Acta Ncuropathologica 5, 1--15 (1965)

O r i g i n a l a r b e i t e n �9 O r i g i n a l I n v e s t i g a t i o n s �9 T r a v a u x o r i g i n a u x

The First Department of Pathology (Director: Prof. N. SUWA) Tohoku University, School of Medicine, Sendal, Japan

Infantile l~euroaxonal Dystrophy (Seitelberger's Disease) Report of an Autopsy Case

By YOSHIO TAKEI

With 5 Figures in the Text

(Received November 19, 1964)

Introduction Neuroaxonal dyst rophy is an unusual degenerative disorder of the central

nervous system, occurring in early life and characterized pathologically by the appearance of numerous discrete round or oval structures, which are called "Schollen" or "spheroids", found mostly in the gray matter . I t s heredofamilial occurrence has been often suspected, but the etiology and pathogenesis are still obscure, and the nosological identification is also under debate.

Since SEITELBERGER'S first description about this rare condition appeared in 1952, of which a further comment was presented again in the following year (SEIT~r.B~nG~,~ 1953), several additional cases have been reported by RABINO- WICZ and WrLDI (1955), G~oss et al. (1957), Cow]~N and 0LMST~AD (1963), and LYoN and S~E (1963). A review of these reported cases reveals tha t the first clinical mani- festation is tha t of difficulty in standing and walking, having its onset before the second year of life after a period of normal development. This is followed by a pro- gressive deterioration of neurological functions, sometimes pyramidal signs, flexion deformities, nystagmus, strabismus, epileptic seizures, incontinence, etc. Pathologi- cally, wide-spread lesions in the form of appearance of numerous "Schollen" in the central nervous system is pathognomonic. Their neuronal origin is indicated by localized swelling of axons, also of dendrites, and degeneration of nerve cell bodies. S~IT~LB~nGEn considered in his first report tha t this change belonged to thesaurismoses and the condition was a peculiar metabolic disease of neurons in the central nervous system. Later, he found tha t the pr imary lesion in affected neurons was degeneration of axons, and that , through histoehemicaI investiga- tions, the "Schollen" were composed mainly of protein. S~IT~LBV~RG~ (1957), therefore, proposed the term of "Neuroaxonale Proteid-Dystr0phie" to express this specific neuropathological change. I%ABI~OWICZ and WXLDI reported a similar case as belonging to thesaurismoses and designated it as "spastic amaurotic axonal idiocy", which, however, was not preferred by other authors.

This specific change is associated furthermore with a series of other neuro- pathological changes, including marked accumulation of fat granules in certain

Acta NeuropathoIogica, Bd. 5 1

2 Yosmo TAKEI :

regions of basal ganglia, e.g. globus pallidus and corpus striatum, cerebellar atro- phy, degeneration of optic pathways, and demyelination of certain nerve tracts in the spinal cord. Thus, the disease appears to constitute a distinctive pathological entity.

In the meantime, SEITELBERGE~ (1955 and 1957), paying his attention to the pallidal lesion as well as to the topographical distribution of "Schollen", extended his discussion to the connection of Hallervorden-Spatz disease to this specific syndrome. According to him, the two diseases constitute a single genetic unit and can only be properly discriminated from each other by dense pigmentation of the pallidum in the former, whereas in the latter this region contains no pig- ment, but is flooded with fat granules. This is because pigmentary maturation of the extrapyramidal centers takes place only after a few years of life. The condition known as Hallervorden-Spatz disease is observed exclusively in adults, while neuroaxonal dystrophy so far reported affected only children. This interest- ing hypothesis, though supported by G~oss et al., requires, however, further evidences 1.

In 1963, COWEN and OLMS~EAD described a post mortem case, and the neuro- pathological features in this desease were extensively studied and reviewed by them with complete survey of visceral organs. They derided the reported cases into two classes, infantile and late-infantile, by the age of onset and death. Late- infantile cases (case of RAm~owIcz and WILDI, and of Gaoss et al.) in which pigment deposits were confirmed, were regarded by the investigators as represent- ing a transitional form between neuroaxonal dystrophy and Hallervorden-Spatz disease. In spite of the presence of this type and of some resemblances of the infan- tile type to the latter disease, their extensive investigation suggested that it was not preferable to classify neuroaxonal dystrophy as an infantile, or late-infantile, non-pigmented form of Hallervorden-Spatz disease, because of much greater abundance of "Schollen" and of the lack of selective involvement of the globus pallidus and zona retieulata of substantia nigra in the former disease.

The case of LYo~ and S~E was that of a 3-year-old girl, and might be regarded as an infantile type. However, the microscopic findings of globus pallidus and cerebellum seemed to bear more resemblance to those seen in the late-infantile type, i.e. the presence of iron-positive pigmenst in pallidum, and mild eerebellar atrophy. The presence of this type would make the problem of nosological identification of the disease more complicated, especially when the connection to so-called late-infantile Hallervorden-Spatz disease is concerned. Nevertheless, their extensive study led them to the conclusion that ~ si aucun des signes ana- tomiques de l'affection d6crite n'est en lui-m6me sp6eifique, il nous semble que l ' importance consid6rable et la topographic si sp6eiale des 16sions axonales, justifie son individualisation darts le cadre des affections h6r6do-d6g6n6ratives de l'enfance, et sa d6signation sous le nora de dystrophic neuro-axonale propos6 par COWEN et OLMSTEAD ~>.

NXK~ et al. (1960) also reported an autopsy ease of a 9 year-old raale child as "Seitel- berger's spastic amaurotic axonal idiocy". But, as COWEN and OLMSTEAD pointed out, this

1 As to the late-infantile Hallervorden-Spatz disease fairly well outlined criteria were given by the studies of G~oss et al.~ SmTELBERGE~ and G~oss (1957), and SWIT~rmERGEI~ et al. (1963).

Infantile neuroaxonal dystrophy

case seems to be rather different from the condition known as "neuroaxonal dystrophy" in both clinical and pathological aspects. Therefore, it may be proper to exclude this case when the series of neuroaxonal dystrophy is dealt with.

I n t h e fo l lowing p a r t o f t h e p r e s e n t r epo r t , an a u t o p s y case o f a 42/8 y e a r - o l d

m a l e chi ld w i t h t y p i c a l i n f an t i l e n e u r o a x o n a l d y s t r o p h y is de sc r ibed w i t h s o m e

discussions.

Clinical and Pathological Findings Clinical History: K. S. male, age 21/2, was admitted to Tohoku University Hospital on

March 11, 1960, and died on June 6, 1962. He was the only child of apparently healthy parents who were consanguineous (second cousins), born at full term and weighing then 2,950 g. Pregnancy had been normal except that the mother had an operation for ovarian cyst in the second month. Labour was normal. At 10 month-old, he could stand for himself and walk when supported. The mother had an impression that he was a bright and intelligent boy when he began to speak at 12 months. Thus, his development had been normal until he was at the age of 14 months, when the parents noticed that the child could not walk, became easy to fall down from his knees, and that he payed no attention to the surroundings. There was a convulsive fit. The parents said that there had been six subsequent fits of the same kind. Then he developed a squint. By the time he was 2 years old, he had been able to roll and crawl about the floor, to stand with holding a chair and to articulate a few simple words, such as "mama" or "papa". When he was two and a quarter he became speechless and could only sit up. In further two months the signs of mental deterioration became more distinct, he retarded progressively in development and could do nothing but lie on the bed, grinding his teeth occasionally. There had been no apparent major disease that could possibly be the cause of these symptoms.

All known members of the family were investigated, but no history of any neurological disorder could be detected in both the paternal and maternal lines.

On examination in the Pediatric Clinic, he was found to be a thin child with a somewhat apathetic face. The skull measured 47 cm in its greatest circumference. Convergent stra- bismus of the right was present with ptosis of the same side. The pupils reacted well to light. The right conjunetiva was seen to be hyperemic. His sight and hearing seemed to be unaffected. He cried when his lower extremities were lifted up as if he felt pain in his back. ~uscles of the extremities were slightly hypotonic without rigidity. Patellar reflex was weakly present, but _&chilies reflex and abdominal reflexes were both absent. There was positive Babinski on both sides but no other pathological reflexes.

Laboratory Examinations: Estimation of creatine and ereatinin in the urine revealed remarkable increase of creatine (28.4 mg/kg per day) and slight decrease of ereatinin (13.3 mg/kg per day). Wenekebach's A - - V block was found on EKG, while nothing particular could be confirmed by EEG or EMG. On later examinations, however, EEG showed dysrhythmia with high voltage suggesting a diffuse brain damage, and EMG indicated degeneration of the nerve cells in the anterior horn. At the same time, muscular atrophy of the lower extremities was demonstrated by biopsy.

One year after admission, he lay in bed with his head retracted, the deep and superficial reflexes were completely suppressed with the exception of the biceps, and horizontal nystagmus appeared. The limbs tended to be held rigidly, especially if handled. The arms were somewhat flexed at the elbow and slightly pronaCed. The fingers showed hyperextension in passive move- ment. The legs were held flexed at the hip in external rotation and also flexed a t the knee with contraeture. He slept most of the time and became corpulent. (This may have been due to steroid treatments.) He reacted to sound by moving his hands, but could not grasp any object that was presented to him. Babinski's was still positive, as were Rossolimo's, lVlendel- Bechterew's and Schaffer's signs. However, these pathological reflexes turned to negative when examined two months later in June 1961 as contraeture became more pronounced. Then, ophthMmological examinations demonstrated simple optic atrophy with entropium, which simulated amaurosis. There was edema in his face, arms and legs, and also incontinence of urine with origuria (200--300 co/day). Urination took place only when the lower abdomen was

1"

4 YosHio TAK]~I:

pressed. A dorsal decubitus ulcer was present. In December 1961, the cornea became clouded and he seemed to be quite blind. The dea th occulted under respiratory distress a t the age of 4 years and 8 months.

Post-mortem Examination. The autopsy was performed four hours after death. The body was extremely obese and in a "frog-like" posture. The arms were flexed a t the elbow and pronated. The legs were flexed a t the knee in r ight angle, and pronated externally, so t h a t the thighs were wide-open. This made the skin of the pubic region so stretched t h a t the scro- t um became only a fiat protuberance, and the testicles were dislocated into the abdominal cavity.

Visceral organs. The abdominal organs were normal in their positions as well as the hear t (145 g), lungs (left 100 g, r ight 140 g), and mediast inum. No gross lesions were found in the liver (635 g), pancreas (60 g), and adrenal glands (left 7 g, r ight 5 g). The spleen was enlarged (135 g) and slightly congested, which, on cut surface, was rich in blood, and its follicles were hypertrophied. Swelling of the thymus (17 g) was found, and lymph nodes were enlarged in the hi lum of the lungs, mediast inum, and in the neck. Part icular ly those of bronchopulmonary and ileocollc regions were markedly engorged. This condition suggested the presence of "s ta tus thymieolymphat ieus" . The thyroid gland (8 g), testicles, gastrointest inal tracfs, kidneys (both 85 g), and the bladder showed no lesions on gross inspection.

Microscopic /indings. Among the microscopic findings of the removed organs notable changes were found in the following. Lungs: Small bronchi and bronchioli were filled with mucous exudate which contained scattered accumulations of bacilli. I n their wall, there was a small number of infiltrating round cells with occasional plasma cells. This change would indicate the presence of recurrent chronic bronchitis. The cause of dea th was asphyxia due to obstruct ion of small bronchi and bronchioli by mucous masses which could not be expectorated. Liver: The normal architecture was well preserved. The slight infiltration of round cells with slight fibrosis was found in the portal area. The liver cells around the central veins contained occasional small fat globules. PAS positive substance (glycogen) was found almost all over the lobules. The sudden death due to asphyxia was probably responsible for the preserved glycogen content in the organ. Neither necrosis of liver cells nor reaction of the Kupffer cells could be found. Spleen: The splenic cords appeared to be slightly dilated and congested. However, proliferation of ret icuhim cells and infil tration of plasma cells were not remarkable. There was no stored substance. The structure of reticulin fibers was normM.

Nervous system. The bra in weighed 930 g. There was no opacity of the leptomeminges. Cerebral convolutions were well formed, and the external surface looked normal. On frontal sections, cerebral cortex looked ra ther th in bu t no t abnormally so. There was no dilatat ion of lateral ventricles. Corpus callosum was well formed. There was neither abnormal pigmenta- t ion nor discoloration in globus pallidus, substant ia nigra, or any other region of the cerebrum. The cerebellum was dist inctly atrophied and felt very firm, almost hard. On cut surface, each arbor vitae of the cerebellum was very small due to sclerosis, and white mat te r thin, whereas the denta te nucleus was fairly well preserved. The pons and medulla oblongata also showed considerable shrinkage. The spinal cord had no external abnormalities, and its segmental and cauda equina roots were unaltered.

Microscopic findings. The most characteristic abnormal i ty in this disease was the presence of numerous spheroid bodies ra r ing in their sizes from about 10 # to 70 # in diameter. Their shapes also varied from a round disc to an irregular oval (Fig. 1) or sometimes to amorphous mass. They were dispersed apparent ly free in the tissue and generally separated from adjacent tissue elements by a th in membranous margin. The distr ibution of the bodies had part icular predilection in the gray ma t t e r of the central nervous system. The cranial nerve nuclei of the medulla oblongata and the dorsal horn of the spinal cord were the most severely affected areas, where, especially in the former, the spheroid bodies showed most variable appearances (Fig. 2), I n Hematoxyl in-Eosin stain (paraffin), they were all eosinophilie, some were ra ther small and evenly stained having homogenous appearance like hyalinoid substance, and others had a central deeply stained core wi th paler zone around this, so t h a t they showed a target- like appea~'ance. Some of the larger ones exhibi ted paler staining reaction, being seen under a high manification to be composed of evenly distr ibuted fine granules or a fine reticular or spongy like arrangement, The spheroid bodies of this type occasionally contained a small compact area in their center or periphery. Vacuolar formations were seen at t imes in the bodies.

Infantile neuroaxonal dystrophy

or sometimes axonal or dendritic processes were extended from them, which were argento- philic in Bodian stain. Similar bodies were found in the anterior horn of the spinal cord, olivary nucleus, tegmentum pontis, dentate nucleus and basal ganglia. A very few of rather smaller ones were observed in the cerebral cortex and white matter. Cerebellar hemispheres also occasionally contained them mainly in the territories of damaged granular layer. Glial

b

Fig. i a and b. General appearance of "Schollen" stained with hematoxylin-eosin in paraffin section a, and frozen section b. Numerous "Schollen'" are densely eosinophilie. Some of them (in b) show central basophilia, which,

however, is not apparent in this picture. Tegmcntum of lower medulla; 150 •

reaction around these bodies was seen, which was more pronounced in the areas with abundant bodies. Astrocytic proliferation with gliosis was a marked feature, and fibrillar astrocytes at times wrapped the bodies with their processes. Microglial nodules were occasionally seen simulating neuronophagia against the spheroid bodies.

The employed methods for the histochemical investigation of the spheroid bodies and their results are presented in the table, Formol fixed materials were used for frozen sec- tions and alcohol-formol fixed tissue slices for paraffin sections. Summarizing the results obtained with these methods, the chemical nature of the bodies was assumed to be a sort of lipo-glyco-protein complex. This finding is identical with that of the previously reported cases. However, it must be born in mind tha t all the bodies did not exhibit the same staining reaction; in PAS stain, some were strongly positive, ethers were weakly so, and it was also found tha t there were the bodies showing definitely negative staining reaction. The same thing could be

6 Yos~t~o TAKEI :

a b

d e f Fig.2a--f . Variable appearance of "Schollen" stained with hematoxylin-eosin in paraffin sections. Tegmentum of medulla. In a two of them apparently originated in necrotic nerve cell bodies (x, y); 300 • In b vacuolated "Schollen" and a glial nodule are seen. One of the "Schollen" is a necrotic nerve cell body (z); 300 • In c a large one with a central core is seen in the left, and a smaUer one in the right has a central residual hole; 600 • d and e show the "Scho]len" of unknown origin with unusual accessories. In d densely eosinophilio granules are gathered in the periphery. In e a "Scholle" is surrounded by glial cells whose cellular margins are obscure. A residual hole is seen in the left; 600 x. In f an axonal swelling with homogeneous eosinopbilic ellipsoid contour is accom-

panied by a small target-like body; 300 •

s a i d a b o u t s u d a n b l a c k B s t a i n , n i le b l u e s t a i n , o r t h e c o u p l e d t e t r a z o n i u m r e a c t i o n , T h i s m a y s u g g e s t t h a t in t h e d e g e n e r a t i n g p r o c e s s t h e b o d i e s a l t e r t h e i r c h e m i c a l n a t u r e . B u t i t w a s

i m p o s s i b l e t o c l a s s i fy t h e m i n t o a ser ies o f d e g e n e r a t i v e s t a g e s a c c o r d i n g t o t h e s t a i n i n g r e a c -

t i ons .

Infantile neuroaxonal dyst rophy

Besides this specific degenerative process, there were several impor tan t changes of different kind. Topographically they were distr ibuted as fol]ows:

Cerebral hemispheres. In general, nerve cells in the cerebral cortex were well preserved, though there was slight reduction in their number in certain areas. The laminar structure appeared to be normal throughout. The deeper layer of the cerebral white mat te r stained ra ther faint in myelin preparations, bu t there were no dist inct plaques of demyelination. I n the occipital lobe, however, fat-granule cells appeared occasionally around the ventricle and nerve fibers were slightly demyelinated.

Table. Histoehemical reactions o/"Schollen"

H-E

Goldner Van Gieson Metachromasia (toluidine blue pH 2.4) Bodian P.A.S. after saliva Feulgen Reaction Turnbul l blue reaction for Fe Seharlachrot Sudan black B Nile blue sulfate Luxol fast blue Smith Dietrich Coupled te t razonium reaction Hg-BPB for protein Polarization

]~&raf~n Froz~3n

Eosinophil

Ponceau Yellow-Brown

Brown - - to =~ or _L

S a l n e

+ to + +

+ +

Eosinophil (occasionally central

basophilia)

D a r k Brown + t o + +

same

+ + to +++ § to++

§

Basal ganglia. A striking change was found in basal g~mglia, especially in globus pallidus and corpus str iatum. The lesion consisted of massive accumulation of fat-granule cells with perivascular cuffing by fat-laden maerophages and fat droplets lying free in the tissue (Fig. 3). These fat granules stained with Scharlachrot and examined with polarisation consisted of two different substances. The one was neutral fat and the other was cholesterol ester. The former was evidently predominant in quanti ty. Marked glial proliferation with formation of bizarre cell form and gliosis was present. No abnormal pigment of any kind could be found anywhere in this region. The tota l number of nerve cells was diminished bu t the surviving ones were mostly in good condition. Slight demyelination was found in myelin preparations, bu t i t was not severe enough to account for the intense accumulation of fa t ty substance. I n the amyg- daloid nucleus and claustrum mild cellular gliosis was present. Thalamus had a similar, bu t ra ther insignificant, change as found in pallidum, but appearance of fat granules was a rare occasion.

Optic pathways. There was a slight loss of axis cylinders along with optic t racts in Bodian s tain and demyelination was seen with moderate gliosis, bu t these lesions were not remarkable at the chiasm.

Brain stem. Except for the appearance of the spheroid bodies there was litt le change in the midbrain. A few nerve cells of the red nucleus and of the substant ia nigra showed part ial degeneration. Format ion of melanin granules was not yet observed. No abnormal pigment deposits were found. The nuclei in the tegmental portion of the pons, part icularly those in the floor of the fourth ventricle and in the areas of reticular formation were in a degenerative process. Cytoplasm of the affected nerve cells contained fine granules which showed partial ly strong eosinophilia, and displaced the Nissl bodies to the cell margin. Bu t the cell bodies were

8 YosIIIO TAKEI:

never enlarged by the storage of granules. The basilar portion of the pens was well preserved. There was no demyclination of the dispersed bundles, and scattered groups of nerve cells of nuclei pontis remained intact. Almost all ~he cranial nerve nuclei in the medulla oblongata were more or less injured and replaced by numerous spheroid bodies. Glial proliferation was pronounced in this area, bizarre cells were formed and neuronophagia was seen occasionally.

b Fig. 3 a and b. Globus pallidus, a Massive fatby accumulation with perivascular cuffing by fat-laden maerophages. Sctlarlact]z'ot slain, frozen section; 150 x ; b ~Fa~ grannie cells in pallidum. A small "S~hoilr is seen in the upper

center of the picture, hematoxylin-eosin, paraffin section; 300 •

On the other hand, hypoglossal and dorsal vagus nuclei were fairly well preserved, though reduced in nerve cell number, most of the surviving cells appeared almost normal. The nerve cells of olivary nucleus were shrunken, lean with pyknotic nuclei, and the Nissl bodies were not apparently recognizable in dense basophilic cytoplasm. These ceils probably represented a certain stage of chronic degeneration, l~ of fibrillar astrocytes was another marked feature. The pyramid appeared to be muck at tenuated and demyelinated, but glial reaction here was far from conspicuous, and no fat graaulcs were demonstrated.

Infant i le neuroaxonal dyst rophy

Cerebellum. Atrophy of cerebellar cortex was extraordinary remarkable. The cortical architecture was almost completely destroyed (Fig.4). The granular layer was devasta ted throughout the cortex. Purkinje cells were also severely damaged. They disappeared almost completely and only one or two damaged bu t surviving ones were observed in a section. The destroyed Purkinje layer was replaced by proliferation of Bergman~'s astrocytes. In Itolzer

b

Fig.4a and b. Cerebellar cortex, a I~ote remarkable devastation with total loss of Purkinje and granule cells. Nissl stain, paraffin section; 150 • ; b A heavy flbrillary gliosis of cerebellar cortex. Holzer stain, paraffin section;

150 •

preparations, heavy fibrillary gliosis was seen in the molecular layer and in the white mat te r of folia, bu t gliosis was milder in the terr i tory of the missing granules. The cerebellar white matter , in general, was fairly well preserved in myelin preparations. Bu t the nerve fibers in folia were apparent ly demyelinated and fihrillary gliosis was very pronounced. The nerve

i0 Yosn lo TAK:EI:

cells in the dentate nucleus were reduced in number but less ~ffected than those of the cortex. The majority was still surviving, though damaged, showing variable degrees of degeneration; shrinkage, strong cytoplasmic eosinophilia with disappearance of Nissl bodies, nuclear pyk- nosis, etc.

Spinal cord. At all levels of the spinal cord, loss of the posterior horn cells was conspicuous, while the anterior horn cells, if compared to the posterior, were less affected. Most of the sur- viving cells appeared normal, but a few of them exhibited degenerative changes. In myelin preparations, the posterolateral column comprising spinocerebellar and pyramidal tracts was apparently demyelinated. GolFs tract was also involved. Pallor of anterior spinothalamic tract indicated a slight demyelination.

Discussion The case presented in this report is so similar in its clinical and pathological

pictures to the cases reported by SnIT~L~G~n, and C o w ~ and OL)/ISTEAD (cases of infantile type), that there can be no doubt that these are the same exam- ples of one disease-process. I t is equally clear that this process differs from any of the known lipidoses or systematic degenerative diseases of the nervous system. The characteristic pathological features of this condition are found mainly in the central nervous system and may be summarized as follows:

1. The presence of numerous eosinophilic spheroid bodies, designated as "Schollen" by S~IT~LBn~GWn, in wide-spread involved regions of the central nervous system.

2. Extraordinary deposits of fat granules in the globus pal]idus and corpus striatum.

3. Intense cerebcllar atrophy with sclerosis.

In association, there are degeneration of the optic nerves, demyclination of certain nerve tracts, such as pyramidal, spinocerebellar, spinothalamic, GolFs tracts, etc.

One of the main problems in these cases is to explain the developmental process of the "Schollen" (Fig. 5). Their predominance in the gray matter suggests their origin in the nerve cell bodies. In fact, the spheroid bodies with a shape by which a nerve cell body is reminded of are occasionally found, and some of them have a certain deeply stained, eosinophflic, homogeneous core, which is apparently basophilic in frozen sections stained with hematoxylin-eosin, shnulating a nuclear formation. They are probably necrotic or degenerated nerve cells. This interpretation is further sustained by occasional presence of homogeneous eosino- philic substance with an ovoid contour in cytoplasm of nerve cells in the anterior horn of the cervical cord. On the other hand, the bodies exist not only in the gray matter, but also in the white matter lying along the nerve fibers. This is particu- larly prominent in the preparations of longitudinal section of the spinal cord. There arc focal swelling of axons, in which the "Schollen" are formed to some ex- tent. Axonal cngorgemcnts are also found in the gray matter, at times attaching to a necrotic nerve cell body. Bodian stain is the method of choice for this observa- tion. Necrotic nerve cell bodies stain rather faint having a core in their centers, whereas swollen axons are evenly impregnated. Both kinds of the bodies were dealt with as "Schollen" by most of the authors and discrimination of their origins was attempted only in rare occasions. Histochemical investigation is not effective

Infantile neuroaxonal dystrophy 11

for this purpose, because the "Schollen" of both origins undergo a series of chemi- e~I decompositions. Neither in the previous reports nor in the present study, their origins can be identified by distinctive histochemical reactions. Our histological

a b

c d

Fig. 5 a - - d . Or ig in of "'Schollen". a An ovoid homogeneous eosinophilic s t ruc ture (x) in the cy toplasm of a nerve cell in the an te r ior horn of the upper cervical cord. Hematoxyl in-eos in , paraf f in section; 1000 • ( immersion) . b Var iable in tens i ty of s t a in ing of "Schol len" wi th the coupled te~razonium react ion (x, y, z). A axonal swell ing is seen in the center. T e g m e n t u m of lower medulla . Pa ra f f in section; 300 • e Vacuolar and honeycomb-l ike fo rmat ion of a nerve cell wi th moull i form swelling of the ex tend ing axon. Nucleus a m b i ~ u s . Bodian s ta in , paraff in section; 800 • d The mos t demonst rable picture showing the two origins of "Schol len" . A necrotic nerve cell body (n) and an axonal engorgement (a x). Poster ior horn of the upper cervical cord. Bodian s ta in , paraff in section ;

300 •

12 u TAKEI:

investigation suggests, however, that necrotic nerve cell bodies take more important par t in the development of the "Schollen" than assumed in the previous reports, in which predominant participation of axons is often stressed.

The discussion on the pr imary site of the lesion is associated with the problem of pathogenesis. The idea tha t the pathological process in which the "Sehollen" are formed is not merely an accumulation of abnormal material due to metabolic disturbances as found in the known lipidoses is accepted by the major i ty of the previous investigators. I t is also true in the present case. I t may be assumed tha t the basic defect is likewise metabolic in nature, which must be, however, severer in its expression in the nerve cell body and leads rapidly to cellular disintegration. Karyolysis and chromatolysis occur in such an early stage tha t an accumulation of abnormal substances as observed in other neuronal storage diesease remain as yet insignificant. Karyolysis seems to represent the initial anatomical injury of the affected nerve cells. I t was impossible to demonstrate definite nuclear rem- nants in the interior of the "Schollen" and not the slightest trace of DNA was detected by Feulgen's method. Along with the changes in karyoplasm, cytoplasm dissolves itself into a homogeneous mass, forming vacuoles, or at times resulting in a honey-comb-like structure, and the cell body tends to show a round or ovoid contour. Further more, axonal engorgement can deliver similar bodies, which often can not be distinguished from the spheroid bodies originated in nerve cell bodies. In spite of the difficulty in accurate determination of the pr imary lesion, intraneuronal origin of all the "Schollen" in some way or other is clearly indicated by general histological observations.

The next problem concerns the origin and nature of the lesion in the basal ganglia, intense a t rophy of the cerebellum and other incidental systematic degenerations. As to the changes in basal ganglia, CowE~ and OL~STEAD noted the presence of cholesterol esters in a large quant i ty in their infantile case. In the present case, however, neutral fat is predominant in quant i ty as in the original case of SEITELBE~GEI~ and in the late-infantile cases. But the topographical predilec- tion is much the same in the present case as in the case of CowEN and 0LMSTEA]), pallidum and s t r ia tum being both involved, whereas in the other cases only the pallidum exhibits distinct lesions. SEITELBEgGER assumed in his infantile case tha t the accumulation of massive fat granules was an abnormally increased "pall idum fat" , which existed in a small quant i ty as a normal cellular component of the ganglion. The fact tha t parenehymal degeneration was too mild to account for the intense f a t ty accumulation in the pallidum may sustain his interpretation. tIistochemical examination of a late-infantile case in which fat droplets and iron-free pigments were both present led SV.ITE~BWgGEg to the conclusion tha t at least a par t of the pigment was formed in the "Schollen", which contained protein substances and glycolipids (S]~ITELBE~GE~ and GRoss 1957). He main- tained tha t the pigment, which was lipopigment in nature, was presumably derived from these lipid elements by way of polymerization of aldehydes produced by oxidation of phosphatides and unsaturated f a t ty acid residues, and, further- more, its histochemical properties were identical with lipopigment found in the normal pallidum and the red zone of the substantia nigra. Informations as to the normal constituents of these centers are quite insufficient at present, and the discussion is to be substantiated by further investigations.

Infantile neuroaxonaI dystrophy 13

Intense cerebellar atrophy seems to be an usual occurrence in the infantile eases. Cerebellar tissues are transformed into glial scars as a result of pronounced destruction of cortical architecture with disappearance of nerve ceils and heavy fibrillary gliosis. The advanced eerebellar devastation indicates that the lesion is to be dated to relatively early, if not the initial, stage of the disease. On the other hand, the lesion is milder in the late-infantile cases. Particularly the nerve cells in the cortex are well preserved in these eases. Is the age of onset and death alone responsible for the distinction ? In the case of Gx~oss ctal. , many "Schollen" were found in the subcortical region, and the disappearance of cortical nerve cells was not remarkable. Much the same findings were reported in the infantile case of LYo~ and S~E. However, CowE~ and OLMSTEAD described about their infantile ease that the number of spheroids in the cerebellum was too small to account for the intense loss of nerve cell here. Therefore, they assumed that some metabolic disturbance in the cells, independent of the development of spheroids, was the cause of their breakdown and disappearance. I t seems also probable in the present ease. Thus, the cerebellar lesion appears rather different in its origin and nature from the other two main pathological changes in this disease. Severe cerebellar atrophy with attenuation of both molecular and granular layers is also observed in some other diseases of the central nervous system. Among them, a striking resemblance of cerebellar lesion was found in the ease of degenerative encephalo- pathy of J~gvis (1957).

He described a case of 5 year-old male child who had an unusual type of cerebral cortical degeneration, cholesterinosis of the pallidum and striatum, and marked cerebellar atrophy. In his case, cerebellar lesions consisted of severe rarefaction of granular layer and substantial involvement of Pnrkinje cells, which had completely disappeared and not a single element had been found in numerous sections examined. Extensive destruction of Purkinje cells in such diseases of the central nervous system is often attributed to their vulnerability to the vascular disturbances associated with epilepsy or birth injury, but no lesions appropriate to such condi- tions were confirmed anywhere in the brain. Furthermore, some spheroid bodies, 4 to 5 times the size of a granule, were present throughout the granular layer. JEgvls considered these spheroid bodies to be derived from axonal swellings.

The similarity of the cerebellar changes to those in the present case is thus obvious. This type of cerebellar atrophy can hardly be comprised in any known systematic cerebellar degeneration, and, therefore, deserves further attention in the investigation of the infantile neuroaxonal dystrophy. The relationship between lipid deposits in the pallidum and striatum and the cerebellar atrophy is also interesting. Topographical coincidence of the lesions of the basal ganglia and the cerebellum found in the case of JEl~WS and in the present case may indicate some pathogenic connections between the lesions of apparently different characters. However, a satisfactory explanation for the combination of these two patholo- gical features and also of the other important change, the appearance of "Sehol- len", including the incidental systematic degeneration of nerve tracts is hardly possible at the present stage. I t is further questionable whether the total pathological features is sufficiently characterized by the expression of "neuro- axonal dystrophy". The author, therefore, would prefer the designation of "Seitelberger's disease", which might be more comprehensive to express the whole syndromes, until more exact evidences are available in reference to its pathogenesis.

14 Yosmo TA~EI:

The discussion is to be concluded with a brief notice to the relation of Haller- vorden-Spatz disease to neuroaxonal dystrophy. Possible association of the two diseases comes into problem only in the so-called late-infantile type (case of RA- B~TOWICZ and WILD~, and of GROSS et al.) and infantile case of Lu and Sfi]~, in which abnormal pigments are present in certain regions of the central nervous system. In infantile type, histological findings do not indicate any connection to Hallervorden-Spatz disease except for the localization of the lesions. An extensive study and review of this problem was already made by Cow~N and OLMST~.AD, and also by LYoN and S ~ .

Summary An autopsy case of 4 ~/3 year-old male child with the typical features of infantile

neuroaxonal dystrophy was described. His parents were consanguineous (second cousins), but no history of neurological disorder was found in his family. The most characteristic pathological features were found in the central nervous system and may be summarized in the following three groups; 1. the presence of numerous spheroid bodies, designated as "Schollen" by S~IT~LB~GV, R, 2. extraordinary accumulation of neutrM fat in the globus pallidus and corpus striatum, and 3. in- tense cerebellar atrophy with sclerosis. The "Schollen" were assumed to be of intraneuronal origin and presumably to develop on the basis of some unknown metabolic disorder. The pathogenesis of the other two major changes remained undetermined in the present report.

This case, together with two similar cases reported by S]~ITWLB~OV, R, and Cow]~ and OL~STWAD was regarded to represent a fairly well defined disease entity.

Zusammenfassung Es handelt sieh in diesem Berich$ um den Sektionsfall eines 42/aj~hrigen

Knaben, der die typisehen klinischen und anatomischen Zeiehen yon infantiler neuroaxonaler Dystrophie (SEITEL]3ERCV.R) aufwies. Seine Eltern waren als Ge- sehwisterenkel derselben Familie Blutsverwandte. Sonst war jedoch die Familien- anamnese unauffallig.

Die kennzeiehnenden pathologischen Ver~nderungen des Zentralnerven- systems lassen sich in folgende drei Gruppen zusammenfassen : 1. Auftreten zahl- reieher kugelfSrmiger K6rperchen, der ,,Schollen" (SEITV, LBE~O~R), besonders im Bereieh der Medulla oblongata bis zu den HinterhSrnern des Rfickenmarks, aber auch generalisiert in der gesamten grauen Substanz des Zentralnervensystems. 2. AuBerordentlich starke Ansammlung yon Neutralfett in Globus pallidus und Corpus striatum ohne nachweisbare Pigment- und Eisenablagerung. 3. Hoeh- gradige Kleinhlrnatrophie mat fortgeschrittener Fasergliose.

Die histologisehen Untersuchungen weisen auf den intraneuronalen Ursprung der ,,Schollen" bin. Sic k6nnen auf dem Boden noch ungekl~rter Stoffwechsel- stSrungen sowohl aus den Zelleibern als auch aus den Axonen der Nervenzellen entstehen. Die ausgepr/~gte Fettansammlung in den Stammganglien ist haupt- s/~ehlieh auf eine Stoffwechselst6rung nnd nieht einfach auf Zerfall der Gehirn- substanz in diesen Regionen zuriickzuffihren, da keine entsprechende Entmarkung bzw. Erweichung naehweisbar ist. Die extrem starke Kleinhirnver6dung bis

Infantile neuroaxonal dystrophy 15

zu fas t vollst/~ndigem N a r b e n z u s t a n d m a c h t die rela~iv frfihzeit ige Bete i l igung des Kle inh i rns im Ver lauf des Krankhe i t sp rozesses wahrscheinl ich.

Dieser F a l l s te l l t m i t zwei/~hnlichen Sektionsf/ i l len von SEIT~LBZl~OZ~ (1952) sowie yon CowE~ u. OL~STEAD (1963) eine wohl abgegrenz~e K ra nkhe Rs - e inhei t dar .

The author is greatly indebted to Prof. F. SEITELBERGER for the information of his histological survey of this case. The author is also obliged to Prof. T. INos~ and Ass. Prof. S. YOKOL Medical College Yokohama, for their valuable advices.

R e f e r e n c e s

Cow,N, D., and E.V. OLMSTEAD: Infantile neuroaxonal dystrophy. J. Neuropath. exp. NeuroL 22, 175--236 (1963).

Gl~oss, H., E. KALT~N~XCK, and B. UIBERA~: Uber eine sp~tinfantile Form der Hallervorden- Spatzschen Krankheit. I. Mitteilung: Klinische-anatomische Befunde. Dtsch. Z. Nerven- heilk. 176, 77--103 (1957).

JERVIS, G. A.: Degenerative eneephalopathy of childhood. J. Neuropath. exp. hTeurol. 16, 308--320 (1957).

LYON, G., and G. S~E: La d6g6n6rescence neuro-axonale infantile. (Maladie de Seitelberger.) Rev. neurol. 109, 133--155 (1963).

N ~ , H., B. H. LA~Dr~G, and W. K. SChUBErT: Seitelberger's spastic amaurotio axonal idiocy. Pediatrics $5, 441--449 (1960).

tlABI~OWICZ, T., and E. WILDI: Spastic amautoric axonal idiocy, p. 34. Cerebral Lipidoses. A symposium. (Antwerp, July 26--27, 1955) J. N. CcMI~os (Ed.). Oxford: Blackwell 1957.

SEITELB~gGER, F.: Eine unbekannte Form yon infantiler Lipoidspeicherkrankheit des Ge- hirns, p. 323. In: Proe. 1st Internat. Congr. Neuropath. (Rome, Sept. 8--13, 1952), Vol. 3. Turin: Rosenberg and Sellier 1952.

- - Eine eigenartige Stoffwechselerkrankung der Ganglienzellen im Zentralnervensystem, p. 484. In: Proc. 5th Internat. Neurol. Congr. (Lisbon, Sept. 7--12, 1953), Vol. 3. Lisbon: Comptes-Rendus 1954.

-- In discussion of paper by RABmOWICZ, T., and E. WILDI (1955). - - Zur Morphologie und Itistochemie der degenerativen Axonveri~nderungen im Zentral-

nervensystem, p. 127. In: III . Congr~s Ingernat. Neuropath. (Bruxelles, Juillet 1957). Brussels, Les Editions: Acta reed. belg. 1957.

-- , and H. GROSS: ~ber eine sp~tinfantile Form tier Hallervorden-Spatzschen Krankheit. II . Mitteilungen: Histochemische Befunde. Er6rterung tier Nosologie. Dtsch. Z. Nerven- heilk. 176, 104--125 (1957).

-- E. GooTz, and H. Ggoss: Beitrag zur sp~tinfantilen Hallervorden-Spatzschen I~ankheit. Acta neuropath. (Berl.) 8, 16--28 (1963).

Yoshio Takoi, M. D., First Dept. of Pathology, Tohoku University School of Medicine, Sendai, Japan