Cerebral cortical pathology of sporadic olivopontocerebellar atrophy

41

.lournal ~1"the Neurological Sciences, l 16 (1993) 41-46 ,.'~ 1993 Elsevier Science Publishers B.V. All rights reserved 0022-510X/93/$(16.(10

JNS [13979

Cerebral cortical pathology of sporadic olivopontocerebellar atrophy Tsuneo Fujita a, Mikio Doi b, Takesaburo Ogata c, Ichiro Kanazawa d and Hidehiro Mizusawa ~' " DtTmrtment (~[",Veurolo,~,3', htstitute q[" (Tinical Medicine, Unicers'ity ~[' Z~'ukuba. Tsukuha, Japan, h D~7)artmenl ~[' Pathology. T~'ukuha Medical

Center H(~spital, Z~ukuba, Japan, c Department of Patholoj,% Institute ()f Basic Medicine, Unit'ers'ity o]" 71s'ukuha. "Fsukuha, Japan and ,I Department 0[ Neurology'. Institute (~["Brain Re~'earch, Faculty of Medicine, Unit'ersity ~f' Tokyo, Tokyo. Japan (Received 12 June, 1992) (Revised, received 4 November, 1992) (Accepted 11 November, 1992t

Key words. Oliw)pontocerebellar atrophy (OPCA); Motor cortex; Astrocytosis: Pyramidal tract; Glial cytoplasmic inclusion: [mmunohistochemistry Summary We examined the cerebral cortices of six brains from patients with sporadic olivopontoccrcbcllar atrophy (s-OPCA), five control brains including four from patients who had died without neurological disease, and one from a patient with Holmes-type ccrebellar cortical atrophy. Distinct laminar astrocytosis of the motor cortices in the fifth layer were demonstrated in 4 of 6 s-OPCA eases and in none of the control cases by immunohistochemistry for glial fibrillary acidic protein. The astrocytosis localized in the primary motor cortex and its distribution pattern were clearly different from those of so-called g[ial cytoplasmic inclusion. This cortical astrocytosis appears to be characteristic of s-OPCA and may reflect the pathology of the primary motor cortex.

Introduction In sporadic olivopontocerebellar atrophy (s-OPCA), the pathology of the olivopontocerebellar system, striatonigral system and spinal cord, including the autonomic nervous system, is well established (Oppenheimer 1984). Although pyramidal tract signs and mental changes may occur in the later stages of this disorder (Eadie 1975), the morphological changes in the cerebral cortex remain obscure. Recently, Papp et al. (1989, 19921 and others (Nakazato et al. 1990; Kato et al. 1991; Arai et al. 1992; Fukutani et al. 1992; Kobayashi et al. 1992) have demonstrated intracytoplasmic argyrophilic inclusions of oligodendrocytes (glial cytoplasmic inclusion, GCI) distributed throughout the central nervous system including the cerebral cortex in cases of s-OPCA. In this report, we describe a morphological study of brains from s-OPCA patients and a characteristic astrocytosis in the primary motor cortex.

Correspondence to: Dr. T. Fujita, Department of Neurology, Tsukuba Souai Hospital, 1(108 Takasaki, Kukizaki-machi, lbaragi, Japan. Te1.:((1298) 73-2511; Fax: ({)298) 72-3820.

Materials and methods Six brains from patients with s-OPCA were used. All the patients had shown clinical signs and symptoms of involvement of the pyramidal tract, basal ganglia, cerebellum and autonomic nervous system (Table la). As controls, we used the brains of four patients who had died of non-neurological diseases and one patient with familial cerebellar cortical atrophy (Holmes-type CCA) (Table lb). The mean ages of the patients were 60.8 _+ 10.0 years in the s-OPCA group and 65.3 + 13.9 years in the control group, with no significant difference by Wilcoxon's test. The brains were fixed in 1(t% buffered formalin for 2 weeks. Parasagittal sections containing precentral and postcentral gyri and subcortical white matter, and coronal sections of the middle frontal gyms, inferior parietal Iobule, temporal lobe, visual cortex, basal ganglia and thalamus, and axial sections from the cerebellum, brainstem and spinal cord were embedded in paraffin wax and sectioned. The specimens were stained with hematoxylin-eosin (HE), and by the KlfiverBarrera (KB) and modified Bielschowsky methods. Immunohistochemical studies were performed using monoclonal anti-glial fibrillary acidic protein antibody

42 TABLE 1 CLINICAL SUMMARY

O F (a) s - O P C A C A S E S a n d (b) C O N T R O L

CASES

Case No.

Age ~ Sex

Diagnosis

Clinical

Py. tr.

Extra-py.

CerebeUar

course (year)

sign ~'

sign

sign

Autonomic sign

Cause of d e a t h

1

58M

OPCA

5

+

-b

+ b

q_

pneumonia

2

78M

OPCA

5

+

+

+ b

+

pneumonia

3

56M

OPCA

6

+

+

+ h

+

pneumonia

4

50F

OPCA

11

+

+ b

+

+

bronchial

5 6

56F 67M

OPCA OPCA

8 11

+ +

+ +

+ b +

+ + b

hemorrhage pneumonia pneumonia

Age

Sex 7

66M

8 9

48M 65F

10 11

82F 68F

Clinical diagnosis

Neurological sign

a c u t e heart failure arrhythmia a c u t e myocardial infarction traumatic shock Holmes-type cerebellar cortical atrophy

cerebellar sign

a Patient age (years); py.tr., pyramidal tract. b Initial symptom. c See also Table 5.

(anti-GFAP, Dako Japan, Kyoto, Japan) and polyclonal anti-ubiquitin antibody (anti-Ub, provided by Dr. S-H. Yen, Department of Pathology, Albert Einstein College of Medicine, New York, USA) for detection of reactive astrocytosis and GCI, respectively. After incubation with these antibodies for 2 h at room temperature, the specimens were stained by the avidin-biotin peroxidase complex method (Vector Laboratories, Burlingame, USA). Nerve cells larger than 30/~,m in the shortest diameter with clear nucleoli and Nissl bodies on KB staining

TABLE 2 NEURONAL

LOSS AND ASTROCYTOSIS

Case

Mc

Hc

SN

1

++

-

2 3 4 5 6

++ ++ ++

+

++ ++

+ +

++ ++ ++

IN s-OPCA CASES

PL

DR

OPC

Iml

Ah

Onuf

-

-

+++ +++ +++ +++ +++ +++

+

-

+ + + NE +

NE -

NE + + NE NE NE

Mc, motor cortex; Hc, hippocampus; SN, striatum and substantia

nigra; PL, pallidum and Luys body; DR, dentate nucleus and red nucleus; O P C , olivary nucleus, pontine nucleus and cerebellar cortex; Iml, i n t e r m e d i o l a t e r a l nucleus; A h , anterior horn; O n u f , O n u f r o w i c z nucleus. + + + , s e v e r e ; + + , m o d e r a t e ; + , mild, - :

NE, not examined.

within normal limit;

were regarded as Betz cells. All Betz cells, which were scattered in the fifth layer of the precentral gyrus, were counted in three non-serial sections and the average numbers were calculated.

Results

General histological .findings All of the six patients with s-OPCA had olivopontocerebellar lesions (Table 2). Striatonigral lesions were also present in all except Case 3. In the cerebral cortices examined, neuronal loss and astrocytosis were not apparent in HE, KB and modified Bielschowsky preparations. In the control cases, small lacunar lesions in the frontal subcortical white matter (Cases 7 and 9), and mild senile changes in the hippocampus (Case 9) were found. Case 11 showed cerebellar lesions compatible with those reported in Holmes-type CCA (Holmes 1907). Astrocytosis in the motor cortices of s-OPCA cases Immunostaining with anti-GFAP antibody revealed laminar astrocytosis in the primary motor cortices in 4 of 6 s-OPCA cases (Cases 1, 4, 5 and 6). The laminar astrocytosis was mostly localized in the fifth layer of the cortex (Figs. la and 2a). In Cases 4, 5 and 6, the astrocytosis was found only in the primary motor cor-

43

•• •+

•i~i

iiii~i~ ~•.i~!iiT~! ¸ ~!~• ~•~•.

'~i ~: i~iiii~)!~i!~ii~!i~ i!i ~ii~i!! ~~ii~i~ i~ ! ~ •

,

•~ i~

.•~

~

•

•

%

.J

4"

¢f] 1

Fig. 1. M o r p h o l o g i c a l f e a t u r e s of a s t r o c y t e s a n d G C l - p o s i t i v e cells in t h e p r i m a r y m o t o r c o r t e x ( C a s e 1). A s t r o c y t e s w h i c h have p r o m m e n l c y t o p l a s m a n d m a n y p r o c e s s e s (a) a r e clearly distinct f r o m G C I - p o s i t i v e cells s h o w i n g s m o o t h s u r f a c e wilh few p r o c e s s e s (b). (a. a n t i - G F A P i m m u n o s t a i n ; b, a n t i - u b i q u i t i n i m m u n o s t a i n : × 5(10).

tex, whereas in Case 1 the lesions extended partially to the postcentral gyrus. No astrocytosis was found in the cerebral cortex of the other lobes of the brain• Such cortical astrocytosis was completely absent in all control cases.

Demonstration of GCI and its distribution GCIs stained by the modified Bielschowsky method were more clearly demonstrated by immunostaining using anti-Ub antibody (Fig. 2b). GCl-positive cells were widely distributed throughout the brain tissue

TABLE 3 DISTRIBUTION

AND FREQUENCY

OF GLIAL CYTOPLASMIC

INCLUSIONS

(GCIs)

case

Mc

Mw

mFw

Tw

Ow

aIC

Pu

pIC

CP

Cp

I

++ ++ + +++ ++ ++

?++ +++ ~ ~++ -~ + +++

+

+

+

++ ++ +++ + + -

+ ++ +++ + +

+ ++ ++ + +

++ +++ +++ +++ + ++ ++

++÷ ++ ++ ++ ++ +

+++ +++ +++ +++ ++ + +++

++ ++ ++ ++ + + ++

+++ ++ + ++ ++ ++

2 3 4 5 6

Cf + +

PN

Py

IC

p("

+++ +++ +++ +++ ++ + +++

4 + ++ ++ ++ + + ±+

+ ? + + + ++ NE +

. NE -

Mc, m o t o r cortex; Mw, s u b c o r t i c a l w h i t e m a t t e r ( W M ) o f Mc; m F w , W M o f m i d d l e f r o n t a l gyrus; ] ' w , W M of t e m p o r a l lobe: O w , W M o f o c c i p i t a l lobe; a I C , a n t e r i o r limb o f i n t e r n a l c a p s u l e ; Pu, p u t a m e n , p l C , p o s t e r i o r limb of IC; C P , c e r e b r a l p e d u n c l e ; ('p, c e r e h e l l o p e t a l tract: Cf, c e r e b e l l o f u g a l tract; PN, p o n t i n e n u c l e u s ; Py, p y r a m i d o f m e d u l l a o b l o n g a t a ; IC, lateral c o l u m n of t h o r a c i c c o r d : pC, posteri¢~r c o l u m n of t h o r a c i c cord. + + + , high: + + , m o d e r a t e ; + , mild~ - , n o n e ; N E , n o t e x a m i n e d •

44 (Table 3) and morphologically different from astrocyte immunostained by anti-GFAP antibody (Fig. 2a). In the motor cortices, the GCI-positive cells were found in the deep layer and spread continuously into the white matter. The distribution of GCIs in the motor cortex was clearly different from that of astrocytosis (Fig. la,b).

Relationship between cort&al astrocytosis and other pathological findings All s-OPCA cases exhibited myelin pallor on KB staining of the pyramidal tract below the pyramid of the medulla oblongata. These changes were not apparent in the proximal portion, including the internal capsule, in any of the examined cases. On the other hand, myelin pallor of the cerebral peduncles was observed in Cases 1, 4, 5 and 6, which showed astrocytosis in the primary motor cortices. The cases without cortical astrocytosis (Cases 2 and 3) showed no pallor on myelin staining in the cerebral peduncle (Table 4). The number of Betz cells in the OPCA cases did not show apparent correlation with the laminar astrocytosis either (Table 5). There was no difference in the mor-

TABLE 4 R E L A T I O N S H I P BETWEEN ASTROCYTOSIS OF M O T O R CORTICES A N D MYELIN PALLOR IN PYRAMIDAL TRACTS Case

Astrocytosis in Mc

Myelin pallor in IC

CP

Py

l

+

-

+

+

+ +

2 3 4 5 6

. . + + +

+ + +

r ++ + + + + ++

~++ ++ NE ++

. .

.

. .

. . --

LC

Mc, motor cortex; IC, internal capsule; CP, cerebral peduncle; Py, pyramid of medulla oblongata; LC, Lateral column of thoracic cord. + + , moderate demyelination; + , mild; - , within normal limit; NE, not examined.

phologic features of Betz cells between s-OPCA cases and controls.

Relationship between cortical astrocytosis and clinical signs Cases which showed stratified astrocytosis in the motor cortices had a tendency to have a relatively

J

b Fig. 2. The distribution patterns of astrocytes and GCI-positive cells in the primary motor cortex (Case 1). Cortical astrocytosis is laminar in the fifth layers (a), whereas GCl-positive cells show continuous distribution from the cortex to the white matter (b). Arrowheads indicate the cortico-medullary junction. (a, anti-GFAP immunostain; b, anti-ubiquitin immunostain: x 10).

45 TABLE 5 RELATIONSHIP

BETWEEN CORTICAL ASTROCYTOSIS AND

NUMBERS OF BETZ CELLS IN THE PRIMARY MOTOR CORTEX case

astrocytosis

Betz cell number *

1

-

2

-

2

5

3 4

+

10 17

5

+

7

~ control

+ -

16 l1

* m e a n w d n e s of cell n u m b e r s w h i c h w e r e c o u n t e d

longer duration of illness (Cases 4, 5 and 6), although the number of cases examined was not sufficient for statistical analysis.

Discussion Pathology of the cerebral cortex in s-OPCA receives little attention in the textbooks (Oppenheimer, 1984), and reports concerning cortical changes of s-OPCA are sparse in the literature. Berciano (1982) documented cortical damage in 10 of 63 cases of s-OPCA, although these included inadequate or atypical cases, which are briefly described below. Bakker (1924) described cytoplasmic change in Betz cells and small pyramidal cells in the third layer of the precentral gyrus in a case of s-OPCA. Van Bogaert et al. (1929) described a case of s-OPCA which showed stratified cortical degeneration in the third, fifth and sixth layers of the bilateral prefrontal and temporal lobes, and gliosis in the first, fifth and sixth layers. Noica et al. (1936) reported an area of plaque-like cerebral cortical degeneration from which corticopontine fibers originated. T6bel (1952) found gliosis in the deep cortical layer and subcortical region associated with cytoplasmic changes in Betz cells in a case of s-OPCA. Vascular changes have also been reported in some cases (Fickler, 1911 and Stauffenberg, 1918). Newmann (1977) described senile changes including amyloid angiopathy, and Lambie et al. (1947), Ishida et al. (1962) and Popp et al. (1962) mentioned mild changes in the frontal or temporal lobes. Using G F A P immunostaining, we clearly demonstrated cortical astrocytosis in 4 out of 6 brains of s-OPCA patients. The astrocytosis occurred in a laminar pattern and was localized in the fifth cortical layer of the motor cortex. The change was mild, but clearly visible after immunostaining. Its higher incidence (66.7%) in s-OPCA and the absence in control cases suggest that cortical astrocytosis may be one of the characteristic changes in this disease. Partial astrocyto-

sis in the postcentral gyrus, which was found in Case 1, may be explained by the evidence that the primary motor cortex extends to the postcentral gyrus (Brodal 1981). The pyramidal tract degeneration in s-OPCA has generally been emphasized in the distal portion (Mizutani 1986). The laminar astrocytosis which was found in our investigation was associated with severe degeneration of the pyramidal tract (Table 4). Betz cells showed neither apparent morphological changes nor any changes correlating with the cortical astrocytosis in these areas, although the number of Betz cells remain to be evaluated more precisely using many cases. Sobue et al. (1987) reported three cases of Shy-Drager syndrome which showed loss of small myelinated fibers and preservation of large myelinated fibers in the thoracic corticospinal (pyramidal) tract. It is possible that the cortical laminar astrocytosis in s-OPCA may result from degeneration of small neurons in the primary motor cortex. Papp et al. (1989) reported GCI to be one of the characteristic findings in s-OPCA. Recently, the nature of these inclusions has been further elucidated. (Nakazato et al. 1990; Kato et al. 1991; Arai et al. 1992; Fukutani et al. 1992; Kobayashi et al. 1992; Papp et al. 1992). In our present study, the distribution of GCIpositive cells did not wholly coincide with that of cortical astrocytosis. Along the vertical direction, the astrocytosis had a laminar pattern in the fifth layer, with a spared zone in the deeper cortical layer, although GCI-positive cells were distributed in a continuous pattern from the deep cortex to the subcortical white matter. Along the tangential direction, the astrocytosis was localized almost exclusively within the primary motor cortex, in contrast with GCl-positive cells which were widely distributed beyond the motor cortex. These results suggest that GCIs arc not directly related to the occurrence of cortical astrocytosis in the brain of patients with s-OPCA. In conclusion, this study suggests that the primary motor cortex may be involved in a laminar pattern which is not directly related to GCI in s-OPCA. The laminar astrocytosis may reflect mild impairment of the small neurons in the primary motor cortex. Note added in proof After submission of this paper, the following reports describing GCIs were published: Murayama S. et al. (1992) Immunocytochemical and ultrastructural studies of neuronal and oligodendroglial cytoplasmic inclusions in multiple system atrophy; 2. Oligodendroglial cytoplasmic inclusions. Acta Neuropathol., 84: 32-38.; Mochizuki, A. et al. (1992) Argentophilic intracytoplasmic inclusions in multiple system atrophy. J. Neurol., 239: 311-316.

46 References Arai, N., M. Nishimura, M. Oda, Y. Morimatsu, R. Ohe and H. Nagatomo (1992) Immunohistochemical expression of microtubule-associated protein 5 (MAP5) in glial cells in multiple system atrophy. J. Neurol. Sci., 109: 102-106. Bakker, S.P. (1924) Atrophia olivo-pontocerebellaris. Z. Ges. Neurol. Psychiatr., 89: 213-246. Berciano, J. (1982) Olivopontocerebellar atrophy; a review of 117 cases. J. Neurol. Sci., 53: 253-272. Bogaert, L. van and I. Bertrand (1929) Une vari&6 d'atrophie olivopontine a 6volution subaigu~ avec troubles drmentiels. Rev. Neurol., 1: 165-178. Brodal, A. (1981) Neurological anatomy, 3rd Edn., Oxford University Press, New York, p. 228. Eadie, M.J. (1975) Olivo-ponto-cerebeUar atrophy (Dejerine-Thomas type). In: Vinken, P.J. and G.W. Bruyn (Eds.), Handbook of Clinical Neurology, Vol. 21. North-Holland Publishing Co., Amsterdam, p. 426. Fickler, A. (1911) Klinische und pathologisch-anatomische Beitr~ige zu den Erkrankungen des Kleinhirns. Dtsch. Z. Nervenheilk., 41: 306-375. Fukutani, Y., K. Katsukawa, K. Kobayashi, I. Nakamura, K. Miyazu, N. Yamaguchi and K. Watanabe (1992) Sporadic olivopontocerebellar atrophy with 'Subcortical Dementia' and hallucinatory paranoid state; report of an autopsy. Dementia, 3: 95-100. Holmes, G.M. (1907) A form of familial degeneration of the cerebellum. Brain, 30: 466-489. Ishida, Y., K. Fukai, T. Numabe and T. Hisiyama (1962) Olivoponto-cerebellar atrophy; report of a case with its histopathologic study. Gunma J. Med. Sci., 11: 83-94. Kato, S., H. Nakamura, A. Hirano, H. Ito, J.F. Llena and S-H. Yen (1991) Argyrophilic ubiquitinated cytoplasmic inclusions of Leu7-positive glial cells in olivopontocerebellar atrophy (multiple system atrophy). Acta Neuropathol., 82: 488-493. Kobayashi, K., K. Miyazu, K. Katsukawa, Y. Fukutani, M. Mukai, I. Nakamura, N. Yamaguchi, R. Matsubara and K. Isaki (1992) Cytoplasmic protein abnormalities in patients with olivopontocerebellar atrophy; an immunocytochemical and Gallyas silver impregnation study. Neuropathol. Appl. Neurobiol., 18: 237-249.

Lambie, C.G., O. Latham and L.G. McDonald (1947) Olivo-pontocerebellar atrophy (Marie's ataxia). Med. J. Aust., 2: 626-632. Mizutani, T. (1986) Pathology of cerebellar degeneration. In: Ito, M., I. Sobue, A. Komatsuzaki and G. Hirose (Eds.), Neurology of Cerebellum. Igaku Shoin, Tokyo, pp. 246-267. Nakazato, Y., H. Yamazaki, J. Hirato, Y. Ishida and H. Yamaguchi (1990) Oligodendroglial microtubular tangle in olivopontocerebellar atrophy. J. Neuropathol. Exp. Neurol., 49: 521-530. Neumann, M.A. (1977) Pontocerebellar atrophy combined with vestibular-reticular degeneration. J. Neuropathol. Exp. Neurol., 36: 321-337. Noica, D., J. Nicolesco and E. Banu (1936) Contribution a l'~tude de l'atrophie olivo-ponto-c~r~belleuse. Rev. Neurol., 66: 285-306. Oppenheimer, D.R. (1984) Diseases of the basal ganglia, cerebellum and motor neurons. In: Hume Adams, J., J.A.N. Corsellis and L.W. Duchen (Eds.), Greenfield's Neuropathology, 4th Edn. Edward Arnold, London, pp. 699-747. Papp, M.I., J.E. Kahn and P.L. Lantos (1989) Gtial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J. Neurol. Sci., 94: 79-100. Papp, M.I. and P.L. Lantos (1992) Accumulation of tubular structures in oligodendroglial and neuronal cells as the basic alteration in multiple system atrophy. J. Neurol. Sci., 107: 172-182. Popp, C. and J-E. Gruner (1962) D~g~n~rescence nigro-pontine; Hypertonie parkinsonienne ~t 6volution subaigu~. Rev. Neurol., 106: 43-49. Sobue, G., Y. Hashizume, T. Mitsuma and A. Takahashi (1987) Size-dependent myelinated fiber loss in the corticospinal tract in Shy-Drager syndrome and amyotrophic lateral sclerosis. Neurology, 37: 529-532. Stauffenberg, V. (1918) Zur Kenntnis des extrapyramidalen motorischen Systems und Mitteitung eines Falles yon sogenannter "Atrophie olivo-ponto-crrrbetleuse". Z. Ges. Neur0i. Psychiatr., 39: 1-55. Tfbel, Fr. (1952) Klinischer und anatomischer Beitrag zur Entstehung der extrapyramidalen Symptome bei cerebell~iren Erkrankungen. Arch. Psychiatr. Z. Neurol., 188: 328-338.