Sudanophil leucodystrophy: aCLINICAL HISTORY A.R.W., a girl, was the first born child ofhealthy...

J. Neurol. Neurosurg. Psychiat., 1967, 30, 75

Sudanophil leucodystrophy: a study of inter-sibvariation in the form taken by the

demyelinating process

R. M. NORMAN, the late A. H. TINGEY, J. C. VALENTINE, ANDH. J. HISLOP

From the Burden Neuropathological Laboratory, Frenchay Hospital, Bristol, The Bedford General Hospital,and the Bromham Hospital, Bedford

In 1962 Norman, Tingey, Valentine, and Danbyreported the case of a 3-year-old microcephalic andparaplegic boy whose brain showed pachygyria,cerebellar atrophy, and sudanophil leucodystrophy.This patient had an elder sister whose physicalappearance and neurological signs were so similarthat it was evident that at least certain features ofthis complex condition had been inherited. This girlhas now died at the age of 11 years and is the subjectof the present paper. The two sibs showed remark-able differences in the form taken by the demyelinat-ing process and we believe that these findings arerelevant to current problems concerning theclassification of leucodystrophies of sudanophil type.

CASE REPORT

CLINICAL HISTORY A.R.W., a girl, was the first bornchild of healthy parents. She was admitted to BromhamHospital at the age of 2 years and was found to be amicrocephalic idiot (head circumference 15j in.). Shebore a striking resemblance to her younger brother (thesubject of the previous report in 1962), having curlyginger hair, sharp features, and long, tapering fingers.Her chest was peculiarly shaped, the nipples being highand the lower ribs protuberant. She was unable to sitwithout support and both legs were spastic in exten-sion and adduction. The upper limbs were less stiff butshe was never able to use them to any purpose. Therewas convergent strabismus and nystagmoid movementsof the eyes. The optic discs and fundi were normal.At 6 years of age her head circumference was 16 in.,

height 3 ft. 1 in., weight 29 lb. She was affectionate andsought attention, seeming to recognize her relatives andcertain nurses whom she welcomed with a smile. Shesurvived measles, rubella, infectious hepatitis, mumps,and a fractured femur which united satisfactorily. Duringthe last year of her life she began to have difficulty infeeding, developed a urinary infection and deteriorated,slowly at first but more rapidly during the last fourmonths when she lay helplessly staring at the ceiling. Shedied in an emaciated condition at the age of 11 years.

NECROPSY Death was due to bronchopneumonia.There was mild cylindrical bronchiectasis in the lowerlobe of the right lung. There were no foam cells in thepulmonary alveoli (as had been seen in her brother). Theuterus was rudimentary and the tubes and ovaries werenot found. The cranial cavity was considerably reducedin size, the dura mater normal, and the brain showed asimplified gyral pattern. A detailed necropsy revealed noother significant abnormality. Microscopically, the onlyunusual findings outside the nervous system wereintimal thickening and elastic tissue hyperplasia of thecoronary arteries, and periductal lymphocytic infiltrationin a salivary gland without cytomegalic inclusions.

STUDY OF THE CENTRAL NERVOUS SYSTEM

MACROSCOPIC The brain weighed 377 g., thecerebellum and brain-stem contributing 56 g. Ineach frontal lobe there were shallow sulci runningsagittally and more clearly defined on the right sidewhere three main frontal gyri were present (Fig. 1).The postcentral gyrus was well demarcated. Therewere no interparietal sulci and the direction taken bythe shallow sulci in the parietal region were in thedirection of the Sylvian fissure. Both parieto-occipital fissures were carried over for a considerabledistance on the convexity. The temporal lobes wereasymmetrical and the configuration of the sulci wasirregular (Fig. 2). Here and there, some shallowbossing of the gyral surfaces was seen. The inferiorsurface of the brain was unremarkable, as were thevessels and cranial nerves. On the medial surfacesthe cingulate gyri and calcarine fissures wereidentified and a thin corpus callosum was present.The cerebellum showed no gross malformation butits consistency was abnormally dense and thelateral lobes splayed out so that the inferior vermiswas unduly visible. On sectioning the cerebralhemispheres, it was seen that parts of the cortex inthe frontal cortex were abnormally thick and that

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R. M. Norman, the late A. H. Tingey, J. C. Valentine, and H. J. Hislop

the white matter was reduced in depth with enlarge-ment of the lateral ventricles (Figs. 2 and 3). In thefrontal and occipital poles, there was a patchydiscoloration of the white matter suggestingdemyelination.

MICROSCOPIC Representative areas of the brain werestudied in large celloidin and frozen sections stainedfor nerve cells, myelin, axis cylinders, fibrous glia,and lipid.

Changes in the cerebral white matter Axiscylinders were normally present in all parts of thebrain (Fig. 5b) and the changes in the myelin sheathsto be described represent demyelination in the strictsense. Large parts of the hemispheric white matterstained poorly for myelin, particularly the gyralcores which peripherally were sometimes severelydemyelinated (Figs. 3 and 4). The body of thecorpus callosum stained well at some levels, butelsewhere often showed a patchy loss of myelin in itsventral part. The anterior part of the left frontallobe contained a large focus of demyelinated tissueoccupying the lateral and ventral walls of theventricle (Fig. 5a). The margin was vaguelydemarcated and patches of better preserved fibresgave a coarsely mottled appearance to -the area. Onthe right side a section taken at a more anteriorlevel showed a slighter myelin loss in the samelocalization. In the occipital lobes there wasconspicuous, patchy demyelination, vaguely demarc-ated from a background generally poor in myelinatedfibres. Greatly dilated perivascular spaces gave afenestrated appearance to many parts of the whitematter (Fig. 6).The myelin sheaths in the cerebral cortex were

often entirely absent over large areas or werepartially preserved in a discontinuous way, as in thestria of Gennari. In parts of the malfonned cortexa remarkable mottled appearance was given by thepatchy degeneration of the myelin, the preservedfibres being particularly well myelinated (Fig. 6).

In the basal ganglia the compact fibre bundles ofthe putamina and caudate nuclei were completelydemyelinated. Each globus pallidus stained a uniformgrey in myelin stains (Fig. 3). The thalami weremuch better myelinated and gave a normalimpression except that patches of almost completemyelin loss, roughly symmetrical on the two sides,were seen at the margins of the medial nucleus(Figs. 4 and 7).The internal capsules were well myelinated. Both

optic tracts contained central areas of myelin pallor.Brain-stem A patchy, discontinuous type of

demyelination was a conspicuous feature of thetegmentum of the otherwise well-stained mid-brainand pons (Figs. 8a and b). The medulla was much

FIG. 1. Frontal lobes showing broad, irregular con-volutions.

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FIG. 2. Lateral view of left cerebral hemisphere showingabnormal gyral pattern of the temporal and parietal lobes.

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FIG. 3. Coronal section showing increased depth of partsof the frontal grey matter, reduced extent of the centrumovale, and diffuse pallor of much of the white matter.Heidenhain x 1.

FIG. 4. Coronal section of left hemisphere at mid-thalamic level showing focal accentuation of the demyelina-tion in the corpus callosum, lateral parts of the medialthalamic nucleus, and midbrain. Heidenhain x 15.

FIG. 5a. Left frontal pole showing discontinuous 4*demyelination. Kultschitsky-Pal x 16.

a - =S vt

FIG. 5b. Preserved axis cylinders in a severely demyelin- FIG. 6. Flaky demyelination of the cerebral cortex-ated patch (corresponding section to Fig. Sa). Gros- Dilated perivascular spaces in the gyral core. Kults-Bielschowsky x 440. chitsky-Pal x 8.

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Ay1FIG. 8a. Midbrain showing symmetrical areas of demy-elination in the tegmentum. Kultschitsky-Pal x 3-2.

FIG. 7a. Right thalamus showing patches of myelin loss(cf Fig. 4). Kultschitsky-Pal x 3 5.

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FIG. 7b. Perivascular myelin island in a patch ofdemyelination in the thalamus. Kultschitsky-Pal x 54.

less affected and at the level of the decussation of thepyramids appeared normal.

Cerebellum Myelination was normal except forsome small foci near the dentate nuclei and forcentrally placed demyelination of parts of severalgyral cores in the vermis and lateral lobes (Fig.9).

Gliosis In the centrum ovale there was a diffuseand mild fibrous gliosis which became ratherdenser in some of the areas of more obvious myelindefect. The foci of demyelination in the thalamusand in the grey matter of the cortex, however, didnot contain demonstrable glial fibrils. In thecerebellum fibrous gliosis was confined to the white

FIG. 8b. Pons showing symmetrical patches of demyelina-tion in the tegmentum. Kultschitsky-Pal x 3 9.

matter and tended to be diffuse, no differences beingseen in corresponding sections between demyelinatedand well-myelinated gyral cores. In the brain-stemthe patchily demyelinated tegmentum containedalmost no glial fibrils except in areas adjoining theventricle.

Lipid The cerebral and cerebellar white mattercontained scanty patches of microglial cells contain-ing bright red sudanophil lipid (Fig. 10). Similarlipid was sometimes seen in the perivascular spaces,particularly in those showing marked dilatation. Adoubly refractile component was occasionally presentand many of the phagocytes stained positivelywith Marchi's method.

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Sudanophil leucodystrophy: a study of inter-sib variation in the form taken by the demyelinating process 79

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FIG. 9. Cerebellum showing patchy demyelination in the FIG. 10. Sudanophil lipid in the centrum ovale. Scharlachwhite matter. Kultschitsky-Pal x 4. R. and haematoxylin x 200.

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FIG.11FIG. 12

noG. 1 1.Coronal section of left temporal lobe showing microgyric malformation and absence oi'the dentate fasciain the cornu Ammonis. Carbol azure x 3.

FIG. 12. Type ofgiant astrocytic nucleusfound throughout the cerebral cortex. Carbol azure x 650.



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FIG. 13. Cerebellum showing atrophy of the granularlayer andpreservation ofPurkinje cells. Carbol azure x 36.

CHANGES IN GREY MATTER The thickness of thecortex in the malformed gyri showed considerablevariation and was often clearly pachygyric withstrands or islands of heterotopic cells forming anindistinct boundary with the white matter. In someareas, as in the temporal lobes, a suggestion ofmicropolygyria was given by the presence ofirregularities in the superficial layer of the cortexand the penetration into the grey matter of acellularstrips representing the undivided molecular layer(Fig. 11).A peculiar finding throughout the cerebral cortex

was the presence of scanty, very large nuclei ofastrocytic type surrounded by a narrow rind ofcytoplasm (Fig. 12). These nuclei resembled theAlzheimer I cells of Wilson's disease. Sometimes, tworather smaller nuclei were contained in the samecytoplasmic envelope and here and there clusters ofmuch smaller astrocytic nuclei were seen. No nucleiof Alzheimer type 2 were found.

In both cornua Ammonis the dentate fascia wasabsent and the pyramidal cell band incompletelyrolled up. There was no sectorial neuronal losssuggestive of an anoxic process.The cerebellar cortex showed a marked reduction

in the density of the granular layer especially in itssuperficial parts (Fig. 13). The Purkinje cells werewell preserved. No defect was seen in the fibresystems of the cortex and the Purkinje dendritesshowed no swellings.

CHEMISTRY The brain had been in formal salinefor two weeks before analysis, which was made bymethods previously used in this laboratory (Tingeyand Edgar, 1963). The results are shown in theTable, in which comparisons are made with thefindings in the previously reported younger brother,G.P.W. (Norman et al., 1962).The chemical findings in the white matter of

A.R.W. (with the exception of sphingomyelin)reflected the much better overall myelination andthe far fewer fat granule cells compared with thebrain of the brother. The substances showing amarked increase over normal were common to bothcases and their values would be appropriate to amuch younger individual. A point of interest wasthe reduced lipid hexosamine compared with thevalue in the other sib and this level cannot beregarded as sufficiently high to be suggestive of aleucodystrophy.

TABLEVALUES OF CHEMICAL BRAIN CONSTITUENTS'

Brain Constituent

Total lipidTotal lipid hexoseNeutral hexoseLipid hexosamineNeuraminic acidResidue hexosamineCholesterol freeCholesterol esterTotal phospholipidLecithinSphingomyelinCephalinWater

White Matter

Normal Case A.R.W. Case G.P.W.

62-03-722-000-0450058019514-0Nil22-96-32612271-6

46-31-870-80O-C690-2430-4018-80418 09-82-35.9

84-6

35-61-060-170-1160-3920-479403-4

11-06-72-67-1

81-8

Cerebral Cortex

Normal Case A.R. W. Case G.P. W.

3701-060400-1460 40904855-80-219-86-02-110-584-7

43-40940260-1480-4020-5125-4

Nil18-310-82-94-6

87-4

3000-890-200-2100-4460 5403 00 315-27.91-0

12-389-3

"All values (except water) in g./100 g. of dry tissue

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Sudanophil leucodystrophy: a study of inter-sib variation in theform taken by the demyelinating process 81

The cerebral cortex showed little abnormalityexcept for the low neutral hexose (cerebroside) andthe neonatal level of lecithin.

DISCUSSION

CHANGES IN THE WHITE MATTER There were strikingdifferences between the form taken by the demyelin-ating process in this brain and in the brother's. Aclose resemblance between the two was only seen inparts of the frontal lobe where the myelin pallorwas diffuse (Fig. 3). Elsewhere, in the present case,a new element was introduced by the focal, oftenroughly symmetrical, patches of severe demyelina-tion. Except for the preservation of axis cylindersthese patches had no feature in common with plaquesof multiple sclerosis. Their margins were ill-definedand they sometimes contained perivascular myelin-ated fibres. Fibrous gliosis was either absent or notsufficiently intense to give more than a vaguesuggestion of the localization of the focus. Fatgranule cells were scanty or absent and there wasnone of the later products of myelin degradation.We mention these points because some authors stillregard Schilder's disease (and its transitional formshowingplaques similar to those ofmultiple sclerosis)as synonymous with sudanophil leucodystrophy.Certainly Schilder's disease (Schilder, 1912), asdefined by Poser and van Bogaert (1956), could notbe confused with the present condition.When patches of myelin loss occurred in close

proximity, as in the cerebellum and the tegmentumof the brain-stem, the appearance of discontinuousdemyelination was given (as in so-called 'Pelizaeus-Merzbacher disease'), but it was especially in partsof the malformed cerebral cortex that a closely-set,flaky type of myelin loss was most obvious. In thissituation the unusual density of the remainingmyelinated fibres was probably a feature of themalformation, since we have seen diffuse 'hyper-myelination' of the cerebral cortex in cases ofmicropolygyria which were unassociated withleucodystrophy or other destructive process.Changes of the type just described were not

observed in the brother's brain in which thedemyelination was diffuse in the centrum ovale,while in the cerebellum and brain-stem there wasa less marked but nevertheless obvious generalreduction in the intensity of myelin staining. In thebrother's brain it is unlikely that an acute phase ofthe demyelinating process had obliterated previouslyexisting focal lesions because the abundant fatgranule cells which were present in the white matterwere evenly distributed and showed no suggestion ofa patchy localization.The conclusion may be drawn that these seem-

ingly distinctive forms of demyelination, whetherflaky or diffuse, may be alternative expressions ofa single genetic defect. In their analysis of therecorded cases of 'Pelizaeus-Merzbacher' diseaseDiezel and Huth (1963) have pointed out that thedistinguishing pathological feature shared in com-mon is a flaky type of myelin loss. The present casecould, therefore, well be classified as an example ofthis 'disease', whereas another name would have tobe found for the brother's condition, for example,'diffuse sudanophil leucodystrophy'. It follows fromthis that the definition of Pelizaeus-Merzbacherdisease based on this single pathological criterion ofdiscontinuous demyelination ('myelin islands') be-comes even more inadequate than previous studieshave already suggested (Norman, Tingey, Harvey,and Gregory, 1966). If the eponym is to beperpetuated (and it is probably too firmly establishedto be abandoned), it can properly be used either todenote a purely clinical syndrome, as advocated byZeman, Demyer, and Falls (1964), or to denote amorphological type of sudanophil leucodystrophyrather than a separate nosological entity.

OTHER FEATURES The presence of pachygyria inboth sibs confirms the conclusion reached in aprevious paper that prenatal malformation of thebrain may be an early expression of the abnormalgene responsible for the leucodystrophy (Normanet al., 1966). Another inherited malformation was theselective aplasia of the dentate fascia, for the sameabnormality was also found on re-examining thebrother's brain. This phenomenon has not, to ourknowledge, been reported before and it has not beenfound in any of our other specimens of micro- orpachygyria.Atrophy of the granular layer ofthe cerebellum was

also present in both sibs and is not uncommon insudanophil or metachromatic leucodystrophy.The large astrocytic nuclei in the cerebral cortex

were peculiar to the present case. Apparently similarcells have been described in familial spongydegeneration of the white matter (van Bogaert andBertrand, 1949) and we have seen nuclei of this typein an unclassified case of a child of 5 years withcavitation in parts of the centrum ovale. Bischoff(1961) has also described large 'dysplastic' glialnuclei in a familial condition showing cavitation ofthe white matter of unknown cause. No explanationcan be given of this rare finding but its associationwith disease of the white matter is evident.

SUMMARY

The brain of an 11-year-old spastic and micro-cephalic girl showed pachygyria, cerebellar atrophyof the granular layer, and partial demyelination in



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R. M. Norman, the late A. H. Tingley, J. C. Valentine, and H. J. Hislop

the centrum ovale, cerebellar white matter, andbrain-stem. These changes have been compared withthose previously reported in the patient's younger

brother who closely resembled his sister clinically.In the present case the demyelination was seen

mainly as flaky, discontinuous loss of myelin sheathsin parts of the cerebral cortex and cerebellum and as

small, usually symmetrically placed and ill-demarc-ated patches of myelin loss in the centrum ovale,thalamus, and brain-stem. These focal lesions hadnot been found in the brother's brain in which thedemyelination was diffuse. The scanty sudanophillipid in the degenerated areas was also in contrast tothe abundant breakdown products of similar typein the brother. In both brains, axis cylinders were

well preserved. Chemically there were more myelinlipids and less lipid hexosamine in the sister's brain.This inter-sib variation in the form taken by thedemyelinating process shows that the same geneticabnormality can produce either a diffuse or a

discontinuous type of myelin loss. The latter is not,therefore, by itself an adequate criterion for classify-ing 'Pelizaeus-Merzbacher disease' as a nosological

entity and thus separating it from the main group ofsudanophil leucodystrophies.

REFERENCES

Bischoff, A. (1961). Familidres Syndrom des Sauglingsalters mitMyoklonie (Blitz-Nick-Krampfen), Hypsarythmie undschwerem psychomotorischem Entwicklungsruckstand. Psy-chiat. Neurol. Neurochin. (Amst.), 64, 133-148.

Diezel, P. B., and Huth, K. (1963). Pelizaeus-MerzbacherscheErkrankung mit familiarem Befall. Dtsch. Z. Nervenheilk., 184,264-287.

Norman, R. M., Tingey, A. H., Harvey, P. W., and Gregory, A. M.(1966). Pelizaeus-Merzbacher disease: a form of sudanophilleucodystrophy. J. Neurol. Neurosurg. Psychiat., 29, 521-529.

- , Valentine, J. C., and Danby, T. A. (1962). Sudanophilleucodystrophy in a pachygyric brain. Ibid., 25, 363-369.

Poser, C. M., and van Bogaert, L. (1956). Natural history and evolu-tion of the concept of Schilder's diffuse sclerosis. Acta psychiat.scand., 31, 285-331.

Schilder, P. (1912). Zur Kenntnis der sogenannten diffusen Sklerose.(Ober Encephalitis periaxialis diffusa). Z. ges. Neurol. Pyschiat.,10, 1-60.

Tingey, A. H., and Edgar, G. W. F. (1963). A contribution to thechemistry of the leucodystrophies. J. Neurochem., 10, 817-823.

van Bogaert, L., and Bertrand, I. (1949). Sur une idiotie familialeavec d6g6n6rescence spongieuse du n6vraxe. Acta neurol. belg.,49, 572-587.

Zeman, W., Demyer, W., and Falls, H. F. (1964). Pelizaeus-Merz-bacher disease: a study in nosology. J. Neuropath., exp.Neurol., 23, 334-354.

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