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Folia Psychiatrica et Neurologica Japonica, Vol. 26, No. 1, 1972

A Sporadic Case of Cerebral Lipidosis in an Adult (Kufs) -Pathological and Histochemical Findings-

Hiroshi ISHINO, M.D. Department of Neuropsychiatry, Okayama University Medical School, Okayama

Hiroshi ISHIZU, M.D. and Keisuke SARAI, M.D. Department of Neuropsychiatry, Hiroshima University School of Medicine, Hiroshima

After considering several diagnoses, it was decided that a 42 year-old female, whose illness had lasted at least 15 years, was suffered from amaurotic idiocy.

The present report is concerned with the clinical and anatomical features of a sporadic case of adult type (Kufs) of this disease. The clinical course was characterized by dementia, myoclonia, cerebellar signs and muscular rigidity. The major histologic features were enlargement of neurons by lipid deposits. The histochemical investigations were also carried out and the results will be presented.

CASE REPORT K.S., a married female aged 42 year-old

at the time of death. No history of family disease of the nervous system. Previous personal history not significant. After good performance in a primary school and a girls’ high school, the patient became a schoolteacher. She had married at the age of 27. She was a person of few words, gentle and diligent.

The present illness began in 1955, when she was 27 years. Soon after the marriage, husband and family noticed a change in her behaviour-she became apathetic, disinter-

Received for publication March 8. 1972.

ested in her surroundings, did not prepare the meal and clear the table. When her house was on fire, she lay indifferently in bed. When the husband asked her to help to put out a fire, she replied calmly that it was not she who had set fire to the house, and refused to help.

Since 1957 she has been forced to change school in secluded place every one year, because she became inadequate to the post of teacher.

From April 1961, she began to stumble on several occasions, and consulted a doc- tor. In June of the same year she retired from school. Afterwards speech difficulties slowly developed.

The first investigation (Neuropsychiatric Clinic, Hiroshima University), in August 1963, revealed tremor of the hands. Whilst speaking, her voice stopped suddenly several times. Epilepsy was suspected,

Subsequently tic-like cramp of the lower jaw appeared, and speech difficulty progres- sively worsened. Reinvestigation, in Janu- ary 1965, showed the following findings: fasciculation of the tongue, marked finger tremor, muscular rigidity and exaggeration of the deep reflexes. Parkinson’s disease was then suspected, and anticholinergic drugs were administered. In the evening of the same day, a generalized convulsion was

56 H. Ishino, H. Ishizu and K. Sarai

noted. In April of the same year, an EEG showed a very irregular basic activity with high voltage slow wave bursts accompanied with paroxysmal spikes. With a provisional diagnosis of epilepsy, anticonvulsants were added to anticholinergic drugs without ef- fect. In July of the same year, muscle cramp of the lower limbs as well as pulsion phenomenon was noted. In October she was observed to be having small absence which lasted several seconds. In Novem- ber tic-like movements aggravated and her walking became more unsteady. Intention tremor also appeared. She was admitted, in December 1965, on suspicion of brain organic lesion. Two days after admission, opisthotonus accompanied with loss of con- sciousness was noted. Afterwards she became bedridden but was discharged from the Clinic without amelioration in her con- dition.

She was re-admitted in April 1966. Ex- amination on admission revealed clonic twitchings of the facial muscles including the upper eyelids and coarse fibrillation of the tongue. Her muscles of four limbs were found hypotonic and there were sudden rhythmic contractions of all four limbs re- sembling myoclonias, which were dominant in the distal portions of both upper and lower extremities. Outstretching forwards of both upper limbs was impossible for her, because of jerky lowering of the upper limbs. Deep reflexes were hyperactive on both sides, but neither clonus nor abnormal reflexes were noted. Co-ordinate movements were impaired and Holmes-Stewart rebound phenomenon was positive. Sensation appeared normal. General examination revealed no physical abnormality.

Psychiatric examination revealed the following findings: The patient was apathetic, facial expression was mask-like. She re-

mained euphoric, and showed no interest in her surroundings. Comprehension was markedly impaired, and she replied to all questions “Yes”. Disorientation, amnesia, memory disturbance and confabulation were noted. She was childlike, laughed without reason and sometimes displayed frenzy. From time to time she was incontinent.

The puls, blood pressure, and tempera- ture were normal. The blood picture, blood chemistry and liver function tests were all normal. Wassermann reaction of both blood and CSF was negative. EEG records made on April 25, 1966 were poor in a- waves and showed marked dysrhythmia. Ocular fundi and X-ray of the skull were normal. The air-encephalogram showed a slight enlargement of the third ventricle and a moderate enlargement of the lateral ventricles.

In July 1966 she was transfered to an- other hospital. Afterwards she continued to deteriorate. In February she died of pneumonia at the age of 42 years. The illness lasted about 15 years.

Autopsy findings of the brain. Macroscopic findings : The brain weighed

900 g. Meninges were normal and on coronal sections there was nothing relevant aside from a moderate enlargement of the lateral ventricles.

Microscopic findings: The cerebral cortex in Nissl preparations was normal in cyto- architecture and there was only some loss of the nerve cells. The prominent feature was the swelling of the nerve cells extend- ing over the more or less entire nervous system (Fig. 1 ) . Their nuclei were clear and well preserved, but displaced to the base of apical dendrite by the storage substance. Nissl substance was dissolved and the cytoplasm was homogeneously blue, i.e. they showed the change of Schaffer-Spiel-

A Sporadic Case of Cerebral Lipidosis in an Adult (Kufs) 57

Table 1 . Histochemical characteristics of storage substance in the nerve cells of the frontal cortex

Lipid Sudan 111 orange Oil red reddish-brown Sudan black B yellowish-black Nile blue bluish-black

Okamoto’s sulphuric-acetic acid

Modified Molisch-Okamoto

Okamoto’s mercuric nitrate

Okamoto’s separation test

Hirsch-Pfeiffer (-1

(for cholesterin) (-1

(for glycolipids) (-)

(for phospholipids and cerebroside) ( + I

(for sphingomyelin) ( + I

PAS (+)

Bial (for neuraminic acid) (-1

Pol ysaccharide

Protein

meyer (Fig. 2). This was marked in the third, fifth and sixth layer of the cerebral cortex. In PAS preparations, cytoplasm of the neurons was filled with brightly red small granules. Around the nuclei of the small nerve cells of the second and fourth layer there were densely PAS-positive granules. These granules were also found around the nuclei of the astrocytes. In Bodian preparations, the neurofibrillae were opressed to the periphery of the cell body and the cytoplasm was filled with granular materal (Fig. 3). This storage material was unstained by the Sugamo-Heidenhain method for myelin, and stained a orange with Sudan 111. Holzer stain did not show fibrous gliosis in the cerebral cortex and white mat- ter. In the occipital cortex, only the scat- tered larger neurons of the fifth layer were distended.

In the basal ganglia, the nerve cells of the lateral nuclei of the thalamus showed a moderate swelling. In the striatum, some loss of the large neurons was noted, the remaining nerve cells were irregular in shape

and showed hyperchromatosis. In the pallidum, only a slight degree of swelling of the nerve cells was noted. Holzer stain showed a slight fibrous gliosis in the anterior nuclei of the thalamus and in the pallidum.

In the mid brain, the neurons of the substantia nigra and oculomotor nuclei showed a similar change and were filled with PAS- positive substance. Particularly in the substantia nigra, Nissl stain revealed loss of melanin pigments and the cytoplasm of the nerve cells was covered by the relatively large granules stained blue.

In the pons, the change was marked and the neurons of the pontine nuclei were balooned by the lipid material, which was yellow with H-E. stain. The eccentric nuclei showed pycnosis (Fig. 4). In addition Holzer stain showed a moderate fibrous gliosis.

In the medulla oblongata, these changes were also noted. The nuclei of the nerve cells showed pycnosis and Nissl stain revealed a diffuse homogeneous blue. There


was fibrous gliosis (Fig. 5) . The nerve cells of the hypoglossal nuclei and the reticular formation were slightly balooned and showed chromatolysis.

In the cerebellum, the base of the dendrite of Purkinje cell was distended and filled with yellow granular material in H-E. preparations (Fig. 6 ) . In Bodian preparations, the basket fibers were well preserved. The granular layer was almost normal. The nerve cells of the dentate nuclei showed marked swelling, and in Holzer preparations a slight gliosis in the arca surrounded by the dentate nuclei was observed.

In the spinal cord, there was some loss of the anterior horn cells and the remaining neurons showed a moderate enlargement.

Histochemical investigations of the storage substance in the nerve cells of the frontal cortex were carried out and its results are showed in Table 1. The substance was considered as consisted of sphingomyelin and probably PAS-positive glycolipid.

DISCUSSION Because of the distention of the nerve

cells by a lipid material, this case is considered to be an example of that form of cerebral lipidosis termed amaurotic idiocy. Amaurotic idiocy is divided, as generally well known, into infantile (Tay-Sachs), late- infantile (Bielschowsky ), juvenile (Vogt- Spielmeyer) and adult (Kufs) type by the age of onset of the first symptoms. There were, however, cases of Tay-Sachs's disease unaccompanied by retinal abnormality which have been considered to be pathognomonic to this type of cerebral lipidosis, and fur- thermore infantile cases have been reported with selective vulnerability of certain cen- ters as well as with protracted course ex- tending over 30 yearss*20.21).

In adult type, the symptoms manifest in

adolescence or adulthood, but one must ask whether the present case had a protracted form of the juvenile type. In keeping with presently accepted definitions, this case should be classified as an adult form since the patient did not show signs of nervous system disease until age 27, when the family noted a change in her behaviour.

As to the genetic factors, of 26 cases in the literature, including 19 cases cited in the review of Fine2), 5 cases6JsJ4J7) in Japan, and one case of Zeman22) and Mittyus'?), in 9 cases a family history of the disease was lacking. The apparent family history has been reported in 15 cases (57.7%). Thus sporadic cases occur relatively fre- quently.

As to the pathology of amaurotic lipidoses, according to Kufs, with increasing age the degree of storing process decreases and the nerve cells are less strongly distended. In this case loss of the nerve cells was slight and the process of distention was not so marked as in infantile type.

In the adult type, there has been ten- dency for certain parts of the brain to be preferentially selected by the disease process. Thus in the case of Inose et al") the process was accentuated in the cerebellum and striatum, and in 2 siblings reported by Misao et all3) in the spinal motor neurons. In particular in younger case of Misao et alla), the changes were dominant in the spinal motor neurons, medial geniculate body, accessary olivary nuclei and ambiguus nuclei. In the present case the distention of the neurons was encountered in more or less almost all parts of the nervous system. However, the process was more marked in the cerebral cortex, thalamus, substantia nigra, pontine nuclei, olivary nuclei and dentate nuclei. Among these areas, the nerve cells of the pontine nuclei and lipophil oli-


vary and dentate nuclei showed pycnosis of the nuclei and the changes were somewhat marked. On the other hand, lipophob Pur- kinje cells showed also distention.

As to the pathology of the cerebellum in amaurotic idicoy, it has been known, since Bielschowsky, that in late-infantile form the degeneration is a cereballo-petale type, i.e. the mossy fibers, climbing fibers, granule cells and basket fibers are severely affected. In our case, as contrary to this, Purkinje cells were expanded by a lipid material with preservation of the granular layer. How- ever, decrease in number of Purkinje cells was not noted, and there was no gliosis in “Vlies”, so that in our case cerebellar lesion was a cerebello-fugal type. The same type of cerebellar degeneration has been describ- ed by Hallervorden‘) and by otherssJ2J7). Inose et a P , KufsO) (Case 1) and van Bo- gaertlO) reported cases with both types of cerebellar degeneration. In the case of van Bogaert et all8) and Case 3 of KufslO), the cerebellum was well preserved. As men- tioned above, cerebellar lesions in adult type of amaurotic idiocy are variable.

Only a few reports exist on histochemical study in adult type2J2J6J7*2s). As to Bial reaction’) specific to neuraminic acid, a con- stituent of a ganglioside stored in the neurons of this disease, case of Seitelberger et all5); positive, case of Fine et a12); positive in Purkinje cells and nerve cells of the spinal ganglia, case of Tokuda et all7); slightly positive, 3 cases of Zeman et aP2); negative, case of Mhttyus12); negative. The bio- chemical studies by h o s e et alB) did not show an increase in ganglioside except for in the case of infantile form. In 2 cases of juvenile and one case of adult type, Zeman et a122) was also unable to find an increase in neuraminic acid which indicates that no excess ganglioside was present. In the pre-

sent case Bial reaction was negative and the storage substance in the nerve cells was consisted mainly of phospholipid, in particular sphingomyelin, with PAS-positive glycolipid. Cases of infantile and juvenile type with negative Bial test have been also reportedlet 21). This fact depends on problematic Bial reaction on one hand. On the other hand the quantity of ganglioside remains normal in juvenile formz0), and ganglioside is enough instable to release easily neuraminic acid. Particularly in the presence of formol, ganglioside in the brain releases neuraminic acid under the influence of formoP. These factors are complexly bound to interfere with revealing neuraminic acid histochemi- cally.

SUMMARY The authors reported a sporadic case of

adult type of amaurotic idiocy. A female patient who had no specific

hereditary taint had well worked as a primary schoolteacher until she married at the age of 27. About the same time she showed slight mental disturbance such as personal- ity change and mild dementia. Subsequent- ly her mental deterioration aggravated, so that she was obliged to retire from school 6 years after the onset of the disease. Then a gait disturbance and the following symptoms successively appeared : muscular rigidity, finger tremor, cerebellar symptoms, myo- clonic jerks of the four limbs and generalized convulsions. EEG showed generalized spike and wave complex. The patient died of pneumonia at the age of 42 after the clinical course of 15 years.

At autopsy, the brain weighed 900 g. and a moderate enlargement of the lateral ventricles was noted.

Histologically the prominent feature was the swelling of the nerve cells of the cere-


bra1 cortex except for the area striata. In the regions other than the cerebral cortex, the distention of the neurons was found in the thalamus, oculomotor nucleus, substantia nigra, pontine nucleus, olivary nucleus, Purkinje cells, dentate nucleus and anterior horn cells of the spinal cord.

Histochemical examination revealed the storage substance in the nerve cells consisted mainly of phospholipid with PAS- positive glycolipid. Among the phospholipid sphingomyelin was dominantly exhibited.

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REFERENCES Diezel, P. B.: Histochemical study of primary lipidoses, In Cerebral Lipidoses, A Symposium, Chairman L. van Bogaert, ed. by J. N. Cumings and A. Lowenthal: 11-3 1, 1957, Blackwell Sci Publ, Oxford. Fine, D. I. M., Barron, K. D. and Hirano, A.: Central nervous system lipidosis in an adult with atrophy of the cerebellar granular layer. A case report, J Neuropathol Exp Neurol, 19: 355-369, 1960. Friedrich, G.: Untersuchungen iiber den Fett- und Lipoidabbau in anamischen Nekro- senherden bei einem Spatfall von amaurotischer Idiotie, Z Neur, 160: 713-727, 1938. Hallervorden, J.: Spatform der amaurotischen Idiotie unter dem Bilde der Paralysis agitans, Mschr Psychiat Neurol, 99: 74-80, 1938. hose, T. and Kajiyama, S.: On a retarded form of amaurotic idiocy (A contribution to cerebellar pathology), Brain and Nerve, 2: 275-280, 1950. (in Japanese) hose, T., Sakai, M., Inoue, K. and Tano, T.: Chemical analysis of brain lipids and histo- chemistry of amaurotic family idiocy, Ad- vances in Neurological Sciences, 9: 50 1-507, 1965. (in Japanese) hose, T. and Tano, T.: Amaurotic idiocy, Shinryo, 21: 1105-1 112, 1968. (in Japanese) Jervis, G. R.: Familial idiocy due to neu- ronal lipidosis (so-called late amaurotic idiocy), Am J Psychiat, 107: 409-414, 1950. Kufs, H.: Uber eine Spatform der amauro- tische Idiotie und ihre heredofamiliaren Grundlagen, Z New, 65: 169-188, 1925. Kufs, H.: Uber einen Fall von Spatform

der amaurotischen Idiotie mit atypischem Verlauf und mit terminalen schweren Sto- rungen des Fettstoffwechsels im Gesamt- organismus, Z Neur, 122: 395-415, 1929.

1 1 ) Kufs, H.: Uber einen Fall von spatester Form der amaurotischen Idiotie mit dem Beginn im 42. und Tod im 59. Lebensjahre in klinischer, histologischer und vererbungs- pathologischer Beziehung, Z Neur, 137: 432-448, 1931.

12) Mhttyus, A.: Familiare Kleinhirnataxie mit extrapyramidalmotorischem Endzustand bei Lipoidose, In IV. Internationaler Kon- gress fiir Neuropathologie, ed. by H. Jacob: 274-280, 1962, Georg Thieme Verlag Stutt- gart.

13) Misao, T. and Shimoda, K.: Spatform der amaurotischen Idiotie, Rinsho-Kenkyu, 21 : 210-213, 1944. (in Japanese) 6maru, I.: An autopsy case of late form of amaurotic idiocy, Kurume-Igakukai-Zas- shi, 11: 256-259, 1948. (in Japanese) Seitelberger, F. and Nagy, K.: Zur Histo- pathologie und Klinik der Spiitform von amaurotischer Idiotie, Dtsch Z Nervenheilk,

Shirahige, I.: Two cases of the juvenile form of amaurotic idiocy. The clinical and the histological studies, Okayama Igakukai- Zasshi, 78: 365-386, 1966. (in Japanese) Tokuda, Y., Harada, K., Yamagami, M. and Shiraki, H.: An autopsy case of a late form of familial amaurotic idiocy in com- parison to the clinical and pathological findings on the two siblings with the same disease, Psychiat Neurol Jap, 69: 401-428, 1967. (in Japanese) van Bogaert, L. and Borremans, P.: Uber eine adulte, sich bis ins Prasenium hinzie- hende Form der familiaren amaurotischen Idiotie, Z Neur, 159: 136-157, 1937. van Bogaert, L.: Sur une form familiale tr&s tardive de l’idiotie amaurotique (Deux- ibme observation de la famille Ae. . .), Dtsch Z Nervenheilk, 168: 267-280, 1952. van Bogaert, L.: Les idioties amaurotiques, In Maladies Nerveuses G6nBtiques d’ordre MBtabolique: 17-3 1, 1962, Vaillant-Car- manne, Libge. Wakutani, K., Nakamura, H., Fukuda, M., Inagaki, T. and Makihara, S.: An autopsy case of Vogt-Spielmeyer type of cerebral lipidosis, Clin Neurol, 7: 81-87, 1967. (in Japanese)

177: 577-596, 1958.


2 2 ) Zeman, W. and Hoffman, J.: Juvenile and family, J Neurol Neurosurg Psychiat, 25: late forms of amaurotic idiocy in one 352-362, 1962.

LEGENDS FOR FIGURES

Fig. I . Deeper third layer of the frontal cortex. Nerve cells are swollen. Nissl, x l 0 0 Fig. 2. Higher magnification of the frontal cortex. Swollen cytoplasm of the nerve cells.

The nuclei are well preserved and displaced to the base of apical dendrite. Nissl, ~ 2 5 0 Fig. 3. Neurofibrillae of the nerve cells are opressed to the periphery. Cytoplasm is

filled with argyrophilic granules. Bodian, x250 Fig. 4. Swollen cytoplasm of the nerve cells of pontine nuclei is homogeneously yellow.

Eccentric nuclei show pycnosis. H-E, x250 Fig 5 . Fibrillary gliosis of “Vlies” and hilus of the olivary nuclei and of the pyramidal

tracts. Holzer. Fig. 6. Base of dendrite of Purkinje cells is swollen and contains yellow granules. H-E,

X 250

62 H. Ishino. H. lshizu and K. Sarai
