Neuropatholvgy and Applied Neurvbiolvgy 1979, 5, 311-317
CASE R E P O R T W I D E S P R E A D INTRANUCLEAR N E U R O N A L CORPUSCLES (MARINESCO B O D I E S ) A S S O C I A T E D WITH A F A M I L I A L S P I N A L D E G E N E R A T I O N WITH CRANIAL A N D P E R I P H E R A L N E R V E I N V O L V E M E N T
I. JANOTA Department of Neuropathology, The Institute of Psychiatry and the Bethlem Royal and the Maudsley Hospital, London Accepted for publication 12 January 1979
Janota I. (1979) Neuropathvlvgy and Applied Neurobivlvgy 5 , 311-317 Case report.Widespread intranuclear neuronal corpuscles(Marinescobodies) associated with a familial spinal degeneration with cranial and peripheral nerve involvement Widespread intranuclear, paranucleolar, acidophilic corpuscles, known as Marinesco bodies, were found i n association with degeneration of the posterior columns of the spinal cord, posterior root ganglia and cranial nerves. The patient was a man dying a t t h e age of 45 years. Neurological examination of his sister (aged 51 years) indicates that she is suffering from the same disease. The cases appear to belong t o the predominantly spinal form of spino-cerebellar degenerations or Friedreich’s ataxia. This report, which includes a n electron microscope examination, considers the pathological significance of Marinesco bodies.
Introduction Marinesco bodies have been known in the substantia nigra and locus coeruleus of normal subjects for a long time (Marinesco, 1902; 1909). Greenfield (1958) wrote that they become larger, more sharply defined and more numerous with increasing age. Yuen & Baxter (1963) found them in a majority of 160 randomly chosen subjects over 21 years old. They have no known pathological significance, but it has been speculated that they may represent an involutional change in ageing pigmented nerve cells.
Case history A left-handed bachelor, agricultural labourer and gardener, first noticed that his left foot ached and knocked against the right foot at the age of 35 years. Three years 0305-lS46/79/0S00-0311!302.00
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later his limbs tended t o jerk and he had a difficulty i n initiating micturition and in emptying his bladder, and sometimes the fingers of the left hand were numb. On examination he had a slight dysarthria and his gait was ataxic, on a broad base. He could not walk heel-to-toe. The cranial nerves were ‘intact’. All tendon reflexes were lost and the plantar responses were flexor. There was impairment of the appreciation of joint position and vibration in all limbs, and heel-shin and finger-nose ataxia. Romberg’s test was positive. There were involuntary movements of the limbs when he was apprehensive. The blood and cerebrospinal fluid (CSF) serology was negative. The CSF contained five white cells per cmm and 0.03 g of protein per litre. Other clinical investigations, including EEG and EMG, were negative, and the nerve conduction studies were technically unsatisfactory. At the age of 38 he ceased to work. He lived alone. His sister, who was four years older, called t o cook his meals. Although his symptoms did not change dramatically they must have become gradually more troublesome. When he was 42 years old there was doubt whether he could manage on his own much longer. He had written letters to his doctor, quite legible and to the point, clearly addressed. A few days before his death he was admitted to hospital following a fall. In addition to the neurological abnormalities recorded earlier, the eye movements were slow. He died a t the age of 45 years. General post-mortem examination showed bronchopneumonia, bronchiectasis and cystitis, but no obvious muscle wasting.
Family history Both parents died young before the age of onset of neurological signs i n their son and daughter. The only other member of the family known to be affected is a sister 4 years older. From the age of 45 she developed progressive ataxia. She was recently examined by a neurologist when 51 years old, and found to be ataxic and areflexic with signs of a spinocerebellar degeneration and electrophysiological evidence of peripheral nerve involvement. The family tree is shown in Figure 1.
Pathological findings The fresh brain weighed 1360 g (cerebellum 134 g). The third, fifth (Figure 2a) and sixth cranial nerves were thin and grey, but there was no other obvious abnormality i n the brain. The spinal cord was smaller than normal, with very shrunken and grey posterior white columns. The posterior spinal nerve roots were grey.
Microscopical examination This included samples of the viscera, muscles, nerves, nerve roots and ganglia and from the central nervous system. The main abnormality in the nervous system was
Marinesco bodies i n spinal degeneration
t 33 silicosis
313
t 43 'brain tumour'
22 19 Figure 1. The family tree. 0,not affected;
0 , affected;
t, dead.
a loss of nerve cells in the posterior root ganglia with an excess of nodules of Nageotte, loss of nerve fibres in the posterior spinal nerve roots with fibrosis and a very severe loss of nerve fibres in the shrunken posterior white columns of the spinal cord (Figure 2b). There was some degeneration of the spinal nerves distal to the posterior root ganglia. Muscle spindles in lumbrical and flexor carpi radialis were abnormal in that the capsule was thickened and fibrous, and there was an increase of intracapsular connective tissue. In addition there was mild neurogenic atrophy. Although there was no obvious wasting of the anterior spinal nerve roots, and the number of cells in the spinal anterior grey horns appeared normal, the nuclei of some nerve cells were eccentric and some nerve cells appeared shrunken. There was an unusual widespread phenomenon, seen in greatest numbers in the posterior root ganglia and in the brainstem: one or more acidophilic corpuscles in the nuclei of nerve cells. The corpuscles were generally a little larger than the nucleolus which was often seen alongside (Figure 2c-f). Neurones in the inferior olives, cuneate nuclei, nuclei portis, substantia nigra and third nerve nuclei were particularly rich in these bodies, but they were found also elsewhere in the brainstem with an occasional one in the spinal cord and the cerebral cortex. In the cerebellum there was only a mild loss of Purkyne cells with a little gliosis in the molecular layer. Some Purkyni! cells and dentate nerve cells were large and rounded. Similar rounded cells, often with an eccentric nucleus were seen in the inferior olives and in the nuclei pontis. Sections of the cranial nerves that looked thin showed loss of nerve fibres. The optic nerves and tracts were normal, and there was no obvious abnormality in the cerebral hemispheres or deep grey matter.
Ultrastructural findings Samples of posterior root ganglia and brainstem were post-fixed in glutaraldehyde E
314
I. Janota
d
Figure 2. a grey shrunken fifth nerves (arrowheads). b pale staining, wasted posterior columns. Cervical cord, Luxol fast blue and Nissl, x 8. c-f intranuclear corpuscles. Haematoxylin and eosin, x 460. c, d substantia nigra. The dark nucleolus is seen in c. e , f double corpuscles in a cervical posterior root ganglion. The dark nucleolus is shown to the left of the two corpuscles in e .
Marinesco bodies in spinal degeneration
315
and processed for electron microscopy. The intranuclear bodies (Figure 3a-d) consisted of a fibrillary mesh of varying density. Individual filaments of some 10-12 nm in diameter appeared to curve and to criss-cross. At high magnifications there was a suggestion of periodic constrictions or areas of higher density in the filaments.
Discussion Marinesco bodies are among the early discoveries in neuropathology. Their original description by Marinesco (1902) remains so apt that it merits quoting:
‘J’ai trouve constamment chez l’adulte B l’interieur du noyau des cellules du locus niger et frequemment dans celles du locus coeruleus des corpuscules en nombre variable situes au voisinage du nuclkole. Ces corpuscules prennent toujours la couleur acide.’ Marinesco compared his intranuclear corpuscles with other larger ones in the cytoplasm : ‘C’est ainsi que parfois j’ai pu voir dans la masse du pigment noir des corpuscules colores en rouge brique ou en rouge venitien par la methode de Romanowski, corpuscules qui, cependant, sont plus volumineux que ceux qu’on voit l’interieur du noyau. En outre ils sont entoures d’une large aureole.’ These are now known as Lewy bodies. An ultrastructural study of Marinesco bodies on formalin fixed post mortem material of one case was carried out by Leestma & Andrews (1969). They found aggregates of 20 nm granules in varying combinations with a delicate filamentous lattice-like structure formed by alternating layers of closely approximated parallel filaments 10-12 nm in diameter. Similar appearances were found by Best (1978), but the granular element was lacking in the present case. It may be that the intranuclear bodies in the present case, although they look the same on light microscopy, are not identical with the ordinary nigral Marinesco bodies, or that the ‘Marinesco body’ conceals a variety of ultrastructural appearances. This case belongs to the predominantly spinal group of Friedreich’s ataxia (Greenfield, 1954). Several associated pathological features are unusual but not unique. The involvement of various cranial nerves has been reported in spinocerebellar degenerations. Although degeneration of the descending trigeminal tracts is apparently quite common, wasting of the fXth nerve with changes in the Gasserian ganglion as seen in this case is rare and there is only one report of clinical involvement of the nerve (Biemond, 1951; 1954). When ocular movements are affected difficulty may arise in distinguishing ocular myopathy from denervation atrophy (Stephens et al., 1958). When peripheral nerves are involved Friedriech’s ataxia may appear to overlap or merge with Charcot-Marie-Tooth disease both on clinical and pathological grounds (Salisachs, 1976). This case also illustrates the widespread intranuclear acidophilic inclusions closely resembling Marinesco bodies. They are unlike any viral or lipid structures.
316
I . Janota
Marinesco bodies in spinal degeneration
317
This has not been reported before in spino-cerebellar degenerations, peroneal muscular atrophy or, indeed, in any other neuropathological condition.
Acknowledgements I am grateful to Drs P. C. Farrant, T. Fowler, R. Hierons and B. B. J. Nixon for their clinical collaboration and to Mrs P. Adler and Mr A. Davey for help with the illustrations.
References BESTP. (1978) Personal communication BIEMONDA. (1951) Les d6g6n6rations spino-cCr6belleuses. Folia psychiatrica, neurologica et neurochirurgica Neerlandica 54, 216-222 BIEMOND A. (1954) La forme radiculo-cordonnale posterieure des deg6n6rescences spino-c6rdbelleuses. Revue neurologique 91, 1-21 GREENFIELD J.G. (1954) The Spinocerebellar Degenerations. Blackwell, Oxford GREENFIELD J.G. (1958) Greenfield’s Neuropathology. Edward Arnold, London LEESTMA J.E. & ANDREWS J.M. (1969) The fine structure of the Marinesco body. Archives of Pathology 88, 431436 MARINESCO J . (1902) Sur la presence des corpuscules acidophiles paranucl6olaires d a m les cellules du locus niger et du locus coeruleus. Comptes rendus de l’Acad6mie des Sciences, Paris 134,1000-1002 MARINESCO J. (1909) La Cellule Nerveuse. Doin, Paris SALISACHS P. (1976) Charcot-Marie-Tooth disease associated with ‘essential tremor’. Report of 7 cases and a review of the literature. Journal of the Neurological Sciences 28, 1 7 4 0 STEPHENS J., HOOVER M.L. & DENSTJ. (1958) On familial ataxia, neural amyotrophy and their association with progressive ophthalmoplegia. Brain 81, 556-566 YUEN P. & BAXTERD.W. (1963) The morphology of Marinesco bodies (paranucleolar corpuscles) in the melanin pigmented nuclei in the brainstem. Journal of Neurology, Neurosurgery and Psychiatry 26, 178-183
Figure 3. Electron microscopy of intranuclear corpuscles in a cervical posterior root ganglion. a x9000. b (detail of a) x 90 000. Edge of the nucleolus at the top. e a double, dumbell corpuscle, x 9000. Edge of nucleolus on the right. d (detail of c) x 45 000.
CASE R E P O R T W I D E S P R E A D INTRANUCLEAR N E U R O N A L CORPUSCLES (MARINESCO B O D I E S ) A S S O C I A T E D WITH A F A M I L I A L S P I N A L D E G E N E R A T I O N WITH CRANIAL A N D P E R I P H E R A L N E R V E I N V O L V E M E N T
I. JANOTA Department of Neuropathology, The Institute of Psychiatry and the Bethlem Royal and the Maudsley Hospital, London Accepted for publication 12 January 1979
Janota I. (1979) Neuropathvlvgy and Applied Neurobivlvgy 5 , 311-317 Case report.Widespread intranuclear neuronal corpuscles(Marinescobodies) associated with a familial spinal degeneration with cranial and peripheral nerve involvement Widespread intranuclear, paranucleolar, acidophilic corpuscles, known as Marinesco bodies, were found i n association with degeneration of the posterior columns of the spinal cord, posterior root ganglia and cranial nerves. The patient was a man dying a t t h e age of 45 years. Neurological examination of his sister (aged 51 years) indicates that she is suffering from the same disease. The cases appear to belong t o the predominantly spinal form of spino-cerebellar degenerations or Friedreich’s ataxia. This report, which includes a n electron microscope examination, considers the pathological significance of Marinesco bodies.
Introduction Marinesco bodies have been known in the substantia nigra and locus coeruleus of normal subjects for a long time (Marinesco, 1902; 1909). Greenfield (1958) wrote that they become larger, more sharply defined and more numerous with increasing age. Yuen & Baxter (1963) found them in a majority of 160 randomly chosen subjects over 21 years old. They have no known pathological significance, but it has been speculated that they may represent an involutional change in ageing pigmented nerve cells.
Case history A left-handed bachelor, agricultural labourer and gardener, first noticed that his left foot ached and knocked against the right foot at the age of 35 years. Three years 0305-lS46/79/0S00-0311!302.00
8 1979 Blackwell Scientific Publications
311
312
I. Janota
later his limbs tended t o jerk and he had a difficulty i n initiating micturition and in emptying his bladder, and sometimes the fingers of the left hand were numb. On examination he had a slight dysarthria and his gait was ataxic, on a broad base. He could not walk heel-to-toe. The cranial nerves were ‘intact’. All tendon reflexes were lost and the plantar responses were flexor. There was impairment of the appreciation of joint position and vibration in all limbs, and heel-shin and finger-nose ataxia. Romberg’s test was positive. There were involuntary movements of the limbs when he was apprehensive. The blood and cerebrospinal fluid (CSF) serology was negative. The CSF contained five white cells per cmm and 0.03 g of protein per litre. Other clinical investigations, including EEG and EMG, were negative, and the nerve conduction studies were technically unsatisfactory. At the age of 38 he ceased to work. He lived alone. His sister, who was four years older, called t o cook his meals. Although his symptoms did not change dramatically they must have become gradually more troublesome. When he was 42 years old there was doubt whether he could manage on his own much longer. He had written letters to his doctor, quite legible and to the point, clearly addressed. A few days before his death he was admitted to hospital following a fall. In addition to the neurological abnormalities recorded earlier, the eye movements were slow. He died a t the age of 45 years. General post-mortem examination showed bronchopneumonia, bronchiectasis and cystitis, but no obvious muscle wasting.
Family history Both parents died young before the age of onset of neurological signs i n their son and daughter. The only other member of the family known to be affected is a sister 4 years older. From the age of 45 she developed progressive ataxia. She was recently examined by a neurologist when 51 years old, and found to be ataxic and areflexic with signs of a spinocerebellar degeneration and electrophysiological evidence of peripheral nerve involvement. The family tree is shown in Figure 1.
Pathological findings The fresh brain weighed 1360 g (cerebellum 134 g). The third, fifth (Figure 2a) and sixth cranial nerves were thin and grey, but there was no other obvious abnormality i n the brain. The spinal cord was smaller than normal, with very shrunken and grey posterior white columns. The posterior spinal nerve roots were grey.
Microscopical examination This included samples of the viscera, muscles, nerves, nerve roots and ganglia and from the central nervous system. The main abnormality in the nervous system was
Marinesco bodies i n spinal degeneration
t 33 silicosis
313
t 43 'brain tumour'
22 19 Figure 1. The family tree. 0,not affected;
0 , affected;
t, dead.
a loss of nerve cells in the posterior root ganglia with an excess of nodules of Nageotte, loss of nerve fibres in the posterior spinal nerve roots with fibrosis and a very severe loss of nerve fibres in the shrunken posterior white columns of the spinal cord (Figure 2b). There was some degeneration of the spinal nerves distal to the posterior root ganglia. Muscle spindles in lumbrical and flexor carpi radialis were abnormal in that the capsule was thickened and fibrous, and there was an increase of intracapsular connective tissue. In addition there was mild neurogenic atrophy. Although there was no obvious wasting of the anterior spinal nerve roots, and the number of cells in the spinal anterior grey horns appeared normal, the nuclei of some nerve cells were eccentric and some nerve cells appeared shrunken. There was an unusual widespread phenomenon, seen in greatest numbers in the posterior root ganglia and in the brainstem: one or more acidophilic corpuscles in the nuclei of nerve cells. The corpuscles were generally a little larger than the nucleolus which was often seen alongside (Figure 2c-f). Neurones in the inferior olives, cuneate nuclei, nuclei portis, substantia nigra and third nerve nuclei were particularly rich in these bodies, but they were found also elsewhere in the brainstem with an occasional one in the spinal cord and the cerebral cortex. In the cerebellum there was only a mild loss of Purkyne cells with a little gliosis in the molecular layer. Some Purkyni! cells and dentate nerve cells were large and rounded. Similar rounded cells, often with an eccentric nucleus were seen in the inferior olives and in the nuclei pontis. Sections of the cranial nerves that looked thin showed loss of nerve fibres. The optic nerves and tracts were normal, and there was no obvious abnormality in the cerebral hemispheres or deep grey matter.
Ultrastructural findings Samples of posterior root ganglia and brainstem were post-fixed in glutaraldehyde E
314
I. Janota
d
Figure 2. a grey shrunken fifth nerves (arrowheads). b pale staining, wasted posterior columns. Cervical cord, Luxol fast blue and Nissl, x 8. c-f intranuclear corpuscles. Haematoxylin and eosin, x 460. c, d substantia nigra. The dark nucleolus is seen in c. e , f double corpuscles in a cervical posterior root ganglion. The dark nucleolus is shown to the left of the two corpuscles in e .
Marinesco bodies in spinal degeneration
315
and processed for electron microscopy. The intranuclear bodies (Figure 3a-d) consisted of a fibrillary mesh of varying density. Individual filaments of some 10-12 nm in diameter appeared to curve and to criss-cross. At high magnifications there was a suggestion of periodic constrictions or areas of higher density in the filaments.
Discussion Marinesco bodies are among the early discoveries in neuropathology. Their original description by Marinesco (1902) remains so apt that it merits quoting:
‘J’ai trouve constamment chez l’adulte B l’interieur du noyau des cellules du locus niger et frequemment dans celles du locus coeruleus des corpuscules en nombre variable situes au voisinage du nuclkole. Ces corpuscules prennent toujours la couleur acide.’ Marinesco compared his intranuclear corpuscles with other larger ones in the cytoplasm : ‘C’est ainsi que parfois j’ai pu voir dans la masse du pigment noir des corpuscules colores en rouge brique ou en rouge venitien par la methode de Romanowski, corpuscules qui, cependant, sont plus volumineux que ceux qu’on voit l’interieur du noyau. En outre ils sont entoures d’une large aureole.’ These are now known as Lewy bodies. An ultrastructural study of Marinesco bodies on formalin fixed post mortem material of one case was carried out by Leestma & Andrews (1969). They found aggregates of 20 nm granules in varying combinations with a delicate filamentous lattice-like structure formed by alternating layers of closely approximated parallel filaments 10-12 nm in diameter. Similar appearances were found by Best (1978), but the granular element was lacking in the present case. It may be that the intranuclear bodies in the present case, although they look the same on light microscopy, are not identical with the ordinary nigral Marinesco bodies, or that the ‘Marinesco body’ conceals a variety of ultrastructural appearances. This case belongs to the predominantly spinal group of Friedreich’s ataxia (Greenfield, 1954). Several associated pathological features are unusual but not unique. The involvement of various cranial nerves has been reported in spinocerebellar degenerations. Although degeneration of the descending trigeminal tracts is apparently quite common, wasting of the fXth nerve with changes in the Gasserian ganglion as seen in this case is rare and there is only one report of clinical involvement of the nerve (Biemond, 1951; 1954). When ocular movements are affected difficulty may arise in distinguishing ocular myopathy from denervation atrophy (Stephens et al., 1958). When peripheral nerves are involved Friedriech’s ataxia may appear to overlap or merge with Charcot-Marie-Tooth disease both on clinical and pathological grounds (Salisachs, 1976). This case also illustrates the widespread intranuclear acidophilic inclusions closely resembling Marinesco bodies. They are unlike any viral or lipid structures.
316
I . Janota
Marinesco bodies in spinal degeneration
317
This has not been reported before in spino-cerebellar degenerations, peroneal muscular atrophy or, indeed, in any other neuropathological condition.
Acknowledgements I am grateful to Drs P. C. Farrant, T. Fowler, R. Hierons and B. B. J. Nixon for their clinical collaboration and to Mrs P. Adler and Mr A. Davey for help with the illustrations.
References BESTP. (1978) Personal communication BIEMONDA. (1951) Les d6g6n6rations spino-cCr6belleuses. Folia psychiatrica, neurologica et neurochirurgica Neerlandica 54, 216-222 BIEMOND A. (1954) La forme radiculo-cordonnale posterieure des deg6n6rescences spino-c6rdbelleuses. Revue neurologique 91, 1-21 GREENFIELD J.G. (1954) The Spinocerebellar Degenerations. Blackwell, Oxford GREENFIELD J.G. (1958) Greenfield’s Neuropathology. Edward Arnold, London LEESTMA J.E. & ANDREWS J.M. (1969) The fine structure of the Marinesco body. Archives of Pathology 88, 431436 MARINESCO J . (1902) Sur la presence des corpuscules acidophiles paranucl6olaires d a m les cellules du locus niger et du locus coeruleus. Comptes rendus de l’Acad6mie des Sciences, Paris 134,1000-1002 MARINESCO J. (1909) La Cellule Nerveuse. Doin, Paris SALISACHS P. (1976) Charcot-Marie-Tooth disease associated with ‘essential tremor’. Report of 7 cases and a review of the literature. Journal of the Neurological Sciences 28, 1 7 4 0 STEPHENS J., HOOVER M.L. & DENSTJ. (1958) On familial ataxia, neural amyotrophy and their association with progressive ophthalmoplegia. Brain 81, 556-566 YUEN P. & BAXTERD.W. (1963) The morphology of Marinesco bodies (paranucleolar corpuscles) in the melanin pigmented nuclei in the brainstem. Journal of Neurology, Neurosurgery and Psychiatry 26, 178-183
Figure 3. Electron microscopy of intranuclear corpuscles in a cervical posterior root ganglion. a x9000. b (detail of a) x 90 000. Edge of the nucleolus at the top. e a double, dumbell corpuscle, x 9000. Edge of nucleolus on the right. d (detail of c) x 45 000.
