Widespread multiple system degeneration in a patient with familial amyotrophic lateral sclerosis

Journal of the Neurologtcal Sctences, 120 (1993) 15-21

© 1993 Elsevier Science Pubhshers B V All rights reserved 0022-510X/93/$06_00

15

JNS 04143

Widespread multiple system degeneration in a patient with familial amyotrophic lateral sclerosis Hitoshi Takahashi a,,, Kiyomitsu Oyanagi b, Fusahiro Ikuta a, Masami Tanaka c, Tatsuhiko Yuasa c,1 and Tadashi Miyatake c,1 Departments of ~ Pathology and c Neurology, and b The Center for Matertals of Bram Dtseases, Bratn Research Inst, tute, Nugata Umcerstty, Asahtmacht 1, Nugata 951, Japan

(Recewed 31 December, 1992) (Revised, recewed 7 June, 1993) (Accepted 17 June, 1993) Key words Famlhal amyotrophic lateral sclerosis, Multiple system degeneration, Thalamus, Mammlllary body, Accumulation of

neurofilament, Respiratory support, Prolonged survival

Summary We report a 57-year-old woman with famihal amyotrophlc lateral sclerosis (ALS) with posterior column Involvement of 11 years duration The patient had been on a respirator for more than 5 years before death In addition to the well established pathology of this form of famlhal ALS, there were obvious degeneratwe changes in the bralnstem tegmentum, including the reticular formation, cerebellar cortex, dentate and red nuclei, thalamus and mammfllary body. Of great interest in this case was mtracytoplasmlc accumulation of neurofilaments in the remaining neurons in these areas, some of which, for instance, those in the oculomotor and abducens nuclei, still showed only mlmmal loss. This patient had survived considerably beyond the point of respiratory failure, which ~s the final stage in the natural history of the disease. We considered that in this paUent the underlying degenerative process of the disease had become manifested in wider areas than recognized previously during the prolonged chnlcal course due to respiratory support However, whether or not such widespread degeneration would occur m all patients with this disease who survwe longer with the help of respiratory support awaits further studies.

Introduction I n the past, respiratory failure was the m a i n cause of d e a t h in p a t i e n t s with sporadic as well as familial amyotrophlc lateral sclerosis (ALS), a fatal n e u r o d e generative disease of u n k n o w n cause. However, with r e c e n t advances in the use of life-support a p p a r a t u s , A L S p a t i e n t s can live b e y o n d the p o i n t of respiratory failure, which is no longer c o n s i d e r e d to be the terminal p o i n t of the disease (Hayashl a n d Kato 1989). With this b a c k g r o u n d , the q u e s t i o n of w h e t h e r only the m o t o r n e u r o n system d e g e n e r a t e s selectively in A L S ( H o l m e s 1909, Smith 1960; I k u t a et al 1979; O y a n a g l et al 1983, 1989) appears to have b e c o m e m o r e import a n t t h a n before, a n d clinlcopathological studies of ALS p a t i e n t s showmg p r o l o n g e d survival d u e to respiratory s u p p o r t have recently received m u c h a t t e n t i o n

* Corresponding author Tel 81-25-223-6161 (ext 5152), Fax 81-25-223-7503 1 Present address Department of Neurology, Tokyo Medical and Dental University, Tokyo, Japan

(Akiyama et al 1987, H a y a s h i a n d Kato 1989; Sasakl et al. 1992; M i z u t a n i et al. 1992; T a k a h a s h l et al. 1992). In this c o m m u n i c a t i o n , we describe the clinical a n d n e u r o p a t h o l o g i c a l findings in such an example of familial ALS. T h e p a t i e n t died at the age of 57 years, 11 years after the onset of symptoms, and had b e e n o n a respirator for m o r e t h a n 5 years before death.

Case report The patient, a 57-year-old woman, had been healthy until the age of 46 years, when she first noticed twitches m her right leg Over the next 2 years, weakness and wasting of the muscles developed gradually in both legs In March 1982, at the age of 49 years, she was admitted to Nugata Unlverstty Hospital for neurologtcal evaluation From accounts given by the pattent, there was a family history of a stmdar neurological disease affecting her brother and her two maternal uncles, one of whom had one affected daughter Later, we were able to confirm the family history by reviewing the mdwldual medical records avadable On examlnahon, weakness and atrophy of the muscles were evident m the lower and upper extremities, being more pronounced in the d~stal parts Fasoculattons were also encountered No bulbar symptoms were observed All deep tendon reflexes were hyperactive and Babmskl's sign was present on both stdes No

16 sensory abnormalities were noted Both electromyography (EMG) and muscle biopsy showed a neurogemc pattern The pahenl v~as dmgnosed as hawng famdml ALS In August 1983, at the age of 51) years, she became unable to walk In January 1984, distal dominant muscular weakness and atrophy were aggravated and fasclculat~ons were no longer encountered m the extremities All tendon reflexes had become diminished Babmskfs sign remained on both sides SensatLon for all modahttes was intact No veslcorectal incontinence developed, and there was no ewdence of dementm In December 1984, at the age of 52 years, dyspnea due to progresswe weakness of the respiratory muscles developed From January 1985, the patient required artificial respiratory support In August 1986, atrophy with fasclculatmn of the tongue became apparent, and dysphagm appeared In October 1980, she experienced hypoxlc anoxaa due to respirator trouble, and fell into an unconscmus state Towards the end of 1988, she began to respond to vocal orders with tmprovement of facial expression, but was unable to communicate appropriately During the course of her illness, results of laboratory tests, including CSF and blood, were unremarkable, serum anti-HTLV-I tlter was not elevated In January 1990, a tumorous mass became palpable m the eptgastrlurn, and subsequently increased m size rapidly In April 1990, the patient died at the age of 57 years, about 11 years after onset c,f the disease

Pathological examination General autopsy showed gastric cancer, diagnosed histologically as mucinous adenocarcinoma, with metastases to the regional and abdominal paraaort~c lymph nodes. The brain was small and weighed 950 g before fixation. In sections, the thalamus, especially its medial part, was markedly atrophic with brownish discoloration. The cerebral cortex showed only mild atrophy. In the bralnstem, the tegmentum looked much smaller in comparison with the base, and this was more evident in the pons The entire spinal cord was markedly atrophic and there was wasting of the anterior roots Formahn-flxed, paraffin-embedded sections of the brain and spinal cord were stained with hematoxylin and eosm, Kliiver-Barrera, Holzer and Bodlan's method. Selected sections were studied by the avidmbiotin-peroxidase method with a mouse monoclonal antibody against neurofilament polypeptides (70 and 200 kDa) (Sanbio BV, Uden, The Netherlands; diluted 1.50), a mouse monoclonal antibody against a phosphorylated neurofilament epltope (SMI 31, Sternberger Monoclonals Inc., Baltimore, MD, USA, diluted 1:1000) and a purified rabbit antibody against ubiquitin (Dakopatts, Glostrup, Denmark; diluted 1:100). An ultrastructural study was also performed on tissue of the thalamus fixed with 3% g l u t a r a l d e h y d e / l % paraformaldehyde in phosphate buffer. The most prominent changes were evident in the spinal cord. T h e r e was severe loss of neurons and myelin with gliosxs throughout the anterior horns. These changes were also detectable in the intermediate zone and posterior horns, except for the substantia gelati-

Fig 1 The spinal cord shows marked myehn pallor m the antcrolateral column as well as m the middle mot zone of the posterior column Cervical (C4, top) and thoracic (T8, bottom) segments KB, " 1 2

nosa Clarke's column was ghotic with no remaining neurons The mtermediolateral and sacral autonomic nuclei as well as the Onufrowicz nucleus were relatively well preserved. In the white matter, severe degeneration was seen in the entire anterior and lateral columns (Fig. 1). In addition, degeneration was observed in the middle root zone of the posterior column (Fig. 1). In the cervical and lumbar dorsal root ganglia, there was mild sensory neuron loss, with scattered residual nodules of Nageotte. In the brainstem, there was severe neuronal loss and gliosls in the motor nucle~ of the trigeminal and facial nerves and hypoglossal nucleus Neuronal loss and gllosls was also evident in the reticular formation, accessory cuneate nucleus, vestibular nuclei, being more marked in the lateral nucleus, and in the posterior column nuclei, being more marked m the gracde nucleus. Myelin pallor and ghosis were observed in the superior cerebellar peduncle, central tegmental tract, medial lemniscus and medial longitudinal fascicle The oculomotor and abducens nuclei were welt preserved. In the cerebellar cortex, severe toss of Purkinje cells with proliferation of Bergmann's gila was observed, being more pronounced in the superior vermls. Mild to moderate loss of granule ceils was also present. The dentate nucleus showed moderate neuronal loss in the ghosed background, and the amlculum and hilus were rarefied_

17 In the precentral gyrus, only a few Betz cells could be recognized The thalamus and mammillary body also showed moderate neuronal loss and ghosls Diffuse, mild neuronal loss was noted throughout the entire cerebral cortex. A m m o n ' s horn was of normal appearance One interesting feature was that intracytoplasmlc filamentous conglomerates were present in the remainlng neurons in various areas including the spinal anterior horn (F~g 2A), intermediate zone and posterior horn (Fig. 3A), accessory cuneate nucleus, motor nucleus of the trlgeminal nerve, oculomotor, abducens (Fig 2B) and hypoglossal nuclei, tegmental reticular formation (Fig. 3B), medial and ventrolateral nuclei of the thalamus, mammillary body and motor cortex (Betz cells). In the thalamus, a significant number of spheroids and cord-like, swollen neuronal processes were also observed. Immunohlstochemlcally, the conglomerates, spheroids and cord-hke, swollen neuronal processes were positive for neurofilament polypeptldes (70 kDa and 200 kDa) (Figs 2C, 3C) and a phosphorylated neurofilament epitope (Figs. 2D, 3D), but were negative for ublqultln. Ultrastructurally, the conglom-

erates consisted of interwoven neurofilaments (Fig 4) No typical Lewy body-hke inclusions or convincing Bunlna bodies were observed.

Discussion The chnlcal features of this patient were compatible w~th those of ALS, and the family history suggested that the disease was inherited as an autosomal dominant trait Our pathological diagnosis was essentially familial ALS with posterior column involvement Familial ALS with posterior column involvement is one of the common forms of familial ALS Degeneration of the lower and upper neurons and cortlcOsplnal tracts, as well as the posterior columns, Clarke's column and splnocerebellar tracts, is a constant neuropathologlcal feature (H~rano et al 1967, Nakano et al 1984; Mizusawa 1990) However, degeneration beyond these systems is rare (Tanaka et al. 1984, Sakal et al. 1988), although the bralnstem reticular formation IS also involved to a certain extent (Kato and Hxrano 1992). In the present case, degenerative changes were

FLg 2 Accumulation of neurofilaments m the cytoplasm of motor neurons A thoracic anterior horn cell Bodlan, × 500 B neuron ol abducens nucleus The same accumulation of neurofilaments is also evident m a neunte, probably an axon (arrows) H & E , ×501) C neuron ot hypoglossal nucleus Neurofilament polypeptldes, × 500 D Betz cell m precentral gyrus SMI 31, ×500

18 widespread; in addition to very advanced degeneration of the spinal cord, the brainstem tegmentum, cerebellar cortex, dentate and red nuclei, thalamus and mammillary body were obvtously involved A survey of the hterature revealed one interesting autopsy case of familial ALS with posterior column involvement, which resembled ours climcopathologlcally. Tanaka et al. (1984) reported two sibling female pattents, one of whom demonstrated addttlonal wtdespread degeneratton involving the lntermedlolateral nucleus, Onuf's nucleus, spinothalamlc tract, graclle and cuneate nuclei, brainstem reucular formatton, medial lemniscus, central tegmental tract, medial longitudinal fascicle, oculomotor and abducens nuclei, red nucleus, substantla nlgra and cerebellar Purklnje cells Their patient showed raptdly progressive symptoms and died at the age of 45 years, 2 years and 1 month after onset of the disease. Surprisingly, she had been on a respirator for one year and 8 month before death It was noteworthy that her elder sister also showed rapidly progressive symptoms of ALS and died at the age of 41 years, 1 year and 3 months after onset

of the disease, with only 4 months of respiratory support before death (Tabucht et al 1983). The autopsy revealed pathological features typical of famthal ALS wRh posterior column involvement without any other significant findings (Tanaka et al. 1984). Does this simply represent phenotypic heterogeneity of a hereditary disorder affecting the two siblings? In this form of famxtlal ALS, there have so far been a few autopsy reports concerning pa~rs of affected siblings who died of respiratory failure without artificial respiratory support; the findings were typical of the disease and essentmlly the same in the two indwiduals (Engel et al. 1959; Tsukada et al. 1978; Nakano et al. 1984). Therefore, it is possible to consider that the addittonal widespread degeneration described m one sibling by Tanaka et al. (1984) may have developed during the prolonged clinical course due to artificial respiratory support Hayashl and Kato (1989) reported 4 patients with sporadic ALS who had been on respiratory support for several years and had developed a "totally locked-in" state. In two autopsied patients, wtdespread pathologa-

Fig_ 3 Accumulation of neurofilaments m the cytoplasm ot non-motor neurons. A lumbar posterior horn cell Bodtan, × 500. B' neuron of reticular formation m the medulla oblongata (arrow) H & E , )<500. C_ neuron of mammillary body Neurofilament polypeptldes, × 5 0 0 D neuron of ventrolateral nucleus of the thalamus SMI 31, x 500

19 cal changes were described, the entire pathological picture in these cases was somewhat slmdar to that in a case reported by Tanaka et al (1984) and in our case reported here The latter authors considered that the entire manifestation reflecting the total course of ALS might be represented clinically as a "totally locked-re" state and pathologically as widespread degeneration beyond the lower and upper motor neuron systems However, it was also pointed out that even if the patients with sporadic ALS survived longer due to respiratory support, such widespread degeneration was not encountered m all of them (Nakano 1990, 1992), throwing some doubt on whether sporadic ALS is a single clinical entity The most striking finding in the present case was the intracytoplasmic accumulation of neurofilaments m various areas including the motor neuron system. Intracytoplasmlc accumulatton of neurofilaments ~s known to be one of the characteristic alterations of lower motor neurons in ALS (Schochet et al. 1969; Hughes and Jerrome 1971; Kondo et al. 1986) So far, there has been only one report of such a broad distribution of this alteration m a respirator-supported patient with sporadic ALS (Kondo et al, 1986). The

present ~mmunohlstochemlcal study revealed that the accumulated intracytoplasmic neurofilaments were phosphorylated, but not ublqultmated Slmdar staining properties were also demonstrated in spheroids and cord-hke swollen neuronal processes observed in the thalamus. The results were m agreement with those reported previously m sporadic (Schmldt et al. 1987, Munoz et al 1988; Manetto et al. 1988, Kato et al. 1989) and familial ALS (Murayama et al. 1989; Mlzusawa et al. 1989) Ubiquitin-posltive filamentous inclusions have recently been described in neurons of various central nervous system regions in sporadic cases of ALS with long-term arttflclal respiration (Mlzutam et al. 1992) The constituting filamentous structures are different m ultrastructure from neurofilaments, and not immunoreactive with antibodies against phosphorylated neurofilament proteins (Mlzusawa et al. 1991; Mizutani et al. 1992). The accumulation of neurofilaments m the neurons of both the motor neuron and other neuron systems in this case appears to be of great importance, suggesting the presence of a certain common et~ology of neuronal degeneration m these systems. In the affected areas, the degree of neuronal loss and the frequency of thts

Fig 4 Electron mtcrograph showing mtracytoplasmlc accumulation of neurofllaments m a neuron of the ventrolateral nucleus of the thalamus Small clusters of hpofuscln granules and other organelles are intermingled :x:13 000

20

neuronal alteration tended to be reversely related to each other It IS also noteworthy that m the oculomotor and abducens nuclet, which are generally spared in ALS, there was no obvious evidence of neuronal degeneration except for a few neurons that showed lntracytoplasmic accumulation of neurofilaments Therefore, this alteration may represent an early stage of neuronal change resembling spheroids, which are similar accumulations of neurofilaments in the proximal axons (Carpenter 1968) The possible pathomechanisms responsible for the accumulation of neurofllaments may include uncontrolled synthesis, inhibition of the proteolytic mechanism and disturbance of axonal flow (Kondo et al. 1986). The patient experienced an episode of hypoxia during the clinical course. Histologically, the hypoxic brain damage appeared to be mild, because no marked changes were present in the cerebral cortex and basal ganglia, and Ammon's horn was well preserved Accumulation of neurofilaments observed in various degenerated areas ~s not a feature of brain hypoxia. In addition, we considered that severe loss of Purkinje cells in the cerebellar cortex was difficult to explain only m terms of hypoxta (Takeda and Ikuta 1992). On the basis of chnlcopathological considerations, ~t is possible that the present case of familial ALS w~th posterior column involvement could be regarded as an example demonstrating more widespread degeneration than recognized previously, due to the prolonged clinical course resulting from artificial respiratory support. However, even if our interpretation ~s correct with regard to the present case, the possible presence of pathological heterogeneity in the disease designated as familial ALS with posterior column involvement ts a matter for further study. In other words, it is still uncertain whether such widespread degeneration would occur tn all patients with this disease who survive longer due to respiratory support. Molecular studies to identify the gene (or genes) responsible for the disease will be necessary to clarify thts aspect. Fmally, we feel that comparative clinlcopathological studies of a large number of non-respirator-supported and respirator-supported pattents would be tmportant for understanding the enttre pathological picture (Takahashi et al. 1992) in sporadic and familial ALS, as well as the relationships existing between the two forms. Acknowledgements The authors thank Mr K Kobayashl, Mrs H Kobayashi and Mr S. Egawa for their technical assistance, and Mms K Murayama for her help in preparing the manuscript_ This work was supported in part by a research grant for CNS degeneratwe diseases from the Mimstry of Health and Welfare, Japan

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