diffuse cerebral degeneration in infancy (alpers' disease)

13 Pages·2007·4.17 MB·English

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Arch. Dis. Childh., 1963, 38, 193. h
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DIFFUSE CEREBRAL DEGENERATION IN INFANCY : firs
(ALPERS' DISEASE) t pu
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W. BLACKWOOD, P. H. BUXTON, J. N. CUMINGS, D. J. ROBERTSON and S. M. TUCKER s 1
From the Institute ofNeurology, Queen Square, Maida ValeHospitalforNervous Diseases, 0
andtheMiddlesex Hospital .1
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(RECEIVED FOR PUBLICATION JULY 18, 1962) /a
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In 1931 Alpers described a condition in which beganwithextensionoftherighthandinaclawposition; .3
there was a peculiar form of degeneration of the the child 'shivered', fell forward limp and remained 8.1
cerebral grey matter. Subsequently other examples unconscious for four hours; clonic movements of the 9
of this disorder in association with epilepsy, extremities then occurred. The patient was observed 9.1
bspeaesnticiptuyb,limsyhoecdl.onuTsheasnedd2e4mecnatsieas,inteoagreltyhleirfehwaivteh iflnuihdoswpeirtaelnfoorrma1l0.days; temperature and cerebrospinal 93 o
During the next two months the patient became less n
eight oftheir own, have been summarized by Wolf active and more irritable. A second convulsion, 1
and Cowen (1954) under the name of 'diffuse similar to the first, occurred at 17 months, and sub- Ju
progressive cerebral cortical atrophy', although the sequently there were progressively more frequent ne
cerebellum and basal ganglia were also involved. episodesofjerkingoftheextremitieswithhyperextension 1
Asthecondition isuncommonitwasthoughtworth ofthe back, without loss ofconsciousness. 96
winhilwehitcohrecceorredbrfiavlecbaisoeps,syocwcaursripnegrifnorthmreede;faomnilitehs,e werAetch2a3ramcotenrtihzsedobfylaogsesoffoccaolnscseiiozuusrneesssbaegnadn.twitTchheisneg cop3. D
four which subsequently died, histological and o3f0 tthoe l6ef0t ssiedceonodfs.theThfeascee aoncdculrerfetdarwmi,theaicnhcrleaasstiinngg yrigown
chemicalexaminationofthebrainwascarriedout. frequency, being almost continuous when the patient ht.loa
was admitted to hospital. d
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Case Reports QuTeheen pSaqtuiaernet,waatsthaedmaigtetoefd2t4omtohnethNsa,tioonnaJlanHuoaspriyta1l3,, d fro
Case 1. The health of the parents had been good. 1958, under the care ofDr. E. A. Carmichael. He was m
Therewasnoknownfamilyhistoryofepilepsyormental aphysically well-developed child who was inattentive to h
illness. An only sibling constitutes the second case of his surroundings, did not speak, and was unable to ttp
thiTshirsepofrutl.l-term male infant was the product of the mmayionctlaoinnictjheerkssiotftianlgl epxotsrietmiiotni.es.TheHreeadwceirrecumffreerqeunecnet ://ad
mother'sfirstpregnancyandweighed6ilb.(2-9kg.). The was45cm. c.b
membranesruptured48hoursbeforedeliveryandlabour The child occasionally followed objects and persons m
lasted 24 hours. The child was shocked at birth and with his eyes. Both optic discs were pale; the maculae j.c
appeared cyanotic one hour later; oxygen was adminis- were normal. He responded to sounds. The left arm o
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tered. He was apparently well when discharged from was held immobile by the side; there were spontaneous
hospital on the tenth day. movements ofthe other limbs but strength was reduced. o/
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Diphtheria-pertussis inoculations were given at 6, 7 Deep reflexes were brisk and symmetrical; there was J
and 8 months, and vaccination was carried out at 10 bilateral ankle clonus, and plantar responses were a
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months, without complications. extensor. Abdominal reflexes were present. He res- u
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At 10months ofagethechild broke a femur and was ponded to light touch and painful stimuli applied to the ry
in hospital for six weeks. There was no apparent head trunkandlimbs; lessresponsewas obtained inthelower 1
injury. extremities. 2
Theparentsthoughtthatthechilddeveloped normally The child remained in hospital for 17 months, until , 2
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until the age of 15 months. He sat at 6 months if his deathattheage of31 years. Duringthistimethere 2
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supported. At 10months hecouldform simplephrases wasprogressivedeterioration. Myoclonicjerksoccurred b
but was unable to crawl. However, the clinicians almostcontinuouslyforthefirstyear,despitemedication, y
considered from a review of home movies, that motor then becameless frequent and ceasedentirely duringthe gu
retardation had begun at about 8 months ofage. last few weeks. He became blind during the first year e
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The first convulsion, which occurred at 15 months, in hospital, and pupillaryreflexes disappeared. Sucking t. P
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194 ARCHIVES OF DISEASE IN CHILDHOOD rch
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and swallowing ceased, and nutrition was maintained she was noted to have bilateral optic atrophy, was is
by gastric tube. During the last few weeks of life the apparently deafandwasnon-responsive. C
child lay motionless and non-responsive. There was Investigations. Haemoglobinwas 12-8g. per 100ml.; h
marked spasticity of the limbs; the deep reflexes were white blood cells numbered 15,600 c.mm.; neutrophils ild
DhyepIaentrvheascttfiiogvlaeltioownuesnd.tialHrtaeeserpmmioirngaatlloolrbyyiniwnfhweeactnsio1nt3.h-e3yg.dpiesrapp1e0a0remdl.. Iu6rn9i%nte.h,ebtNuetoretbhmreeortseapciwnhaarslomrfaaltiusiiedcdtslhuyesbrisentea,wnachsiestwIiadlisnyemfpaohunondcdyctyisentiptneher.e : first p
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on admission to hospital, falling to 8-9 g. per 100 ml. c.mm.;protein10mg.per100ml. Theelectroencephalo- b
before death. White blood cells numbered 11,800 per gram showed generalized abnormality with asymmetry lis
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c.mm.;therewasanormaldifferentialcount. Wassermann between the activities of the two hemispheres. A e
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reaction was negative. cortical biopsy of the right frontal region revealed the a
Bone marrow at 31 months was slightly hyperplastic; following: 'The subarachnoid space was moderately s
there were no abnormal cells. Urine at 37 months did deep. Theunderlying gyriwererathershrunken, butof 1
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not contain any metachromatic material. Cerebro- normal colour and consistency.' The histological and .1
spinal fluid at 27 months revealed 2 lymphocytes per chemical findings are described later. 13
c.mm.; there were no erythrocytes. Protein was less 6
than 10 mg. per 100 ml. Pandy test was negative. Case 3. A full-term female infant was admitted on /ad
Lange 0121000000. Wassermann reaction was negative. May21, 1957, attheageof11 months(Dr.E. W. Hart), c.3
At 36months white blood cellcount revealed 4lympho- birth weight 6 lb. 7 oz. (2-9 kg.). She had progressed 8
cytes per c.mm.; erythrocytes, 3,000 perc.mm.; protein, normally until the age of 11 months, when she began .1
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40 mg. per 100 ml.; Pandy test doubtful; Lange shrugging shoulders; this was followed by vomitingand 9
5554420000; Wassermann reaction negative. twitchings involving all four limbs. Frequent akinetic .1
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Radiographs ofskull and chest at 24 months showed seizures developed despite sedation and these gradually 3
no abnorrnality. A ventriculogram at 24 months increasedinfrequencyandseverity. Fundiwerenormal. o
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showed, 'Both lateral ventricles, the third ventricle, Investigations. Haemoglobin 11 g. per 100 ml.; 1
aqueduct and fourth ventricle have been well demon- electrolytes consistently normal. Chromatography J
strated. There is enlargement ofboth lateral ventricles, revealed normal urine. The cerebrospinal fluid had un
but no displacement. Air has passed out ofthe ventri- 1 lymphocyte per c.mm.; protein 160 mg. per 100 ml. e 1
cular system over the cerebral cortex and marked Anairencephalogram had anormalpattern; anelectro- 9
caebrnTeoobrxrmoaapllliaatstymroohspaihssybehteeasnstsebaeetne.n'23demmoonnstthrastedw.asNnoegaottihvee.r eConrcHteeiprchaalglebonigeorrpaaslmycwsoahnsodwitetaidkoensnevodeenrteeOrcigtoeornbaetereardli22zo,evde1r9a5b71n.0ormmaolnitthys. copy63. Do
Electroencephalogram: Several records were made. withcontinuingconvulsions untildeathat20monthson rigwn
(In2i-t4iacl.lpy.sa.t) 2f4rommonbtohtsh stihdeerse, wbeurteobfilsamtearlallerslaomwplwiatvuedse aMraerdcehsc1r2i,be1d95l8a.ter.Thehistologicalandchemicalfindings ht.loa
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on the right, and numerous irregular spike-and-wave e
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nfoormlsonogenrtphreesleefntt.. TAworewceoerkdsaltattehrethaegeasoyfm2m9etmroyntwahss E.CWa.seHar4.t),Twhaisstchaeseb,roatdhemritotfeCdasoen3.JunHeis1,bir1t9h59wei(gDhr.t from
showed a background almost devoid of rhythmic was 7 lb. (3'4 kg.) and delivery was normal. He h
aavctatriiivaintttiyeo,rnvwaliisnthfoeofnrmoarbamonuodtusdoinnsutermibpbeuetrrisosnoe.fcotnArdat,ns3is3ehnomtwodinintsghcsh,agrrgteehaset hlpiremobgbsre,egseassnepedvcionamolirltymialnlegfltyasniuddnet,iflwaietlrehedentaoogwethnoroiftvee1d.8,amTnowdnittthchshe,isnegwwsheeronef ttp://a
record was of low voltage, free of spike activity and later replaced by myoclonic type movements of greater dc
consisted only of irregular slow waves. The pattern severity and increased frequency. Fundi were pale, .b
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p2e7rsmiostnetdhsunrteivlealdeedatho.n bCootrhtiocaclcasbiioonpssitehsatatthe25coratnedx livIenrvaesntdigsaptlioenesn.weHraeenmootgplaolbpianble1.4 g. per 100 ml.; white j.co
as described by the surgeon was atrophic and the white blood cells numbered 17,700 per c.mm.; electrolytes m
matter unusually firm. A thin subdural hygroma was werenormal. Therewasexcessofhistidineandglutamic o/
sfeocuonnddobvieorpstyh.e left occipital lobe on the occasion ofthe raecivdesaloedn c1hlryommpahtoocgyrtaephpyerofc.umrmin.e;.prCoetreeibnro1s4p0inmagl.flpueird n Ja
The histological and chemical findings are reported 100 ml. The electroencephalogram was abnormal but nu
later. Jnuonl-ysp6,eci1f9i5c9. pattern. Cortical biopsy was taken on ary 1
Case 2. An infant girl, admitted at the age of 19 Myoclonic convulsions continued with hyperreflexia 2
months, birth weight 6j lb. (2-9 kg.), was a sister of and gradual deterioration. The child died on July 13, , 2
Case 1 and was born six months after the latter's death. 1959, at the age of 10 months, following a laparotomy 02
Taghee,rewhweans nmoernmtaall naenodnapthaylsipcraolgredsesveulnotiplme1n2tmboengtahns toof ffionrdiinntgesstairnaeldoebssctrriubcetdiolna.ter.Thehistologicalandchemical 3 by
deteriorate. Episodic jerking was noted with hyper- g
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reflexia, and thefirst convulsion occurred at 16 months. Case5. Afemaleinfant,youngestofsixchildren,was e
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Shewas admitted to hospital (Dr. P. H. Sandifer) where admitted on August 28, 1958 (Dr. P. H. Sandifer). Her t. P
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DIFFUSE CEREBRAL DEGENERATION IN INFANCY 195 rch
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birth weight was 8 lb. (3-6 kg.). She had a normal philic, non-metachromatic and anisotropic. A few is
delivery and neonatal life. A brother, the fourth child P.A.S.-positive granules were present in some of the C
aCibtnhteaergstoaeahpnegh5eytfodoawemfhiviatle1vyhl8,eompccdoeooednmnvtpvehneulsolno.rsspimaeoatdnlAoslr,nyycolfruiahmnniyitalcidelaldrlloyttcdhoeifepaotghrhanargoli1esvu0iessowfaewonefa1dk0scsde,wimreeeaetdbdkhreseaa.,nlt nvTmiehasrceAcvrrueeotersapo,hpwaasangyisdenFcsil.msnuueddvsiiecnnrlggeesst(bhtiwehleraertleeeirvaearuln,ndrblearymohamnarpclkhfhaobhpnlooneudereusosm,naofntgpierearor.sidspehaetTarhhna)de.l hild: first pu
when convulsions first occurred. These continued for microscopic examination. b
the next four months almost daily, associated with The brain weighed 435 g. The subarachnoid space lish
marked rigidity and hyperreflexia. Frequent myoclonic was greatly enlarged. The brain was shrunken, with e
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convulsions occurred subsequently until her death at smallgyriandbroadened sulci, thesechangesbeingmost a
theageof11 months. severeintheoccipitalandtemporallobes. Cutsections s 1
Investigations. These were carried out when the ofthe unfixed brain showed agreat loss ofcentral white 0
infant was between 6 and 71 months. Haemoglobin matterandventricular dilatation(Fig. Ia,bandc). The .1
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was 12 6 g. per 100 ml.; white blood cells: 14,000 per cortex showed two zones-the outer being grey, and the 3
c.mm. No abnormal constituents were present in the inner reddish brown. Both grey and white matter were 6/a
urine. The cerebrospinal fluid had no cells; protein veryfirm and tough. d
20 mg. per 100 ml. An air encephalogram revealed The left cerebral hemisphere and left cerebellar c.3
cerebral atrophy. An electroencephalogram showed hemisphere were submitted for chemical study and the 8
abnormality with gross asymmetry between the two remainder of the brain and cord was fixed in formol- .1
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sides, and a fairly extreme cortical lesion was suggested. saline for histological examination. 9
Cortical biopsyrevealedanextremelydeepsubarachnoid MicroscopicFindings .19
ssuplacci.e wTithheagyrroiuwgehrearfaicrhmnoainddmpealmeb.rane and with side evi(da)encCeerteobrsaulggeshtemtihsapthmearre:kedTphreorgeresswiaosnofhitshteolloegsiicoanls 3 on
had occurred in the one and a halfyear period between 1
Pathological Findings the cortical biopsies and death. Whereas earlier, con- Ju
Methods. The cerebral biopsy specimens were fixed siderablemyelinhadbeenpresent,therewasnowvirtually ne
in formol-saline. Scharlach R, haematoxylin P.A.S., complete demyelinization of the hemisphere examined, 1
toluidine blue, Cajal's gold chloride, Bielschowsky and only a few myelinated fibres remaining in the internal 96
sHeocrttieognas,'samnidcrohgaleimaaltosxtyailnisnwaenrde peeosrifno,rmheademoantoxfyrloizne-n cdaipmsiunlisehaedn.d baFsaatl-lgaadneglnia.phaAgxoocyntseswerweecroerrepsrpeosnednitngliyn cop3. D
vspaiNnnuaGlmieercsooorundsasonebdcttaLiioonnyesedozfasstteaviaenrusatloopnrsegypiaorwanfesfrioenftsehemectbbierodansid.nesdanidn vnsmeoartlyalblmynaurlmeksbesedrnsuamsettrrhoorcuoyustgihtcohaugntlioitsnihsethethhebrmiioosupspgihheeosru.et,Ttbhhueetrewwhweiartsee yright.ownloa
celloidin, and stained by haematoxylin van Gieson, matter. de
Nissl, Loyez, Gross-Bielschowsky andP.A.S. techniques. Thecortex was abnormal in all regions examined, the d
Frozen sections of selected regions were stained by temporal, postero-frontal andoccipital lobes being most fro
Scharlach R, haematoxylin, toluidine blue, P.A.S., affected. There was moderate loss ofneurones from all m
Cajal's gold chloride and Holzer. layers, particularly in the outer half of the cortex, and h
in the severely altered regions there was status spon- ttp
Case I giosus ofthe second and outer layers. Gliosis, present ://a
Brain Biopsies. The specimens, obtained at 25 and throughout the cortex, was most marked in the outer d
27 months, were similar and are described together. third and again in the deeper layers. The inner part c.b
Cortical lamellation was well preserved and the of the third layer tended to be least involved (Figs. m
number of nerve cells was not appreciably diminished. 2and 3). j.c
Macrophages distended with sudanophilic material were (b) Basal ganglia: The thalamus was markedly o
m
psirxetshe.ntMinosaltl lwaeyreres,dbisuttripbruitnecdipaslilnygliyn,tbhuetfirosct,cafsiiftohnaalnldy dshernusnekgelni,osisw.ithThgerogsslobruesdupcatliloindusinwanseulraorngeelsydaenvdoivderoyf o/
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were aggregated in groups oftwo or three. There was nervecellsandmyelinandcontained manymacrophages. J
a diffuse increase in astrocytes with many nuclear pairs Gliosis was dense. The caudate nucleus and putamen an
in all layers. Rather dense gliosis of the subpial zone were essentially uninvolved. Only occasional myelin u
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was present. sheaths remained in the optic tract, and there was well- ry
In the white matter, myelin sheaths were moderately marked gliosis. The cortico-spinal tracts of the brain- 1
wfeolulndpresaenrdved.numHeorwoeuvser,faot-cfcialsleidonamlamcyreolpihnagbealsls wweerree satfeemwsmhaocwreodphpaaglelso.r ofThmeyeploinntisntaeintiengg,mewnittuhmglcioonstisaiannedd 2, 20
scattered throughout the specimens, along groups of an excessive number ofprominent microglial nuclei and 2
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fibres, andclusteredperivascularly. Thesechangeswere somephagocytes,buttherewasnoobviouslossofmyelin b
well marked in the subcortical region as well as more or loss of neurones. The inferior olives were intact. y
deeply. Astrocytes showed pronounced hypertrophy Inthecerebellum, thecortexshowedextensive degenera- gu
and hyperplasia. tion involving the posterior aspect of the vermis and es
Thelipid inbothcortex andwhitematterwassudano- hemispheres, most marked at the apices ofthe folia and t. P
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196 ARCHIVES OF DISEASE IN CHILDHOOD rc
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FIG la, b,c. Case 1: Coronal sections, frontal, centralandoccipital, showing shrinkage ofhemisphere, due to thinning ofthecortex and J
loss of white matter, with widening of sulci and enlargement of ventricles. In the frontal slice (a) the scar of the biopsycan beseen u
(top left). ne
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FIG. 2.-Case 1: Insular cortex, showing relative preservation of FIG.3.-Case1:Insularcortexandwhitematter,showinganincrease g
laminarpattern, lossofnervecellsbutincreaseofglia. ofastrocytic fibres in the superficial and deepest part ofthe cortex u
(Celloidinsectionstainedhaematoxylin vanGieson x 84.) andinthewhitematter. es
(Celloidinsectionstained phosphotungsticacidhaematoxylin x 45.) t. P
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DIFFUSE CEREBRAL DEGENERATION IN INFANCY 197 h
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FIG.4.-Case 1:Cerebellum, showingfewPurkinjecellsandgranule FIG. 5.-Case 1:Cerebellum, showingdenseglialfibreformation in u
cells with an increase in number of Bergmann astrocytes and of themolecularlayerandinthewhitematter. ne
astrocytesinthewhitematter. (Phosphotungsticacidhaematoxylin x 124.) 1
(Haematoxylin vanGieson x 144.) 9
6
least marked in their bases. In the involved areas both Therewasageneralloss ofmyelinin thewhitematter cop3. D
granule and Purkinje cells were diminished in number. with areas of complete demyelination, particularly sub- yo
A few empty baskets were found, and very occasional cortically, that produced patchy status spongiosus. rigwn
c'etlolrs.pedoTehse'rewerweaspremsaerntkeodn aprxoolnisferoaftisounrviovfingBePrugrkmiannjne iAnxotnhesdweemryeelgiennaertaeldlyardeiamsi;nitshehreedwinasnunmobesprarainndgaobfsetnhte ht.load
astrocytes with dense glial fibre formation. In the tangential fibres. ed
awhnidtenmuatmteerro,utsherfeatw-afisllpedartimaalclroospshoafgeasxonwsearnedmpyreelsienn,t botLihpiidn tsthaeincsorstheoxwaenddmianneyvesnudgarneoaptheirlincummbaecrrsopihnagtehse from
(Figs. 4 and 5). In the dentate nucleus the most pro- white matter. These cells were diffusely scattered h
minent change was an intense gliosis. Nerve cells were without clear perivascular arrangement. The lipid ttp
ver(yc)reTdhueceSdpiinnalnuCmobredr:.In the crossed pyramidal tracts mcahtreormiaatlicwaallsyPw.iAt.hS.tonleugiadtiinvee,blauen.d iIttdwiadsnaontissottarionpimce.ta- ://a
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therewasadiffusereductionofmyelinatednervefibres. c
The leptomeninges were slightly thickened in some Autopsy Findings. The body wasvery wasted. There .b
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tpiltaicalesfainbdrounsormtahilckeelnsienwhgereo.f cAappairlltarfiresomisnligthhteadmvoesnt- wabasscesbsil.ateTrahlecloinvfelruehnatdbaronnocrhmoaplnewueimgohntiaofa4n8d0ag.lbuuntg j.co
severely involved areas of cortex, inflammatory infil- was rather pale. m
tration of meninges or perivascular spaces was not The brain weighed 600 g. The arachnoid showed o/
found. gelatinous thickening to 0 25 in. (6 mm.), with occa- n J
sional cortical adhesions in most areas. The brain was a
Case2. Thechanges were essentially similartothose firmer than normal and this was particularly so in the nu
seen inthebiopsies fromthefirstcase. bocectiwpeiteanllgobreesy. aTnhderewhaiptpeeamraetdtetro.beTahzeonecaorfotcildeavaangde ary 1
CBraasien3Biopsy. Corticallaminationwasstilldiscernible, wveerrteebnroarlmaarlt.eries and main vessels ofthe circle ofWillis 2, 2
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but there was loss ofnerve cells and degenerate forms, 2
particularly in the 3rd and 5th layers. There was a Microscopic Findings 3 b
marked microglial increase in all layers of the cortex (a) Liver: Early cirrhosis, infiltration of portal tracts y
and endothelial hyperplasia of blood vessels, most by lymphocytes and polymorphs, some proliferation of gu
apparent in thedeeperlayers, wherethere was amarked bile-ducts and increased connective tissue extending es
fibrillary gliosis. around lobules. No distension of bile-ducts or portal t. P
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198 ARCHIVES OF DISEASE IN CHILDHOOD h
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FIG. 6.-Case 3: Liver, showing cellular infiltration ofportal tracts FIG.9.-Case4:Liver,showinglargevacuolatedcellstowardscentre 9
andocca(sHiaoneamlatvoaxcyuloilnatainondoefospianrexnc8h0y.m)alcells. oflobule;portalce(lHlualeamraitnofixlytlrmaiatniloanc,neldalsne.dosfirningxe8o0f.s)urvivingparenchy- cop63. D
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vsehionsw.edSvoamceuoloaftiotnhe wmiothreflceecnktsralofpayreellnocwhympailgmecenltl,s cPe.lAl.sS.staoirnegdlyncoorgmeanllstyai(nFsi.g.T6)h.e apparently healthy liver right.wnloa
probably bile pigment. These vacuolated cells gave the d
staining reactions ofneutral fats and did not stain with (b) Cerebral hemispheres: The cortex was very ed
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FIG. 7.-Case 3:Occipitallobe, showingdiffusedemyelination most gu
markedaroundtheposteriorhornoftheventricle. Extensivecortical FIG. 8.-Case 3: SerialsectionofFig. 7,showinggliosisinareas of e
(Heidleanmhianianrmneetchroosdisfoirsmaylseolisneenx.1*4.) m(yHeollzienrlomsestphaordticxula1r*l4yfaorronuenudrotghleiavlenftirbirclees.) st. P
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DIFFUSE CEREBRAL DEGENERATION IN INFANCY 199 h
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abnormal; extensive neuronal loss was apparent in all biopsy. The blood vessels and meninges appeared is
layers, particularly the 3rd and 5th, where, in some normal. C
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areas of the occipital, temporal, insular and frontal MicroscopicFindings ild
rinegitohnes,2ntdheraenwdas3rldamlaiynearrs.necCraopsiilslaanrydpstraotluisfesrpaotinogniowsauss rou(an)diLnigver:eacEhxtenlsobiuvlee,cirbrihloes-idsu,ctfibprrootliicferbaatnidons saunrd- : firs
marked in the most severely affected areas ofthecortex. lymphocytic infiltration in portal tracts. No distension t p
Diffusegliosiswaspresentthroughoutthegreyandwhite ofbile-ducts or portal veins. u
b
matter, being most marked in the subpial and sub- Towards the centres of the lobules there were large lis
ependymal regions, and about blood vessels. Sections parenchymal cells with vacuolated cytoplasm giving the h
ofthe occipital lobe stained for myelin and for glia by staining reactions ofneutralfat(theyfailed to stainwith ed
Holzer's method showed complementary demyelination P.A.S. or glycogen stain, although the peripheral a
s
and gliosis (Figs. 7 and 8). There was a general diffuse apparentlyhealthylivercellsstainednormally(Fig.9)). 1
loss of myelin and axons in the internal capsules and (b) Cerebral hemispheres: The changes were far less 0
basal ganglia. The subcortical white matter was the severe than those ofthefirst case. There was a general .11
most severely affected. The loss of myelin was not moderate lossofcorticalnervecells, mostmarked inthe 3
6
selectively perivascular, though in some areas it was third and fifth layers, but the cortical laminar pattern /a
more marked about vessels. was preserved. Many of the nerve cells showed mild d
c
Fat stains showed sudanophilic material in macro- distensionoftheircytoplasmwithoccasionalvacuolation. .3
phages scattered diffusely in all areas ofthe cortex and Nissl substance was lost and many such degenerating 8.1
white matter oraggregated in smallgroups, occasionally neurones had glial satellites. 9
in relation to vessels. The lipid material did not stain Subpial and subependymal gliosis was present to a 9.1
with P.A.S., nor was it metachromatic with toluidine minor degree-far less than in Case 3. But there was 9
blue; it was anisotropic. some patchy fibrillary gliosis in the white matter, par- 3 o
Internal capsule, thalamus, globus pallidus, putamen ticularlyoftheoccipitallobe. n
and caudate were similar to Case 1. Subthalamic Myelin loss was very patchy and of minor degree, 1
nucleus showed nerve cell loss; the remaining neurones most often found subcortically. Axon loss was also Ju
showedmarkeddegenerativechanges, andmoderateglial slightandinthesameareas. Thetangential,subcortical ne
proliferation. Optic nerve: no apparent demyelination fibres were not preferentially affected. 1
inthesmallpieceavailable. Cerebellum:cortexshowed Fat stains showed only very occasional sudanophilic 96
ctiocnusliadrelryaibnlehelmoisssphoefrePsu,rkwihnijlee tahnedvegrramniuslawrascerlells,atipvaerl-y wmhaictreopmhaatgteers,;mtahiensleywienrteheseoecncipbiottahl lionbet.he cortex and cop3. D
sbpeardeids.cernNedo.defAisntirtoecfyotliicalgplaitotsiesrnasofindeCgaesneer1a.tioDnenctoautled cel(lc)losTsh;almaomduesraatnedinscurbetahsaelaimniacstnruocclyetii:cNnuoclegir.ossGlnoebruvse yrigown
nucleus: considerable nerve cell loss and dense glial pallidus showed slight nerve cell loss, some degenerate ht.loa
fibre formation. Inferior olive: moderate nerve cell nerve cells with satellitosis. Mild glial fibre formation. d
e
loss and many degenerate forms, glial infiltrated but no Putamen and caudate were as in Case 1. Optic nerve d
neuronophagia. was normal. Cerebellum: a few folia in the infero- fro
medial partofthehemisphere and in thevermis showed m
Case 4 lossofPurkinjecellsandgranularcellswithproliferation h
of Bergmann astrocytes and fibrillary gliosis. The ttp
butBrtahienBnieorpvsey.cellCsoritnicaalll llaaymeirnsataipoanrtwafsrowemllthperesseurbvpeida,l eOxbceerpstteitnheeraflfaeycetredpeorsniesst.edSolviegrhtalnlertvheecceelrlebleolslsarinfotlhiea ://ad
rpaergaifofninwseecrteionsg.rossTlhyeddiisstteennsdieodn wiansbdoutehtofrboazlelnoonainndg sdleingthattefinburcilleluasry,mgalriokseisd.inIcnrfeearsieorofaolsitvreocystihcownuecdlei,slaignhdt c.bm
Noifsstlhesunbusctleain,cewihnicthhelpeeftriakartyhoinn.rimTheofsedadrisktleyndsetdaicneilnlgs ngleiravleficberlelslwosesr,easnedenmoindeHroaltzeerglpiralepianrcarteiaosnes.with scanty j.co
failed to stain with fat stains or P.A.S. and would have m
been considered 'water change' artefact if it had not Case 5 o/
been for the microglial increase in all layers with early Brain Biopsy (Figs. 10, 1la, b and c). Cortical archi- n J
fibrillary gliosis in the deeper layers of the cortex and a
tecture was well preserved, with noevident loss ofnerve n
subTchoerrteicawlaswhmitienimmaatlterm.yelin and axon loss. caenllds.sizTehoefremiwcarosglaiacoinnspaillcusotuagsesinocfretarsaensiintitohnebneutmwbeeern uary
Lipid stains showed no free lipid and no lipid macro- restingandcompound granularcells,mostevidentinthe 1
phages. 2
first, fifth and sixth cortical layers. Scharlach R pre- , 2
AutopsyFindings. Thelungsshowedbilateralbroncho- parations demonstrated these cells to contain abundant 0
pneumonia; noabnormality ofthegastro-intestinal tract tiny drops and larger masses of sudanophilic material. 23
could be seen; the spleen (weight 15 g.) showed pro- Similar material was present in a few capillary endo- b
minent malpighian corpuscles. The liver was small thelial cells. Astrocytes were moderately increased in y g
(285 g.), firm, tawny coloured, and slightly greasy on number in the superficial cortex and much increased u
e
section. The brain (weight 735 g.) showed no obvious inthedeeperlayers. s
abnormality apart from the scar of the right frontal Inthewhitematter, myelinwasmoderatelyreducedin t. P
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200 ARCHIVES OF DISEASE IN CHILDHOOD h
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fFrIoGz.en10s.e-ctCiaosne(5S:chaBriloapcshy.RChoaretmeaxtoxaynldinundxer3l0y)i,ngshwohwiitnegmpartetseerr,- mFaIgG.nifIilcaa.t-iSounper(fxicial130p).ortiSoundanoofphciolritcex mfartoemriaFlig.ap1p0earats hdiagrhke.r e 19
vation of cortical architecture, and reduction in the number of Notetheabundanceofsuchmaterialinthisregion. 6
myelinsheathsinthewhitematter. cop3. D
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FIG. 1lb.Middle region of cortex from Fig. 8 (x 300). Note FIG. 1Ilc.-JunctsonofcortexandwhitematterfromFig.10(x 130), gu
nerve cells (N), rod cells (R), and (A) a pair of astrocytic nuclei showing sudanophilic lipid in the deepest layers ofthe cortex and e
indicating hyperplasia. reduction ofmyelin sheathsfromthewhitematter, in which phago- s
cytescontainingfinesudanophilicparticlesarepresent. t. P
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DIFFUSE CEREBRAL DEGENERATION IN INFANCY 201 h
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TABLE is
CEREBRAL LIPIDS (g./100 g. dry tissue) C
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Substance AuCtaatospAesgye1,on BiCaoatpsAseyg2eo,n AuCtaatospAesgy3e,on AuCtaatospAesgy4e,on AuCtaatospAesgy5e,on NaotrAmgael : firs
4years 1 year6months 2years I month 10months 1 year 3years t p
White Cortex White Cortex White Cortex White Cortex White Cortex White Cortex ub
TTSooptthaaillngcpohhmoolyseepslhtioenlriopli..d.. ...... 1721-7838 1065*-*0947 -85*63 12-5-*76 11233-**337 1282-*745 21174*-899 1836-**230 21411*-*192 1629--*742 21035-**110 1465-*-706 lished
CEsetreerbirfoiesdidceholester..ol .... 23-93 31-*55 -17 0-3 48-19 25-65 116*57 100 6 90-68 03-44 106 0 05 0 as
TWNoeatutarelarmh(ie%nx)iocsaamciinde.. ... 801248 8030*-34906 750-938 73-0-281 8-01*123 8-08--291 830-*-563 8008*--72226 810-535 8005*-64337 750-*74 8004-*7737 10.1
1
3
6
a diffuse distribution involving subcortical as well as The results of these examinations in all five cases /ad
deeper fibres. A large number ofmicroglia containing can beseen in theTable. c
sudanophilic material were widely distributed, showing There is some loss of phospholipid, total cholesterol .38
little tendency for perivascular aggregation. Astrocytes and ofcerebroside in all cases in both the white matter .1
were much hypertrophied and hyperplastic. Axons and the cortex, although the changes are less marked 99
appeared as numerous as myelin sheaths. in Cases 4 and 5, more particularly in the white matter. .1
Autopsy Findings. This was limited to examination Esterified cholesterol is present in excess in four out of 93
ofthecentralnervoussystem. Thelefthalfofthebrain, five cases. In Case 4 there was no esterified cholesterol o
n
fixedin 10%formolsaline,andspinalcordwerereceived in the cortex, and in Case 5 the amounts present were 1
from Dr. R. D. Clay, Central Laboratory, Portsmouth, not significant. Total hexosamine and neuraminic J
who had performed the autopsy. The right halfofthe acid werenotabnormalin any ofthefivecases. un
brain was submitted for biochemical study. Theresultsoftheexaminationofthebiopsyspecimens e
ThebrainwassimilartoCase 1 exceptthatthefrontal werenot significantly different from the results obtained 19
aCocancsdiepitt1ae.lmpolTerhaaselt.trheMagilicaormnosusscwowpeaircse fsmiionmsdiiltnagrsintvowoelrCveaesdesiam1in.ldarTthhteeo toinsTsuheeex.sameinfaitnidoinngsofitnhdeicpatoest-amoqrutietem sdpefeicniimteensdeogfreberaionf copy63. Do
globus pallidus was preserved. In the putamen there demyelination and damage to the white matter and the rigwn
wreagsioansdiaflfumsoestinccroemapsleetinealsotsrsocoyfticnenruvcelecielalsndwiitnhsedveenrsael cerebral cortex. Discussion ht.load
fibrillary gliosis. The subthalamic nucleus was intact. e
Bproanisnosrtemm:ednulolaa.bnoIrnmalpiarttyicwualsarfotuhendbaisnitshepomnitdibsraainnd, a cDaiufsfueseofpprrooggrreessssiivveeddeegmeenenrtaitaioinn eoafrltyhelifberaiisnleasss d fro
m
cbassieeniupflrmrpeleifrrablaeireaccolreirlwaathobroioflltyCietcavahosalermrtetayehetr1xeet,dnme.uibricsunlptavehnoiteldhrveweirtesnehrgeeawnapddsaiernnttsttaiehaccvettue.elrvaeernrlCuamyecliltrseee.trubhaseetliTwolhsenueurmpoeefcrewnitraoohestre- ccdsdiyeuofsrcmftehumrbsoorepaunhmlid'ceye,osgn.aerdnneieAdptrloiahproitetnsireosdnunan(tmd1ho9eeaf3rn1i)sttthohdhefeeetsecgltnriritiupelbiyseedeoddosmfaeaasntst'eaaPexnrnroadegmropplefolesuenstciyohovm-eef http://adc.b
(Greenfield, Blackwood, McMenemey, Meyer and m
Biochemical Findings Norman, 1958). Other descriptive terms applied to' j.c
similar reported cases include 'poliodystrophia om
Portions ofcerebral white matter and cortex from the
biopsy specimens and from the post-mortem material cerebri progressiva (infantilis)' (Christensen and o/
Krabbe, 1949), 'diffuse cortical sclerosis' (Rusk and n
wsuebrsetanecxeasm.ined for water content and various lipid Nixon, 1927) and 'familial degeneration of the Ja
The tissues were dried to constant weight at 370 C. grey matter in childhood' (Ford, Livingston and nu
in vacuo and the water content estimated. Cerebral Pryles, 1951). Wolfand Cowen (1954), in an exten- ary
lipids were extracted by the procedure of Folch, Lees sive review of the literature, cited 24 previously 1
maentdhaSnloolanesolSvteanntley(v/(v)1.957)Estuismiantgioans2o:n1 tchhelorexotfroarcmt-s rheeapdoirntge'ddiefxfaumspelpersogarnesdsiavdedceedreberiaghltcocratsiecsaluantdreorphyt'h.e 2, 20
were made of total phospholipid, sphingomyelin, total The clinical features, as carefully summarized by 23
and freecholesterol and ofcerebroside (Cumings, 1953), Wolfand Cowen (1954), were: normal development b
hexosamine (Cumings, 1957), while the method for y
nperuorcaemdiunriecofacLiodngeamnpdloSyteadplefsol(l1o95w9e)d witthhe theextrcaocltoirvie- faonrdsmeevenrtaallwreeetkasr,datmioonnthwsi,thorfoyceaalrso,rtgheennermaloitzoerd gue
metrictechnique ofSvennerholm (1957). convulsions, myoclonic jerking, occasional blind- st. P
2 ro
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202 ARCHIVES OF DISEASE IN CHILDHOOD rch
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ness, choreoathetosis and tremor. In all cases the lipid wasfoundinmacrophages in damaged regions is
course was one of progressive deterioration with ofboth grey and white matter. It stained intensely C
development of profound dementia and spastic red with Scharlach R, was non-metachromatic hild
pfiavrealaysnids.a hDalefatyeharosc;cuornreedexicnephtailofnatlhecacsaseessuwrivtihviend A(tolfueiwdinPe.bAl.uSe.)apnodsintoinv-ehagermaantuolxeysliwnoeprheilpirce(sLeonytez)in. : firs
for 69 years. macrophages in all cases. Anisotropic crystalline t p
Ford et al. (1951) divided eight cases, on the lipids were also present. These findings are similar ub
basis oftheir clinical courses, into two groups: to those associated with non-specific myelin break- lis
(a) An infantile group, in which symptoms down occurring in relation to infarcts andtraumatic he
appeared during the first year of life, and here the lesions, and in multiple sclerosis and sudanophilic d a
longest survival was two and a halfyears. diffuse sclerosis, and are not regarded as being of s 1
(b) A juvenile group, characterized by an onset significance in the differential diagnosis. 0
between 3 and 6 years of age, and with a duration None of the cases provided evidence of inflam- .11
as long as 16 years. matory infiltration either of the meninges or of the 36
The five cases in the present report fall into brain. There was patchy leptomeningeal fibrosis /a
Ford's infantile group; the age of onset of these in some areas. The blood vessels weie unremark- dc
cases varied between 10 weeks and 12 months, and ableapartfromslightpericapillary fibrosis and mild .38
the longest survival from the onset of symptoms endothelialproliferationinseverelydamagedregions. .1
9
was three and a halfyears (Case 1). In portions of cerebral cortex that were largely 9
Thepathological findings in thecasesreviewed by destroyed, capillaries appeared numerous, but this .19
Wolf and Cowen (1954) consisted principally of appearance may have been due to partial collapse 3 o
widespread loss of neurones with microglial pro- ofthe tissue. n
liferation and astrocytic gliosis. The lesions were In the four cases examined consecutively by 1
most severe in the cerebral and cerebellar cortices biopsy and autopsy, progression of the lesions in Ju
n
and thalamus, and were frequently present in the grey and white matter was clearly evident. e
corpus striatum, inferior olivary nuclei and basis The presence ofesterified cholesterol on chemical 19
pwtoianostnitsoh.foauxgIohnntstthoaenbwdehimstyeeeclominandtatsrehyreatttohheslodvsesagroirfeedenegourfreoadntelesyst.rauncd- pelrexsoaicmoeinsnsaewsth.iiocnhThcieanndaimbcoeatuefnsotuniasdngrienaatcaetsintvueimnbadecertmiyvoeeflpidlniaasqteuiaensgse copy63. Do
Thefourcasesreportedhere,whocametoautopsy, of multiple sclerosis and in sudanophilic diffuse rigwn
had in common diffuse degeneration ofgrey matter sclerosis. However, in this latter condition there ht.loa
in many parts ofthe brain, particularly the cerebral is an increase in total hexosamine not found in our d
e
cortex, cerebellar cortex, thalamus and basal five cases, and further there is evidence in our cases d
ganglia. The changes in these regions consisted of of cortical damage not seen in diffuse sclerosis. fro
reduction in the number of nerve cells with pro- The degree of biochemical abnormalities is usually m
gallixifooesnrisast.iionnTohalfelrmeciacwsreaossg,lsivoaimrateunaldlolsaysstocrfoomcmpyytleeelstienansidhneaftithbhersilfalianrrsdyt maondTdehrteartafueimlnayd.ilnegssssienveroeuirnccearseebsraclotnifssouremfrwoimthinftahrocstes http://a
d
case where life had been prolonged. previously described and reinforce the clinical and c
Therewasnodefiniteevidence inany ofthecases pathological features ofthis separate disease entity. .bm
of active neuronal disease; a few shrunken hyper- The aetiology, however, remains totally obscure. j.c
chromatic nerve cells could be found but were not Variouspossibleaetiologicalandpathogenicmechan- o
m
arsesporceisaetnetded wpiotsht-mnoerutreomnocphhaanggiea. aInndthemafiyfthhcaavsee iosnmesswhialvlebebediesncussusgegdeshtereed.in the past, and certain on/
ferrugination of a few neurones was found in the Ja
thalamus, and in the fourth case many neurones Genetic Factors. Although many ofthe reported nu
were vacuolated. These changes provide minimal cases have been sporadic in occurrence, familial ary
evidence of neuronal degeneration and are non- cases have been reported by Ford et al. (1951) and 1
sfpoerciifniccl.usiAoncbaordeifeusl, bsueatrncohnweawsasmaiddeentiifineda.llTchaesrees cbaysesP,altihnesfkaym,iliKaolzpiantnterannidssZtraihktinzg.(19I5t4i)s.appIanreontu,r 2, 20
wasnoevidence oflipiddepositionwithinneurones, too, that the age of onset and appearance of early 23
although numerous sections, stained by a variety symptoms were similar in each pair of siblings. b
y
oftechniques (videsupra), wereexamined by several Our data do not permit us to determine whether g
observers. the familial pattern is due to heredity, chance or ue
In all cases, in both biopsy and autopsy material, common environmental factors. st. P
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