Journal of the Neurological Sciences, 108 (1992) 137-148 © 1992 Elsevier Science Publishers B.V. All rights reserved 0022-510X/92/$05.00
137
JNS 03718
Extrapyramidal system involvement in motor neuron disease K a z u k o H a s e g a w a i, H i s a y u k i K o w a i a n d S a b u r o Y a g i s h i t a 2 ! Department of Neurology, lOtasato University, School of Medicine, and z Dit'ision of Pathology, Kanagawa Rehabilitation Center, Kanagawa (Japan) (Received 27 March, 1991) (Revised, received 4 October, 1991) (Accepted 10 October, 1991) Key words: Amyotrophic lateral sclerosis; Motor neuron disease; Spheroid; Primary lateral sclerosis; Nigro-pallido-luysian system Summary Three cases of motor neuron disease (MND), in which neuropathological findings were atypical, are reported. The first case manifested widespread and severe degeneration of the spinal cord, as in spinal fibrosis. Case 2 revealed severe degeneration of the pyramidal tract with many spheroids, which made it difficult to differentiate from primary amyotrophic lateral sclerosis. The last case revealed degeneration of the nigro-pallido-luysian system, even though no clinical manifestation of extrapyramidal a n d / o r cerebellar symptoms had been noted throughout the clinical course. In MND, degeneration might occur in various locations other than the motor system.
Introduction
Case reports
The neuropathological hallmarks of motor neuron disease (MND) are the primary degeneration of motor neurons, with relative sparing of other systems of the central nervous system. Recently, however, it has been noticed that the clinical features of MND are modified by prolonged survival resulting from artificial ventilation and tube feeding. We have observed three MND cases, which when compared with banal MND cases, have lesions in addition to those in motor neuron systems. The three subjects, part of a group of 42 MND autopsy cases in our hospital, exhibited atypical pathological findings. The brain and spinal cord in each case was fixed in 10% formalin and representative sections were embedded in paraffin wax. Thin sections were stained with hematoxylin-eosin (HE), Kliiver-Barrea (KB), Bodian or modified Bielshowsky silver impregnation, and Holzer stain for glial fiber.
Case 1: male aged 58 (KEH : O0-57-860) The patient had been well until age 55, when he felt weakness and twitching sensations of his upper limbs. He was admitted to our hospital because of muscle weakness of 5 months duration. Bulbar 'signs, muscular atrophy and weakness of all limbs were observed during neurological examination. All deep tendon reflexes were diminished, and no pathological reflexes were elicited. Electrophysiologically, neurogenic changes were revealed in all extremities and in the tongue on the electromyogram, and the sensory and motor nerve conduction velocities were normal in several nerves examined. He reached a totally de-efferented state 7 months after the onset. Swallowing and verbal conversation was impossible due to bulbar palsy, so that nasogastric tube feeding was started. Fourteen months later, the patient became blind due to lagophthalmic ophthalmia secondary to facial palsy. Two years after the onset, he developed great difficulty in communication; even using ocular movement (mainly of the vertical system). The patient died of pneumonia in 32 months. The patient's clinical symptoms were always limited to those of the lower motor neurons. The clinical progression was very rapid; paralysis of the respiratory muscle and complete paralysis of the extremities by 5
Correspondence to: K. Hasegawa, Department of Neurology, Kitasato University, School of Medicine, Kitasato 1-15-1, Sagamiharacity, Kanagawa, 228 Japan. Tel.: (03)0427-48-9111, Fax: (03)427-489117.
138
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Fig. 1. Extensive degeneration of the spinal cord. Case 1. (KB stain). A: 3rd cervical segment; B: 7th cervical segment; C: 3rd lumbar segment. Marked pallor of myelin and attenuation of the cord are seen. The posterior column is relatively spared. D: complete loss of neurons with astrocytosis in the gray matter at the 3rd cervical segment of the spinal cord. HE, x 12.
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140 and 7 months, respectively. Neither pyramidal nor cerebellar signs were noted throughout the clinical course. Disturbance of ocular movement was seen only at the terminal stage, although the reflectoric ocular movements remained well throughout. Ophthalmological examination showed no evidence of nuclear or infranuclear ophthalmoplegia. There were no abnormalities in the immune system nor in the endocrinological system. There was no family history of MND. Clinical diagnosis: Advanced spinal muscular atrophy.
flexes including sucking and snouting were positive; palmomental reflex was also present. No artificial ventilation was applied throughout the course. Deep tendon reflexes were constantly exaggerated, and pathological reflexes were always positive. Clinically, the symptoms of the upper motor neuron system were more severe than those of the lower motor neuron system. Manifested dementia and extrapyramidal symptoms were not observed. There was no family history. The patient died of aspiration pneumonia 35 months after the onset.
Clinical diagnosis: ALS. Neuropathological findings Extensive degeneration was seen throughout the spinal cord, not being limited to the upper motor and lower motor systems. The neurons in the anterior horn and in the spinal gray matter such as Clarke's column, disappeared almost completely at the level of the cervical to lumbar segments, replaced by glial scar tissue and lipid-laden macrophages. The white matter of the spinal cord was also totally destroyed, involving most long and propriospinal tracts (Fig. 1). In constrast, the posterior column was relatively spared, and the fiber loss was more severe in the gracilis than the cuneatus fasciculus. The anterior root nerves had also degenerated, the posterior counterpart being relatively spared. In the cranial motor nuclei, remarkable neuronal degeneration and loss were observed in the level up to the facial nerve nucleus. Neurons in the oculomotor complex were preserved comparatively well. Loss of the pigmented neurons in the substantia nigra was also observed (Fig. 2). Degeneration of the spinal white matter was traced upwards to the brain-stem, and the changes of the corticospinal tracts could be observed even at the level of the midbrain, but not in the internal capsule. In the spinocerebellar tracts, degenerative changes were traced up to the level of the bulbar dorsoanterior fascicules and inferior cerebellar peduncles. However, no particular abnormality was noted in the deep cerebellar nuclei and cerebellar cortex.
Extensive and severe degeneration of the pyramidal tract was observed in the spinal cord (Fig. 3). The pyramidal tract was completely destroyed below the level of the midbrain. The myelinated fibers, both large and small in caliber, completely disappeared in the pyramidal tracts of the spinal cord up to the ports. Many spheroids (fusiform axonal swellings) were seen in the cerebral peduncles and distal internal capsules. They were most numerous in the cerebral peduncles, and less in number in the upper portion of the internal capsule and corona radiata (Fig. 4). These spheroids were strongly positive for anti-highly phosphorylated neurofilament antibody stain similar to the banal globules of the lower motor neuron in MND. Degeneration of neurons in the anterior horn of the spinal cord and in the hypoglossal nuclei was mild, in contrast to severe degeneration in the pyramidal tracts. No globules (small, round to fusiform swellings of the axons) as seen in banal MND were observed in the anterior horn of the spinal cord. Another characteristic finding in case 2 was neurofibrillary tangles and granulovacuolar degeneration confined to the hippocampal and dentate neurons. No senile plaque was seen anywhere. Mild deciduation of pigmented neurons and reparative gliosis were seen in the substantia nigra. Thus, this case does not correspond to ALS combined with Alzheimer's disease.
Case 2: female aged 65 (KEH : 00-69-884)
Case 3: male aged 60 (KEH : O0-58.106)
The patient' s disease started with dysarthria at age of 61. Muscle weakness of all extremities gradually progressed, and her verbal communication became impossible within one year. The patient was admitted to our hospital and was diagnosed as having amyotrophic lateral sclerosis (ALS). Nasogastric tube feeding was commenced because of severe dysphagia and dysarthria. Although she could not walk, the function of her upper limbs remained comparatively well, so she could handle a tube for suction of her saliva by herself. About 2 years after the onset, the patient developed apraxia of eye-lid closure, i.e., blinking was impossible and voluntary eye-closing was difficult. Primitive re-
Neuropathological findings
The patient's illness started with hygrostoma at age 53, followed by dysarthria and dysphagia. He was admitted to a university hospital because of difficulty of mastication and dysphagia, and was diagnosed as having progressive buibar palsy. Swallowing and speaking became impossible by 3 years after the onset. Hence he was admitted to our hospital, and tube feeding was started. However, the motor function of his extremities remained relatively intact, and ambulation was still possible. In additon the patient was able to handle a suction tube to remove his saliva and sputum by himself. Electromyography revealed the neurogenic changes for all four extremities and tongue. Nerve
141
Fig. 2, Substantia nigra. Case 1. Considerable dropout o f pigmented neurons with reparative gliosis. H E + luxol fast blue stain, × 5.
TABLE 1 COMPARISON O F CLINICAL AND P A T H O L O G I C A L FINDINGS A M O N G R E P O R T E D CASES O F P R I M A R Y L A T E R A L SCLEROSIS BP: bulbar palsy; GD: gait disturbance; UE: upper extremities; LE: lower extremities; gl: 81iosis; AHC: anterior horn ceil.
Age of onset/sex Duration (year) Initial sign Clinical symptoms pseudobulbar palsy spasticity of U E pathological reflex (UE) spasticity of LE Babinski sign posture lower motoneuron sign Pathological findings motor cortex internal capsule c m s cerebri pons pyramid corticospinal tract spinal AHC hypoglossal nucleus temporal lobe
Beal et al.
Younger et al.
Fisher et al.
Kuzuhara et al.
present case 2
66 F 3.5 pseudo-BP
71 M 6.0 GD
60 M 0.8 GD
67 F 5.5 GD
52 F 19.0 GD
64 F 2.9 pseudo-BP
+ +
-
+ ? + ? spastic
+ + ? + + + ?
+ + + ? + + + ?
+ ? + + + ?
÷+ ++ ? ÷+ +
+÷ ÷ + .i÷÷ +
.
.
.
-
+ + + +
? + + +
+
. . -
+
. .
-
.
+ +
. .
decerebrate paraplegia in extension
+ + + +
+ .9 +
+
+
?
?
++ ÷ + + ÷ +
. . ?
+(gl)
÷
++(S+) ++(S+) ++ ++ ++ + + +
-
,it
P
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143
C
D Fig. 3. Macroscopical view of spinal cord and brainstem. Case 2. A: midbrain; B: medulla oblongata; C: 4th cervical segment; D: 5th thoracic segment; E: 3rd lumbar segment. Marked pallor of myelin in the lateral pyramidal tracts. The other tracts are spared. KB stain.
144
Fig. 4. Many spheroids are seen in the cerebral peduncle (A) and inferior part of the internal capsule (B). Bodian silver impregnation, x50.
145
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o o"
Fig. 5. Basal ganglia. Case 3. A: substantia nigra; B: giobus pallidus; C: subthalamic nucleus. Severe gliosis is seen in nigro-pailido-luysian system. Both inner and outer segements of globus pallidus are equally affected. Holzer stain.
146 TABLE 2 COMPARISON
BETWEEN
REPORTED
CASES WITH N-P-L DEGENERATION
AND OUR CASE 3
PD: Parkinson's disease; MR: mental retardation; GPi: internal segment of globus pallidus; GPe: external segment of globus pallidus; LB: s u b t h a l a m i c n u c l e u s ; A H C : a n t e r i o r h o r n cell; # : M a n y s p h e r o i d s a r e s e e n . * d u e t o rigidity * * P D - l i k e * * * P D - l i k e ? o r p s e u d o - B P ?
Age of onset/sex Duration (years) Family history Clinical symptoms bulbar palsy muscle atrophy spasticity dementia rigidity dystonia c e r e b e l l a r sign Pathological findings hypoglossal nucleus spinal AHC pyramidal tract posterior column n i g r a : cell loss gliosis O P i : cell loss gliosis G P e : cell loss gliosis LB: cell loss gliosis putamen
G r a y e t al.
S e r r a t r i c e e t al.
M o s s a k o w s k i e t al.
Present Case 3
34 F 2.0 + (PD, MR)
54 F 11 -
47 M 4.0 -
60 M 7.5 -
+ * + + + + + ?
+ ** + + + -
+ *** + + + ? ?
+ + -
+ + + + + + + + + + + -
? + + + + + + + + -
+ + + + + + + + + + -
+ + + + + + + + + + + +
+
+
+ + + +
+ + + +
conduction velocities were normal in examined nerves. Five years after the onset, muscular weakness extended gradually to the neck and truncal muscle groups. By 7 years, he could not hold his head up without support. A neck supporter became necessary and he walked with a dropped head. About that time, he developed hepatic dysfunction. The complication of primary liver carcinoma was diagnosed from the laboratory data. He died due to massive hemorrhage from the hepatoma 77 months after the onset. Throughout the clinical course, neither dementia, oculomotor disturbance, neural deafness, pyramidal, extrapyramidal nor cerebeUar symptoms were observed. Clinically, muscle power of all extremities had remained well, especially in the upper limbs, in contrast to the cases with severe bulbar palsy. He had been ambulatory until his later stage. He had never undergone blood transfusion. He was, however, a heavy drinker for some 30 years. There was no family history. Clinical diagnosis: ALS with prominent bulbar and spinal muscular atrophy, and primary carcinoma of the liver without systemic metastasis.
Pathological findings Primary hepatocellular carcinoma was confirmed, and its rupture induced massive hemorrhage. No metastatic lesion was confirmed.
~ ~ + + + + + +
+ # + # + + # +
~ + + + + + + + +
+ + + + + +
Neuropathological findings Marked neuronal loss in the hypoglossal nuclei and anterior horn of the spinal cord was observed, while the pyramidal tract was spared with only a few lipidladen macrophages scattered there. Although extrapyramidal symptoms and signs were absent throughout the clinical course, severe degenerative change was found in the nigro-pallido-luysian (NPL) system; disappearence of the neurons and reparative gliosis were observed in this system (Fig. 5). Both inner and outer segments of the pailidum were equally involved. Otherwise, no significant lesions were detected in the other nervous systems.
Discussion
It has been reported that white matter of the spinal cord other than the pyramidal tracts is involved in the progression of MND (Homes 1909; Ikuta et al. 1979; Auerback and Crocker 1981). The degeneration includes the spinocerebellar tracts, gracilis fascicles and neurons in Clarke's column. In general, the lesions in these regions are very mild and are expressed as myelin paucity and slight decrease in the number of their neurons. However, the degeneration in the spinal cord in Case 1 was much more severe and extensive. Neu-
147 rons, sensory as well as motor, in the spinal cord had almost completely disappeared, and myelinated fibers in the cord were also totally lost, except those in the posterior column. The spinal cord lesions in Case 1 were severe. However, the lesions were confined to the level below the pons as in the case of banal MND. Considering the unusual pathology in Case 1, it is noteworthy that the clinical progression was very rapid. The natural course might have been about only 6 months if artificial ventilation had not been applied. The successive usage of a ventilator prolonged his life, which might have induced further extensive destruction of the spinal cord and other regions. Holmes (1909) referred to degeneration of Betz cells in the motor cortex and of the corpus callosum in ALS. In Case 1, no degenerative lesion was seen in the cerebrum, though degeneration in the spinal cord was marked. So, the lesions described by Holmes might be distinct from the classical lesions in ALS. In any event, it is suggested that the lesions, as seen in Case 1, may become more prevalent by the usage of a ventilator. Case 2, in which the upper motor neurons were more severely involved than the lower ones in both clinical and pathological aspects, is unlikely to be primary lateral sclerosis (1)1.3). The mode of pyramidal tract degeneration in this case may support the classical hypothesis that the degenerative process in the pyramidal tract starts distally and ascends to the midbrain along with the clinical course. However, the pyramidal lesion in Case 2 was severe and extensively affected, and the tract below the level of the pons was completely destroyed. In addition, many spheroids were present in the crus cerebri and the internal capsule, while Betz cells in the motor cortex did not show any pathological changes. Case 2 was superficially similar to PLS. To date, only 6 cases of PLS have been definitely identified (Beal et al. 1981; Kuzuhara et al. 1986; Fisher 1987; Younger et ai. 1988). The comparison between these previously reported cases and Case 2 is shown in Table 1. In all the previous cases there were no lower motor neuron signs. PLS is distinct from famiiial spastic paraplegia in that their clinical course is very rapid. Since some loss of neurons in the spinal cord was seen in Case 2, it is reasonable that this case is different from PLS in neuropathology, being more similar to ALS. Degeneration of the somata in the upper motor neurons is thought to be a primary pathogenic focus in PLS. However, no such significant change was observed in Case 2. Many spheroids were revealed in the crus cerebri and in the internal capsule in Case 2. Spheroids in the pyramidal tracts have been reported in only two papers to our knowledge; spheroids were found in the spinal cord to the polls (Okamoto et al. 1991), and in the cerebral cortex (Wikstrom et al. 1982). Small spheroids in MND, usually termed as globules, are recognized to be the focal
swelling of the proximal axons as a sequence of the secondary motor neurons, and are distributed mainly in the anterior horn and propriospinal tract in the spinal cord (Carpenter 1968; Sasald et al. 1988). On the other hand, the spheroids in Case 2 were formed by axonal swelling of the upper motor neurons, being far from the cell body. The different distribution of spheroids in our case from those in common MND might be reflected by the different process of their formation and/or their histogenesis. Two cases of Okamoto's study and our case may comprise a subgroup of MND. In this regard, further similar case reports may shed some light on this issue. In most degenerative diseases, multiple systems are generally pathologically involved and the term of multiple system atrophy is often used, although patients do not always develop the clinical symptoms of multiple system involvement. Case 3 is of a great interest in consideration of the relation of MND to multiple system atrophy. Nigro-pallido-luysian system involvement in MND has been rarely reported (Gray et al. 1985; Serratrice et al. 1983; Mossakowski and Rentawek 1987). In addition, the reported cases had either dementia or extrapyramidal symptoms, or both, and their clinical signs and symptoms are different from ours. Our case did not develop extrapyramidal symptoms a n d / o r dementia, and showed a clinicopathological discrepancy in this point. The clinical differences between the previous cases and ours are compared in Table 2. Recently, a case of familial MND with nigropallido-luysian atrophy was reported (Sakai et al. 1988) and it was virtually identical to that of our Case 3, aside from its positive family history. There has been so far a trend to neglect the basal ganglia once a clinical diagnosis of MND is made. According to Hughes (1982), however, the expansion of pathological lesions of MND, including the basal ganglia, would be more often found if each ALS case were assessed carefully. Nigro-pallido-luysian degeneration is seen in Hallervorden-Spatz disease and Hunt's disease (Davison 1954). Case 3 was different from these diseases since there was no family history, and because of different clinical symptoms and the absence of neuroaxonal spheroids. Our 3 cases did not show stereotyped pathological changes as in MND. Pigmented neurons in the nigra were pointed out as a common degenerative target besides the anterior cell of the spinal cord and pyramidal tracts as in MND. Nigral degeneration has been described in a series of MND cases with dementia (Horoupian et al. 1984), but less attention is paid to the lesions since nigral neurons are generally considered to be vulnerable in hypoxia, i. e., a primary lesion or not. Conclusively, various degenerative lesions may occur in the nervous system other than the motor systems in
148 MND. Underestimation of these lesions in MNS may lead us to miss the possible heterogeneous character of MND. From a historical point of view, bulbo-spinal muscular atrophy and Hirayama's disease were found to be distinct from the classical MND, and the accumulation of the cases with additional lesions outside the motor neuron systems is desired.
References Auerback, P. and Crocker, P. (1981) Regular involvementof Clarke's nucleus on sporadic amyotrophic lateral sclerosis. Arch. Neurol., 39: 155-156. Beal, M.F. and Richardson, R.P. (1981) Primary lateral sclerosis: a case report. Arch. Neurol., 38: 630-633. Carpenter, S (1968) Proximal axon enlargement in motor neuron disease. Neurology, 18:841-851. Davison, C. (1954) Pallido-pyramidal disease. J. Neuropathol. Exp. Neuroi., 13: 50-59. Fisher, C.M. (1987) Pure spastic paralysis of corticospinal origin. Can. J. Neurol. Sci., 4: 251-258. Gray, F., Eizenbaum, J.F., Gherardi, R., Degos, H.D. and Poirierl, J. (1985) Luyso-pallido-nigralatrophy and amyotrophic lateral sclerosis. Acta Neuropathol. (Bed.), 66: 78-82. Holmes, G. (1909) The pathology of amyotrophic lateral sclerosis. Rev. Neurol. Psychiat., 7: 693-725. Horoupian, D.S., Thai, L., Katzman, R., Terry, R.D., Davies, P., Hirano, A., DeTeresa, R., Fuld, P.A., Petite, C., Blass, J. and Ellis, J.M. (1984) Dementia and motor neuron disease: morphometric, biochemical,and Golgi studies. Ann. Neurol., 16: 305-313. Hughes, J.T. (1982) Pathology of amyntrophic lateral sclerosis, in
J.P. Rowland (Ed.), Human Motor Neuron Disease. Raven Press, New York, pp. 61-74. Ikuta, F., Makifuchi, T. and Ichikawa, T. (1979) Comparative studies of tract degeneration in ALS and other disorders. In Tsubaki and Y. Toyokura (Eds.), Amyotrophic Lateral Sclerosis. Tokyo Univ. Press, Tokyo, pp. 177-200. Kuzuhara, S., and Okawa, Y. (1986) Primary lateral sclerosis: report of 2 autopsy cases. Annual Report of the Research of CNS Degenerative Disease, The Ministry of Health and Welfare of Japan, pp. 72-78. Mossakowski, M.J. and Rentawek, K. (1987) Amyotrophic lateral sclerosis with generalized neuroaxonal degeneration and selective involvement of the nigropailidal system. Neuropathol. PoL, 25: 539-553. Okamoto, K., Hirai, S., Shoji, M., Senoh, Y. and Yamazaki, T. (1991) Axonal swelling of the corticospinal tracts in amyotrophic lateral sclerosis. Acta NeuropathoL, 80: 222-226. Sakai, M., Hashizume, Y., Muroga, T., Murakami, N. and Yamamoto, H. (1988) Neuropathological studies of familial amyotrophic lateral sclerosis with special reference to systemic degeneration of dentato-rubrai system and neuronal loss of Onufs nuclei. Clin. Neurol. (Tokyo), 28: 1197-1205. Sakai, S., Kamei, H., Yamane, K. and Maruyama, S. (1988) Swelling of neuronal processes in motor neuron disease. Neurology, 38: 1114-1118. Serratrice, G.T., Toga, M. and Pellissier, F. (1983) Chronic spinal muscular atrophy and pallido-nigral degeneration: report of a case. Neurology, 33: 306-310. Wikstrom, J., Paetau, A., Pale, J., Sulkava, R. and Haltia, M. (1982) Classic amyotrophic lateral sclerosis with dementia. Arch. New roL, 39: 681-683. Younger, D.S., Chou, S., Hays, A.P., Lange, D.J., Emerson, R., Brin, M., Thompson, H. and Rowland, P. (1988) Primary lateral sclerosis: a clinical diagnosis reemerges. Arch. Neurol., 45: 1304-1307.
137
JNS 03718
Extrapyramidal system involvement in motor neuron disease K a z u k o H a s e g a w a i, H i s a y u k i K o w a i a n d S a b u r o Y a g i s h i t a 2 ! Department of Neurology, lOtasato University, School of Medicine, and z Dit'ision of Pathology, Kanagawa Rehabilitation Center, Kanagawa (Japan) (Received 27 March, 1991) (Revised, received 4 October, 1991) (Accepted 10 October, 1991) Key words: Amyotrophic lateral sclerosis; Motor neuron disease; Spheroid; Primary lateral sclerosis; Nigro-pallido-luysian system Summary Three cases of motor neuron disease (MND), in which neuropathological findings were atypical, are reported. The first case manifested widespread and severe degeneration of the spinal cord, as in spinal fibrosis. Case 2 revealed severe degeneration of the pyramidal tract with many spheroids, which made it difficult to differentiate from primary amyotrophic lateral sclerosis. The last case revealed degeneration of the nigro-pallido-luysian system, even though no clinical manifestation of extrapyramidal a n d / o r cerebellar symptoms had been noted throughout the clinical course. In MND, degeneration might occur in various locations other than the motor system.
Introduction
Case reports
The neuropathological hallmarks of motor neuron disease (MND) are the primary degeneration of motor neurons, with relative sparing of other systems of the central nervous system. Recently, however, it has been noticed that the clinical features of MND are modified by prolonged survival resulting from artificial ventilation and tube feeding. We have observed three MND cases, which when compared with banal MND cases, have lesions in addition to those in motor neuron systems. The three subjects, part of a group of 42 MND autopsy cases in our hospital, exhibited atypical pathological findings. The brain and spinal cord in each case was fixed in 10% formalin and representative sections were embedded in paraffin wax. Thin sections were stained with hematoxylin-eosin (HE), Kliiver-Barrea (KB), Bodian or modified Bielshowsky silver impregnation, and Holzer stain for glial fiber.
Case 1: male aged 58 (KEH : O0-57-860) The patient had been well until age 55, when he felt weakness and twitching sensations of his upper limbs. He was admitted to our hospital because of muscle weakness of 5 months duration. Bulbar 'signs, muscular atrophy and weakness of all limbs were observed during neurological examination. All deep tendon reflexes were diminished, and no pathological reflexes were elicited. Electrophysiologically, neurogenic changes were revealed in all extremities and in the tongue on the electromyogram, and the sensory and motor nerve conduction velocities were normal in several nerves examined. He reached a totally de-efferented state 7 months after the onset. Swallowing and verbal conversation was impossible due to bulbar palsy, so that nasogastric tube feeding was started. Fourteen months later, the patient became blind due to lagophthalmic ophthalmia secondary to facial palsy. Two years after the onset, he developed great difficulty in communication; even using ocular movement (mainly of the vertical system). The patient died of pneumonia in 32 months. The patient's clinical symptoms were always limited to those of the lower motor neurons. The clinical progression was very rapid; paralysis of the respiratory muscle and complete paralysis of the extremities by 5
Correspondence to: K. Hasegawa, Department of Neurology, Kitasato University, School of Medicine, Kitasato 1-15-1, Sagamiharacity, Kanagawa, 228 Japan. Tel.: (03)0427-48-9111, Fax: (03)427-489117.
138
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Fig. 1. Extensive degeneration of the spinal cord. Case 1. (KB stain). A: 3rd cervical segment; B: 7th cervical segment; C: 3rd lumbar segment. Marked pallor of myelin and attenuation of the cord are seen. The posterior column is relatively spared. D: complete loss of neurons with astrocytosis in the gray matter at the 3rd cervical segment of the spinal cord. HE, x 12.
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140 and 7 months, respectively. Neither pyramidal nor cerebellar signs were noted throughout the clinical course. Disturbance of ocular movement was seen only at the terminal stage, although the reflectoric ocular movements remained well throughout. Ophthalmological examination showed no evidence of nuclear or infranuclear ophthalmoplegia. There were no abnormalities in the immune system nor in the endocrinological system. There was no family history of MND. Clinical diagnosis: Advanced spinal muscular atrophy.
flexes including sucking and snouting were positive; palmomental reflex was also present. No artificial ventilation was applied throughout the course. Deep tendon reflexes were constantly exaggerated, and pathological reflexes were always positive. Clinically, the symptoms of the upper motor neuron system were more severe than those of the lower motor neuron system. Manifested dementia and extrapyramidal symptoms were not observed. There was no family history. The patient died of aspiration pneumonia 35 months after the onset.
Clinical diagnosis: ALS. Neuropathological findings Extensive degeneration was seen throughout the spinal cord, not being limited to the upper motor and lower motor systems. The neurons in the anterior horn and in the spinal gray matter such as Clarke's column, disappeared almost completely at the level of the cervical to lumbar segments, replaced by glial scar tissue and lipid-laden macrophages. The white matter of the spinal cord was also totally destroyed, involving most long and propriospinal tracts (Fig. 1). In constrast, the posterior column was relatively spared, and the fiber loss was more severe in the gracilis than the cuneatus fasciculus. The anterior root nerves had also degenerated, the posterior counterpart being relatively spared. In the cranial motor nuclei, remarkable neuronal degeneration and loss were observed in the level up to the facial nerve nucleus. Neurons in the oculomotor complex were preserved comparatively well. Loss of the pigmented neurons in the substantia nigra was also observed (Fig. 2). Degeneration of the spinal white matter was traced upwards to the brain-stem, and the changes of the corticospinal tracts could be observed even at the level of the midbrain, but not in the internal capsule. In the spinocerebellar tracts, degenerative changes were traced up to the level of the bulbar dorsoanterior fascicules and inferior cerebellar peduncles. However, no particular abnormality was noted in the deep cerebellar nuclei and cerebellar cortex.
Extensive and severe degeneration of the pyramidal tract was observed in the spinal cord (Fig. 3). The pyramidal tract was completely destroyed below the level of the midbrain. The myelinated fibers, both large and small in caliber, completely disappeared in the pyramidal tracts of the spinal cord up to the ports. Many spheroids (fusiform axonal swellings) were seen in the cerebral peduncles and distal internal capsules. They were most numerous in the cerebral peduncles, and less in number in the upper portion of the internal capsule and corona radiata (Fig. 4). These spheroids were strongly positive for anti-highly phosphorylated neurofilament antibody stain similar to the banal globules of the lower motor neuron in MND. Degeneration of neurons in the anterior horn of the spinal cord and in the hypoglossal nuclei was mild, in contrast to severe degeneration in the pyramidal tracts. No globules (small, round to fusiform swellings of the axons) as seen in banal MND were observed in the anterior horn of the spinal cord. Another characteristic finding in case 2 was neurofibrillary tangles and granulovacuolar degeneration confined to the hippocampal and dentate neurons. No senile plaque was seen anywhere. Mild deciduation of pigmented neurons and reparative gliosis were seen in the substantia nigra. Thus, this case does not correspond to ALS combined with Alzheimer's disease.
Case 2: female aged 65 (KEH : 00-69-884)
Case 3: male aged 60 (KEH : O0-58.106)
The patient' s disease started with dysarthria at age of 61. Muscle weakness of all extremities gradually progressed, and her verbal communication became impossible within one year. The patient was admitted to our hospital and was diagnosed as having amyotrophic lateral sclerosis (ALS). Nasogastric tube feeding was commenced because of severe dysphagia and dysarthria. Although she could not walk, the function of her upper limbs remained comparatively well, so she could handle a tube for suction of her saliva by herself. About 2 years after the onset, the patient developed apraxia of eye-lid closure, i.e., blinking was impossible and voluntary eye-closing was difficult. Primitive re-
Neuropathological findings
The patient's illness started with hygrostoma at age 53, followed by dysarthria and dysphagia. He was admitted to a university hospital because of difficulty of mastication and dysphagia, and was diagnosed as having progressive buibar palsy. Swallowing and speaking became impossible by 3 years after the onset. Hence he was admitted to our hospital, and tube feeding was started. However, the motor function of his extremities remained relatively intact, and ambulation was still possible. In additon the patient was able to handle a suction tube to remove his saliva and sputum by himself. Electromyography revealed the neurogenic changes for all four extremities and tongue. Nerve
141
Fig. 2, Substantia nigra. Case 1. Considerable dropout o f pigmented neurons with reparative gliosis. H E + luxol fast blue stain, × 5.
TABLE 1 COMPARISON O F CLINICAL AND P A T H O L O G I C A L FINDINGS A M O N G R E P O R T E D CASES O F P R I M A R Y L A T E R A L SCLEROSIS BP: bulbar palsy; GD: gait disturbance; UE: upper extremities; LE: lower extremities; gl: 81iosis; AHC: anterior horn ceil.
Age of onset/sex Duration (year) Initial sign Clinical symptoms pseudobulbar palsy spasticity of U E pathological reflex (UE) spasticity of LE Babinski sign posture lower motoneuron sign Pathological findings motor cortex internal capsule c m s cerebri pons pyramid corticospinal tract spinal AHC hypoglossal nucleus temporal lobe
Beal et al.
Younger et al.
Fisher et al.
Kuzuhara et al.
present case 2
66 F 3.5 pseudo-BP
71 M 6.0 GD
60 M 0.8 GD
67 F 5.5 GD
52 F 19.0 GD
64 F 2.9 pseudo-BP
+ +
-
+ ? + ? spastic
+ + ? + + + ?
+ + + ? + + + ?
+ ? + + + ?
÷+ ++ ? ÷+ +
+÷ ÷ + .i÷÷ +
.
.
.
-
+ + + +
? + + +
+
. . -
+
. .
-
.
+ +
. .
decerebrate paraplegia in extension
+ + + +
+ .9 +
+
+
?
?
++ ÷ + + ÷ +
. . ?
+(gl)
÷
++(S+) ++(S+) ++ ++ ++ + + +
-
,it
P
~i i I i ~¸. . . . ,'' ~!~,~,,," ii~ii ~ !~i ~ ~ ii ~
143
C
D Fig. 3. Macroscopical view of spinal cord and brainstem. Case 2. A: midbrain; B: medulla oblongata; C: 4th cervical segment; D: 5th thoracic segment; E: 3rd lumbar segment. Marked pallor of myelin in the lateral pyramidal tracts. The other tracts are spared. KB stain.
144
Fig. 4. Many spheroids are seen in the cerebral peduncle (A) and inferior part of the internal capsule (B). Bodian silver impregnation, x50.
145
A
o o"
Fig. 5. Basal ganglia. Case 3. A: substantia nigra; B: giobus pallidus; C: subthalamic nucleus. Severe gliosis is seen in nigro-pailido-luysian system. Both inner and outer segements of globus pallidus are equally affected. Holzer stain.
146 TABLE 2 COMPARISON
BETWEEN
REPORTED
CASES WITH N-P-L DEGENERATION
AND OUR CASE 3
PD: Parkinson's disease; MR: mental retardation; GPi: internal segment of globus pallidus; GPe: external segment of globus pallidus; LB: s u b t h a l a m i c n u c l e u s ; A H C : a n t e r i o r h o r n cell; # : M a n y s p h e r o i d s a r e s e e n . * d u e t o rigidity * * P D - l i k e * * * P D - l i k e ? o r p s e u d o - B P ?
Age of onset/sex Duration (years) Family history Clinical symptoms bulbar palsy muscle atrophy spasticity dementia rigidity dystonia c e r e b e l l a r sign Pathological findings hypoglossal nucleus spinal AHC pyramidal tract posterior column n i g r a : cell loss gliosis O P i : cell loss gliosis G P e : cell loss gliosis LB: cell loss gliosis putamen
G r a y e t al.
S e r r a t r i c e e t al.
M o s s a k o w s k i e t al.
Present Case 3
34 F 2.0 + (PD, MR)
54 F 11 -
47 M 4.0 -
60 M 7.5 -
+ * + + + + + ?
+ ** + + + -
+ *** + + + ? ?
+ + -
+ + + + + + + + + + + -
? + + + + + + + + -
+ + + + + + + + + + -
+ + + + + + + + + + + +
+
+
+ + + +
+ + + +
conduction velocities were normal in examined nerves. Five years after the onset, muscular weakness extended gradually to the neck and truncal muscle groups. By 7 years, he could not hold his head up without support. A neck supporter became necessary and he walked with a dropped head. About that time, he developed hepatic dysfunction. The complication of primary liver carcinoma was diagnosed from the laboratory data. He died due to massive hemorrhage from the hepatoma 77 months after the onset. Throughout the clinical course, neither dementia, oculomotor disturbance, neural deafness, pyramidal, extrapyramidal nor cerebeUar symptoms were observed. Clinically, muscle power of all extremities had remained well, especially in the upper limbs, in contrast to the cases with severe bulbar palsy. He had been ambulatory until his later stage. He had never undergone blood transfusion. He was, however, a heavy drinker for some 30 years. There was no family history. Clinical diagnosis: ALS with prominent bulbar and spinal muscular atrophy, and primary carcinoma of the liver without systemic metastasis.
Pathological findings Primary hepatocellular carcinoma was confirmed, and its rupture induced massive hemorrhage. No metastatic lesion was confirmed.
~ ~ + + + + + +
+ # + # + + # +
~ + + + + + + + +
+ + + + + +
Neuropathological findings Marked neuronal loss in the hypoglossal nuclei and anterior horn of the spinal cord was observed, while the pyramidal tract was spared with only a few lipidladen macrophages scattered there. Although extrapyramidal symptoms and signs were absent throughout the clinical course, severe degenerative change was found in the nigro-pallido-luysian (NPL) system; disappearence of the neurons and reparative gliosis were observed in this system (Fig. 5). Both inner and outer segments of the pailidum were equally involved. Otherwise, no significant lesions were detected in the other nervous systems.
Discussion
It has been reported that white matter of the spinal cord other than the pyramidal tracts is involved in the progression of MND (Homes 1909; Ikuta et al. 1979; Auerback and Crocker 1981). The degeneration includes the spinocerebellar tracts, gracilis fascicles and neurons in Clarke's column. In general, the lesions in these regions are very mild and are expressed as myelin paucity and slight decrease in the number of their neurons. However, the degeneration in the spinal cord in Case 1 was much more severe and extensive. Neu-
147 rons, sensory as well as motor, in the spinal cord had almost completely disappeared, and myelinated fibers in the cord were also totally lost, except those in the posterior column. The spinal cord lesions in Case 1 were severe. However, the lesions were confined to the level below the pons as in the case of banal MND. Considering the unusual pathology in Case 1, it is noteworthy that the clinical progression was very rapid. The natural course might have been about only 6 months if artificial ventilation had not been applied. The successive usage of a ventilator prolonged his life, which might have induced further extensive destruction of the spinal cord and other regions. Holmes (1909) referred to degeneration of Betz cells in the motor cortex and of the corpus callosum in ALS. In Case 1, no degenerative lesion was seen in the cerebrum, though degeneration in the spinal cord was marked. So, the lesions described by Holmes might be distinct from the classical lesions in ALS. In any event, it is suggested that the lesions, as seen in Case 1, may become more prevalent by the usage of a ventilator. Case 2, in which the upper motor neurons were more severely involved than the lower ones in both clinical and pathological aspects, is unlikely to be primary lateral sclerosis (1)1.3). The mode of pyramidal tract degeneration in this case may support the classical hypothesis that the degenerative process in the pyramidal tract starts distally and ascends to the midbrain along with the clinical course. However, the pyramidal lesion in Case 2 was severe and extensively affected, and the tract below the level of the pons was completely destroyed. In addition, many spheroids were present in the crus cerebri and the internal capsule, while Betz cells in the motor cortex did not show any pathological changes. Case 2 was superficially similar to PLS. To date, only 6 cases of PLS have been definitely identified (Beal et al. 1981; Kuzuhara et al. 1986; Fisher 1987; Younger et ai. 1988). The comparison between these previously reported cases and Case 2 is shown in Table 1. In all the previous cases there were no lower motor neuron signs. PLS is distinct from famiiial spastic paraplegia in that their clinical course is very rapid. Since some loss of neurons in the spinal cord was seen in Case 2, it is reasonable that this case is different from PLS in neuropathology, being more similar to ALS. Degeneration of the somata in the upper motor neurons is thought to be a primary pathogenic focus in PLS. However, no such significant change was observed in Case 2. Many spheroids were revealed in the crus cerebri and in the internal capsule in Case 2. Spheroids in the pyramidal tracts have been reported in only two papers to our knowledge; spheroids were found in the spinal cord to the polls (Okamoto et al. 1991), and in the cerebral cortex (Wikstrom et al. 1982). Small spheroids in MND, usually termed as globules, are recognized to be the focal
swelling of the proximal axons as a sequence of the secondary motor neurons, and are distributed mainly in the anterior horn and propriospinal tract in the spinal cord (Carpenter 1968; Sasald et al. 1988). On the other hand, the spheroids in Case 2 were formed by axonal swelling of the upper motor neurons, being far from the cell body. The different distribution of spheroids in our case from those in common MND might be reflected by the different process of their formation and/or their histogenesis. Two cases of Okamoto's study and our case may comprise a subgroup of MND. In this regard, further similar case reports may shed some light on this issue. In most degenerative diseases, multiple systems are generally pathologically involved and the term of multiple system atrophy is often used, although patients do not always develop the clinical symptoms of multiple system involvement. Case 3 is of a great interest in consideration of the relation of MND to multiple system atrophy. Nigro-pallido-luysian system involvement in MND has been rarely reported (Gray et al. 1985; Serratrice et al. 1983; Mossakowski and Rentawek 1987). In addition, the reported cases had either dementia or extrapyramidal symptoms, or both, and their clinical signs and symptoms are different from ours. Our case did not develop extrapyramidal symptoms a n d / o r dementia, and showed a clinicopathological discrepancy in this point. The clinical differences between the previous cases and ours are compared in Table 2. Recently, a case of familial MND with nigropallido-luysian atrophy was reported (Sakai et al. 1988) and it was virtually identical to that of our Case 3, aside from its positive family history. There has been so far a trend to neglect the basal ganglia once a clinical diagnosis of MND is made. According to Hughes (1982), however, the expansion of pathological lesions of MND, including the basal ganglia, would be more often found if each ALS case were assessed carefully. Nigro-pallido-luysian degeneration is seen in Hallervorden-Spatz disease and Hunt's disease (Davison 1954). Case 3 was different from these diseases since there was no family history, and because of different clinical symptoms and the absence of neuroaxonal spheroids. Our 3 cases did not show stereotyped pathological changes as in MND. Pigmented neurons in the nigra were pointed out as a common degenerative target besides the anterior cell of the spinal cord and pyramidal tracts as in MND. Nigral degeneration has been described in a series of MND cases with dementia (Horoupian et al. 1984), but less attention is paid to the lesions since nigral neurons are generally considered to be vulnerable in hypoxia, i. e., a primary lesion or not. Conclusively, various degenerative lesions may occur in the nervous system other than the motor systems in
148 MND. Underestimation of these lesions in MNS may lead us to miss the possible heterogeneous character of MND. From a historical point of view, bulbo-spinal muscular atrophy and Hirayama's disease were found to be distinct from the classical MND, and the accumulation of the cases with additional lesions outside the motor neuron systems is desired.
References Auerback, P. and Crocker, P. (1981) Regular involvementof Clarke's nucleus on sporadic amyotrophic lateral sclerosis. Arch. Neurol., 39: 155-156. Beal, M.F. and Richardson, R.P. (1981) Primary lateral sclerosis: a case report. Arch. Neurol., 38: 630-633. Carpenter, S (1968) Proximal axon enlargement in motor neuron disease. Neurology, 18:841-851. Davison, C. (1954) Pallido-pyramidal disease. J. Neuropathol. Exp. Neuroi., 13: 50-59. Fisher, C.M. (1987) Pure spastic paralysis of corticospinal origin. Can. J. Neurol. Sci., 4: 251-258. Gray, F., Eizenbaum, J.F., Gherardi, R., Degos, H.D. and Poirierl, J. (1985) Luyso-pallido-nigralatrophy and amyotrophic lateral sclerosis. Acta Neuropathol. (Bed.), 66: 78-82. Holmes, G. (1909) The pathology of amyotrophic lateral sclerosis. Rev. Neurol. Psychiat., 7: 693-725. Horoupian, D.S., Thai, L., Katzman, R., Terry, R.D., Davies, P., Hirano, A., DeTeresa, R., Fuld, P.A., Petite, C., Blass, J. and Ellis, J.M. (1984) Dementia and motor neuron disease: morphometric, biochemical,and Golgi studies. Ann. Neurol., 16: 305-313. Hughes, J.T. (1982) Pathology of amyntrophic lateral sclerosis, in
J.P. Rowland (Ed.), Human Motor Neuron Disease. Raven Press, New York, pp. 61-74. Ikuta, F., Makifuchi, T. and Ichikawa, T. (1979) Comparative studies of tract degeneration in ALS and other disorders. In Tsubaki and Y. Toyokura (Eds.), Amyotrophic Lateral Sclerosis. Tokyo Univ. Press, Tokyo, pp. 177-200. Kuzuhara, S., and Okawa, Y. (1986) Primary lateral sclerosis: report of 2 autopsy cases. Annual Report of the Research of CNS Degenerative Disease, The Ministry of Health and Welfare of Japan, pp. 72-78. Mossakowski, M.J. and Rentawek, K. (1987) Amyotrophic lateral sclerosis with generalized neuroaxonal degeneration and selective involvement of the nigropailidal system. Neuropathol. PoL, 25: 539-553. Okamoto, K., Hirai, S., Shoji, M., Senoh, Y. and Yamazaki, T. (1991) Axonal swelling of the corticospinal tracts in amyotrophic lateral sclerosis. Acta NeuropathoL, 80: 222-226. Sakai, M., Hashizume, Y., Muroga, T., Murakami, N. and Yamamoto, H. (1988) Neuropathological studies of familial amyotrophic lateral sclerosis with special reference to systemic degeneration of dentato-rubrai system and neuronal loss of Onufs nuclei. Clin. Neurol. (Tokyo), 28: 1197-1205. Sakai, S., Kamei, H., Yamane, K. and Maruyama, S. (1988) Swelling of neuronal processes in motor neuron disease. Neurology, 38: 1114-1118. Serratrice, G.T., Toga, M. and Pellissier, F. (1983) Chronic spinal muscular atrophy and pallido-nigral degeneration: report of a case. Neurology, 33: 306-310. Wikstrom, J., Paetau, A., Pale, J., Sulkava, R. and Haltia, M. (1982) Classic amyotrophic lateral sclerosis with dementia. Arch. New roL, 39: 681-683. Younger, D.S., Chou, S., Hays, A.P., Lange, D.J., Emerson, R., Brin, M., Thompson, H. and Rowland, P. (1988) Primary lateral sclerosis: a clinical diagnosis reemerges. Arch. Neurol., 45: 1304-1307.
