sudanophil leucodystrophy in pachygyric · teeth and the palate was high and arched. there was...

J. Neurol. Neurosurg. Psychiat., 1962, 25, 363

Sudanophil leucodystrophy in a pachygyric brainR. M. NORMAN, A. H. TINGEY, J. C. VALENTINE, AND T. A. DANBY

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

Recent classifications of the diffuse cerebralscleroses have recognized the need to subdividethose cases which share in common the feature ofsudanophil breakdown products of myelin. InSchilder's disease, as represented by the case hedescribed in 1912, there are large, bilocular, sharplydemarcated areas of demyelination in the centrumovale, often associated with smaller plaques similarto those of multiple sclerosis. In contrast to thiscondition, there are cases in which the demyelinationis much more diffuse and involves the gyral cores,the cerebellar white matter, and often parts of thebrain-stem, while the degeneration products, as inSchilder's disease, are neutral fat and cholesterolesters. This group has been given a variety of names:'neutral fat leucodystrophy' (Poser and van Bogaert,1956), 'simple degenerative diffuse sclerosis' (Hal-lervorden, 1957), and 'sudanophil-orthochromaticleucoencephalopathy' (Einarson and Str6mgren,1961). We prefer the simple name 'sudanophilleucodystrophy' because there are other sudanophilsubstances present in addition to neutral fat. Thisgeneric term also includes in its scope the hetero-geneous collection of cases at present classed asPelizaeus-Merzbacher disease.There is often a genetic background to these

sudanophil leucodystrophies which is foreign to theSchilder type, but in sporadic cases it may sometimesbe difficult to distinguish the two conditions bypurely neuropathological criteria (Einarson andStromgren, 1961). At the present time few cases ofsudanophil leucodystrophy have been chemicallyanalysed but there is some evidence pointing todifferences between this group and cases of Schilder'sdisease. We have thought the present case worthrecording not only because of the unusual com-bination of sudanophil leucodystrophy with a grossmalformation of the cortex but because chemicalanalysis of the brain has shown certain featureslinking the condition to other types of inheriteddiseases of the white matter.

CASE REPORT

CLINICAL HISTORY G.P.W., a boy, was born on 29September 1956 and died on 17 January 1959 aged

2 years 4 months. He was the second child of healthyparents. There is an elder sibling, a girl, now 8 years old,who is a microcephalic idiot with severe spastic para-plegia and closely resembles her brother in appearanceand neurological state. She has nystagmus with squintand no optic atrophy or changes in the fundus. Herfingers are long and tapering, suggesting arachnodactyly.A second cousin who died in early childhood is said tohave had a very small head.The patient was admitted to a ho3pital for mental

defectives at the age of 18 months. He was a micro-cephalic idiot with head circumference of 15 in. (38 cm.),large ears, receding chin, a creamy pallor of face, and amass of red curls. Concomitant squint and nystagmuswere noted. He suffered from spastic paraplegia and wasdifficult to feed owing to regurgitation of food. Hehabitually held his thumbs tightly in the palms of hishands. Death occurred unexpectedly after a suddencollapse.

NECROPSY FINDINGS The body was that of a thin but notwasted boy, apparently about 18 months of age. The headwas small and somewhat elongated. The ears appearedextraordinarily large. The mouth contained naturalteeth and the palate was high and arched. There wasgeneralized pallor of the skin, the fingers of both handswere extremely long and tapering, and there was con-siderable oedema of the backs of the hands. Both feetwere somewhat elongated and showed non-pittingoedema. The testes were not found in the scrotum.The heart (27 g.) and blood vessels were normal. The

lungs showed diffuse bronchopneumonia. The spleen(17 g.), bone marrow, and lymph nodes were normal inappearance. The liver (535 g.) was considerably enlargedand showed a uniform pale yellow colour with a fine,light brown reticulation. The intestinal tract, kidneys,ureters, bladder, suprarenals, and thyroid were normal.The skeletal muscles appeared normal when allowancewas made for the fact that this patient had been all hislife in bed.The cranial sutures were all united and the dura mater

was firmly adherent to the vault of the skull. There wasno evidence of infection in the middle ears. The roof ofthe orbits bulged upwards into the cranial cavity but thebone was not thickened. There was a considerable excessof cerebrospinal fluid over the surface of the brain.

BACTERIOLOGY No virus was detected in the lung tissue.Specimens from the heart and lungs gave a mixed growthof staphylococci, pneumococci, and haemophilus.

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R. M. Norman, A. H. Tingey, J. C. Valentine, and T. A. Danby

HISTOLOGY There was a diffuse bronchopneumonia. Themajority of alveoli contained vacuolated cells containingsudanophil lipid which was not doubly refractile and didnot reduce osmic acid. The spleen was congested. Noabnormal phagocytes or lipid were seen. The liver showedgross fatty change. The majority of cells, with the excep-tion of a few around the portal areas, showed the cyto-plasm to be occupied by a single, large, clear vacuole.There was some polymorphonuclear infiltration of theportal areas. The pancreas was normal. The muscle cellsof the heart muscle appeared normal. There was per-haps slight thickening of the endocardium. The kidneyswere normal except for foamy degeneration of the cellsof the proximal convoluted tubules.

STUDY OF THE CENTRALNERVOUS SYSTEM

MACROSCOPIC After fixation in formol saline thebrain weighed 353 g., the cerebellum and brain-stemaccounting for 57 g. The cranial nerves and bloodvessels were unremarkable. The convolutionalpattern was grossly abnormal. The frontal lobes weresmooth except for shallow sulci demarcating broad'superior frontal' gyri and the gyri recti. In eachhemisphere the frontal region was bordered pos-teriorly by a deep sulcus running downwards andforwards towards the anterior end of the Sylvianfissure (Fig. 1). In the parietal lobes shallow sulciran in the same direction and no interparietal sulci

were present. The occipital lobes were more normallyconvoluted, transverse occipital and calcarine fissuresbeing identified. The temporal lobes were almostsmooth on the convexity (Fig. 2). The hippocampalgyri were well developed. A thin corpus callosumwas present. No malformation was seen in thecerebellum but there was obvious atrophic shrinkageof the lateral lobes.

MICROSCOPIC Representative regions of the cerebralhemispheres, basal ganglia, cerebellum, and brain-stem were examined by frozen and celloidin sectionsstained for nerve cell bodies, axis cylinders, myelin,fibrous neuroglia, and lipid.

Changes in the white matter Large celloidinsections stained by Heidenhain's method revealedan almost complete absence of myelin in the centrumovale and gyral cores, except for a feeble staining inparts of the cingulate and hippocampal gyri (Fig. 3).Similar changes were seen in frozen sections stainedby Kultschitsky-Pal's method. The anterior part ofthe corpus callosum contained some well-stained butbeaded fibres. Gros-Bielschowsky preparationsshowed that axis cylinders were well preserved inall these areas, though some fibres showed beading(Fig. 4). The Holzer stain revealed a slight diffusefibrous gliosis which became denser beneath thecalcarine cortex in the demyelinated occipital lobe.Closely packed microglial phagocytes filled withscarlet staining and doubly refractile lipids wereuniformly dispersed throughout the whole whitematter and showed little tendency to aggregatearound blood vessels (Fig. 5). There was no meta-chromatic or P.A.S.-positive material in the tissues.

In the basal ganglia (Fig. 3) the thalami hadretained their normal pattern of myelinated fibres

FIG. 1. Dorsal aspect of brain showing irregularity of FIG. 2. Lateral aspect of left hemisphere showing agyricconvolutional pattern. temporal lobe.

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FIG. 3. Coronal section showing poverty of myelin in thecentrum ovale. Heidenhain x 14.

FIG. 4. Frontal white matter showing well preserved axiscylinders. Gros-Bielschowsky x 255.

FIG. 5. Occipital white matter showing diffusely dis-tributed fat granule cells. Scharlach R and haematoxylinx 40.

FIG. 6. Pons showing fat granule cells in the corticalprojection tracts. Scharlach R and haematoxylin x 60.

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but these stained rather less intensely than normal.Only the subthalamic nuclei and tegmental radiationsappeared fully myelinated. The fibre systems of theglobus pallidus and putamen on each side wereseverely demyelinated and contained large numbersof fat granule cells. The internal capsule, optic tract,and anterior pillars of the fornix contained numerouspalely staining, swollen fibres and were clearlymarked out in fat preparations by the presence ofclosely packed sudanophil phagocytes.

Similar appearances were presented by the corticalprojection systems in the crura, pons, and pyramids(Fig. 6), though in the cerebral peduncles an outerrim of well-myelinated fibres was present. Myelinsheaths were absent or scanty in the substantianigra, the reticular formation of the medulla, andthe hila of the inferior olives (Fig. 7). These areascontained few or no fat granule cells. Feeblestaining rather than frank demyelination was afeature of the transverse fibres of the pons. Themesial fillet contained abundant fat granule cellsonly at pontine level. In the medulla the pyramidswere of neonatal size and the inferior olives normallyconvoluted.

In all areas of severe or partial demyelination theaxis cylinders were well preserved. Fibrous gliosis

FIG. 7. Medulla showing general poor staining of themyelin and demyelination of the olivary hila, mesial fillet,and reticular formation. Kultschitsky-Pal x 3.

was generally inconspicuous in the pes pontis, themesial fillet at pontine level, and in the hila of theolives.The cerebellar white matter in the vermis and

lateral lobes was shrunken and showed an incompleteloss of myelin sheaths (Fig. 8), the individual fibresoften appearing pale with irregular swellings.Rather better staining of fibres was seen peripherallyin the gyral cores and in the granular layer. Gliosiswas mild except in some of the medullary cores ofthe semilunar and quadrangular lobes. Axis cylinders

FIG. 8. Lateral lobe of cerebellum showing diffuse de-myelination. Kultschitsky-Pal x 1J5.

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Sudanophil leucodystrophy in a pachygyric brain

TABLERESULTS OF CHEMICAL ANALYSIS OF THE BRAIN IN GRAMS PER 100 GRAMS OF DRY TISSUE

White Matter Cerebral Cortex

Case G.P. W. Neonatal

Total lipidTotal lipid hexoseNeutral hexoseLipid hexosamineNeuraminic acidLipid sulphurTotal hexosamineResidue hexosamineCholesterol freeCholesterol esterTotal phosphatideLecithinSphingomyelinCephalin BWater

35-61-060-170 1160-3920 0500 5950 479403-4

11-06-72-6

nil81-8

35.91-050-3600810 3540-0640-6620-5815-30423-410-40-11-5

89-1

Normal 21 Years Case G.P. W. Neonatal

'From a normal 1 year control.

were well preserved. Large numbers of phagocyticand transitional microglial cells containing sudano-phil lipid were present in the central white matterbut not in the central cores of the gyri.

Changes in the nerve cells The malformed areasof the cerebral cortex showed the usual changes ofpachygyria. The depth of the grey matter wasincreased, there was no granular layer, and a broad,ill-defined zone of heterotopic islands of nervecells lay beneath the more compact cortical layer ofgrey matter. No abnormally large nerve cells wereseen. There was no evidence of a destructive processaffecting nerve cells in any part of the brain except inthe cerebellum where the granular layer was de-generated selectively. The greatest loss of granuleswas in the posterior part of the lateral lobes andvermis, but elsewhere this layer showed a diffusereduction in cell density. The Purkinje cells, thebasket and tangential fibres, and the dentate nucleiwere intact (Fig. 9). The atrophied areas showedfibrillary gliosis of the gyral cores and proliferationof the Bergmann fibrils.The leptomeninges, choroid plexus, and intra-

cerebral vessels appeared normal.

CHEMISTRY The results of the analysis of thecerebral grey and white matter are given in theTable. The methods used are those cited in a previouspaper (Norman, Oppenheimer, and Tingey, 1961).The brain had been in formalin for three monthsbefore analysis. The normal control of two and ahalf years had been fixed for four years. We havealso included figures for the normal neonatal brainbased on averages of several specimens fixed informalin for about a year.

DISCUSSION

Signs of a progressive neurological illness had notbeen observed in this patient, probably becausethey had been masked by the severe cortical mal-formation. This latter finding is extremely rare inthe leucodystrophies and the only comparableexample we are aware of is the first of Seitelberger's(1954) cases of Pelizaeus-Merzbacher disease inwhich a patch of micropolygyria was found in thefrontal cortex. The 'megalencephaly' often reportedin other types of infantile leucodystrophy may beattributed to the inbibition of fluid by the degeneratedwhite matter and not to pre-existing malformation.The combination of leucodystrophy and widespreadpachygyria in our case is unique. In other recordedexamples of this malformation, and in agyria, thewhite matter has usually been well myelinated,though its volume is reduced and the lateral ventriclesenlarged. An exception is the case recorded byKramer (1956) in which death had occurred at theage of 1 year. The myelination of the cerebral andcerebellar white matter was poor but considerablybetter than in the present case. Droplets of fat werepresent in the microglial cells and free in the tissuesboth in the white matter and in the cerebral cortex.In a personal communication Kramer says thatthe condition did not suggest a leucodystrophy, andit seems likely that anoxia during the terminalillness may have been responsible for the changes.

It is generally held that an important pathogeneticfactor responsible for this disorder of developmentis a retardation in the migration of the neuroblastsfrom the ependymal matrix to the periphery of thehemisphere. Since the chances of two rare conditionsoccurring together in the same brain are very small,

367

5072-431-5300450-1300-11602850-24012-6nil15 47-42-61 4

76-4

3000-890-200 2100-4460 1470 7500-540300 315-27.91.01-7

89-3

32-81-150-160-0960-35200850-7160-6874-30-02

22-010-80330

88-2

Normal 2j Years

3030850-29004804900 075'0-415'0-1965-30-114-78-31-71-2

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it may be suggested that both the malformative anddegenerative processes are the expressions of agenetic influence manifesting itself at different stagesof cerebral development. A similar hypothesis hasbeen advanced to explain the occurrence of wide-spread neuronal degeneration in certain brains withcerebellar hypoplasia (Norman and Urich, 1958;Norman, 1961).While it is not known whether the other sib in

this family is suffering from a demyelinating con-dition, the extraordinarily close physical resemblancebetween the brother and sister leaves little doubt thatthe same type of cerebral malformation is commonto both.The diffuse distribution of the fat granule cells

throughout much of the demyelinated or poorlymyelinated regions in this brain suggests that thedegeneration was of recent origin. On the other hand,there were areas of severe demyelination withoutfatty products, as in the inferior olives. The intensi-fication of the gliosis in the latter situation mayindicate that the lesions were older and had reachedtheir final stage, though it is possible that an elementof arrested myelination may have been present. Asin other leucodystrophies and lipidoses of earlylife there are probably faults of anabolism as well asthe more overt signs cf myelin catabolism (Poser,1961).The selective degeneration of the granular layer

of the cerebellum found in this brain has beenreported in metachromatic leucodystrophy (Peiffer,1959; Norman, Urich, and Tingey, 1960) and is awell known feature of the Batten type of amauroticfamily idiocy.The results of the chemical analysis of the white

matter are also consistent with the findings in otherleucodystrophies. The lipid hexosamine, and parti-cularly its neuraminic acid component, were raisedabove normal levels for this age group. Accordingto Edgar (1957, 1961b) an increased lipid hexo-samine constantly distinguishes a leucodystrophyfrom Schilder's disease, and in our other casesof leucodystrophy, of the Krabbe, metachromaticand sudanophil types, the lipid hexosamine andthe neuraminic acid levels have also shown signi-ficant elevations. In the present case hexosaminewas also markedly increased in the grey matter,which in other respects did not show any significantchemical change. The residue hexosamine (a measureof polysaccharides) was also substantially increasedboth in the white and grey matter, but according toEdgar this may occur in demyelinating conditionsother than leucodystrophy. The amount of themyelin-forming constituents, with the exception ofsphingomyelin, was considerably reduced. We believethat this latter finding is correct since similar values

for sphingomyelin have been obtained in duplicateestimations by difference in the choline fractions.The poor myelination in this case cannot, therefore,be attributed to a simple retardation in myelinformation, even though the levels of the othermyelin-forming constituents closely approximatedto the neonatal state. Edgar (1961a) has also founddiscrepancies between the degree of histologicaldemyelination and the amounts of sphingomyelinin cases of sclerosing encephalitis of the van Bogaerttype. It is of interest to note that the lipid sulphur was.reduced in this brain, as in a previously recordedcase of Pelizaeus-Merzbacher disease (Norman andTingey, 1961). In two other forms of sudanophilleucodystrophy which were reported in the samepaper, sulphur was present in normal amountdespite the severe demyelination. The abnormallyhigh figure for cholesterol ester is not surprising inview of the large amount of doubly refractile lipid inthe tissues.

Finally, the presence of foam cells in the alveoliof the lungs requires some comment. The histologicalappearances suggest that this is a lipoid pneumoniaand the failure to reduce osmium tetroxide suggeststhe presence of a saturated fatty acid. It is doubtful,however, whether osmium tetroxide reduction is ofmuch value in determining the nature of fats(Pearse, 1960). We have been able to exclude liquidparaffin and cod liver oil so that some food materialseems the likely source. Nevertheless the fact thatthe child suffered from a sudanophil leucodystrophynaturally raises the question of whether the lunglesions were in some way related. In a true lipidosis,such as Niemann-Pick's disease or the visceral formof Tay-Sachs disease, histiocytes are present bothin the lung alveoli and in the parenchyma (Norman,Urich, Tingey, and Goodbody, 1959). We thereforedo not think that the alveolar foam cells in thepresent case can be plausibly related to the cerebralcondition, but certainly the lungs of further casesshould be carefully examined in an attempt to settlethe point.

SUMMARY

The brain of a paraplegic, microcephalic idiot, aged2 years 4 months at death, showed pachygyria anddiffuse demyelination of the centrum ovale, cere-bellar white matter, and parts of the brain-stem.The degenerated areas were crowded with microglialphagocytes containing sudanophil and doublyrefractile lipids. Axis cylinders were well preserved.Nerve cells were unaffected except in the cerebellarcortex where there was a selective degeneration ofthe granular layer. This demyelinating conditionhas been classed as a sudanophil leucodystrophy.

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Sudanophil leucodystrophy in a pachygyric brain

Chemical analysis of formalin-fixed material revealeda general reduction in the myelin-forming consti-tuents with the exception of the sphingomyelin.Cholesterol esters were abnormally increased aswere neuraminic acid, lipid hexosamine, and residuehexosamine. An elder sibling shows a closelysimilar clinical picture.

This work has been done with the help of the NuffieldFoundation.

REFERENCES

Edgar, G. W. F. (1957). In CerebralLipidoses, p. 48, ed. J. N. Cumings.Blackwell, Oxford.

-(1961a). In Encephalitides, p. 648, ed. L. van Bogaert, J. Rader-mecker, J. Hozay, and A. Lowenthal. Elsevier, Amsterdam.

(1961b). Neurochemistry Symposium. 7th International Con-gress of Neurology. Rome. (In the press.)

Einarson, L., and Stromgren, E. (1961). Acta Jutland, 33, 1.Hallervorden, J. (1957). In Handbuch der speziellen pathologischen

Anatomie und Histologie, Vol. 13, Pt. 1, p. 716, ed. 0 Lubarsch,F. Henke, and R. Rossle. Springer, Berlin.

Kramer, W. (1956). J. Neuropath. exp. Neurol., 15, 471.Norman, R. M. (1961). Arch. Dis. Childh., 36, 96.

Oppenheimer, D. R., and Tingey, A. H. (1961). J. Neurol.Neurosurg. Psychiat., 24, 223.

-, and Tingey, A. H. (1961). Neurochemistry Symposium. 7thInternational Congress of Neurology. Rome. (In the press.)

, and Urich, H. (1958). Arch. Dis. Childh., 21, 159.,-, and Tingey, A. H. (1960). Brain, 83, 369.,_,_and Goodbody, R. A. (1959). J. Path. Bact., 78,

409.Pearse, A. G. E. (1960). Histochemistry, Theoretical and Applied,

2nd ed., p. 310. Churchill, London.Peiffer, J. (1959). Arch. Psychiat. Z. Neurol., 199, 417.Poser, C. M. (1961). Arch. Neurol. (Chic.), 4, 323.

, and Bogaert, L. van (1956). Acta Psychiat. (Kbh.), 31, 285.Schilder, P. (1912). Z. Neurol. Psychiat., 10, 1.Seitelberger, F. (1954). Wien. Z. Nervenheilk., 9, 228.

The August 1962 Issue

THE AUGUST 1962 ISSUE CONTAINS THE FOLLOWING PAPERS:

Sources of error in the biochemical diagnosis ofmuscular dystrophy W. H. S. THOMSON

Observations on peripheral servo mechanisms inParkinsonian rigidity WILLIAM WARD HOFMANN

The completion of visual forms across hemianopicfield defects ELIZABETH K. WARRINGTON

Diffuse hypertrophy of the cerebellum THOMASCOOK, SHIRLEY HOLT, and P. o. YATES

Studies in the development and breakdown of theuse of names GERARD ROCHFORD and MOYRAWILLIAMSI The relationship between nominal dysphasia andthe acquisition of vocabulary in childhoodII Experimental production of naming disordersin normal people

Toxic polyneuritis in Bombay due to orthocresyl-phosphate poisoning D. D. VORA, DARAB K. DASTUR,BEATRIZ M. BRAGANCA, L. M. PARIHAR, C. G. S.IYER, R. B. FONDEKAR, and K. PRABHAKARAN

Mental disturbances after thalamolysisWATKINS and D. R. OPPENHEIMER

E. S.

Some observations on memory impairment aftertemporal lobectomy for epilepsy EUSTACE A.SERAFETINIDES and MURRAY A. FALCONER

Changes in tactile discrimination and in visualreaching after successive and simultaneous bilateralposterior parietal ablations in the monkey G.ETTLINGER and J. E. KALSBECK

Perephlebitis retinae and multiple sclerosis E. J.FIELD and J. B. FOSTER

Myoclonic encephalopathy of infants M. KINS-BOURNE

The relation between complaints of persistent painand family size THOMAS A. GONDA

Report by the Commission of Neuroradiology(World Federation of Neurology)Book reviews

Copies are still available and may be obtained from the PUBLISHING MANAGER,BRITISH MEDICAL ASSOCIATION, TAVISTOCK SQUARE, W.C.I, price 17s. 6D.

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