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Cytoplasmic body neuromyopathy presenting as respiratory failure and weight loss
Journal of the Neurological Sciences, 1979, 41 : 1-9
© Elsevier/North-Holland Biomedical Press
CYTOPLASMIC BODY N E U R O M Y O P A T H Y P R E S E N T I N G AS RESPIRAT O R Y F A I L U R E A N D W E I G H T LOSS
F. JERUSALEM, H. LUDIN, A. BISCHOFF and G. HARTMANN DepartmentofNeurology, UniversityofZiirich, CH-8091ZiirichandDepartmentofNeurology, University of Bern, CH-30IO Bern (Switzerland)
(Received 1 August, 1978) (Accepted 18 September, 1978)
SUMMARY This report describes the clinical, laboratory, biopsy and autopsy studies of a woman with a sporadic and chronic progressive neuromyopathy, presenting as respiratory failure and loss of weight. A weakness of her neck muscles could already be observed during childhood. When she was 22 years old, abnormal fatigue, headache and then papilloedema developed. 4 years later there was a steady loss of weight, and in the following years severe shortness of breath occurred during exercise and later at rest, leading to intermittent somnolence. The respiratory function studies revealed a decrease of the vital capacity, total lung capacity, forced expiratory volume and an increase of residual volume. At the age of 31 the patient died from complications of the respiratory failure. In addition to the myopathy the two muscle biopsies showed numerous cytoplasmic bodies in 25 ~o of the muscle fibres; only type 1 fibres contained the inclusions. Axonal alterations were detected in the sural nerve biopsy, and the E M G revealed neurogenic changes in several muscles tested. The autopsy revealed normal anterior horn cells, roots and peripheral nerves, but several muscles including intercostal muscles, showed a neurogenic atrophy. As in a similar sporadic and fatal case and in cases of autosomal dominant benign myopathies with cytoplasmic body inclusions (reported earlier), the cause of the disease presented here remains obscure.
INTRODUCTION Respiratory insufficiency may occur in such diverse neuromuscular disorders as myasthenia gravis, muscular dystrophy, myotonic dystrophy, inflammatory myoReprint requests to Dr. Jerusalem, Department of Neurology, University of Z0rich, CH-8091 Zfirich, R/imistrasse 100, Switzerland.
pathies, congenital benign myopathies, acid maltase deficiency and motor neurol~ disease. Usually the respiratory failure and pulmonary complications develop in the late stages of these diseases, but occasionally the initial clinical picture of the neuromuscular disease is dominated by respiratory insufficiency. The neuromuscular cause may then be unsuspected or overlooked. Investigation by respiratory function tests, including the maximal static respiratory pressures, by electromyographic studies and by muscle biopsies lead to the correct diagnosis. Two muscle biopsies in the case reported here of chronic respiratory insufficiency and loss of weight from a neuromyopathy of unknown origin, were characterized by an excess of cytoplasmic bodies in type 1 fibres. The cytoplasmic body consists of filamentous material and represents a basic pathological reaction of the Z disk. The term "cytoplasmic body" is relatively satisfactory and rarely occurring myopathies with an excess of such bodies were described earlier as "Atypical myopathy with myofibrillar aggregates" (Kinoshita et al. 1975) or "Autosomal dominant myofibrillar inclusion body myopathy" (Clark et al. 1978). Cytoplasmic bodies in skeletal muscle fibres are spheroids and consist of 3 concentric portions: the central body, the intermediate halo, and the outer shell (Engel 1962). The ATPase activity may be retained but there are no oxidative enzyme activities in the body and halo area. In the electron microscope the cytoplasmic bodies are characterized by their origin in the Z disk, a dense filamentous core, a surrounding lighter halo, randomly orientated thin and finer filaments in the halo, lack of a tetragonal filamentous array regardless of the plane of the section, an accompanying focal decrease of mitochondria from the affected fibre region and its restriction to white (type 2) fibres (MacDonald and Engel 1969). Cytoplasmic bodies are said to be not specific for any one pathological condition and have been observed in several human and experimentally induced neuromuscular diseases (MacDonald and Engel 1969). REPORT OF A CASE AND LABORATORY RESULTS The family history, gestation period, birth, and postnatal development of the woman, who was born in 1946, were normal. Since childhood she suffered from a slight weakness of neck muscles causing difficultyin lifting the head from a supine position. In 1968,an abnormal fatigue and headache developed. Shortly afterwards, a temporary iron-deficient anaemia and papilloedema were found. In 1972,the patient lost her appetite, and there was a steady loss of weight down to 43 kg (170 cm body height). From 1973 an amenorrhoea persisted. The patient complained of early fatigue. The medical examination revealed a respiratory insufficiency of unknown origin. In 1977, she developed severe shortness of breath initially during mild exercise, and later at rest. There were periods of somnolence in the morning. Assisted respiration (Bird) was necessary during the night and occasionally during the day. The neurological examination (1974) revealed weakness and atrophy of the sternocleidomastoideus, shoulder, thoracic and abdominal muscles. Tendon reflexes and sensation were normal. Normal laboratory data included haematologic and urine tests, serum electrolytes, creatinine, folic acid, GOT, GPT, CPK, alkaline phosphatase, blood lipids, serum electrophoresis, glucose tolerance test, vitamin Bla absorption, thyroid function (Ta, T4), bone marrow punetion, ECG, EEG, X-ray of the skull and cervical spine, pneumoencephalography and vertebral angiography. The respiratory function studies gave the followingresults (figuresin parentheses represent normal values): Vital capacity 900 ml (4380), residual volume 2530 (1450), total lung capacity 3430 (5830), forced expiratory volume 800 (3065), p,O~ 56 torr, SOn 83.7%, paCO2 57.6 torr, pH 7.37. Electromyography. Conventional needle electromyography showed signs of active denervation
Fig. 1. Fresh frozen muscle sections stained with modified trichrome (A, B). Many muscle fibres contain numerous cytoplasmic bodies, which appear purple red in trichrome-stained sections. A pathologic caliber variation of muscle fibres is present in the deltoid muscle (A), and a severe increase of connective tissue can be seen in the intercostal muscle (B). Cytoplasmic bodies also occur in the fibres of the intercostal muscle. A: x 290, B: x 360.
Fig. 2. Fresh frozen muscle section reacted for NADH-dehydrogenase (A), and a paraffin-embedded section stained with hematoxylin-eosin (B). The cytoplasmic bodies do not show oxidative enzyme activities (+-A). Only type 1 fibres contain the inclusion bodies. A grouped atrophy of muscle fibres is clearly seen in the intercostal muscle taken at autopsy (B). A x 290, B × 120.
Fig. 3. Phase-optic micrograph of longitudinally sectioned muscle fibres demonstrate focal accumulations of cytoplasmic bodies, < 320.
Fig. 4. Electron micrograph of muscle fibre which contains cytoplasmic bodies, x 6400.
Fig. 5. Electron micrograph of a longitudinally sectioned muscle fibre showing streaming (arrows) of Z disk. × 8000. in the form of fibrillations and positive sharp waves in the deltoid and extensor digitorum brevis muscle. There was a reduced recruitment pattern, but no spontaneous activity in the tibialis anterior and intercostal muscle. No fasciculations, a normal number of polyphasic potentials and only slightly increased action potential amplitudes were found in all the muscles examined. Using Buchthal's (1952) method and normal values, the mean duration of the motor unit action potentials was significantly prolonged in all muscles examined: 67 ~ in the deltoid, 28 ~ in the tibialis anterior, and 70 ~ in the extensor digitorum brevis muscle. The motor and sensory nerve conduction velocities as well as the distal latencies were within normal limits. The median sensory nerve action potential, however, showed an abnormally prolonged temporal dispersion between wrist and elbow, indicating peripheral neuropathy. Repetitive nerve stimulations at rates of 2, 3, 10, 20 and 50/sec produced no myasthenic decrement. Muscle and sural nerve biopsies. Numerous cytoplasmic bodies were identified in modified trichrome-stained sections in 25 ~ of the cross-sectioned fibres in the biopsied deltoid and intercostal muscle (March 1974) (Fig. 1). There were no oxidative and myofibrillar ATPase activities in the body and halo area of the cytoplasmic bodies, which occurred only in type 1 fibres (Fig. 2), but the acid phosphatase reaction was positive in the muscle fibre areas which contained the inclusions. A normal TABLE 1 H I S T O M E T R Y OF THE BIOPSIED LEFT DELTOID MUSCLE (calculations from Brooke and Engel 1969; Dubowitz and Brooke 1973) Type 1 Number and percentage of fibres in a randomly chosen area Mean diameter (/~m) Standard deviation Atrophy factor Hypertrophy factor Variation coefficient
143 (72 ~ ) 48.6 20.9 245 273 430
Type 2
57 (28 %) 74.0 24.2 158 1456 327
Fig. 6. Electron m i c r o g r a p h s of myelinated nerve fibres. A dilatation of the s m o o t h - s u r f a c e d e n d o plasmic reticulum in the axon is present (A). In B an axonal shrinkage a n d destruction of the myelin sheat c a n be seen. A: x 36500, B: ~ 5900.
checkerboard pattern of different fibre types was preserved. Longitudinally orientated muscle fibre sections demonstrated the segmental accumulation of the cytoplasmic bodies well seen with the phase microscope (Fig. 3). Under the electron microscope they had the characteristic features of cytoplasmic bodies (Fig. 4). Many nemaline structures and Z disk streaming and thickening were found (Fig. 5). In addition, with the light microscope, a pathological caliber variation with atrophic and hypertrophic type 1 and type 2 fibres (Table 1), central nuclei and clumps of pyknotic nuclei, and degenerative changes were present. About 60 ~ of the muscle tissue in the intercostal muscle was replaced by connective tissue (Fig. 1D). Both muscle biopsies were classified as myopathic; a neurogenic pattern was not present. The sural nerve biopsy (1974) showed a dilatation of the smooth surfaced endoplasmic reticulum in many myelinated and unmyelinated axons (Figs. 6 and 7), shrinkage of axons and vacuolar as well as granular myelin breakdown (Fig. 6B). These alterations were present in 20 7ooof the nerve fibres. Autopsy. In August 1977 the patient died from complications induced by the chronic respiratory failure. The autopsy revealed an acute brain oedema, normal anterior horn cells, nerve roots and peripheral nerves, but several muscles (intercostal, psoas, gastrocnemius, quadriceps) showed a grou!ced atrophy and clumps of pyknotic nuclei, clearly indicating a neurogenic muscle atrophy (Fig. 2D). The peripheral nerves examined were the intercostal, sciatic and femoral. No morphological evidence was found to account for the neurogenic atrophy.
Fig. 7. Electron micrograph of unmyelinated nerve fibres with dilatations of the smooth-surfaced endoplasmic reticulum in the axons, × 36,500.
DISCUSSION The disorder in the case presented, with the cardinal symptoms of respiratory failure and loss of weight, had probably begun with a weakness of the neck muscles during childhood. In 1968, when the patient was 22 years old, she developed abnormal fatigue and headache. These, together with the documented papilloedema, were probably due to a respiratory insufficiency, which was first diagnosed in 1973. Together with a steady loss of weight, this insufficiency slowly progressed up to the patient's death in 1977. Various respiratory function tests and electromyography revealed that a neuromuscular condition was the cause of the respiratory failure. The biopsy of the deltoid and intercostal muscle in 1974 demonstrated numerous cytoplasmic bodies in 25 ~ of the cross-sectioned muscle fibres. The fact that these inclusions showed a segmental localization, leads us to assume, that the real number of affected fibres was even higher. Our observations are similar to those in a case observed by Kinoshita et al. (1975), in which there was segmental aggregation of numerous cytoplasmic bodies in the muscle biopsy. The woman, at the age of 16, had large calves, tended to walk on her toes and also tended to look backwards by turning her shoulders instead of her head. Then she gradually developed shortness of breath, loss of weight and weakness of shoulders and thighs. At the age of 23 the vital capacity was 600 ml and 8 months later she died from respiratory insufficiency and congestive heart failure. Whereas these two reports concern sporadic and fatal cases with respiratory failure and loss of weight, Clark et al. (1978) recently reported an autosomal dominant benign myopathy of late adult onset with myofibrillar inclusion bodies in 3 symptomatic and 7 asymptomatic family members of a large kindred. The cytoplasmic bodies which occasionally occur in several neuromuscular disorders, are localized in type 2 fibres, but they were only found in type 1 fibres in our case and in the biopsies reported by Clark et al. (1978). By reason of clinical, electromyographic and myopathologic findings Kinoshita et al. (1975) and Clark et al. (1978) classified their observations as a myopathy. The biopsies of the deltoid and intercostal muscles of our case also showed a myopathic syndrome but the E M G and sural nerve biopsy carried out at the same time and the myopathology, demonstrated at autopsy 3 years later, clearly indicated a neurogenic process. We, therefore, describe our case as a neuromyopathy. None of the clinical and laboratory tests, biopsy and autopsy examinations revealed its cause. In particular, none of the common causes of a chronic neuropathy involving motoneurons such as lead, and other toxic substances, porphyria, polyarteritis nodosa, neoplasia, amyloidoses, chronic radiculopathy or spinal muscular atrophy could be found. There was also no indication of a neuromuscular disorder such as acid maltase deficiency, which may present with a respiratory failure (Goldstein et al. 1974; Rosenow and Engel, 1978). The neuromuscular disorders described here and previously (Kinoshita et al. 1975; Clark et al. 1978) were characterized in the muscle by numerous cytoplasmic bodies ("myofibrillar aggregates" or "myofibrillar inclusion bodies"). Although cyto-
plasmic bodies are occasional findings in various n e u r o m u s c u l a r diseases, the pred o m i n a n c e o f these inclusions in these cases characterizes this disease. These cases d o n o t fit into o u r present s p e c t r u m o f well-defined disorders. A classification based on a m o r p h o l o g i c a l finding alone is n o t satisfactory, but, as in o t h e r muscle diseases, a m o r p h o l o g i c a l classification a p p e a r s reasonable, as long as the cause a n d b i o c h e m i c a l n a t u r e o f the c y t o p l a s m i c bodies is u n k n o w n . I n view o f the different clinical, genetic, m o r p h o l o g i c a l a n d e l e c t r o p h y s i o l o g i c a l aspects o f the various cases which have this excess o f c y t o p l a s m i c bodies, several features indicate t h a t these disorders are heterogenous a n d n o t a single disease entity. ACKNOWLEDGEMENT W e wish to t h a n k D r . R. F r i e d e for his c o m m e n t s on the spinal c o r d a n d nerve p a t h o l o g y , a n d Miss Lea K1/iusli, Miss Vreni Siegrist a n d Mrs. U r s u l a Schill for t h e i r assistance.
REFERENCES Brooke, M. H. and W. K. Engel (1969) The histographic analysis of human muscle biopsies with regard to fibre types, Part 2 (Disease of the upper and lower motor neuron), Neurology (Minneap.), 19: 378-393. Buchthal, F. (1952) for references see Ludin, H. P. (1976) Praktische Elektromyographie, Enke, Stuttgart. Clark, J. R., A. N. d'Agostino, J. Wilson, R. R. Brooks and G. C. Cole (1978) Autosomal dominant myofibrillar inclusion body myopathy - - Clinical, histologic, histochemical, and ultrastructural characteristics, Neurology (Minneap.), 28:399 (Abstr.). Dubowitz, V. and M. H. Brooke (1973) Muscle Biopsy - - A Modern Approach, Saunders, London. Engel, W. K. (1962) The essentiality of histo- and cytochemical studies of skeletal muscle in the investigation of neuromuscular disease, Neurology (Minneap.), 12: 778-794. Goldstein, R. L., R. W. Hyde, L. W. Lapham, K. Gazioglu and Z. G. De Papp (1974) Peripheral neuropathy presenting with respiratory insufficiency as the primary complaint - - Problem of recognizing alveolar hypoventilation due to neuromuscular disorders, Amer. J. Med., 56: 443-449. Kinoshita, M., E. Satoyoshi and Y. Suzuki (1975) Atypical myopathy with myofibrillar aggregates, Arch. Neurol. (Chic.), 32: 417-420. MacDonald, R. D. and A. G. Engel (1969) The cytoplasmic body - - An other structural anomaly of the Z disk, Acta neuropath. (Berl.), 14: 99-107. Rosenow, E. and A. G. Engel (1978) Acid maltase deficiency in adults presenting as respiratory failure, Amer. J. Med., 64: 485-491.
© Elsevier/North-Holland Biomedical Press
CYTOPLASMIC BODY N E U R O M Y O P A T H Y P R E S E N T I N G AS RESPIRAT O R Y F A I L U R E A N D W E I G H T LOSS
F. JERUSALEM, H. LUDIN, A. BISCHOFF and G. HARTMANN DepartmentofNeurology, UniversityofZiirich, CH-8091ZiirichandDepartmentofNeurology, University of Bern, CH-30IO Bern (Switzerland)
(Received 1 August, 1978) (Accepted 18 September, 1978)
SUMMARY This report describes the clinical, laboratory, biopsy and autopsy studies of a woman with a sporadic and chronic progressive neuromyopathy, presenting as respiratory failure and loss of weight. A weakness of her neck muscles could already be observed during childhood. When she was 22 years old, abnormal fatigue, headache and then papilloedema developed. 4 years later there was a steady loss of weight, and in the following years severe shortness of breath occurred during exercise and later at rest, leading to intermittent somnolence. The respiratory function studies revealed a decrease of the vital capacity, total lung capacity, forced expiratory volume and an increase of residual volume. At the age of 31 the patient died from complications of the respiratory failure. In addition to the myopathy the two muscle biopsies showed numerous cytoplasmic bodies in 25 ~o of the muscle fibres; only type 1 fibres contained the inclusions. Axonal alterations were detected in the sural nerve biopsy, and the E M G revealed neurogenic changes in several muscles tested. The autopsy revealed normal anterior horn cells, roots and peripheral nerves, but several muscles including intercostal muscles, showed a neurogenic atrophy. As in a similar sporadic and fatal case and in cases of autosomal dominant benign myopathies with cytoplasmic body inclusions (reported earlier), the cause of the disease presented here remains obscure.
INTRODUCTION Respiratory insufficiency may occur in such diverse neuromuscular disorders as myasthenia gravis, muscular dystrophy, myotonic dystrophy, inflammatory myoReprint requests to Dr. Jerusalem, Department of Neurology, University of Z0rich, CH-8091 Zfirich, R/imistrasse 100, Switzerland.
pathies, congenital benign myopathies, acid maltase deficiency and motor neurol~ disease. Usually the respiratory failure and pulmonary complications develop in the late stages of these diseases, but occasionally the initial clinical picture of the neuromuscular disease is dominated by respiratory insufficiency. The neuromuscular cause may then be unsuspected or overlooked. Investigation by respiratory function tests, including the maximal static respiratory pressures, by electromyographic studies and by muscle biopsies lead to the correct diagnosis. Two muscle biopsies in the case reported here of chronic respiratory insufficiency and loss of weight from a neuromyopathy of unknown origin, were characterized by an excess of cytoplasmic bodies in type 1 fibres. The cytoplasmic body consists of filamentous material and represents a basic pathological reaction of the Z disk. The term "cytoplasmic body" is relatively satisfactory and rarely occurring myopathies with an excess of such bodies were described earlier as "Atypical myopathy with myofibrillar aggregates" (Kinoshita et al. 1975) or "Autosomal dominant myofibrillar inclusion body myopathy" (Clark et al. 1978). Cytoplasmic bodies in skeletal muscle fibres are spheroids and consist of 3 concentric portions: the central body, the intermediate halo, and the outer shell (Engel 1962). The ATPase activity may be retained but there are no oxidative enzyme activities in the body and halo area. In the electron microscope the cytoplasmic bodies are characterized by their origin in the Z disk, a dense filamentous core, a surrounding lighter halo, randomly orientated thin and finer filaments in the halo, lack of a tetragonal filamentous array regardless of the plane of the section, an accompanying focal decrease of mitochondria from the affected fibre region and its restriction to white (type 2) fibres (MacDonald and Engel 1969). Cytoplasmic bodies are said to be not specific for any one pathological condition and have been observed in several human and experimentally induced neuromuscular diseases (MacDonald and Engel 1969). REPORT OF A CASE AND LABORATORY RESULTS The family history, gestation period, birth, and postnatal development of the woman, who was born in 1946, were normal. Since childhood she suffered from a slight weakness of neck muscles causing difficultyin lifting the head from a supine position. In 1968,an abnormal fatigue and headache developed. Shortly afterwards, a temporary iron-deficient anaemia and papilloedema were found. In 1972,the patient lost her appetite, and there was a steady loss of weight down to 43 kg (170 cm body height). From 1973 an amenorrhoea persisted. The patient complained of early fatigue. The medical examination revealed a respiratory insufficiency of unknown origin. In 1977, she developed severe shortness of breath initially during mild exercise, and later at rest. There were periods of somnolence in the morning. Assisted respiration (Bird) was necessary during the night and occasionally during the day. The neurological examination (1974) revealed weakness and atrophy of the sternocleidomastoideus, shoulder, thoracic and abdominal muscles. Tendon reflexes and sensation were normal. Normal laboratory data included haematologic and urine tests, serum electrolytes, creatinine, folic acid, GOT, GPT, CPK, alkaline phosphatase, blood lipids, serum electrophoresis, glucose tolerance test, vitamin Bla absorption, thyroid function (Ta, T4), bone marrow punetion, ECG, EEG, X-ray of the skull and cervical spine, pneumoencephalography and vertebral angiography. The respiratory function studies gave the followingresults (figuresin parentheses represent normal values): Vital capacity 900 ml (4380), residual volume 2530 (1450), total lung capacity 3430 (5830), forced expiratory volume 800 (3065), p,O~ 56 torr, SOn 83.7%, paCO2 57.6 torr, pH 7.37. Electromyography. Conventional needle electromyography showed signs of active denervation
Fig. 1. Fresh frozen muscle sections stained with modified trichrome (A, B). Many muscle fibres contain numerous cytoplasmic bodies, which appear purple red in trichrome-stained sections. A pathologic caliber variation of muscle fibres is present in the deltoid muscle (A), and a severe increase of connective tissue can be seen in the intercostal muscle (B). Cytoplasmic bodies also occur in the fibres of the intercostal muscle. A: x 290, B: x 360.
Fig. 2. Fresh frozen muscle section reacted for NADH-dehydrogenase (A), and a paraffin-embedded section stained with hematoxylin-eosin (B). The cytoplasmic bodies do not show oxidative enzyme activities (+-A). Only type 1 fibres contain the inclusion bodies. A grouped atrophy of muscle fibres is clearly seen in the intercostal muscle taken at autopsy (B). A x 290, B × 120.
Fig. 3. Phase-optic micrograph of longitudinally sectioned muscle fibres demonstrate focal accumulations of cytoplasmic bodies, < 320.
Fig. 4. Electron micrograph of muscle fibre which contains cytoplasmic bodies, x 6400.
Fig. 5. Electron micrograph of a longitudinally sectioned muscle fibre showing streaming (arrows) of Z disk. × 8000. in the form of fibrillations and positive sharp waves in the deltoid and extensor digitorum brevis muscle. There was a reduced recruitment pattern, but no spontaneous activity in the tibialis anterior and intercostal muscle. No fasciculations, a normal number of polyphasic potentials and only slightly increased action potential amplitudes were found in all the muscles examined. Using Buchthal's (1952) method and normal values, the mean duration of the motor unit action potentials was significantly prolonged in all muscles examined: 67 ~ in the deltoid, 28 ~ in the tibialis anterior, and 70 ~ in the extensor digitorum brevis muscle. The motor and sensory nerve conduction velocities as well as the distal latencies were within normal limits. The median sensory nerve action potential, however, showed an abnormally prolonged temporal dispersion between wrist and elbow, indicating peripheral neuropathy. Repetitive nerve stimulations at rates of 2, 3, 10, 20 and 50/sec produced no myasthenic decrement. Muscle and sural nerve biopsies. Numerous cytoplasmic bodies were identified in modified trichrome-stained sections in 25 ~ of the cross-sectioned fibres in the biopsied deltoid and intercostal muscle (March 1974) (Fig. 1). There were no oxidative and myofibrillar ATPase activities in the body and halo area of the cytoplasmic bodies, which occurred only in type 1 fibres (Fig. 2), but the acid phosphatase reaction was positive in the muscle fibre areas which contained the inclusions. A normal TABLE 1 H I S T O M E T R Y OF THE BIOPSIED LEFT DELTOID MUSCLE (calculations from Brooke and Engel 1969; Dubowitz and Brooke 1973) Type 1 Number and percentage of fibres in a randomly chosen area Mean diameter (/~m) Standard deviation Atrophy factor Hypertrophy factor Variation coefficient
143 (72 ~ ) 48.6 20.9 245 273 430
Type 2
57 (28 %) 74.0 24.2 158 1456 327
Fig. 6. Electron m i c r o g r a p h s of myelinated nerve fibres. A dilatation of the s m o o t h - s u r f a c e d e n d o plasmic reticulum in the axon is present (A). In B an axonal shrinkage a n d destruction of the myelin sheat c a n be seen. A: x 36500, B: ~ 5900.
checkerboard pattern of different fibre types was preserved. Longitudinally orientated muscle fibre sections demonstrated the segmental accumulation of the cytoplasmic bodies well seen with the phase microscope (Fig. 3). Under the electron microscope they had the characteristic features of cytoplasmic bodies (Fig. 4). Many nemaline structures and Z disk streaming and thickening were found (Fig. 5). In addition, with the light microscope, a pathological caliber variation with atrophic and hypertrophic type 1 and type 2 fibres (Table 1), central nuclei and clumps of pyknotic nuclei, and degenerative changes were present. About 60 ~ of the muscle tissue in the intercostal muscle was replaced by connective tissue (Fig. 1D). Both muscle biopsies were classified as myopathic; a neurogenic pattern was not present. The sural nerve biopsy (1974) showed a dilatation of the smooth surfaced endoplasmic reticulum in many myelinated and unmyelinated axons (Figs. 6 and 7), shrinkage of axons and vacuolar as well as granular myelin breakdown (Fig. 6B). These alterations were present in 20 7ooof the nerve fibres. Autopsy. In August 1977 the patient died from complications induced by the chronic respiratory failure. The autopsy revealed an acute brain oedema, normal anterior horn cells, nerve roots and peripheral nerves, but several muscles (intercostal, psoas, gastrocnemius, quadriceps) showed a grou!ced atrophy and clumps of pyknotic nuclei, clearly indicating a neurogenic muscle atrophy (Fig. 2D). The peripheral nerves examined were the intercostal, sciatic and femoral. No morphological evidence was found to account for the neurogenic atrophy.
Fig. 7. Electron micrograph of unmyelinated nerve fibres with dilatations of the smooth-surfaced endoplasmic reticulum in the axons, × 36,500.
DISCUSSION The disorder in the case presented, with the cardinal symptoms of respiratory failure and loss of weight, had probably begun with a weakness of the neck muscles during childhood. In 1968, when the patient was 22 years old, she developed abnormal fatigue and headache. These, together with the documented papilloedema, were probably due to a respiratory insufficiency, which was first diagnosed in 1973. Together with a steady loss of weight, this insufficiency slowly progressed up to the patient's death in 1977. Various respiratory function tests and electromyography revealed that a neuromuscular condition was the cause of the respiratory failure. The biopsy of the deltoid and intercostal muscle in 1974 demonstrated numerous cytoplasmic bodies in 25 ~ of the cross-sectioned muscle fibres. The fact that these inclusions showed a segmental localization, leads us to assume, that the real number of affected fibres was even higher. Our observations are similar to those in a case observed by Kinoshita et al. (1975), in which there was segmental aggregation of numerous cytoplasmic bodies in the muscle biopsy. The woman, at the age of 16, had large calves, tended to walk on her toes and also tended to look backwards by turning her shoulders instead of her head. Then she gradually developed shortness of breath, loss of weight and weakness of shoulders and thighs. At the age of 23 the vital capacity was 600 ml and 8 months later she died from respiratory insufficiency and congestive heart failure. Whereas these two reports concern sporadic and fatal cases with respiratory failure and loss of weight, Clark et al. (1978) recently reported an autosomal dominant benign myopathy of late adult onset with myofibrillar inclusion bodies in 3 symptomatic and 7 asymptomatic family members of a large kindred. The cytoplasmic bodies which occasionally occur in several neuromuscular disorders, are localized in type 2 fibres, but they were only found in type 1 fibres in our case and in the biopsies reported by Clark et al. (1978). By reason of clinical, electromyographic and myopathologic findings Kinoshita et al. (1975) and Clark et al. (1978) classified their observations as a myopathy. The biopsies of the deltoid and intercostal muscles of our case also showed a myopathic syndrome but the E M G and sural nerve biopsy carried out at the same time and the myopathology, demonstrated at autopsy 3 years later, clearly indicated a neurogenic process. We, therefore, describe our case as a neuromyopathy. None of the clinical and laboratory tests, biopsy and autopsy examinations revealed its cause. In particular, none of the common causes of a chronic neuropathy involving motoneurons such as lead, and other toxic substances, porphyria, polyarteritis nodosa, neoplasia, amyloidoses, chronic radiculopathy or spinal muscular atrophy could be found. There was also no indication of a neuromuscular disorder such as acid maltase deficiency, which may present with a respiratory failure (Goldstein et al. 1974; Rosenow and Engel, 1978). The neuromuscular disorders described here and previously (Kinoshita et al. 1975; Clark et al. 1978) were characterized in the muscle by numerous cytoplasmic bodies ("myofibrillar aggregates" or "myofibrillar inclusion bodies"). Although cyto-
plasmic bodies are occasional findings in various n e u r o m u s c u l a r diseases, the pred o m i n a n c e o f these inclusions in these cases characterizes this disease. These cases d o n o t fit into o u r present s p e c t r u m o f well-defined disorders. A classification based on a m o r p h o l o g i c a l finding alone is n o t satisfactory, but, as in o t h e r muscle diseases, a m o r p h o l o g i c a l classification a p p e a r s reasonable, as long as the cause a n d b i o c h e m i c a l n a t u r e o f the c y t o p l a s m i c bodies is u n k n o w n . I n view o f the different clinical, genetic, m o r p h o l o g i c a l a n d e l e c t r o p h y s i o l o g i c a l aspects o f the various cases which have this excess o f c y t o p l a s m i c bodies, several features indicate t h a t these disorders are heterogenous a n d n o t a single disease entity. ACKNOWLEDGEMENT W e wish to t h a n k D r . R. F r i e d e for his c o m m e n t s on the spinal c o r d a n d nerve p a t h o l o g y , a n d Miss Lea K1/iusli, Miss Vreni Siegrist a n d Mrs. U r s u l a Schill for t h e i r assistance.
REFERENCES Brooke, M. H. and W. K. Engel (1969) The histographic analysis of human muscle biopsies with regard to fibre types, Part 2 (Disease of the upper and lower motor neuron), Neurology (Minneap.), 19: 378-393. Buchthal, F. (1952) for references see Ludin, H. P. (1976) Praktische Elektromyographie, Enke, Stuttgart. Clark, J. R., A. N. d'Agostino, J. Wilson, R. R. Brooks and G. C. Cole (1978) Autosomal dominant myofibrillar inclusion body myopathy - - Clinical, histologic, histochemical, and ultrastructural characteristics, Neurology (Minneap.), 28:399 (Abstr.). Dubowitz, V. and M. H. Brooke (1973) Muscle Biopsy - - A Modern Approach, Saunders, London. Engel, W. K. (1962) The essentiality of histo- and cytochemical studies of skeletal muscle in the investigation of neuromuscular disease, Neurology (Minneap.), 12: 778-794. Goldstein, R. L., R. W. Hyde, L. W. Lapham, K. Gazioglu and Z. G. De Papp (1974) Peripheral neuropathy presenting with respiratory insufficiency as the primary complaint - - Problem of recognizing alveolar hypoventilation due to neuromuscular disorders, Amer. J. Med., 56: 443-449. Kinoshita, M., E. Satoyoshi and Y. Suzuki (1975) Atypical myopathy with myofibrillar aggregates, Arch. Neurol. (Chic.), 32: 417-420. MacDonald, R. D. and A. G. Engel (1969) The cytoplasmic body - - An other structural anomaly of the Z disk, Acta neuropath. (Berl.), 14: 99-107. Rosenow, E. and A. G. Engel (1978) Acid maltase deficiency in adults presenting as respiratory failure, Amer. J. Med., 64: 485-491.