J. Bethlem

THE DISTRIBUTION OF LEWY BODIES IN THE CENTRAL AND AUTONOMIC NERVOUS SYSTEMS IN IDIOPATHIC PARALYSIS AGITANS

The hyaline inclusions in the pigmented ganglion cells of the substantia nigra and the locus coeruleus in patients suffering from idiopathic paralysis agitans are known as Lewy bodies after their discoverer, Lewy (1913). A detailed description of these bodies was presented by Greenfield and Bosanquet in 1953. The intracytoplasmic bodies are always surrounded by a light halo, and often have a central core which stains differently from the remainder of the body. If these morphological and staining characteristics are taken into account, confusion with other cytoplasmic inclusions is impossible. Greenfield and Bosanquet found Lewy bodies in each of their 19 cases of idiopathic paralysis agitans, and in none of their 10 cases of postencephalitic Parkinsonism or in their 22 control cases. These findings were confirmed by Bethlem and den Hartog Jager (1960) in 15 cases of idiopathic paralysis agitans, four cases of post-encephalitic Parkinsonism, and 20 control cases. We have since found the Lewy bodies in nine new cases of Parkinsons disease. We failed to find them in a case of Parkinson following CO intoxication and in the case of Friedreichs ataxia combined with hereditary Parkinsonism, previously described by Biemond and Sinnege (1955). In contrast with the above are the findings of Redlich (1930) and Godlowski (1931), each of whom found Lewy bodies in two cases of post-encephalitic Parkinsonism. Alvord (1958) described Lewy bodies in four out of 14 post-encephalitic cases. Lipkin (1959) also found Lewy bodies in four out of nine verified cases of post-encephalitic Parkinsonism. Lewy bodies have so far been chiefly described in the pigmented ganglion cells of the substantia nigra and the locus coeruleus (Tretiakoff, 1919; BeheimSchwarzbach, 1952; Greenfield and Bosanquet, 1953). Lewy himself (1913, 1923) described these bodies in the nucleus of the substantia innominata, the periventricular nucleus, and the dorsal vagal nucleus. Von Buttlar-Brentano (1955) found Lewy bodies in the nucleus of the substantia innominata (nucleus basalis) in each of 16 cases of paralysis agitans. In 13 cases of post-encephalitic Parkinsonism, no Lewy bodies were found in this nucleus. Bethlem and den Hartog Jager found Lewy bodies in the nucleus of the substantia innominata in nine out of 15 cases of Parkinsons disease. Greenfield and Bosanquet described Lewy bodies as found in the oculomotor nucleus (Case 9) and in the nucleus of Roller (Case 10) in idiopathic paralysis agitans. In idiopathic paralysis agitans, Lipkin found Lewy bodies in the ganglion cells of the dorsal vagal nucleus (three cases), the cerebral cortex (one case), and the inferior olive (one case). Herzog (1928), Wohlwill (1928), and Hechst and Nussbaum (1931) found Lewy bodies in the ganglion cells of the sympathetic vertebral chain in paralysis agitans, and were therefore the first investigators to encounter Lewy bodies outside the central nervous system. They do not indicate whether Lewy bodies were also present in the central nervous system in these cases. They did report having found Lewy bodies in the sympathetic ganglia in patients not suffering from paralysis agitans, although of considerably less marked intensity and spread. The purpose of this paper is to present a description of the exact distribution of Lewy bodies in Parkinsons disease, both in the central and in the peripheral autonomic nervous systems.

Familial "myotubular" myopathy.

THE EXISTENCE of central nuclei, so-called myotubes, or type I fiber hypotrophy in muscle diseases has been described by several authors. These diseases were given different names. Spiro et al.,l Kinoshita et a1.,2 and Coleman et al.3 described their cases as “myotubular myopathy,” because the main pathology consisted of fibers resembling fetal myotubes. Sher et aL4 and Bethlem et al.5 called their cases “centronuclear myopathy,” because they regarded the presence of the many centrally placed nuclei as the most characteristic feature. Engel et al.6 reported a case as “type I fiber hypotrophy and central nuclei,” thus describing the two principal histopathological features. Bethlem et al.7 listed <‘type I fiber atrophy, central nuclei, and myotube-like structures” as the most conspicuous findings in their patient. The clinical picture of these cases was variable. Both males and females were affected. The onset was at birth or in early infancy. All patients showed widespread muscle involvement combined with areflexia. Involvement of extraocular or facia1 muscles or both was a frequent but not constant finding. In the family to be described, at least 6 siblings suffered from a muscle disease that showed many similarities to the above-mentioned cases.

X‐linked myotubular myopathy with fatal neonatal asphyxia

A second family with X-linked myotubular myopathy is described. The clinical picture includes decreased fetal movements; hydramnios, in at least three cases, probably resulting from insufficient swallowing in utero; and asphyxia at birth. In three autopsy cases many myotubes were found in the muscle tissue. In five definite female carriers, muscle biopsy revealed changes, including myotubes in four. This family probably is not related to the earlier described family with X-linked myotubular myopathy, from which it differs in its 100 percent fatal outcome in the neonatal period, as compared with 25 percent in the earlier described family. A most important finding, in both families, is the possibility of recognizing clinically healthy female carriers by muscle biopsy.

Neuromuscular disease with type I fiber atrophy, central nuclei, and myotube‐like structures

A MUSCULAH DISEASE, characterized by the presence of muscle fibers with central areas devoid of myofibrils and with central nuclei, was described in 1966 by Spiro, Shy, and Gnatas.’ These fibers resembled the myotubes ordinarily found in early fetal life. I t was postulated that the finding of myotubes indicates an arrest in development of the muscle at a cellular level, and the disease was consequently described as “myotubular myopathy.” Sher, Rimalovski, Athanassiades, and Aronson? found similar histopathological changes in two sisters. Since the pathogenesis of this unusual disease remained obscure, they preferred the descriptive term “familial centronuclear myopathy .” What appeared to be the same condition was described by Bethlem, Meijer, Schellens, and Vroom,s who found the above-mentioned abnormalities in both type I and type ‘TI fibers and also in fibers with medium enzyme activity. The clinical picture was strikingly similar in all these cases: onset in the first year of life, slow progression, involvement of the extraocular muscles and the muscles of the face, neck, and limbs, and absence of the deep tendon reflexes. There was no involvement of the extraocular muscles in the patient with myotubular myopathy described by Kinoshita and Cadman.4 In this case, too, both type I and type I1 fibers were affected. Another condition characterized by the presence of central nuclei was described by Engel, Gold, and Karpati.5 Their case showed a pattern of widespread hypotrophy and central nuclei affecting virtually all type I fibers and a minority of the type I1 fibers. This congenital muscular abnormality was described as “type I fiber hypotrophy and central nuclei.” We found type I fiber atrophy, myotube-like structures, and central nuclei in a patient who also showed indications of neurogenic muscle involvement. Reports will be presented on this patient, her diseased brother, and their clinically healthy parents and sister.

Neurogenic muscle involvement in myasthenia gravis: A clinical and histopathological study

An investigation was made into the occurrence of muscular atrophy and muscular pathology in a series of 170 patients with myasthenia gravis. The results can be summarized as follows: (1) Of the 148 patients with generalized myasthenia gravis, 14 showed local muscular atrophies. Of 10 biopsies from atrophic muscles, eight showed neurogenic changes, with or without lymphocytic infiltrations. One biopsy showed lymphocytic infiltrations only, and one showed type II-fibre atrophy (Table 1). No relationship was demonstrable between the presence of clilnical muscular atrophy and age, sex, duration of the disease, severity of the disease, presence of a thymoma, or drug resistant ophthalmoplegia. (2) In this group of patients 61 biopsies were examined from 46 individuals; 40 of these biopsies were taken from the quadriceps muscle. A thymoma was present in 17 patients. Examination disclosed neurogenic changes in 17 biopsies, lymphocytic infiltrates in 21, and myositis in one biopsy (Table 2). A distinct correlation was established between the presence of a thymoma and lymphocytic infiltrates, but none was demonstrable between thymoma and neurogenic changes (Table 3). (3) An enzyme-histochemical study was carried out in 35 cases, including 12 with neurogenic changes. A normal differentiation of type I- and type II-fibres was observed in eight instances, type grouping of type II-fibres in three, and type II-fibre atrophy in two cases. (4) In 21 patients and 19 controls, the smallest mean diameter was determined in the quadriceps muscle. Both type I- and type II-fibres proved to have a smaller mean diameter in the female patients than in the controls. In the male patients this could not be proven. (5) Of the eight patients who had died without disorders of ventilation, 90 muscle specimens were examined postmortem. Four of these patients had a thymoma. Lymphocytic infiltrations, found in 32 biopsy specimens, were mostly observed in the presence of a thymoma. Neurogenic changes were apparently unrelated to the presence of a thymoma (Tables 5 and 6). The post mortem examination included the spinal cord in five, and peripheral nerves in three cases. No abnormalities were found. (6) The muscular atrophy found in patients with myasthenia is not a myopathy but an affection of the lower motor neurone. Neurogenic changes were regularly found in the muscles of patients with myasthenia, even without muscular atrophy. The finding of these changes is no reason to reject the diagnosis. It is postulated that denervation occurs at the neuromuscular junction as a result of permanent absence of acetylcholine.

Changes in motor innervation and histochemical pattern of muscle fibers in some congenital myopathies

Changes in motor innervation were compared with histologic and histochemical pattern of muscle fibers in three biopsies of central core disease, four biopsies of nemaline myopathy, one biopsy of myotubular myopathy, and three biopsies of mitochondrial myopathy. Evidence of collateral reinnervation was obtained only in one biopsy from central core disease. In other biopsies, no structural or ultrastructural abnormality of axis cylinders, myelin, or myoneural junction suggesting denervation were observed. The only relevant change found in centronuclear myopathy and to a lesser extent in nemaline myopathy was an unusual smallness and simplification of motor endings, suggesting delayed or impaired maturation. Muscle fibers strongly reactive for both adenosinetriphosphatase and nicotinamide-adenine dinucleotide diaphorase, observed in central core disease and mitochondrial myopathy, were not associated with increased terminal innervation ratio.

Familial focal loss of cross striations

SummaryTwo patients, a brother and sister, both suffering from congenital generalized muscle weakness with a progressive course are reported. Muscle biopsy revealed areas with loss of cross striations in the muscle fibers, electronmicroscopically presenting complete disorganization of the myofibrils with streaming of the Z discs and absence of mitochondria. Vesicular nuclei with prominent nucleoli were present in these areas. There was a type I fiber prodominance in both cases. The mean diameter of the type I muscle fibers in one of the cases was too small. Motor endplate alterations in this patient gave no evidence of denervation but were suggestive of a delayed development of motor nerves.ZusammenfassungEs werden zwei Patienten beschrieben, Bruder und Schwester, beide an einer kongenitalen, generalisierten, progressiven Muskelschwäche leidend. Die Muskelbiopsie zeigte Zonen mit Verlust der Querstreifung in den Muskelfasern, und bei elektronenmikroskopischer Untersuchung zeigte sich eine totale Unordnung der Myofibrillen mit Strömung der Z-Scheiben und Fehlen von Mitochondrien. In diesen Bezirken fanden sich blasige Kerne mit prominenten Nukleolen. In beiden Fällen zeigte sich ein starkes Überwiegen der Typ-I-Fasern. Der mittlere Durchmesser der Typ-I-Muskelfasern war in einem der Fälle zu gering. Veränderungen in der motorischen Endplatte in diesem Fall zeigten keine Denervierung, sondern deuteten auf eine verzögerte Entwicklung der motorischen Nerven.

Further investigations on benign myopathy with autosomal dominant inheritance

SummarySix members of a family suffered from benign myopathy over four generations. The clinical, laboratory, electromyographic, histological and genetic data were consistent with benign myopathy with autosomal dominant inheritance. Congenital torticollis was a feature in one patient. Linkage studies revealed no linkage between the locus of this myopathy and the locus of any of 17 genetic markers investigated. This family was of Polish descent, which indicates a widespread occurrence of this benign hereditary myopathy. The data presented are a strong argument in favor of a specific new disease entity.ZusammenfassungIn 4 Generationen einer Familie litten 6 Glieder an einer gutartigen Myopathie. Die klinischen Daten, Laboratoriumsbefunde, der elektromyographische und histologische Befund sowie die genetischen Besonderheiten waren mit der Annahme einer gutartigen Myopathie von autosomal dominantem Erbgang vereinbar. Bei einem Patienten lag ein angeborener Torticollis vor. Es ließ sich keine Koppelung zwischen dem Lokus dieser Myopathie und dem Lokus irgendeiner der 17 untersuchten genetischen Lokalisationen feststellen. Da die beschriebene Familie aus Polen stammte, weist dies auf die starke Verbreitung dieser gutartigen hereditären Myopathie hin. Die hier vorgelegten Elemente sprechen sehr für eine eigenständige neue Erkrankung.

The incidence of lobulated fibres in the facioscapulohumeral type of muscular dystrophy and the limb-girdle syndrome

Abstract A description is given of the histopathological and electron-microscopic properties of a hitherto unreported structural change of the muscle fibre. In transverse sections these fibres have a lobulated aspect and are therefore termed “lobulated fibres”. Lobulated fibres were found in 13 of 300 consecutive muscle biopsies from patients suffering from neuromuscular diseases. Of these 13 cases there were 7 with the facioscapulohumeral type of muscular dystrophy, 2 with the limb-girdle type of muscular dystrophy, 2 with chronic spinal muscular atrophy and 2 with an autosomal dominant hereditary neuromuscular disease that could not be classified. It is stressed that of 7 patients with the facioscapulohumeral type of muscular dystrophy 4 showed signs indicative of a neurogenic pathogenesis. Although lobulated fibres constitute a nonspecific structural change of muscle fibres, their frequent occurrence in the facioscapulohumeral type of muscular dystrophy appears to be a significant finding.

Observations on central core disease

Abstract A description is given of 2 patients who had cores in their muscle fibres. Patient 1 was a 5-year-old girl suffering from a non-progressive myopathy mainly involving the pelvic girdle. Histochemical investigation of the muscle tissue did not permit a differentiation into type I and type II fibres. Cores were present in 10% of the muscle fibres. Patient 2 was a 12-year-old boy suffering from a severely progressive myopathy. The first manifestation of the disease was facial diplegia. Cores were found in 10% of the type I fibres. The father and mother of both patients showed myopathic features on electromyographic examination.