe re In the 6 orher s it was a dysshy

arthria Sensory im pa irme n t in volving one side of th e bod y

as recorded in 4 cases This was associa ted with a hcmi pa resis on th e same side in 3 In th e case of L loyd and Ur ich th e onl y evide nce of a unila teral disord er was numbncss down th e left side of th e boc1y wi th im pa ir ed sensat ion and d irn ini sh ed vibrashytion sense below the left knee

Im pa irrnen t in swa llowing ( dysphagia ) pro ba bly occurred in many of th e pa tien ts as th e end neared ir was speci fica IJy recorded how ever in on ly 4

In 2 pa Lients (Cases 8 a nd 9 ) the pri ncipal ncushyrologic sym ptorns a nd signs were referable to lesions in the cerebe llum and brain stem These consisted of vershyt igo a tende ncy to Iall to one side (Case 8 ) nystagshymus (Case 9) dysph agia (C ase 9) unilateral a taxia (presen t a lso in Case 6 ) and in Case 9 crossed signs (left -facia l-m usce wea kn ess right-sided a taxia)

Unsteadiness oiacute gai t not further specified w as reshycorde d in 2 cases In a sing le case (Case 2 of Halshylervord en ) th ere was a mavement disarder of a type associa ted with basal-gangion disease ~ that is gene ra lized choreiform mo vemen ts

H eadach es were inf requ ent They were m ention ed as a pr ominent symp tom in on ly 2 cases and were eit her absen t or minimal in th e o ther s None of the pashytient s had convu lsive seizures

i Cerebrospinal-Fluid Findings

A consistent and significan t Iearure of the en tire group of cases was th e minimal degr ee of abnormality in the cereb rospina l fluid T hus of the 11 cases in which th e cerebros pina l fluid was exa mined th e findmiddot ings were en tire ly normal in 6 In 2 the onl y abnorshymalit y was a sligh t elevat ion of pressur e (275 mm and 200 mm la) A sligbt in crease in ce Jls was recordshyed in 2 ~ 25 lymphocytes per cu bic millimeter (C ase 1) and 6 white blood celis per cubic mitlimeter ll the cell cou n t was normal or not mentioned in th e others In 2 cases there were minimal eleva tions of to ta l protein a s light rise 7 and 50 mg per 100 ml l1

respecti vely

Electroencephalographic Findings

Electroencephalograpby was a bno rmal in every case in wh ich it was done (7 of the 22 ) The re ports were kindly reviewed by D r J ohn A Abbott who summ ashyr iacutezed the findings as f01l0s D iffuse sow-wave (delta 0 1 th eta ) actiacutevi ty of a sort in no way distin ctive of this disorder with normal activity pe rsisting 01

obliterat ed a nd wirh asym me tr ies correspon ding wit h the structura l abnorrnali ties in 1 case (Case 1) flatshy

The ca~e oC Fisher e l al8 (who kindly allolcd me ~o see their unp ubliexclshed ma nusc riacutept ) is no t indudcd In thiacutes the pIOtcin was elevated (43j mg per l OO mL ) on a single cX3mina tion clone whi le t-h e pa rient was under obse latjon rOl chro nic periph era l neuropltHhy bdorc evi middot cltn cc oC cerebra l d lsease had appearecl

tenin g and sharp waves were noted on tb e side of greater struc tu ral a bnorrnali ty

Radio logic Findings

Plain films of the skul l whenever taken inva r iabl y were nor mal In a ll 3 cases in wh ich pn eu moenc ephashylography was performed (Case 6 a nd those of C hrisshytensen and Fog and Bat ern an et al ) the findings exc lude d a space-occupying lesiono In the on ly case in which cereb ral angiog raphy was done tbi s showed a normal va scular pattern

A Iocalization study using a radioac tive iso tope (As ) wa s don e in on ly 1 ca se (Case 2 ) with normal find ings

PathologicaJ Aspects

Alt hough the lesions in the cen tral nervou s syst em were of the same character in a l 22 cases th ey varie d considerably from case to ea se in location and cx tc rrt A s a rule thc y w cro JT10St n un ic rous in the cere bral hernispheres bu iacute oiacuteten the brain stern and cere be tlum were severely affcc ted The spina I cord when exarnined was normal or at m ost showed minishymal changes In the pre vious publication evidence was give n for considering progr essive mutifocaJ leukoshyencepha lopathy to be a dist inct neuropathologic en tiacutety that cannot be classified with hitherto recognized diseases of the cen tra l nervous system The com binashytion of multiple demyelin ative lesions of a l po ssiacuteble gra da tions in size an d stage of evolu tion (F ig 1) with remar kable cha nges in oligodendroey tes (F ig 2) and oft en in astrocytes (F ig 3 ) does not occur in any othe r disease known to me The appe a rance of th e lesions suggests th at prog ression of th e c1in ica disorde r result s from th e enJargeme n t and confluen ce oI sma lI lesions and th e con tin uous ad ditions oI new ones The ea rlier d escription 1 placed conside rable emphasis on th e hyperplasia of ast rocy tes iexclnto bizarre gian t Ior ms whiacutech resembled neopl astic ce lIs It is now a pparent however th at the astrocytes do not unde rgo this altera bo n in al cases On th e o ther hand en la rgemen t oI oligode ndrocyte nuclei with dense basophiJia an d loss of nuclear det ail Iacutes inshyvaria bly presen t Eosinophilic intranuclear inclusions have been seen within th ese ab normal oligo de ndroshycytes in nearly every case (F ig 4 ) but mal no t always be found (lor exam ple in C ase 4 and in the case oI Dolman and Ca irnsl1

) Exp elience with the ad di tiona l cases here repor ted has sugge sted sti ll ano the r fonn of ce llu lar hypert rophy unkn own to us from previous expel ience In Cases 2 8 and 9 th erc were in esions in th e gra nule -ce ll layer of the cer eshybellar cortex Iarge nucl ei wh ich [rom th eir form loca tion -_and a rrangernen t have been tentati vely iden tified as altered cere belIar gra nule neurons (F igmiddot 5 ) Althoug h the identity of these cels ha s not been established beyond all doubt thi s ce ll- change seemS

r

=- -

822 THE -EW ENG LA N D

to be of suflicient int erest to wai rant a pre liminary note

Frcun s 5 Ph otonn crogr ap ]i o i lp e C ereb ellar C ortes in Case 8 Shoioing Llnus uai Nu elei m th e Granular L ay er ( H emashy

tox y lin arul E osin S ta in X250 )

Near ilie t op [u st be ncatn the sp artely ce llu lar molecular laye r al e norm al granule neu aniexcl lJelow th eJe simii arl) grOllped m io clu sters m e lal ger n u clei bel onging lO eell r

Iha l may be path ologrcall y en lar ged gran ule n eu l on s

The earlier im prcssion tha t lh e lesions ha middotc a pre shydom ina ndy pe rivascular dis tri bution 1 h as DOt been borne O L1L b y th e p e~ en t stu di es Exa mina tiacuteon 01 ser ia l SCltlions gen er ally cliscoses at Jeast one m in u te esse ith in e en smal l e~ions bu t in view o f the Iarg e n um bers of such esse ls nonnally pre~en t in the braiacuten iL canno l be sta tccl lh a( lhis r ela tion iacutes a significa n t on e T his conelusion is in agreernen t wi lh iexclhe find ings of F isber e t aLs On t1w ol her hand

JOUR NA L OF MED IC Il E 0 l ~6 1961

ihe add itional case materia l does con firrn lhe pr C iou findi ng th a i infl amma tio n in the Iorrn ol pe ivascu l a~ lymphocyuc in filtra tions is with rarc l cepl ions mi n imal or absen t

T he par hologic changes in orga ns oihei i han the cen tral ncrvous system were in cach l l Se lypieal of n the pa rticular d isea se pr esent T herc wns no e iden ce

P iha t th e cases o iacute ch ro n ic d isease a ssocia ted wit h pro shygrcs s i v~ mu ltifoc a l lcukoe ricepha lopa thy di lfcred [rOI11 ot hc rs o f the same di sease in which chis n eurolooic disorder was p resent A h hough in m ost cases J1e underly ing d isease was such tha t in i tself it would ha e b ccn cxpect ed u lt im a tely to han been fa tal iexcln an y of (he pa t ien ts a p pa re ntly d ied a s a rewiexcl of Che de vastating efTects of the lesions in thc brain 1t seern s rc asonable to su ppose that if th e cerebr a l disease cou ld ha vc bee n pre ven ied 0 1 eflecrivelv

[( (

tr eated m a ny of the patien ts wo uld h ave SHVi ed ur

tilonger th an they di d

Etiologi c Consid erations

The cause and p athogenesis o f progressive muln shyfoca l leu koen cephalop athy rem ain uul now n H owshy

I eve r it occu rs with cond i tions in wh ich iacutemmu noshylogic h ypo re a c tivi ty has b cen de rno nsn-atcd (Iym shy Il

reph om asV leu kem ia13 sarcoidosisUl ca rcinornato shy (

S i S ~ a nd o ld age9) and thcrcforc decrea sed resisishy

ance to inf ection s m ight be expected Thc ch anges in o ligoclen d rocy tic an d as tr ocyt ic nuclei c1 escri bed a boye are consisten t with th e cyto pa tho logic effects a l a virus w hich in th e p resen ce of impaired iin shymu no logic respon ses could result in a typical lesions I t is hopecl that in the Iutu re cases of thi s sort wi ll be recognizecl so th al ap propria te investigat ions may be underta ken duri ng life and stu dies ca rr iecl out on fres h tissues ob taine d at au to psy

SUMMARY AND CONCLUSIONS

T en cases of progr essive multifocal leuk oen ccphalop shya thy a n un usual ce ntr al -ne rvous-systern d isease with

j

distin ctive neu ro pathologic fea tur es occu rring la te in L

the co u rse of severa] forros of chronic illn css ar e presented 10 these are aclded 12 cases stud ied by others g iving a to tal of 22 13

Th e ou tsra nd ing cliacuten ica Iea tures of th is con dition a re t hose uf a rapid ly p rogressi e focal or aS)l11me tric d isord cr of ihc bra in unaccompa ni ed by increascd fl in tracrania l p reSSllre 0 1 sign ifican l cereb rospina I-fluid i

changes Ir has mos t fr cgu en tly been asociatcd w ith ma lign a nt lym phoma or leuktm ia bu l may oCCl r ilh sa rcoidosis carcinom al osis m iliar) tuhcrcdoSis 01 rare acl ancccl age with0u t neoplaslic nI ~ a n u shy

Irloma lous d isease Ei den cc iacutes ci ted that lhe on e bctor CUl11 111 0n l() bull

a 11 the ch ro n icdi seases me l VI iexclth in iexcllis series is lhe p reence o relat ie imm 1l101ogie u nn pont ellemiddot T he cam e nf l og nsi e m uli roca l JeukcHncepbalop shya thy rc m ltl ins Bntildel~no n hu thE sugg eslion i ~ made

e

Vo] 2G5 N o 17 EF FECT O f C H LO R PRO PAM ID E - SIN GER ET AL 82 )

t hat the nervous-system lesions are cons isten t wi th an atypical form of virus infecti on

Further progress in un de rstanding th is cond it ion will depencl upon the stu cly of ca ses during life a nd of Iresh tissue samples For these purp oses recogshynition of cases during Iife which shoul d now be possib le is u rgecl

T wo a dd itiona l cas es both asso ciatc d with long stand ing chr onic lvrnph a tic leukernia have kiridl v bcen b rough t to mv altcn tio n a nd I have been permit ted to exami ne ne uro shypatho louica l ser tion s fr om both The first fra m DI Ell iott L M an call D ep artme nt oi Neuro loav J efferson Med ica Co llege Ph iladelphia Psnn svlvani a an d to be repo rte d by him is thar of a iacuteort v-on e-vear -old man in wh om the on ly ncu roloc ic abnorrna li iy consisted oiacute gene ralized convulsions five d avs before dea th T he secon d fro m D I C L Do lman Dep ar tment of Pa thologv V an co uver Ge ne ral H osp ita l V ancouver B C occu rred in a fift v-eizht-vear- old ma n with a very o rief terminal neuro logic illness who ha d had gen era liacutezed convu lsive seizu res for Iour years referab le to a n olisndend rogiiorna di scovered p ost rnortern as an incishyd ent a l findi ng

Drs R aymon d D Adams Ben jamin Castl em an C h arles S K ub ik Byron r-L W alcsma n an d Ba rry Amasan oC the M a ssach use t t Gener laquo1 Ho pilal P rofessor Jliu H all er shyvorden Max-Planck-In stiwt [uumlr Hirn forschung Giessen Vestern Ge rm any an d D I John F E nders havc given me friendl y help md encollra gcme n t fo r which 1 am inshyd eed gra te iu l r am grea tly indebted to D r W aksman ior im m uno loic advic c and for sULges ting how viral in Iec rioll could ac count fQr th e ne uro patholo gic Jesions in th is series oC cases

R EFERENCES

lo Astro m K middot E Ma nca ll E L and Richardson E P Jr Promiddot grcssive muJtrocal leuko -cncephalopathy h ithc rto u nlccosnized comp Jication oI chronic lymphat ic leukacm ia Qnd Hodgkrns d~scase Drain 81 93- 111 1958

2 Cavanash ] n G rcenba um D Matshal f l H b a nd R ub iacuten shysrc in L J Cerebral d e mve h na uo n assoc iaied with dis or de rs of re ticulocndor hc lia l system L ance 2 524-)iquest9 1959

3 Llovrl O C a nd Urich H Acu re d issemi ua ted dem ycli ua rion 01 hra in associa red wi th lymphosarcoma L ancet 2)29 1959

4 H all e r vor d cn J E igenar t ige und m ch t rubria iacutecrbarc Prcz essc In H a ndb ucti d er C ciSl eskrrwkheiacutet cn V ol 11 (pan 7) D ie A nfit o mie der P SCe OfeTl Edi tccl by O Bum ke 1136 pp Ber lin Spr ingcr 1930 Pp 1063middot1 107

5 W in kelma n N V an d Moorc 11 T Lv m phogra n ulo ma tosis ( Hod ~k i n~ d isease ) of ncrv o us systc m A rch Nc ur ol amp Psvc hi at 45 304-318 1941

6 Batcrnan O ] J- Squ ircs G a nd T hann ha use- S J H odg shyki ns d isease associa tecl with Sch ilders discase An n l n t Al eJ 22 426-431 1945

7 Ch ristcns en E an d Fog M Case of Schilders d iscase in ad ult wi th re ma rks 0 0 e t iolo g-y a nd pa t hog eocs is Acta Jsch iat el neuro iacute S cand inau 30 14 1-154 19] 5

8 F ishcr C 11 Vil1ianls H W a nd Ving E S Ir Co rnbincd cncephalopa t hy an d nc uropa thy wi th carcinoma ] Nc uropo th amp Ex per JVcUoL (i n p rcss

9 H a ller vorden J Personal com mu nica tion 10 Siblcv W A xnd We isb rg er A S Dem yelinat ing d iscase of

bra in in chronic lym nha ttc le ukemia OCCll1TCncc e l c ase in hosba nd of pat ien t with m ili tiple sclero sis A rch N eurol S 3UumlO-3Uumli 1961

11 Dol man C L bull an d Cairns A R M Le ukoc ncephalopathv assoshyciat ed -i th H orlgkins d isease N eu roiacuteo gy 1) 349~353 1961

12 Schi cr 7 W C uta neous ane rgy a n d H odgktrr s discasc N ew E ng ] M cd 250 353-361 19j 4

13 Epste in V L I nd uc tion o iacute allerg ic con tac t de rma titis in patlcnts w ilh 1)JOphOlna 4 Icukcmia co mple xo ] f rtUes1 D erma 30 39 195U

14 K eJly W D Lamb D -L Vareo R L an d Goa d R A_ Inveacutestiga tion oC H odgkin d iampease wl th respe ct to prohkm 01 ho rno h-iexclnp llJ) la tion 1 7111 N nc Y o rk Acad S e B7 IB7-2uuml2 1960

15 Fr lOu G J S tlldy of Cll la neOlS r eaciexcljons to oid io myciacuten tri choph)shytino and mump s skin te)t ant is cns in patic n ts w it h sarc uiJ mio Yal ] Biot amp M ed 24 533-539 1952

16 Ep s te ln W L and M a yo ck R L [ nJ lc t)OO oC a l h rs~c c on lac t c1 erm~iexcl i ti s_ in pa l ien ll ifu arcoidos Proc Soco Fx per Biol amp Med 95 186 1957

17 Logan J Ddayltd typc o [ alergic leadjon in cancer ate rcd respo ltse t O hJbcrcu li n a ncl m llmps vi ros N cw Zealand M 55 4)amp-41O 19) 6

18 Sou tham C M aud M oore A_ E I ndn ced im mu ni y to ca nce r 19~~ h omo grafts in man o An Tt N ew Y o rk A cad S e 73 635-653

19 Ca ndti~ G LaUergie f ub erc rJeuJe che z lhomme Coll ecti on di llnJf i( u l P aJteur 338 pp Pari$ FJammario n 1946 Pp -4042 and 61

CHLORPROPAMIDE IN PATIENTS ON HIGH IN SULIN DOSAGE

DAVID L SINGE R M D t R OBERT C S T EW ART MD t AN D D AVID HURWlT Z lvLD sect

BOST ON

A RE CEN T review of patien ts [r om w e D iabe tes C lin ic of the Boston C ity H ospita l r eveal ed a

substa n tia l num be r do ing well OIl ch lorpropamidell hose insu lin requir em en t had exceeded 50 uIlits Because it has bec(Piexclne a lm ost ax iomatic tha t th ese palien ts sho uld not be expecte d to do well on t he sulfonylu rea type of agen t the subject was pursuecl furthe r Adcli tiona l p a tien ts reeciving 50 un its of in shysul in 0 1 more a day we re transferred to chlorp ro p ashy

--Frorn thc D Labeles Clinic and the T hornJike 11cmor ial Labora tory Sccon d and Fou rth (H arvard) M cJ icat Se rvjecs Bostoll City H ospital and lhe De par tme nt of M edicine H a rva rd M edical School

Aidcd b y a gran l (2Amiddot5060) (om lhe U ni ted Staacutet cs Public H ea lth Se-rvic~

tRt s e~rch fe llow in medicin e l H arvard M edicaiacute St-hool rt 5carch fellow T hornd lkc M emorial L abora to ry

t Assislan t in medicin e H arvard M ed ica l School iexcl lt~ss1 s t i ng phy~ i dan llm ton Ci ty H ospi tal

Sit an t cJinca l p rofesso r o) m ed ici ne H a rvar d M edl cal 5chool chieL D iabe tes CJin ic aDd vislt ing physlc iall Sccond an d Fourlh (Har shyvar J ~ M edical Servic ~o Bost on Ciry H osp ita l c1uef lfed ical Ser vice 1ount Aub urn HO-5 p i m l ~ Cambridge Massach u~e t ts

~KlDd l y supp hed as D ~ b i n e se b Chltirlcs Pfiu r Jld C O J(Ip a Tl) Tncorporat ed Brool d yn New Y OImiddotk

m ide ancl their response ta bu lated T he resu l ts In

28 pa tie n ts constitu te th e basis 01 thi s report

METHODS AlD M AT ERI ALS

Crileria for inclu sion in the stu d y wer e a s follows th e d iabe tes was of th e m a turity -on set type an d reshyq ui red 50 units of ins ul in or m ore per day al the tim e of transfer to chlorp ropam idej pa tients wit h a hi sto ry of diabe tic acidos is we re excJu ded (ca rbon d iox icl e beJow 15 m illiequiv per lite r ) an d all pn shytients m ust have been main tai n ed on chl orp rop am ide long enough to m alee a cJea r eva luation o f con trol If a goocl r espo nse wa s ob tai ne d a placebo triaJ las giacuteven in ac cordance wiacuteth th e sing le-b lin d cl esign al lhe study a s ou tline cl below The charts of a ll pashytien ts=receiving ch lorpropam id e belore - J une 1960 were -exam ined an d al those ful filliacuteng the cri teria statecL-bo ve were ind udd I n ad cJ iiion a ll pa tien ls seen ircthe clin iacutec between Jul y 1959 a nd J une

amp

I

Vol 265 No iexcl 7 PR OGRESSrVE LEUKOENCEPHALOPATTIY - - RI CHARD SON Bl 9

Although the pre -existing disease was freq uentIy whi ch the record s are sufficien tly complete on th ese of many years du ra tion as iacutendic ated III Table 1 the aspec ts ncurologic illness was re lativ ely bri cf On an averag e T he neurologic sym ptoms and slgns 111 mos t cases le ra n a cou rse from onset lo dea th of th rce to Iour were th ose of a di fiacuteuse but asymmet rica l disease of

TBtE 1 (Con du ded)

Prcscnt report

Ciexclse ) 1

Case 3

Cose 5

Casp 6

Case 7

Case O

Ca se 9

A GE

j-r

71

73

42

55

49

31

82

68

35

A SS OClATID D l S EASZ

Dl ACN O S IS D U RA nON

F C hronic lvrnpha tic 16 yr lcukem ia

F Chro uic lvrnpha tic 5 yr lc u kcm ia

M H odgki n s di sease 10 mo

M C b ron ic rnyc log eno us 2Y~ v r le u ke rn ia

M Lymphosarcorna 2Yl yr

M Hodgkins d iscasc i )T

Coron ary -ar terv plusmn15 yr disease healed a pical tubercushylosis

M Cbro nie myelogen ou s 2 vr Ic ukem la

F CarCllomalosis (pri- 2 yr ma ry 50l1 rce blteast )

M LYUlphosa rcom a 7 yr ( lym rhocY iic Jymp Hgtma )

N EUROlOG IC D l S0 RDIn

l IU N CI PAL MiexclN IF L s nnONS

Pro grc ssive lciacutet -sided hern ipare shysis clcrne nt in visual im shypa irmc nt pro gressmg to ulind uess d ysa rthria

rrrilability amp dcprcs sion headshyac h e anhas ia r-ight -sided hcm ipare sis r igh t-sided hoshymo n ymous hem iancpsia lcad ing ro b lin d ness

Aphasia r-igh t-sided hcmiparcshys iso

Lef t-sid cd h em ipa rcsis - dvsar shyt h r-ia em o tio na l labilit v

R ight -sided he mipa resis intclshylec tual imp a irment la ter aphasia

Ri gh t- sidcd h cmorrym ou s h CIDlshyanops ia amp h emipares is Icf t shysided cere bellar a taxia Ia ter b lind ness

Mental slow ness dysarthria mi n ima l lef t-sid ed h emishypare sis

V er t igo with Ialling to lef t d cmc ntia ter-mi nali v lcf tshysided hernipa re s is

Ver liacutego dysphagia leH-fac ial shymuscle weakness a t altla oC righ t Jimbo nYltagmus

Progressive aphasia amp rish tshysidc d hcmi parcsis dy~ -ph ag ia j rclmiddotminiquestlIl YI coIna

4 mo

middot1 mo

2 mo

ruacuteo

3 roo

7 mo

1 mo

3middotwk

2 mo

3 ~ fil a

O U r ST I N DJK G N E LlRor l H OLOG1C

FF_T lru s

Ri gh r occip ital rcgion most seve rcl y affec- rcd carly Icshysions in le iacute t o ccipi l-a l reshygio n man y gia n t asn-oshyc vtc s sorn e wit h mi toses

WidesprcJcl bilateral iesions most extensivo in IeIt p a r-rcto-ooci p itnl r cgion i ma n y lesio ns in b ra in s tr-rn amp r-e reh c-H a r whi te m at te r pecu lia r ce ll cha nges in cc reb e llcr g ran ~ ll iexcl r Iayer c f Cases 3 amp 9 )

Mulii ple srnall Ioc i mos r abuuda n t in IcUacute pa r ie tal rc gicn gia n t as rrc cv res rareo

Ra thcr aparsc lcsions hi la tcrshya l1y b u r ehie Ay rig h r I rontoparietal no gia nt astroc v tes p lasma cel ls in lcsic ns

M ult ipl c bilateral lcsio ns t yp ical cell chauges

Se ver e lesione b ila re raflv most cx te nsi ve po s te ri o r-Iy amp in left cereb ral h emishysphc re ~ le iacuter ccre bcllar whi te ma t rer sevcre ly affecleu right less so no gia nt as troshye vt es

Sca rtc rcd srnall lcsions in ce re bral h e rrrisp h e r-es ano br ai n stcm many giant a SA trocyres 1 with m itosis

Wjdcsprcad lesic ns m ore exshyt ensivc in rizh r ce r cbr a l hemi sp here uuusual lcsions in granular layer oCcerebclshylar cort egt with rema rkabte cell changes

Lcsions mosl ext ensive iexclu se r ebcll um amp brain stcm fe in c erehra l hemispheres peculiar changes in ce reshyhenar cortex as in Cases 2 amp 8

Extensive ks ions iacuten both cereshybra l hemip hen~ s m Ore o n leh typicaI c cll c han gcs

months HaJlervoIden s first case in which neurologic sym ptoms began one year before death is excep tiona1

TAll L E 2 Pathologicll Sta fes Assoeiated wilh Plogressive M ult ifocal Le ukoencephalojJathy

OJ SEASl

H oclgl in IS di scase ChronIacutec Iym phatic lcukem i Lymphosarcoma Chroni c mtel ogen 0t15 leukemia Sarco idosis C) lCinomalosis wIJlilttry lubc-rcul o5is Coronar) hCltl T t ulscas U nk nown (old age )

TOl a l

No Of CASF$

6 ~

3 2 2 2

22

the cerebral hemispheIes H emiparesis) spastic oI f1 accid was fr equ ent occurring in 17 of lhe 22 cases (9 Idt and 8 right) Bilateral hemiparesis often ocshycurre d in th e terminal phases of the illness bu t was neveI an ea rly sign o In the case rep orted by Dolman and Cairns hemiparesis eventua lly bila teral was prec eded by unila teral ataxia of the limbs and hom oshyla teral lower-cr ania l-ne rve pal sies Some degree of men tal change con sistin g o[ impair ment o[ a war eness 01 orientat ion decline in in lel1ectual abil ities and (in sorne cases) abnorrnal emotional responses occurrec1 sooner oI la teI in nearl y every case

Viuacuteon was irnpai red in a large propor tion iquestf cases Seveiexclr--patients had eeneralizerl visual loss froro the first and 5 had a homonymous hemianopsia Four of the s~12 pa tients becam e totally blind aJthough the pupifi con tinued to react to light T he changes in

In 4 cases the du ra tion oE the neurologic ilne ss Nas one month 01 less The onset wa s gradua l or insidious anc th e COLme relcnt lessly p rogressie in a l cases in

~-

820 T HE NE W ENGLAND

VISlOll mal be ascribed in eac h case to lesions in the visual -projection fibers oiacute the occipi ta l lobes O ther

F IG U R G l I 0 w - P oul e1 P h o t o m ic rogr a iacuterh 0 1 t h e C ereb ra l Cort es an d White M al ler in Case 5 Sh ounng M u tti ple D em Yelin a iw L esion s o] Va ry in g S iee ( L ay a Al et h od [or

Myelin X 3)

FIG UR E 3 Photo m icrograb i 01 a Gian A strocyt e unt h Mul tiple H yp erchrom atic Iuele in C ase Hem at ox y lm

an d E osin S ta in X 900)

ocular a bnonna lities were considerabl y less I req uent Para lysis of con j ugate gaze to the pare tic sicle in ihe pr csen cc of a hemi paresis was occasionall y rccorded (2 cases) nyslagmu s was rnen t io ned in 2 T he on ly c lear isola ted extraocu la r-rnusc le pa lsy was a la teral rectus weakness in Case 2 In the case p resen ted by Fi shcr el a 18 a t ransitory optic neu ri tis preceding the gen eral ized neurolog iacutec illness was associated with

~ Pos t - mo r t cm c-cam ina rio u of the opt ic n er~~ sho wcd no lcvion s

JO URNAL QF MEDICIN E O L 26 1961 ( unila tera l pallor of the opt ic d isk and in tb t I llaquo~ d T h a oDa ternan -gtqUl res an annbau scr- i he Iciacute t d isk Cl

al

h( L di b( 11middot

~ (l(

li

1(

d 1

l i 11

F IG URE 2 Phot om icrograpli in Ca se 5 S h ounne En lareeaacute D e n se iy B aso p iulic Olig o d end ro cytc N ucle i ioit li L o( 01

N uclear Detail ( Hemato s vlin and EOJin Slllin Xf50) Oligoden d roc y te n uclei of no rmal size Ole h own ampy t h e

arro ios a (

1]

e

iexcl

e

11 e

F IG UR E 4 P hotom icrograph in Ca se 5 S h ounn g 1lt00 En shyIarged Ot ig od endroc yt e N uclei Coru ainin g E osm ophilic JIshy

clusto n s ( H em at ox yli n and E osin S tain X 900 ) A n oligo den dr ocy t e ll u ce lLJ 01 norma l siz e iacute iexclIOiexclmiddot n th r

loioer le]t co m er

vas d cscribed a s a trophi c I n al ihc ot licr cases ihe optic disks either we re sta ted to be norma l 0 1 el e

not spccifically men tioned in none was thei e papii- led erna

T h irt een patien ts had ab norrnal iti es 01 spcech I n 7 the a bnormal ify VI as an aphasia gene ra ny wi th both expressive an do receptive cornp oncnt s tha r co uld

E

11

Vol 265 No 17 PROCRESSI VE LE UK OE NC EPHAL OPATHY -- RI CHARD SO N 82 1

be rel aterl to ex tensivo lesions in th e dominant (left ) cerebra l hemiacutesphe re In the 6 orher s it was a dysshy

arthria Sensory im pa irme n t in volving one side of th e bod y

as recorded in 4 cases This was associa ted with a hcmi pa resis on th e same side in 3 In th e case of L loyd and Ur ich th e onl y evide nce of a unila teral disord er was numbncss down th e left side of th e boc1y wi th im pa ir ed sensat ion and d irn ini sh ed vibrashytion sense below the left knee

Im pa irrnen t in swa llowing ( dysphagia ) pro ba bly occurred in many of th e pa tien ts as th e end neared ir was speci fica IJy recorded how ever in on ly 4

In 2 pa Lients (Cases 8 a nd 9 ) the pri ncipal ncushyrologic sym ptorns a nd signs were referable to lesions in the cerebe llum and brain stem These consisted of vershyt igo a tende ncy to Iall to one side (Case 8 ) nystagshymus (Case 9) dysph agia (C ase 9) unilateral a taxia (presen t a lso in Case 6 ) and in Case 9 crossed signs (left -facia l-m usce wea kn ess right-sided a taxia)

Unsteadiness oiacute gai t not further specified w as reshycorde d in 2 cases In a sing le case (Case 2 of Halshylervord en ) th ere was a mavement disarder of a type associa ted with basal-gangion disease ~ that is gene ra lized choreiform mo vemen ts

H eadach es were inf requ ent They were m ention ed as a pr ominent symp tom in on ly 2 cases and were eit her absen t or minimal in th e o ther s None of the pashytient s had convu lsive seizures

i Cerebrospinal-Fluid Findings

A consistent and significan t Iearure of the en tire group of cases was th e minimal degr ee of abnormality in the cereb rospina l fluid T hus of the 11 cases in which th e cerebros pina l fluid was exa mined th e findmiddot ings were en tire ly normal in 6 In 2 the onl y abnorshymalit y was a sligh t elevat ion of pressur e (275 mm and 200 mm la) A sligbt in crease in ce Jls was recordshyed in 2 ~ 25 lymphocytes per cu bic millimeter (C ase 1) and 6 white blood celis per cubic mitlimeter ll the cell cou n t was normal or not mentioned in th e others In 2 cases there were minimal eleva tions of to ta l protein a s light rise 7 and 50 mg per 100 ml l1

respecti vely

Electroencephalographic Findings

Electroencephalograpby was a bno rmal in every case in wh ich it was done (7 of the 22 ) The re ports were kindly reviewed by D r J ohn A Abbott who summ ashyr iacutezed the findings as f01l0s D iffuse sow-wave (delta 0 1 th eta ) actiacutevi ty of a sort in no way distin ctive of this disorder with normal activity pe rsisting 01

obliterat ed a nd wirh asym me tr ies correspon ding wit h the structura l abnorrnali ties in 1 case (Case 1) flatshy

The ca~e oC Fisher e l al8 (who kindly allolcd me ~o see their unp ubliexclshed ma nusc riacutept ) is no t indudcd In thiacutes the pIOtcin was elevated (43j mg per l OO mL ) on a single cX3mina tion clone whi le t-h e pa rient was under obse latjon rOl chro nic periph era l neuropltHhy bdorc evi middot cltn cc oC cerebra l d lsease had appearecl

tenin g and sharp waves were noted on tb e side of greater struc tu ral a bnorrnali ty

Radio logic Findings

Plain films of the skul l whenever taken inva r iabl y were nor mal In a ll 3 cases in wh ich pn eu moenc ephashylography was performed (Case 6 a nd those of C hrisshytensen and Fog and Bat ern an et al ) the findings exc lude d a space-occupying lesiono In the on ly case in which cereb ral angiog raphy was done tbi s showed a normal va scular pattern

A Iocalization study using a radioac tive iso tope (As ) wa s don e in on ly 1 ca se (Case 2 ) with normal find ings

PathologicaJ Aspects

Alt hough the lesions in the cen tral nervou s syst em were of the same character in a l 22 cases th ey varie d considerably from case to ea se in location and cx tc rrt A s a rule thc y w cro JT10St n un ic rous in the cere bral hernispheres bu iacute oiacuteten the brain stern and cere be tlum were severely affcc ted The spina I cord when exarnined was normal or at m ost showed minishymal changes In the pre vious publication evidence was give n for considering progr essive mutifocaJ leukoshyencepha lopathy to be a dist inct neuropathologic en tiacutety that cannot be classified with hitherto recognized diseases of the cen tra l nervous system The com binashytion of multiple demyelin ative lesions of a l po ssiacuteble gra da tions in size an d stage of evolu tion (F ig 1) with remar kable cha nges in oligodendroey tes (F ig 2) and oft en in astrocytes (F ig 3 ) does not occur in any othe r disease known to me The appe a rance of th e lesions suggests th at prog ression of th e c1in ica disorde r result s from th e enJargeme n t and confluen ce oI sma lI lesions and th e con tin uous ad ditions oI new ones The ea rlier d escription 1 placed conside rable emphasis on th e hyperplasia of ast rocy tes iexclnto bizarre gian t Ior ms whiacutech resembled neopl astic ce lIs It is now a pparent however th at the astrocytes do not unde rgo this altera bo n in al cases On th e o ther hand en la rgemen t oI oligode ndrocyte nuclei with dense basophiJia an d loss of nuclear det ail Iacutes inshyvaria bly presen t Eosinophilic intranuclear inclusions have been seen within th ese ab normal oligo de ndroshycytes in nearly every case (F ig 4 ) but mal no t always be found (lor exam ple in C ase 4 and in the case oI Dolman and Ca irnsl1

) Exp elience with the ad di tiona l cases here repor ted has sugge sted sti ll ano the r fonn of ce llu lar hypert rophy unkn own to us from previous expel ience In Cases 2 8 and 9 th erc were in esions in th e gra nule -ce ll layer of the cer eshybellar cortex Iarge nucl ei wh ich [rom th eir form loca tion -_and a rrangernen t have been tentati vely iden tified as altered cere belIar gra nule neurons (F igmiddot 5 ) Althoug h the identity of these cels ha s not been established beyond all doubt thi s ce ll- change seemS

r

=- -

822 THE -EW ENG LA N D

to be of suflicient int erest to wai rant a pre liminary note

Frcun s 5 Ph otonn crogr ap ]i o i lp e C ereb ellar C ortes in Case 8 Shoioing Llnus uai Nu elei m th e Granular L ay er ( H emashy

tox y lin arul E osin S ta in X250 )

Near ilie t op [u st be ncatn the sp artely ce llu lar molecular laye r al e norm al granule neu aniexcl lJelow th eJe simii arl) grOllped m io clu sters m e lal ger n u clei bel onging lO eell r

Iha l may be path ologrcall y en lar ged gran ule n eu l on s

The earlier im prcssion tha t lh e lesions ha middotc a pre shydom ina ndy pe rivascular dis tri bution 1 h as DOt been borne O L1L b y th e p e~ en t stu di es Exa mina tiacuteon 01 ser ia l SCltlions gen er ally cliscoses at Jeast one m in u te esse ith in e en smal l e~ions bu t in view o f the Iarg e n um bers of such esse ls nonnally pre~en t in the braiacuten iL canno l be sta tccl lh a( lhis r ela tion iacutes a significa n t on e T his conelusion is in agreernen t wi lh iexclhe find ings of F isber e t aLs On t1w ol her hand

JOUR NA L OF MED IC Il E 0 l ~6 1961

ihe add itional case materia l does con firrn lhe pr C iou findi ng th a i infl amma tio n in the Iorrn ol pe ivascu l a~ lymphocyuc in filtra tions is with rarc l cepl ions mi n imal or absen t

T he par hologic changes in orga ns oihei i han the cen tral ncrvous system were in cach l l Se lypieal of n the pa rticular d isea se pr esent T herc wns no e iden ce

P iha t th e cases o iacute ch ro n ic d isease a ssocia ted wit h pro shygrcs s i v~ mu ltifoc a l lcukoe ricepha lopa thy di lfcred [rOI11 ot hc rs o f the same di sease in which chis n eurolooic disorder was p resent A h hough in m ost cases J1e underly ing d isease was such tha t in i tself it would ha e b ccn cxpect ed u lt im a tely to han been fa tal iexcln an y of (he pa t ien ts a p pa re ntly d ied a s a rewiexcl of Che de vastating efTects of the lesions in thc brain 1t seern s rc asonable to su ppose that if th e cerebr a l disease cou ld ha vc bee n pre ven ied 0 1 eflecrivelv

[( (

tr eated m a ny of the patien ts wo uld h ave SHVi ed ur

tilonger th an they di d

Etiologi c Consid erations

The cause and p athogenesis o f progressive muln shyfoca l leu koen cephalop athy rem ain uul now n H owshy

I eve r it occu rs with cond i tions in wh ich iacutemmu noshylogic h ypo re a c tivi ty has b cen de rno nsn-atcd (Iym shy Il

reph om asV leu kem ia13 sarcoidosisUl ca rcinornato shy (

S i S ~ a nd o ld age9) and thcrcforc decrea sed resisishy

ance to inf ection s m ight be expected Thc ch anges in o ligoclen d rocy tic an d as tr ocyt ic nuclei c1 escri bed a boye are consisten t with th e cyto pa tho logic effects a l a virus w hich in th e p resen ce of impaired iin shymu no logic respon ses could result in a typical lesions I t is hopecl that in the Iutu re cases of thi s sort wi ll be recognizecl so th al ap propria te investigat ions may be underta ken duri ng life and stu dies ca rr iecl out on fres h tissues ob taine d at au to psy

SUMMARY AND CONCLUSIONS

T en cases of progr essive multifocal leuk oen ccphalop shya thy a n un usual ce ntr al -ne rvous-systern d isease with

j

distin ctive neu ro pathologic fea tur es occu rring la te in L

the co u rse of severa] forros of chronic illn css ar e presented 10 these are aclded 12 cases stud ied by others g iving a to tal of 22 13

Th e ou tsra nd ing cliacuten ica Iea tures of th is con dition a re t hose uf a rapid ly p rogressi e focal or aS)l11me tric d isord cr of ihc bra in unaccompa ni ed by increascd fl in tracrania l p reSSllre 0 1 sign ifican l cereb rospina I-fluid i

changes Ir has mos t fr cgu en tly been asociatcd w ith ma lign a nt lym phoma or leuktm ia bu l may oCCl r ilh sa rcoidosis carcinom al osis m iliar) tuhcrcdoSis 01 rare acl ancccl age with0u t neoplaslic nI ~ a n u shy

Irloma lous d isease Ei den cc iacutes ci ted that lhe on e bctor CUl11 111 0n l() bull

a 11 the ch ro n icdi seases me l VI iexclth in iexcllis series is lhe p reence o relat ie imm 1l101ogie u nn pont ellemiddot T he cam e nf l og nsi e m uli roca l JeukcHncepbalop shya thy rc m ltl ins Bntildel~no n hu thE sugg eslion i ~ made

e

Vo] 2G5 N o 17 EF FECT O f C H LO R PRO PAM ID E - SIN GER ET AL 82 )

t hat the nervous-system lesions are cons isten t wi th an atypical form of virus infecti on

Further progress in un de rstanding th is cond it ion will depencl upon the stu cly of ca ses during life a nd of Iresh tissue samples For these purp oses recogshynition of cases during Iife which shoul d now be possib le is u rgecl

T wo a dd itiona l cas es both asso ciatc d with long stand ing chr onic lvrnph a tic leukernia have kiridl v bcen b rough t to mv altcn tio n a nd I have been permit ted to exami ne ne uro shypatho louica l ser tion s fr om both The first fra m DI Ell iott L M an call D ep artme nt oi Neuro loav J efferson Med ica Co llege Ph iladelphia Psnn svlvani a an d to be repo rte d by him is thar of a iacuteort v-on e-vear -old man in wh om the on ly ncu roloc ic abnorrna li iy consisted oiacute gene ralized convulsions five d avs before dea th T he secon d fro m D I C L Do lman Dep ar tment of Pa thologv V an co uver Ge ne ral H osp ita l V ancouver B C occu rred in a fift v-eizht-vear- old ma n with a very o rief terminal neuro logic illness who ha d had gen era liacutezed convu lsive seizu res for Iour years referab le to a n olisndend rogiiorna di scovered p ost rnortern as an incishyd ent a l findi ng

Drs R aymon d D Adams Ben jamin Castl em an C h arles S K ub ik Byron r-L W alcsma n an d Ba rry Amasan oC the M a ssach use t t Gener laquo1 Ho pilal P rofessor Jliu H all er shyvorden Max-Planck-In stiwt [uumlr Hirn forschung Giessen Vestern Ge rm any an d D I John F E nders havc given me friendl y help md encollra gcme n t fo r which 1 am inshyd eed gra te iu l r am grea tly indebted to D r W aksman ior im m uno loic advic c and for sULges ting how viral in Iec rioll could ac count fQr th e ne uro patholo gic Jesions in th is series oC cases

R EFERENCES

lo Astro m K middot E Ma nca ll E L and Richardson E P Jr Promiddot grcssive muJtrocal leuko -cncephalopathy h ithc rto u nlccosnized comp Jication oI chronic lymphat ic leukacm ia Qnd Hodgkrns d~scase Drain 81 93- 111 1958

2 Cavanash ] n G rcenba um D Matshal f l H b a nd R ub iacuten shysrc in L J Cerebral d e mve h na uo n assoc iaied with dis or de rs of re ticulocndor hc lia l system L ance 2 524-)iquest9 1959

3 Llovrl O C a nd Urich H Acu re d issemi ua ted dem ycli ua rion 01 hra in associa red wi th lymphosarcoma L ancet 2)29 1959

4 H all e r vor d cn J E igenar t ige und m ch t rubria iacutecrbarc Prcz essc In H a ndb ucti d er C ciSl eskrrwkheiacutet cn V ol 11 (pan 7) D ie A nfit o mie der P SCe OfeTl Edi tccl by O Bum ke 1136 pp Ber lin Spr ingcr 1930 Pp 1063middot1 107

5 W in kelma n N V an d Moorc 11 T Lv m phogra n ulo ma tosis ( Hod ~k i n~ d isease ) of ncrv o us systc m A rch Nc ur ol amp Psvc hi at 45 304-318 1941

6 Batcrnan O ] J- Squ ircs G a nd T hann ha use- S J H odg shyki ns d isease associa tecl with Sch ilders discase An n l n t Al eJ 22 426-431 1945

7 Ch ristcns en E an d Fog M Case of Schilders d iscase in ad ult wi th re ma rks 0 0 e t iolo g-y a nd pa t hog eocs is Acta Jsch iat el neuro iacute S cand inau 30 14 1-154 19] 5

8 F ishcr C 11 Vil1ianls H W a nd Ving E S Ir Co rnbincd cncephalopa t hy an d nc uropa thy wi th carcinoma ] Nc uropo th amp Ex per JVcUoL (i n p rcss

9 H a ller vorden J Personal com mu nica tion 10 Siblcv W A xnd We isb rg er A S Dem yelinat ing d iscase of

bra in in chronic lym nha ttc le ukemia OCCll1TCncc e l c ase in hosba nd of pat ien t with m ili tiple sclero sis A rch N eurol S 3UumlO-3Uumli 1961

11 Dol man C L bull an d Cairns A R M Le ukoc ncephalopathv assoshyciat ed -i th H orlgkins d isease N eu roiacuteo gy 1) 349~353 1961

12 Schi cr 7 W C uta neous ane rgy a n d H odgktrr s discasc N ew E ng ] M cd 250 353-361 19j 4

13 Epste in V L I nd uc tion o iacute allerg ic con tac t de rma titis in patlcnts w ilh 1)JOphOlna 4 Icukcmia co mple xo ] f rtUes1 D erma 30 39 195U

14 K eJly W D Lamb D -L Vareo R L an d Goa d R A_ Inveacutestiga tion oC H odgkin d iampease wl th respe ct to prohkm 01 ho rno h-iexclnp llJ) la tion 1 7111 N nc Y o rk Acad S e B7 IB7-2uuml2 1960

15 Fr lOu G J S tlldy of Cll la neOlS r eaciexcljons to oid io myciacuten tri choph)shytino and mump s skin te)t ant is cns in patic n ts w it h sarc uiJ mio Yal ] Biot amp M ed 24 533-539 1952

16 Ep s te ln W L and M a yo ck R L [ nJ lc t)OO oC a l h rs~c c on lac t c1 erm~iexcl i ti s_ in pa l ien ll ifu arcoidos Proc Soco Fx per Biol amp Med 95 186 1957

17 Logan J Ddayltd typc o [ alergic leadjon in cancer ate rcd respo ltse t O hJbcrcu li n a ncl m llmps vi ros N cw Zealand M 55 4)amp-41O 19) 6

18 Sou tham C M aud M oore A_ E I ndn ced im mu ni y to ca nce r 19~~ h omo grafts in man o An Tt N ew Y o rk A cad S e 73 635-653

19 Ca ndti~ G LaUergie f ub erc rJeuJe che z lhomme Coll ecti on di llnJf i( u l P aJteur 338 pp Pari$ FJammario n 1946 Pp -4042 and 61

CHLORPROPAMIDE IN PATIENTS ON HIGH IN SULIN DOSAGE

DAVID L SINGE R M D t R OBERT C S T EW ART MD t AN D D AVID HURWlT Z lvLD sect

BOST ON

A RE CEN T review of patien ts [r om w e D iabe tes C lin ic of the Boston C ity H ospita l r eveal ed a

substa n tia l num be r do ing well OIl ch lorpropamidell hose insu lin requir em en t had exceeded 50 uIlits Because it has bec(Piexclne a lm ost ax iomatic tha t th ese palien ts sho uld not be expecte d to do well on t he sulfonylu rea type of agen t the subject was pursuecl furthe r Adcli tiona l p a tien ts reeciving 50 un its of in shysul in 0 1 more a day we re transferred to chlorp ro p ashy

--Frorn thc D Labeles Clinic and the T hornJike 11cmor ial Labora tory Sccon d and Fou rth (H arvard) M cJ icat Se rvjecs Bostoll City H ospital and lhe De par tme nt of M edicine H a rva rd M edical School

Aidcd b y a gran l (2Amiddot5060) (om lhe U ni ted Staacutet cs Public H ea lth Se-rvic~

tRt s e~rch fe llow in medicin e l H arvard M edicaiacute St-hool rt 5carch fellow T hornd lkc M emorial L abora to ry

t Assislan t in medicin e H arvard M ed ica l School iexcl lt~ss1 s t i ng phy~ i dan llm ton Ci ty H ospi tal

Sit an t cJinca l p rofesso r o) m ed ici ne H a rvar d M edl cal 5chool chieL D iabe tes CJin ic aDd vislt ing physlc iall Sccond an d Fourlh (Har shyvar J ~ M edical Servic ~o Bost on Ciry H osp ita l c1uef lfed ical Ser vice 1ount Aub urn HO-5 p i m l ~ Cambridge Massach u~e t ts

~KlDd l y supp hed as D ~ b i n e se b Chltirlcs Pfiu r Jld C O J(Ip a Tl) Tncorporat ed Brool d yn New Y OImiddotk

m ide ancl their response ta bu lated T he resu l ts In

28 pa tie n ts constitu te th e basis 01 thi s report

METHODS AlD M AT ERI ALS

Crileria for inclu sion in the stu d y wer e a s follows th e d iabe tes was of th e m a turity -on set type an d reshyq ui red 50 units of ins ul in or m ore per day al the tim e of transfer to chlorp ropam idej pa tients wit h a hi sto ry of diabe tic acidos is we re excJu ded (ca rbon d iox icl e beJow 15 m illiequiv per lite r ) an d all pn shytients m ust have been main tai n ed on chl orp rop am ide long enough to m alee a cJea r eva luation o f con trol If a goocl r espo nse wa s ob tai ne d a placebo triaJ las giacuteven in ac cordance wiacuteth th e sing le-b lin d cl esign al lhe study a s ou tline cl below The charts of a ll pashytien ts=receiving ch lorpropam id e belore - J une 1960 were -exam ined an d al those ful filliacuteng the cri teria statecL-bo ve were ind udd I n ad cJ iiion a ll pa tien ls seen ircthe clin iacutec between Jul y 1959 a nd J une

amp

820 T HE NE W ENGLAND

VISlOll mal be ascribed in eac h case to lesions in the visual -projection fibers oiacute the occipi ta l lobes O ther

F IG U R G l I 0 w - P oul e1 P h o t o m ic rogr a iacuterh 0 1 t h e C ereb ra l Cort es an d White M al ler in Case 5 Sh ounng M u tti ple D em Yelin a iw L esion s o] Va ry in g S iee ( L ay a Al et h od [or

Myelin X 3)

FIG UR E 3 Photo m icrograb i 01 a Gian A strocyt e unt h Mul tiple H yp erchrom atic Iuele in C ase Hem at ox y lm

an d E osin S ta in X 900)

ocular a bnonna lities were considerabl y less I req uent Para lysis of con j ugate gaze to the pare tic sicle in ihe pr csen cc of a hemi paresis was occasionall y rccorded (2 cases) nyslagmu s was rnen t io ned in 2 T he on ly c lear isola ted extraocu la r-rnusc le pa lsy was a la teral rectus weakness in Case 2 In the case p resen ted by Fi shcr el a 18 a t ransitory optic neu ri tis preceding the gen eral ized neurolog iacutec illness was associated with

~ Pos t - mo r t cm c-cam ina rio u of the opt ic n er~~ sho wcd no lcvion s

JO URNAL QF MEDICIN E O L 26 1961 ( unila tera l pallor of the opt ic d isk and in tb t I llaquo~ d T h a oDa ternan -gtqUl res an annbau scr- i he Iciacute t d isk Cl

al

h( L di b( 11middot

~ (l(

li

1(

d 1

l i 11

F IG URE 2 Phot om icrograpli in Ca se 5 S h ounne En lareeaacute D e n se iy B aso p iulic Olig o d end ro cytc N ucle i ioit li L o( 01

N uclear Detail ( Hemato s vlin and EOJin Slllin Xf50) Oligoden d roc y te n uclei of no rmal size Ole h own ampy t h e

arro ios a (

1]

e

iexcl

e

11 e

F IG UR E 4 P hotom icrograph in Ca se 5 S h ounn g 1lt00 En shyIarged Ot ig od endroc yt e N uclei Coru ainin g E osm ophilic JIshy

clusto n s ( H em at ox yli n and E osin S tain X 900 ) A n oligo den dr ocy t e ll u ce lLJ 01 norma l siz e iacute iexclIOiexclmiddot n th r

loioer le]t co m er

vas d cscribed a s a trophi c I n al ihc ot licr cases ihe optic disks either we re sta ted to be norma l 0 1 el e

not spccifically men tioned in none was thei e papii- led erna

T h irt een patien ts had ab norrnal iti es 01 spcech I n 7 the a bnormal ify VI as an aphasia gene ra ny wi th both expressive an do receptive cornp oncnt s tha r co uld

E

11

Vol 265 No 17 PROCRESSI VE LE UK OE NC EPHAL OPATHY -- RI CHARD SO N 82 1

be rel aterl to ex tensivo lesions in th e dominant (left ) cerebra l hemiacutesphe re In the 6 orher s it was a dysshy

arthria Sensory im pa irme n t in volving one side of th e bod y

as recorded in 4 cases This was associa ted with a hcmi pa resis on th e same side in 3 In th e case of L loyd and Ur ich th e onl y evide nce of a unila teral disord er was numbncss down th e left side of th e boc1y wi th im pa ir ed sensat ion and d irn ini sh ed vibrashytion sense below the left knee

Im pa irrnen t in swa llowing ( dysphagia ) pro ba bly occurred in many of th e pa tien ts as th e end neared ir was speci fica IJy recorded how ever in on ly 4

In 2 pa Lients (Cases 8 a nd 9 ) the pri ncipal ncushyrologic sym ptorns a nd signs were referable to lesions in the cerebe llum and brain stem These consisted of vershyt igo a tende ncy to Iall to one side (Case 8 ) nystagshymus (Case 9) dysph agia (C ase 9) unilateral a taxia (presen t a lso in Case 6 ) and in Case 9 crossed signs (left -facia l-m usce wea kn ess right-sided a taxia)

Unsteadiness oiacute gai t not further specified w as reshycorde d in 2 cases In a sing le case (Case 2 of Halshylervord en ) th ere was a mavement disarder of a type associa ted with basal-gangion disease ~ that is gene ra lized choreiform mo vemen ts

H eadach es were inf requ ent They were m ention ed as a pr ominent symp tom in on ly 2 cases and were eit her absen t or minimal in th e o ther s None of the pashytient s had convu lsive seizures

i Cerebrospinal-Fluid Findings

A consistent and significan t Iearure of the en tire group of cases was th e minimal degr ee of abnormality in the cereb rospina l fluid T hus of the 11 cases in which th e cerebros pina l fluid was exa mined th e findmiddot ings were en tire ly normal in 6 In 2 the onl y abnorshymalit y was a sligh t elevat ion of pressur e (275 mm and 200 mm la) A sligbt in crease in ce Jls was recordshyed in 2 ~ 25 lymphocytes per cu bic millimeter (C ase 1) and 6 white blood celis per cubic mitlimeter ll the cell cou n t was normal or not mentioned in th e others In 2 cases there were minimal eleva tions of to ta l protein a s light rise 7 and 50 mg per 100 ml l1

respecti vely

Electroencephalographic Findings

Electroencephalograpby was a bno rmal in every case in wh ich it was done (7 of the 22 ) The re ports were kindly reviewed by D r J ohn A Abbott who summ ashyr iacutezed the findings as f01l0s D iffuse sow-wave (delta 0 1 th eta ) actiacutevi ty of a sort in no way distin ctive of this disorder with normal activity pe rsisting 01

obliterat ed a nd wirh asym me tr ies correspon ding wit h the structura l abnorrnali ties in 1 case (Case 1) flatshy

The ca~e oC Fisher e l al8 (who kindly allolcd me ~o see their unp ubliexclshed ma nusc riacutept ) is no t indudcd In thiacutes the pIOtcin was elevated (43j mg per l OO mL ) on a single cX3mina tion clone whi le t-h e pa rient was under obse latjon rOl chro nic periph era l neuropltHhy bdorc evi middot cltn cc oC cerebra l d lsease had appearecl

tenin g and sharp waves were noted on tb e side of greater struc tu ral a bnorrnali ty

Radio logic Findings

Plain films of the skul l whenever taken inva r iabl y were nor mal In a ll 3 cases in wh ich pn eu moenc ephashylography was performed (Case 6 a nd those of C hrisshytensen and Fog and Bat ern an et al ) the findings exc lude d a space-occupying lesiono In the on ly case in which cereb ral angiog raphy was done tbi s showed a normal va scular pattern

A Iocalization study using a radioac tive iso tope (As ) wa s don e in on ly 1 ca se (Case 2 ) with normal find ings

PathologicaJ Aspects

Alt hough the lesions in the cen tral nervou s syst em were of the same character in a l 22 cases th ey varie d considerably from case to ea se in location and cx tc rrt A s a rule thc y w cro JT10St n un ic rous in the cere bral hernispheres bu iacute oiacuteten the brain stern and cere be tlum were severely affcc ted The spina I cord when exarnined was normal or at m ost showed minishymal changes In the pre vious publication evidence was give n for considering progr essive mutifocaJ leukoshyencepha lopathy to be a dist inct neuropathologic en tiacutety that cannot be classified with hitherto recognized diseases of the cen tra l nervous system The com binashytion of multiple demyelin ative lesions of a l po ssiacuteble gra da tions in size an d stage of evolu tion (F ig 1) with remar kable cha nges in oligodendroey tes (F ig 2) and oft en in astrocytes (F ig 3 ) does not occur in any othe r disease known to me The appe a rance of th e lesions suggests th at prog ression of th e c1in ica disorde r result s from th e enJargeme n t and confluen ce oI sma lI lesions and th e con tin uous ad ditions oI new ones The ea rlier d escription 1 placed conside rable emphasis on th e hyperplasia of ast rocy tes iexclnto bizarre gian t Ior ms whiacutech resembled neopl astic ce lIs It is now a pparent however th at the astrocytes do not unde rgo this altera bo n in al cases On th e o ther hand en la rgemen t oI oligode ndrocyte nuclei with dense basophiJia an d loss of nuclear det ail Iacutes inshyvaria bly presen t Eosinophilic intranuclear inclusions have been seen within th ese ab normal oligo de ndroshycytes in nearly every case (F ig 4 ) but mal no t always be found (lor exam ple in C ase 4 and in the case oI Dolman and Ca irnsl1

) Exp elience with the ad di tiona l cases here repor ted has sugge sted sti ll ano the r fonn of ce llu lar hypert rophy unkn own to us from previous expel ience In Cases 2 8 and 9 th erc were in esions in th e gra nule -ce ll layer of the cer eshybellar cortex Iarge nucl ei wh ich [rom th eir form loca tion -_and a rrangernen t have been tentati vely iden tified as altered cere belIar gra nule neurons (F igmiddot 5 ) Althoug h the identity of these cels ha s not been established beyond all doubt thi s ce ll- change seemS

r

=- -

822 THE -EW ENG LA N D

to be of suflicient int erest to wai rant a pre liminary note

Frcun s 5 Ph otonn crogr ap ]i o i lp e C ereb ellar C ortes in Case 8 Shoioing Llnus uai Nu elei m th e Granular L ay er ( H emashy

tox y lin arul E osin S ta in X250 )

Near ilie t op [u st be ncatn the sp artely ce llu lar molecular laye r al e norm al granule neu aniexcl lJelow th eJe simii arl) grOllped m io clu sters m e lal ger n u clei bel onging lO eell r

Iha l may be path ologrcall y en lar ged gran ule n eu l on s

The earlier im prcssion tha t lh e lesions ha middotc a pre shydom ina ndy pe rivascular dis tri bution 1 h as DOt been borne O L1L b y th e p e~ en t stu di es Exa mina tiacuteon 01 ser ia l SCltlions gen er ally cliscoses at Jeast one m in u te esse ith in e en smal l e~ions bu t in view o f the Iarg e n um bers of such esse ls nonnally pre~en t in the braiacuten iL canno l be sta tccl lh a( lhis r ela tion iacutes a significa n t on e T his conelusion is in agreernen t wi lh iexclhe find ings of F isber e t aLs On t1w ol her hand

JOUR NA L OF MED IC Il E 0 l ~6 1961

ihe add itional case materia l does con firrn lhe pr C iou findi ng th a i infl amma tio n in the Iorrn ol pe ivascu l a~ lymphocyuc in filtra tions is with rarc l cepl ions mi n imal or absen t

T he par hologic changes in orga ns oihei i han the cen tral ncrvous system were in cach l l Se lypieal of n the pa rticular d isea se pr esent T herc wns no e iden ce

P iha t th e cases o iacute ch ro n ic d isease a ssocia ted wit h pro shygrcs s i v~ mu ltifoc a l lcukoe ricepha lopa thy di lfcred [rOI11 ot hc rs o f the same di sease in which chis n eurolooic disorder was p resent A h hough in m ost cases J1e underly ing d isease was such tha t in i tself it would ha e b ccn cxpect ed u lt im a tely to han been fa tal iexcln an y of (he pa t ien ts a p pa re ntly d ied a s a rewiexcl of Che de vastating efTects of the lesions in thc brain 1t seern s rc asonable to su ppose that if th e cerebr a l disease cou ld ha vc bee n pre ven ied 0 1 eflecrivelv

[( (

tr eated m a ny of the patien ts wo uld h ave SHVi ed ur

tilonger th an they di d

Etiologi c Consid erations

The cause and p athogenesis o f progressive muln shyfoca l leu koen cephalop athy rem ain uul now n H owshy

I eve r it occu rs with cond i tions in wh ich iacutemmu noshylogic h ypo re a c tivi ty has b cen de rno nsn-atcd (Iym shy Il

reph om asV leu kem ia13 sarcoidosisUl ca rcinornato shy (

S i S ~ a nd o ld age9) and thcrcforc decrea sed resisishy

ance to inf ection s m ight be expected Thc ch anges in o ligoclen d rocy tic an d as tr ocyt ic nuclei c1 escri bed a boye are consisten t with th e cyto pa tho logic effects a l a virus w hich in th e p resen ce of impaired iin shymu no logic respon ses could result in a typical lesions I t is hopecl that in the Iutu re cases of thi s sort wi ll be recognizecl so th al ap propria te investigat ions may be underta ken duri ng life and stu dies ca rr iecl out on fres h tissues ob taine d at au to psy

SUMMARY AND CONCLUSIONS

T en cases of progr essive multifocal leuk oen ccphalop shya thy a n un usual ce ntr al -ne rvous-systern d isease with

j

distin ctive neu ro pathologic fea tur es occu rring la te in L

the co u rse of severa] forros of chronic illn css ar e presented 10 these are aclded 12 cases stud ied by others g iving a to tal of 22 13

Th e ou tsra nd ing cliacuten ica Iea tures of th is con dition a re t hose uf a rapid ly p rogressi e focal or aS)l11me tric d isord cr of ihc bra in unaccompa ni ed by increascd fl in tracrania l p reSSllre 0 1 sign ifican l cereb rospina I-fluid i

changes Ir has mos t fr cgu en tly been asociatcd w ith ma lign a nt lym phoma or leuktm ia bu l may oCCl r ilh sa rcoidosis carcinom al osis m iliar) tuhcrcdoSis 01 rare acl ancccl age with0u t neoplaslic nI ~ a n u shy

Irloma lous d isease Ei den cc iacutes ci ted that lhe on e bctor CUl11 111 0n l() bull

a 11 the ch ro n icdi seases me l VI iexclth in iexcllis series is lhe p reence o relat ie imm 1l101ogie u nn pont ellemiddot T he cam e nf l og nsi e m uli roca l JeukcHncepbalop shya thy rc m ltl ins Bntildel~no n hu thE sugg eslion i ~ made

e

Vo] 2G5 N o 17 EF FECT O f C H LO R PRO PAM ID E - SIN GER ET AL 82 )

t hat the nervous-system lesions are cons isten t wi th an atypical form of virus infecti on

Further progress in un de rstanding th is cond it ion will depencl upon the stu cly of ca ses during life a nd of Iresh tissue samples For these purp oses recogshynition of cases during Iife which shoul d now be possib le is u rgecl

T wo a dd itiona l cas es both asso ciatc d with long stand ing chr onic lvrnph a tic leukernia have kiridl v bcen b rough t to mv altcn tio n a nd I have been permit ted to exami ne ne uro shypatho louica l ser tion s fr om both The first fra m DI Ell iott L M an call D ep artme nt oi Neuro loav J efferson Med ica Co llege Ph iladelphia Psnn svlvani a an d to be repo rte d by him is thar of a iacuteort v-on e-vear -old man in wh om the on ly ncu roloc ic abnorrna li iy consisted oiacute gene ralized convulsions five d avs before dea th T he secon d fro m D I C L Do lman Dep ar tment of Pa thologv V an co uver Ge ne ral H osp ita l V ancouver B C occu rred in a fift v-eizht-vear- old ma n with a very o rief terminal neuro logic illness who ha d had gen era liacutezed convu lsive seizu res for Iour years referab le to a n olisndend rogiiorna di scovered p ost rnortern as an incishyd ent a l findi ng

Drs R aymon d D Adams Ben jamin Castl em an C h arles S K ub ik Byron r-L W alcsma n an d Ba rry Amasan oC the M a ssach use t t Gener laquo1 Ho pilal P rofessor Jliu H all er shyvorden Max-Planck-In stiwt [uumlr Hirn forschung Giessen Vestern Ge rm any an d D I John F E nders havc given me friendl y help md encollra gcme n t fo r which 1 am inshyd eed gra te iu l r am grea tly indebted to D r W aksman ior im m uno loic advic c and for sULges ting how viral in Iec rioll could ac count fQr th e ne uro patholo gic Jesions in th is series oC cases

R EFERENCES

lo Astro m K middot E Ma nca ll E L and Richardson E P Jr Promiddot grcssive muJtrocal leuko -cncephalopathy h ithc rto u nlccosnized comp Jication oI chronic lymphat ic leukacm ia Qnd Hodgkrns d~scase Drain 81 93- 111 1958

2 Cavanash ] n G rcenba um D Matshal f l H b a nd R ub iacuten shysrc in L J Cerebral d e mve h na uo n assoc iaied with dis or de rs of re ticulocndor hc lia l system L ance 2 524-)iquest9 1959

3 Llovrl O C a nd Urich H Acu re d issemi ua ted dem ycli ua rion 01 hra in associa red wi th lymphosarcoma L ancet 2)29 1959

4 H all e r vor d cn J E igenar t ige und m ch t rubria iacutecrbarc Prcz essc In H a ndb ucti d er C ciSl eskrrwkheiacutet cn V ol 11 (pan 7) D ie A nfit o mie der P SCe OfeTl Edi tccl by O Bum ke 1136 pp Ber lin Spr ingcr 1930 Pp 1063middot1 107

5 W in kelma n N V an d Moorc 11 T Lv m phogra n ulo ma tosis ( Hod ~k i n~ d isease ) of ncrv o us systc m A rch Nc ur ol amp Psvc hi at 45 304-318 1941

6 Batcrnan O ] J- Squ ircs G a nd T hann ha use- S J H odg shyki ns d isease associa tecl with Sch ilders discase An n l n t Al eJ 22 426-431 1945

7 Ch ristcns en E an d Fog M Case of Schilders d iscase in ad ult wi th re ma rks 0 0 e t iolo g-y a nd pa t hog eocs is Acta Jsch iat el neuro iacute S cand inau 30 14 1-154 19] 5

8 F ishcr C 11 Vil1ianls H W a nd Ving E S Ir Co rnbincd cncephalopa t hy an d nc uropa thy wi th carcinoma ] Nc uropo th amp Ex per JVcUoL (i n p rcss

9 H a ller vorden J Personal com mu nica tion 10 Siblcv W A xnd We isb rg er A S Dem yelinat ing d iscase of

bra in in chronic lym nha ttc le ukemia OCCll1TCncc e l c ase in hosba nd of pat ien t with m ili tiple sclero sis A rch N eurol S 3UumlO-3Uumli 1961

11 Dol man C L bull an d Cairns A R M Le ukoc ncephalopathv assoshyciat ed -i th H orlgkins d isease N eu roiacuteo gy 1) 349~353 1961

12 Schi cr 7 W C uta neous ane rgy a n d H odgktrr s discasc N ew E ng ] M cd 250 353-361 19j 4

13 Epste in V L I nd uc tion o iacute allerg ic con tac t de rma titis in patlcnts w ilh 1)JOphOlna 4 Icukcmia co mple xo ] f rtUes1 D erma 30 39 195U

14 K eJly W D Lamb D -L Vareo R L an d Goa d R A_ Inveacutestiga tion oC H odgkin d iampease wl th respe ct to prohkm 01 ho rno h-iexclnp llJ) la tion 1 7111 N nc Y o rk Acad S e B7 IB7-2uuml2 1960

15 Fr lOu G J S tlldy of Cll la neOlS r eaciexcljons to oid io myciacuten tri choph)shytino and mump s skin te)t ant is cns in patic n ts w it h sarc uiJ mio Yal ] Biot amp M ed 24 533-539 1952

16 Ep s te ln W L and M a yo ck R L [ nJ lc t)OO oC a l h rs~c c on lac t c1 erm~iexcl i ti s_ in pa l ien ll ifu arcoidos Proc Soco Fx per Biol amp Med 95 186 1957

17 Logan J Ddayltd typc o [ alergic leadjon in cancer ate rcd respo ltse t O hJbcrcu li n a ncl m llmps vi ros N cw Zealand M 55 4)amp-41O 19) 6

18 Sou tham C M aud M oore A_ E I ndn ced im mu ni y to ca nce r 19~~ h omo grafts in man o An Tt N ew Y o rk A cad S e 73 635-653

19 Ca ndti~ G LaUergie f ub erc rJeuJe che z lhomme Coll ecti on di llnJf i( u l P aJteur 338 pp Pari$ FJammario n 1946 Pp -4042 and 61

CHLORPROPAMIDE IN PATIENTS ON HIGH IN SULIN DOSAGE

DAVID L SINGE R M D t R OBERT C S T EW ART MD t AN D D AVID HURWlT Z lvLD sect

BOST ON

A RE CEN T review of patien ts [r om w e D iabe tes C lin ic of the Boston C ity H ospita l r eveal ed a

substa n tia l num be r do ing well OIl ch lorpropamidell hose insu lin requir em en t had exceeded 50 uIlits Because it has bec(Piexclne a lm ost ax iomatic tha t th ese palien ts sho uld not be expecte d to do well on t he sulfonylu rea type of agen t the subject was pursuecl furthe r Adcli tiona l p a tien ts reeciving 50 un its of in shysul in 0 1 more a day we re transferred to chlorp ro p ashy

--Frorn thc D Labeles Clinic and the T hornJike 11cmor ial Labora tory Sccon d and Fou rth (H arvard) M cJ icat Se rvjecs Bostoll City H ospital and lhe De par tme nt of M edicine H a rva rd M edical School

Aidcd b y a gran l (2Amiddot5060) (om lhe U ni ted Staacutet cs Public H ea lth Se-rvic~

tRt s e~rch fe llow in medicin e l H arvard M edicaiacute St-hool rt 5carch fellow T hornd lkc M emorial L abora to ry

t Assislan t in medicin e H arvard M ed ica l School iexcl lt~ss1 s t i ng phy~ i dan llm ton Ci ty H ospi tal

Sit an t cJinca l p rofesso r o) m ed ici ne H a rvar d M edl cal 5chool chieL D iabe tes CJin ic aDd vislt ing physlc iall Sccond an d Fourlh (Har shyvar J ~ M edical Servic ~o Bost on Ciry H osp ita l c1uef lfed ical Ser vice 1ount Aub urn HO-5 p i m l ~ Cambridge Massach u~e t ts

~KlDd l y supp hed as D ~ b i n e se b Chltirlcs Pfiu r Jld C O J(Ip a Tl) Tncorporat ed Brool d yn New Y OImiddotk

m ide ancl their response ta bu lated T he resu l ts In

28 pa tie n ts constitu te th e basis 01 thi s report

METHODS AlD M AT ERI ALS

Crileria for inclu sion in the stu d y wer e a s follows th e d iabe tes was of th e m a turity -on set type an d reshyq ui red 50 units of ins ul in or m ore per day al the tim e of transfer to chlorp ropam idej pa tients wit h a hi sto ry of diabe tic acidos is we re excJu ded (ca rbon d iox icl e beJow 15 m illiequiv per lite r ) an d all pn shytients m ust have been main tai n ed on chl orp rop am ide long enough to m alee a cJea r eva luation o f con trol If a goocl r espo nse wa s ob tai ne d a placebo triaJ las giacuteven in ac cordance wiacuteth th e sing le-b lin d cl esign al lhe study a s ou tline cl below The charts of a ll pashytien ts=receiving ch lorpropam id e belore - J une 1960 were -exam ined an d al those ful filliacuteng the cri teria statecL-bo ve were ind udd I n ad cJ iiion a ll pa tien ls seen ircthe clin iacutec between Jul y 1959 a nd J une

amp

Vol 265 No 17 PROCRESSI VE LE UK OE NC EPHAL OPATHY -- RI CHARD SO N 82 1

be rel aterl to ex tensivo lesions in th e dominant (left ) cerebra l hemiacutesphe re In the 6 orher s it was a dysshy

arthria Sensory im pa irme n t in volving one side of th e bod y

as recorded in 4 cases This was associa ted with a hcmi pa resis on th e same side in 3 In th e case of L loyd and Ur ich th e onl y evide nce of a unila teral disord er was numbncss down th e left side of th e boc1y wi th im pa ir ed sensat ion and d irn ini sh ed vibrashytion sense below the left knee

Im pa irrnen t in swa llowing ( dysphagia ) pro ba bly occurred in many of th e pa tien ts as th e end neared ir was speci fica IJy recorded how ever in on ly 4

In 2 pa Lients (Cases 8 a nd 9 ) the pri ncipal ncushyrologic sym ptorns a nd signs were referable to lesions in the cerebe llum and brain stem These consisted of vershyt igo a tende ncy to Iall to one side (Case 8 ) nystagshymus (Case 9) dysph agia (C ase 9) unilateral a taxia (presen t a lso in Case 6 ) and in Case 9 crossed signs (left -facia l-m usce wea kn ess right-sided a taxia)

Unsteadiness oiacute gai t not further specified w as reshycorde d in 2 cases In a sing le case (Case 2 of Halshylervord en ) th ere was a mavement disarder of a type associa ted with basal-gangion disease ~ that is gene ra lized choreiform mo vemen ts

H eadach es were inf requ ent They were m ention ed as a pr ominent symp tom in on ly 2 cases and were eit her absen t or minimal in th e o ther s None of the pashytient s had convu lsive seizures

i Cerebrospinal-Fluid Findings

A consistent and significan t Iearure of the en tire group of cases was th e minimal degr ee of abnormality in the cereb rospina l fluid T hus of the 11 cases in which th e cerebros pina l fluid was exa mined th e findmiddot ings were en tire ly normal in 6 In 2 the onl y abnorshymalit y was a sligh t elevat ion of pressur e (275 mm and 200 mm la) A sligbt in crease in ce Jls was recordshyed in 2 ~ 25 lymphocytes per cu bic millimeter (C ase 1) and 6 white blood celis per cubic mitlimeter ll the cell cou n t was normal or not mentioned in th e others In 2 cases there were minimal eleva tions of to ta l protein a s light rise 7 and 50 mg per 100 ml l1

respecti vely

Electroencephalographic Findings

Electroencephalograpby was a bno rmal in every case in wh ich it was done (7 of the 22 ) The re ports were kindly reviewed by D r J ohn A Abbott who summ ashyr iacutezed the findings as f01l0s D iffuse sow-wave (delta 0 1 th eta ) actiacutevi ty of a sort in no way distin ctive of this disorder with normal activity pe rsisting 01

obliterat ed a nd wirh asym me tr ies correspon ding wit h the structura l abnorrnali ties in 1 case (Case 1) flatshy

The ca~e oC Fisher e l al8 (who kindly allolcd me ~o see their unp ubliexclshed ma nusc riacutept ) is no t indudcd In thiacutes the pIOtcin was elevated (43j mg per l OO mL ) on a single cX3mina tion clone whi le t-h e pa rient was under obse latjon rOl chro nic periph era l neuropltHhy bdorc evi middot cltn cc oC cerebra l d lsease had appearecl

tenin g and sharp waves were noted on tb e side of greater struc tu ral a bnorrnali ty

Radio logic Findings

Plain films of the skul l whenever taken inva r iabl y were nor mal In a ll 3 cases in wh ich pn eu moenc ephashylography was performed (Case 6 a nd those of C hrisshytensen and Fog and Bat ern an et al ) the findings exc lude d a space-occupying lesiono In the on ly case in which cereb ral angiog raphy was done tbi s showed a normal va scular pattern

A Iocalization study using a radioac tive iso tope (As ) wa s don e in on ly 1 ca se (Case 2 ) with normal find ings

PathologicaJ Aspects

Alt hough the lesions in the cen tral nervou s syst em were of the same character in a l 22 cases th ey varie d considerably from case to ea se in location and cx tc rrt A s a rule thc y w cro JT10St n un ic rous in the cere bral hernispheres bu iacute oiacuteten the brain stern and cere be tlum were severely affcc ted The spina I cord when exarnined was normal or at m ost showed minishymal changes In the pre vious publication evidence was give n for considering progr essive mutifocaJ leukoshyencepha lopathy to be a dist inct neuropathologic en tiacutety that cannot be classified with hitherto recognized diseases of the cen tra l nervous system The com binashytion of multiple demyelin ative lesions of a l po ssiacuteble gra da tions in size an d stage of evolu tion (F ig 1) with remar kable cha nges in oligodendroey tes (F ig 2) and oft en in astrocytes (F ig 3 ) does not occur in any othe r disease known to me The appe a rance of th e lesions suggests th at prog ression of th e c1in ica disorde r result s from th e enJargeme n t and confluen ce oI sma lI lesions and th e con tin uous ad ditions oI new ones The ea rlier d escription 1 placed conside rable emphasis on th e hyperplasia of ast rocy tes iexclnto bizarre gian t Ior ms whiacutech resembled neopl astic ce lIs It is now a pparent however th at the astrocytes do not unde rgo this altera bo n in al cases On th e o ther hand en la rgemen t oI oligode ndrocyte nuclei with dense basophiJia an d loss of nuclear det ail Iacutes inshyvaria bly presen t Eosinophilic intranuclear inclusions have been seen within th ese ab normal oligo de ndroshycytes in nearly every case (F ig 4 ) but mal no t always be found (lor exam ple in C ase 4 and in the case oI Dolman and Ca irnsl1

) Exp elience with the ad di tiona l cases here repor ted has sugge sted sti ll ano the r fonn of ce llu lar hypert rophy unkn own to us from previous expel ience In Cases 2 8 and 9 th erc were in esions in th e gra nule -ce ll layer of the cer eshybellar cortex Iarge nucl ei wh ich [rom th eir form loca tion -_and a rrangernen t have been tentati vely iden tified as altered cere belIar gra nule neurons (F igmiddot 5 ) Althoug h the identity of these cels ha s not been established beyond all doubt thi s ce ll- change seemS

r

=- -

822 THE -EW ENG LA N D

to be of suflicient int erest to wai rant a pre liminary note

Frcun s 5 Ph otonn crogr ap ]i o i lp e C ereb ellar C ortes in Case 8 Shoioing Llnus uai Nu elei m th e Granular L ay er ( H emashy

tox y lin arul E osin S ta in X250 )

Near ilie t op [u st be ncatn the sp artely ce llu lar molecular laye r al e norm al granule neu aniexcl lJelow th eJe simii arl) grOllped m io clu sters m e lal ger n u clei bel onging lO eell r

Iha l may be path ologrcall y en lar ged gran ule n eu l on s

The earlier im prcssion tha t lh e lesions ha middotc a pre shydom ina ndy pe rivascular dis tri bution 1 h as DOt been borne O L1L b y th e p e~ en t stu di es Exa mina tiacuteon 01 ser ia l SCltlions gen er ally cliscoses at Jeast one m in u te esse ith in e en smal l e~ions bu t in view o f the Iarg e n um bers of such esse ls nonnally pre~en t in the braiacuten iL canno l be sta tccl lh a( lhis r ela tion iacutes a significa n t on e T his conelusion is in agreernen t wi lh iexclhe find ings of F isber e t aLs On t1w ol her hand

JOUR NA L OF MED IC Il E 0 l ~6 1961

ihe add itional case materia l does con firrn lhe pr C iou findi ng th a i infl amma tio n in the Iorrn ol pe ivascu l a~ lymphocyuc in filtra tions is with rarc l cepl ions mi n imal or absen t

T he par hologic changes in orga ns oihei i han the cen tral ncrvous system were in cach l l Se lypieal of n the pa rticular d isea se pr esent T herc wns no e iden ce

P iha t th e cases o iacute ch ro n ic d isease a ssocia ted wit h pro shygrcs s i v~ mu ltifoc a l lcukoe ricepha lopa thy di lfcred [rOI11 ot hc rs o f the same di sease in which chis n eurolooic disorder was p resent A h hough in m ost cases J1e underly ing d isease was such tha t in i tself it would ha e b ccn cxpect ed u lt im a tely to han been fa tal iexcln an y of (he pa t ien ts a p pa re ntly d ied a s a rewiexcl of Che de vastating efTects of the lesions in thc brain 1t seern s rc asonable to su ppose that if th e cerebr a l disease cou ld ha vc bee n pre ven ied 0 1 eflecrivelv

[( (

tr eated m a ny of the patien ts wo uld h ave SHVi ed ur

tilonger th an they di d

Etiologi c Consid erations

The cause and p athogenesis o f progressive muln shyfoca l leu koen cephalop athy rem ain uul now n H owshy

I eve r it occu rs with cond i tions in wh ich iacutemmu noshylogic h ypo re a c tivi ty has b cen de rno nsn-atcd (Iym shy Il

reph om asV leu kem ia13 sarcoidosisUl ca rcinornato shy (

S i S ~ a nd o ld age9) and thcrcforc decrea sed resisishy

ance to inf ection s m ight be expected Thc ch anges in o ligoclen d rocy tic an d as tr ocyt ic nuclei c1 escri bed a boye are consisten t with th e cyto pa tho logic effects a l a virus w hich in th e p resen ce of impaired iin shymu no logic respon ses could result in a typical lesions I t is hopecl that in the Iutu re cases of thi s sort wi ll be recognizecl so th al ap propria te investigat ions may be underta ken duri ng life and stu dies ca rr iecl out on fres h tissues ob taine d at au to psy

SUMMARY AND CONCLUSIONS

T en cases of progr essive multifocal leuk oen ccphalop shya thy a n un usual ce ntr al -ne rvous-systern d isease with

j

distin ctive neu ro pathologic fea tur es occu rring la te in L

the co u rse of severa] forros of chronic illn css ar e presented 10 these are aclded 12 cases stud ied by others g iving a to tal of 22 13

Th e ou tsra nd ing cliacuten ica Iea tures of th is con dition a re t hose uf a rapid ly p rogressi e focal or aS)l11me tric d isord cr of ihc bra in unaccompa ni ed by increascd fl in tracrania l p reSSllre 0 1 sign ifican l cereb rospina I-fluid i

changes Ir has mos t fr cgu en tly been asociatcd w ith ma lign a nt lym phoma or leuktm ia bu l may oCCl r ilh sa rcoidosis carcinom al osis m iliar) tuhcrcdoSis 01 rare acl ancccl age with0u t neoplaslic nI ~ a n u shy

Irloma lous d isease Ei den cc iacutes ci ted that lhe on e bctor CUl11 111 0n l() bull

a 11 the ch ro n icdi seases me l VI iexclth in iexcllis series is lhe p reence o relat ie imm 1l101ogie u nn pont ellemiddot T he cam e nf l og nsi e m uli roca l JeukcHncepbalop shya thy rc m ltl ins Bntildel~no n hu thE sugg eslion i ~ made

e

Vo] 2G5 N o 17 EF FECT O f C H LO R PRO PAM ID E - SIN GER ET AL 82 )

t hat the nervous-system lesions are cons isten t wi th an atypical form of virus infecti on

Further progress in un de rstanding th is cond it ion will depencl upon the stu cly of ca ses during life a nd of Iresh tissue samples For these purp oses recogshynition of cases during Iife which shoul d now be possib le is u rgecl

T wo a dd itiona l cas es both asso ciatc d with long stand ing chr onic lvrnph a tic leukernia have kiridl v bcen b rough t to mv altcn tio n a nd I have been permit ted to exami ne ne uro shypatho louica l ser tion s fr om both The first fra m DI Ell iott L M an call D ep artme nt oi Neuro loav J efferson Med ica Co llege Ph iladelphia Psnn svlvani a an d to be repo rte d by him is thar of a iacuteort v-on e-vear -old man in wh om the on ly ncu roloc ic abnorrna li iy consisted oiacute gene ralized convulsions five d avs before dea th T he secon d fro m D I C L Do lman Dep ar tment of Pa thologv V an co uver Ge ne ral H osp ita l V ancouver B C occu rred in a fift v-eizht-vear- old ma n with a very o rief terminal neuro logic illness who ha d had gen era liacutezed convu lsive seizu res for Iour years referab le to a n olisndend rogiiorna di scovered p ost rnortern as an incishyd ent a l findi ng

Drs R aymon d D Adams Ben jamin Castl em an C h arles S K ub ik Byron r-L W alcsma n an d Ba rry Amasan oC the M a ssach use t t Gener laquo1 Ho pilal P rofessor Jliu H all er shyvorden Max-Planck-In stiwt [uumlr Hirn forschung Giessen Vestern Ge rm any an d D I John F E nders havc given me friendl y help md encollra gcme n t fo r which 1 am inshyd eed gra te iu l r am grea tly indebted to D r W aksman ior im m uno loic advic c and for sULges ting how viral in Iec rioll could ac count fQr th e ne uro patholo gic Jesions in th is series oC cases

R EFERENCES

lo Astro m K middot E Ma nca ll E L and Richardson E P Jr Promiddot grcssive muJtrocal leuko -cncephalopathy h ithc rto u nlccosnized comp Jication oI chronic lymphat ic leukacm ia Qnd Hodgkrns d~scase Drain 81 93- 111 1958

2 Cavanash ] n G rcenba um D Matshal f l H b a nd R ub iacuten shysrc in L J Cerebral d e mve h na uo n assoc iaied with dis or de rs of re ticulocndor hc lia l system L ance 2 524-)iquest9 1959

3 Llovrl O C a nd Urich H Acu re d issemi ua ted dem ycli ua rion 01 hra in associa red wi th lymphosarcoma L ancet 2)29 1959

4 H all e r vor d cn J E igenar t ige und m ch t rubria iacutecrbarc Prcz essc In H a ndb ucti d er C ciSl eskrrwkheiacutet cn V ol 11 (pan 7) D ie A nfit o mie der P SCe OfeTl Edi tccl by O Bum ke 1136 pp Ber lin Spr ingcr 1930 Pp 1063middot1 107

5 W in kelma n N V an d Moorc 11 T Lv m phogra n ulo ma tosis ( Hod ~k i n~ d isease ) of ncrv o us systc m A rch Nc ur ol amp Psvc hi at 45 304-318 1941

6 Batcrnan O ] J- Squ ircs G a nd T hann ha use- S J H odg shyki ns d isease associa tecl with Sch ilders discase An n l n t Al eJ 22 426-431 1945

7 Ch ristcns en E an d Fog M Case of Schilders d iscase in ad ult wi th re ma rks 0 0 e t iolo g-y a nd pa t hog eocs is Acta Jsch iat el neuro iacute S cand inau 30 14 1-154 19] 5

8 F ishcr C 11 Vil1ianls H W a nd Ving E S Ir Co rnbincd cncephalopa t hy an d nc uropa thy wi th carcinoma ] Nc uropo th amp Ex per JVcUoL (i n p rcss

9 H a ller vorden J Personal com mu nica tion 10 Siblcv W A xnd We isb rg er A S Dem yelinat ing d iscase of

bra in in chronic lym nha ttc le ukemia OCCll1TCncc e l c ase in hosba nd of pat ien t with m ili tiple sclero sis A rch N eurol S 3UumlO-3Uumli 1961

11 Dol man C L bull an d Cairns A R M Le ukoc ncephalopathv assoshyciat ed -i th H orlgkins d isease N eu roiacuteo gy 1) 349~353 1961

12 Schi cr 7 W C uta neous ane rgy a n d H odgktrr s discasc N ew E ng ] M cd 250 353-361 19j 4

13 Epste in V L I nd uc tion o iacute allerg ic con tac t de rma titis in patlcnts w ilh 1)JOphOlna 4 Icukcmia co mple xo ] f rtUes1 D erma 30 39 195U

14 K eJly W D Lamb D -L Vareo R L an d Goa d R A_ Inveacutestiga tion oC H odgkin d iampease wl th respe ct to prohkm 01 ho rno h-iexclnp llJ) la tion 1 7111 N nc Y o rk Acad S e B7 IB7-2uuml2 1960

15 Fr lOu G J S tlldy of Cll la neOlS r eaciexcljons to oid io myciacuten tri choph)shytino and mump s skin te)t ant is cns in patic n ts w it h sarc uiJ mio Yal ] Biot amp M ed 24 533-539 1952

16 Ep s te ln W L and M a yo ck R L [ nJ lc t)OO oC a l h rs~c c on lac t c1 erm~iexcl i ti s_ in pa l ien ll ifu arcoidos Proc Soco Fx per Biol amp Med 95 186 1957

17 Logan J Ddayltd typc o [ alergic leadjon in cancer ate rcd respo ltse t O hJbcrcu li n a ncl m llmps vi ros N cw Zealand M 55 4)amp-41O 19) 6

18 Sou tham C M aud M oore A_ E I ndn ced im mu ni y to ca nce r 19~~ h omo grafts in man o An Tt N ew Y o rk A cad S e 73 635-653

19 Ca ndti~ G LaUergie f ub erc rJeuJe che z lhomme Coll ecti on di llnJf i( u l P aJteur 338 pp Pari$ FJammario n 1946 Pp -4042 and 61

CHLORPROPAMIDE IN PATIENTS ON HIGH IN SULIN DOSAGE

DAVID L SINGE R M D t R OBERT C S T EW ART MD t AN D D AVID HURWlT Z lvLD sect

BOST ON

A RE CEN T review of patien ts [r om w e D iabe tes C lin ic of the Boston C ity H ospita l r eveal ed a

substa n tia l num be r do ing well OIl ch lorpropamidell hose insu lin requir em en t had exceeded 50 uIlits Because it has bec(Piexclne a lm ost ax iomatic tha t th ese palien ts sho uld not be expecte d to do well on t he sulfonylu rea type of agen t the subject was pursuecl furthe r Adcli tiona l p a tien ts reeciving 50 un its of in shysul in 0 1 more a day we re transferred to chlorp ro p ashy

--Frorn thc D Labeles Clinic and the T hornJike 11cmor ial Labora tory Sccon d and Fou rth (H arvard) M cJ icat Se rvjecs Bostoll City H ospital and lhe De par tme nt of M edicine H a rva rd M edical School

Aidcd b y a gran l (2Amiddot5060) (om lhe U ni ted Staacutet cs Public H ea lth Se-rvic~

tRt s e~rch fe llow in medicin e l H arvard M edicaiacute St-hool rt 5carch fellow T hornd lkc M emorial L abora to ry

t Assislan t in medicin e H arvard M ed ica l School iexcl lt~ss1 s t i ng phy~ i dan llm ton Ci ty H ospi tal

Sit an t cJinca l p rofesso r o) m ed ici ne H a rvar d M edl cal 5chool chieL D iabe tes CJin ic aDd vislt ing physlc iall Sccond an d Fourlh (Har shyvar J ~ M edical Servic ~o Bost on Ciry H osp ita l c1uef lfed ical Ser vice 1ount Aub urn HO-5 p i m l ~ Cambridge Massach u~e t ts

~KlDd l y supp hed as D ~ b i n e se b Chltirlcs Pfiu r Jld C O J(Ip a Tl) Tncorporat ed Brool d yn New Y OImiddotk

m ide ancl their response ta bu lated T he resu l ts In

28 pa tie n ts constitu te th e basis 01 thi s report

METHODS AlD M AT ERI ALS

Crileria for inclu sion in the stu d y wer e a s follows th e d iabe tes was of th e m a turity -on set type an d reshyq ui red 50 units of ins ul in or m ore per day al the tim e of transfer to chlorp ropam idej pa tients wit h a hi sto ry of diabe tic acidos is we re excJu ded (ca rbon d iox icl e beJow 15 m illiequiv per lite r ) an d all pn shytients m ust have been main tai n ed on chl orp rop am ide long enough to m alee a cJea r eva luation o f con trol If a goocl r espo nse wa s ob tai ne d a placebo triaJ las giacuteven in ac cordance wiacuteth th e sing le-b lin d cl esign al lhe study a s ou tline cl below The charts of a ll pashytien ts=receiving ch lorpropam id e belore - J une 1960 were -exam ined an d al those ful filliacuteng the cri teria statecL-bo ve were ind udd I n ad cJ iiion a ll pa tien ls seen ircthe clin iacutec between Jul y 1959 a nd J une

amp

822 THE -EW ENG LA N D

to be of suflicient int erest to wai rant a pre liminary note

Frcun s 5 Ph otonn crogr ap ]i o i lp e C ereb ellar C ortes in Case 8 Shoioing Llnus uai Nu elei m th e Granular L ay er ( H emashy

tox y lin arul E osin S ta in X250 )

Near ilie t op [u st be ncatn the sp artely ce llu lar molecular laye r al e norm al granule neu aniexcl lJelow th eJe simii arl) grOllped m io clu sters m e lal ger n u clei bel onging lO eell r

Iha l may be path ologrcall y en lar ged gran ule n eu l on s

The earlier im prcssion tha t lh e lesions ha middotc a pre shydom ina ndy pe rivascular dis tri bution 1 h as DOt been borne O L1L b y th e p e~ en t stu di es Exa mina tiacuteon 01 ser ia l SCltlions gen er ally cliscoses at Jeast one m in u te esse ith in e en smal l e~ions bu t in view o f the Iarg e n um bers of such esse ls nonnally pre~en t in the braiacuten iL canno l be sta tccl lh a( lhis r ela tion iacutes a significa n t on e T his conelusion is in agreernen t wi lh iexclhe find ings of F isber e t aLs On t1w ol her hand

JOUR NA L OF MED IC Il E 0 l ~6 1961

ihe add itional case materia l does con firrn lhe pr C iou findi ng th a i infl amma tio n in the Iorrn ol pe ivascu l a~ lymphocyuc in filtra tions is with rarc l cepl ions mi n imal or absen t

T he par hologic changes in orga ns oihei i han the cen tral ncrvous system were in cach l l Se lypieal of n the pa rticular d isea se pr esent T herc wns no e iden ce

P iha t th e cases o iacute ch ro n ic d isease a ssocia ted wit h pro shygrcs s i v~ mu ltifoc a l lcukoe ricepha lopa thy di lfcred [rOI11 ot hc rs o f the same di sease in which chis n eurolooic disorder was p resent A h hough in m ost cases J1e underly ing d isease was such tha t in i tself it would ha e b ccn cxpect ed u lt im a tely to han been fa tal iexcln an y of (he pa t ien ts a p pa re ntly d ied a s a rewiexcl of Che de vastating efTects of the lesions in thc brain 1t seern s rc asonable to su ppose that if th e cerebr a l disease cou ld ha vc bee n pre ven ied 0 1 eflecrivelv

[( (

tr eated m a ny of the patien ts wo uld h ave SHVi ed ur

tilonger th an they di d

Etiologi c Consid erations

The cause and p athogenesis o f progressive muln shyfoca l leu koen cephalop athy rem ain uul now n H owshy

I eve r it occu rs with cond i tions in wh ich iacutemmu noshylogic h ypo re a c tivi ty has b cen de rno nsn-atcd (Iym shy Il

reph om asV leu kem ia13 sarcoidosisUl ca rcinornato shy (

S i S ~ a nd o ld age9) and thcrcforc decrea sed resisishy

ance to inf ection s m ight be expected Thc ch anges in o ligoclen d rocy tic an d as tr ocyt ic nuclei c1 escri bed a boye are consisten t with th e cyto pa tho logic effects a l a virus w hich in th e p resen ce of impaired iin shymu no logic respon ses could result in a typical lesions I t is hopecl that in the Iutu re cases of thi s sort wi ll be recognizecl so th al ap propria te investigat ions may be underta ken duri ng life and stu dies ca rr iecl out on fres h tissues ob taine d at au to psy

SUMMARY AND CONCLUSIONS

T en cases of progr essive multifocal leuk oen ccphalop shya thy a n un usual ce ntr al -ne rvous-systern d isease with

j

distin ctive neu ro pathologic fea tur es occu rring la te in L

the co u rse of severa] forros of chronic illn css ar e presented 10 these are aclded 12 cases stud ied by others g iving a to tal of 22 13

Th e ou tsra nd ing cliacuten ica Iea tures of th is con dition a re t hose uf a rapid ly p rogressi e focal or aS)l11me tric d isord cr of ihc bra in unaccompa ni ed by increascd fl in tracrania l p reSSllre 0 1 sign ifican l cereb rospina I-fluid i

changes Ir has mos t fr cgu en tly been asociatcd w ith ma lign a nt lym phoma or leuktm ia bu l may oCCl r ilh sa rcoidosis carcinom al osis m iliar) tuhcrcdoSis 01 rare acl ancccl age with0u t neoplaslic nI ~ a n u shy

Irloma lous d isease Ei den cc iacutes ci ted that lhe on e bctor CUl11 111 0n l() bull

a 11 the ch ro n icdi seases me l VI iexclth in iexcllis series is lhe p reence o relat ie imm 1l101ogie u nn pont ellemiddot T he cam e nf l og nsi e m uli roca l JeukcHncepbalop shya thy rc m ltl ins Bntildel~no n hu thE sugg eslion i ~ made

e

Vo] 2G5 N o 17 EF FECT O f C H LO R PRO PAM ID E - SIN GER ET AL 82 )

t hat the nervous-system lesions are cons isten t wi th an atypical form of virus infecti on

Further progress in un de rstanding th is cond it ion will depencl upon the stu cly of ca ses during life a nd of Iresh tissue samples For these purp oses recogshynition of cases during Iife which shoul d now be possib le is u rgecl

T wo a dd itiona l cas es both asso ciatc d with long stand ing chr onic lvrnph a tic leukernia have kiridl v bcen b rough t to mv altcn tio n a nd I have been permit ted to exami ne ne uro shypatho louica l ser tion s fr om both The first fra m DI Ell iott L M an call D ep artme nt oi Neuro loav J efferson Med ica Co llege Ph iladelphia Psnn svlvani a an d to be repo rte d by him is thar of a iacuteort v-on e-vear -old man in wh om the on ly ncu roloc ic abnorrna li iy consisted oiacute gene ralized convulsions five d avs before dea th T he secon d fro m D I C L Do lman Dep ar tment of Pa thologv V an co uver Ge ne ral H osp ita l V ancouver B C occu rred in a fift v-eizht-vear- old ma n with a very o rief terminal neuro logic illness who ha d had gen era liacutezed convu lsive seizu res for Iour years referab le to a n olisndend rogiiorna di scovered p ost rnortern as an incishyd ent a l findi ng

Drs R aymon d D Adams Ben jamin Castl em an C h arles S K ub ik Byron r-L W alcsma n an d Ba rry Amasan oC the M a ssach use t t Gener laquo1 Ho pilal P rofessor Jliu H all er shyvorden Max-Planck-In stiwt [uumlr Hirn forschung Giessen Vestern Ge rm any an d D I John F E nders havc given me friendl y help md encollra gcme n t fo r which 1 am inshyd eed gra te iu l r am grea tly indebted to D r W aksman ior im m uno loic advic c and for sULges ting how viral in Iec rioll could ac count fQr th e ne uro patholo gic Jesions in th is series oC cases

R EFERENCES

lo Astro m K middot E Ma nca ll E L and Richardson E P Jr Promiddot grcssive muJtrocal leuko -cncephalopathy h ithc rto u nlccosnized comp Jication oI chronic lymphat ic leukacm ia Qnd Hodgkrns d~scase Drain 81 93- 111 1958

2 Cavanash ] n G rcenba um D Matshal f l H b a nd R ub iacuten shysrc in L J Cerebral d e mve h na uo n assoc iaied with dis or de rs of re ticulocndor hc lia l system L ance 2 524-)iquest9 1959

3 Llovrl O C a nd Urich H Acu re d issemi ua ted dem ycli ua rion 01 hra in associa red wi th lymphosarcoma L ancet 2)29 1959

4 H all e r vor d cn J E igenar t ige und m ch t rubria iacutecrbarc Prcz essc In H a ndb ucti d er C ciSl eskrrwkheiacutet cn V ol 11 (pan 7) D ie A nfit o mie der P SCe OfeTl Edi tccl by O Bum ke 1136 pp Ber lin Spr ingcr 1930 Pp 1063middot1 107

5 W in kelma n N V an d Moorc 11 T Lv m phogra n ulo ma tosis ( Hod ~k i n~ d isease ) of ncrv o us systc m A rch Nc ur ol amp Psvc hi at 45 304-318 1941

6 Batcrnan O ] J- Squ ircs G a nd T hann ha use- S J H odg shyki ns d isease associa tecl with Sch ilders discase An n l n t Al eJ 22 426-431 1945

7 Ch ristcns en E an d Fog M Case of Schilders d iscase in ad ult wi th re ma rks 0 0 e t iolo g-y a nd pa t hog eocs is Acta Jsch iat el neuro iacute S cand inau 30 14 1-154 19] 5

8 F ishcr C 11 Vil1ianls H W a nd Ving E S Ir Co rnbincd cncephalopa t hy an d nc uropa thy wi th carcinoma ] Nc uropo th amp Ex per JVcUoL (i n p rcss

9 H a ller vorden J Personal com mu nica tion 10 Siblcv W A xnd We isb rg er A S Dem yelinat ing d iscase of

bra in in chronic lym nha ttc le ukemia OCCll1TCncc e l c ase in hosba nd of pat ien t with m ili tiple sclero sis A rch N eurol S 3UumlO-3Uumli 1961

11 Dol man C L bull an d Cairns A R M Le ukoc ncephalopathv assoshyciat ed -i th H orlgkins d isease N eu roiacuteo gy 1) 349~353 1961

12 Schi cr 7 W C uta neous ane rgy a n d H odgktrr s discasc N ew E ng ] M cd 250 353-361 19j 4

13 Epste in V L I nd uc tion o iacute allerg ic con tac t de rma titis in patlcnts w ilh 1)JOphOlna 4 Icukcmia co mple xo ] f rtUes1 D erma 30 39 195U

14 K eJly W D Lamb D -L Vareo R L an d Goa d R A_ Inveacutestiga tion oC H odgkin d iampease wl th respe ct to prohkm 01 ho rno h-iexclnp llJ) la tion 1 7111 N nc Y o rk Acad S e B7 IB7-2uuml2 1960

15 Fr lOu G J S tlldy of Cll la neOlS r eaciexcljons to oid io myciacuten tri choph)shytino and mump s skin te)t ant is cns in patic n ts w it h sarc uiJ mio Yal ] Biot amp M ed 24 533-539 1952

16 Ep s te ln W L and M a yo ck R L [ nJ lc t)OO oC a l h rs~c c on lac t c1 erm~iexcl i ti s_ in pa l ien ll ifu arcoidos Proc Soco Fx per Biol amp Med 95 186 1957

17 Logan J Ddayltd typc o [ alergic leadjon in cancer ate rcd respo ltse t O hJbcrcu li n a ncl m llmps vi ros N cw Zealand M 55 4)amp-41O 19) 6

18 Sou tham C M aud M oore A_ E I ndn ced im mu ni y to ca nce r 19~~ h omo grafts in man o An Tt N ew Y o rk A cad S e 73 635-653

19 Ca ndti~ G LaUergie f ub erc rJeuJe che z lhomme Coll ecti on di llnJf i( u l P aJteur 338 pp Pari$ FJammario n 1946 Pp -4042 and 61

CHLORPROPAMIDE IN PATIENTS ON HIGH IN SULIN DOSAGE

DAVID L SINGE R M D t R OBERT C S T EW ART MD t AN D D AVID HURWlT Z lvLD sect

BOST ON

A RE CEN T review of patien ts [r om w e D iabe tes C lin ic of the Boston C ity H ospita l r eveal ed a

substa n tia l num be r do ing well OIl ch lorpropamidell hose insu lin requir em en t had exceeded 50 uIlits Because it has bec(Piexclne a lm ost ax iomatic tha t th ese palien ts sho uld not be expecte d to do well on t he sulfonylu rea type of agen t the subject was pursuecl furthe r Adcli tiona l p a tien ts reeciving 50 un its of in shysul in 0 1 more a day we re transferred to chlorp ro p ashy

--Frorn thc D Labeles Clinic and the T hornJike 11cmor ial Labora tory Sccon d and Fou rth (H arvard) M cJ icat Se rvjecs Bostoll City H ospital and lhe De par tme nt of M edicine H a rva rd M edical School

Aidcd b y a gran l (2Amiddot5060) (om lhe U ni ted Staacutet cs Public H ea lth Se-rvic~

tRt s e~rch fe llow in medicin e l H arvard M edicaiacute St-hool rt 5carch fellow T hornd lkc M emorial L abora to ry

t Assislan t in medicin e H arvard M ed ica l School iexcl lt~ss1 s t i ng phy~ i dan llm ton Ci ty H ospi tal

Sit an t cJinca l p rofesso r o) m ed ici ne H a rvar d M edl cal 5chool chieL D iabe tes CJin ic aDd vislt ing physlc iall Sccond an d Fourlh (Har shyvar J ~ M edical Servic ~o Bost on Ciry H osp ita l c1uef lfed ical Ser vice 1ount Aub urn HO-5 p i m l ~ Cambridge Massach u~e t ts

~KlDd l y supp hed as D ~ b i n e se b Chltirlcs Pfiu r Jld C O J(Ip a Tl) Tncorporat ed Brool d yn New Y OImiddotk

m ide ancl their response ta bu lated T he resu l ts In

28 pa tie n ts constitu te th e basis 01 thi s report

METHODS AlD M AT ERI ALS

Crileria for inclu sion in the stu d y wer e a s follows th e d iabe tes was of th e m a turity -on set type an d reshyq ui red 50 units of ins ul in or m ore per day al the tim e of transfer to chlorp ropam idej pa tients wit h a hi sto ry of diabe tic acidos is we re excJu ded (ca rbon d iox icl e beJow 15 m illiequiv per lite r ) an d all pn shytients m ust have been main tai n ed on chl orp rop am ide long enough to m alee a cJea r eva luation o f con trol If a goocl r espo nse wa s ob tai ne d a placebo triaJ las giacuteven in ac cordance wiacuteth th e sing le-b lin d cl esign al lhe study a s ou tline cl below The charts of a ll pashytien ts=receiving ch lorpropam id e belore - J une 1960 were -exam ined an d al those ful filliacuteng the cri teria statecL-bo ve were ind udd I n ad cJ iiion a ll pa tien ls seen ircthe clin iacutec between Jul y 1959 a nd J une

amp

Vo] 2G5 N o 17 EF FECT O f C H LO R PRO PAM ID E - SIN GER ET AL 82 )

t hat the nervous-system lesions are cons isten t wi th an atypical form of virus infecti on

Further progress in un de rstanding th is cond it ion will depencl upon the stu cly of ca ses during life a nd of Iresh tissue samples For these purp oses recogshynition of cases during Iife which shoul d now be possib le is u rgecl

T wo a dd itiona l cas es both asso ciatc d with long stand ing chr onic lvrnph a tic leukernia have kiridl v bcen b rough t to mv altcn tio n a nd I have been permit ted to exami ne ne uro shypatho louica l ser tion s fr om both The first fra m DI Ell iott L M an call D ep artme nt oi Neuro loav J efferson Med ica Co llege Ph iladelphia Psnn svlvani a an d to be repo rte d by him is thar of a iacuteort v-on e-vear -old man in wh om the on ly ncu roloc ic abnorrna li iy consisted oiacute gene ralized convulsions five d avs before dea th T he secon d fro m D I C L Do lman Dep ar tment of Pa thologv V an co uver Ge ne ral H osp ita l V ancouver B C occu rred in a fift v-eizht-vear- old ma n with a very o rief terminal neuro logic illness who ha d had gen era liacutezed convu lsive seizu res for Iour years referab le to a n olisndend rogiiorna di scovered p ost rnortern as an incishyd ent a l findi ng

Drs R aymon d D Adams Ben jamin Castl em an C h arles S K ub ik Byron r-L W alcsma n an d Ba rry Amasan oC the M a ssach use t t Gener laquo1 Ho pilal P rofessor Jliu H all er shyvorden Max-Planck-In stiwt [uumlr Hirn forschung Giessen Vestern Ge rm any an d D I John F E nders havc given me friendl y help md encollra gcme n t fo r which 1 am inshyd eed gra te iu l r am grea tly indebted to D r W aksman ior im m uno loic advic c and for sULges ting how viral in Iec rioll could ac count fQr th e ne uro patholo gic Jesions in th is series oC cases

R EFERENCES

lo Astro m K middot E Ma nca ll E L and Richardson E P Jr Promiddot grcssive muJtrocal leuko -cncephalopathy h ithc rto u nlccosnized comp Jication oI chronic lymphat ic leukacm ia Qnd Hodgkrns d~scase Drain 81 93- 111 1958

2 Cavanash ] n G rcenba um D Matshal f l H b a nd R ub iacuten shysrc in L J Cerebral d e mve h na uo n assoc iaied with dis or de rs of re ticulocndor hc lia l system L ance 2 524-)iquest9 1959

3 Llovrl O C a nd Urich H Acu re d issemi ua ted dem ycli ua rion 01 hra in associa red wi th lymphosarcoma L ancet 2)29 1959

4 H all e r vor d cn J E igenar t ige und m ch t rubria iacutecrbarc Prcz essc In H a ndb ucti d er C ciSl eskrrwkheiacutet cn V ol 11 (pan 7) D ie A nfit o mie der P SCe OfeTl Edi tccl by O Bum ke 1136 pp Ber lin Spr ingcr 1930 Pp 1063middot1 107

5 W in kelma n N V an d Moorc 11 T Lv m phogra n ulo ma tosis ( Hod ~k i n~ d isease ) of ncrv o us systc m A rch Nc ur ol amp Psvc hi at 45 304-318 1941

6 Batcrnan O ] J- Squ ircs G a nd T hann ha use- S J H odg shyki ns d isease associa tecl with Sch ilders discase An n l n t Al eJ 22 426-431 1945

7 Ch ristcns en E an d Fog M Case of Schilders d iscase in ad ult wi th re ma rks 0 0 e t iolo g-y a nd pa t hog eocs is Acta Jsch iat el neuro iacute S cand inau 30 14 1-154 19] 5

8 F ishcr C 11 Vil1ianls H W a nd Ving E S Ir Co rnbincd cncephalopa t hy an d nc uropa thy wi th carcinoma ] Nc uropo th amp Ex per JVcUoL (i n p rcss

9 H a ller vorden J Personal com mu nica tion 10 Siblcv W A xnd We isb rg er A S Dem yelinat ing d iscase of

bra in in chronic lym nha ttc le ukemia OCCll1TCncc e l c ase in hosba nd of pat ien t with m ili tiple sclero sis A rch N eurol S 3UumlO-3Uumli 1961

11 Dol man C L bull an d Cairns A R M Le ukoc ncephalopathv assoshyciat ed -i th H orlgkins d isease N eu roiacuteo gy 1) 349~353 1961

12 Schi cr 7 W C uta neous ane rgy a n d H odgktrr s discasc N ew E ng ] M cd 250 353-361 19j 4

13 Epste in V L I nd uc tion o iacute allerg ic con tac t de rma titis in patlcnts w ilh 1)JOphOlna 4 Icukcmia co mple xo ] f rtUes1 D erma 30 39 195U

14 K eJly W D Lamb D -L Vareo R L an d Goa d R A_ Inveacutestiga tion oC H odgkin d iampease wl th respe ct to prohkm 01 ho rno h-iexclnp llJ) la tion 1 7111 N nc Y o rk Acad S e B7 IB7-2uuml2 1960

15 Fr lOu G J S tlldy of Cll la neOlS r eaciexcljons to oid io myciacuten tri choph)shytino and mump s skin te)t ant is cns in patic n ts w it h sarc uiJ mio Yal ] Biot amp M ed 24 533-539 1952

16 Ep s te ln W L and M a yo ck R L [ nJ lc t)OO oC a l h rs~c c on lac t c1 erm~iexcl i ti s_ in pa l ien ll ifu arcoidos Proc Soco Fx per Biol amp Med 95 186 1957

17 Logan J Ddayltd typc o [ alergic leadjon in cancer ate rcd respo ltse t O hJbcrcu li n a ncl m llmps vi ros N cw Zealand M 55 4)amp-41O 19) 6

18 Sou tham C M aud M oore A_ E I ndn ced im mu ni y to ca nce r 19~~ h omo grafts in man o An Tt N ew Y o rk A cad S e 73 635-653

19 Ca ndti~ G LaUergie f ub erc rJeuJe che z lhomme Coll ecti on di llnJf i( u l P aJteur 338 pp Pari$ FJammario n 1946 Pp -4042 and 61

CHLORPROPAMIDE IN PATIENTS ON HIGH IN SULIN DOSAGE

DAVID L SINGE R M D t R OBERT C S T EW ART MD t AN D D AVID HURWlT Z lvLD sect

BOST ON

A RE CEN T review of patien ts [r om w e D iabe tes C lin ic of the Boston C ity H ospita l r eveal ed a

substa n tia l num be r do ing well OIl ch lorpropamidell hose insu lin requir em en t had exceeded 50 uIlits Because it has bec(Piexclne a lm ost ax iomatic tha t th ese palien ts sho uld not be expecte d to do well on t he sulfonylu rea type of agen t the subject was pursuecl furthe r Adcli tiona l p a tien ts reeciving 50 un its of in shysul in 0 1 more a day we re transferred to chlorp ro p ashy

--Frorn thc D Labeles Clinic and the T hornJike 11cmor ial Labora tory Sccon d and Fou rth (H arvard) M cJ icat Se rvjecs Bostoll City H ospital and lhe De par tme nt of M edicine H a rva rd M edical School

Aidcd b y a gran l (2Amiddot5060) (om lhe U ni ted Staacutet cs Public H ea lth Se-rvic~

tRt s e~rch fe llow in medicin e l H arvard M edicaiacute St-hool rt 5carch fellow T hornd lkc M emorial L abora to ry

t Assislan t in medicin e H arvard M ed ica l School iexcl lt~ss1 s t i ng phy~ i dan llm ton Ci ty H ospi tal

Sit an t cJinca l p rofesso r o) m ed ici ne H a rvar d M edl cal 5chool chieL D iabe tes CJin ic aDd vislt ing physlc iall Sccond an d Fourlh (Har shyvar J ~ M edical Servic ~o Bost on Ciry H osp ita l c1uef lfed ical Ser vice 1ount Aub urn HO-5 p i m l ~ Cambridge Massach u~e t ts

~KlDd l y supp hed as D ~ b i n e se b Chltirlcs Pfiu r Jld C O J(Ip a Tl) Tncorporat ed Brool d yn New Y OImiddotk

m ide ancl their response ta bu lated T he resu l ts In

28 pa tie n ts constitu te th e basis 01 thi s report

METHODS AlD M AT ERI ALS

Crileria for inclu sion in the stu d y wer e a s follows th e d iabe tes was of th e m a turity -on set type an d reshyq ui red 50 units of ins ul in or m ore per day al the tim e of transfer to chlorp ropam idej pa tients wit h a hi sto ry of diabe tic acidos is we re excJu ded (ca rbon d iox icl e beJow 15 m illiequiv per lite r ) an d all pn shytients m ust have been main tai n ed on chl orp rop am ide long enough to m alee a cJea r eva luation o f con trol If a goocl r espo nse wa s ob tai ne d a placebo triaJ las giacuteven in ac cordance wiacuteth th e sing le-b lin d cl esign al lhe study a s ou tline cl below The charts of a ll pashytien ts=receiving ch lorpropam id e belore - J une 1960 were -exam ined an d al those ful filliacuteng the cri teria statecL-bo ve were ind udd I n ad cJ iiion a ll pa tien ls seen ircthe clin iacutec between Jul y 1959 a nd J une

amp