John N. Walton

Skeletal muscle pathology

Skeletal Muscle. Normal Morphology, Development and Innervation. Muscle Biopsy. Pathological Reactions of Skeletal Muscle. Immunopathology of Skeletal Muscle. Developmental Disorders of Muscle. Congenital Myopathies. The Muscular Dystrophies. Myotonic Disorders. Periodic Paralysis and Electrolyte Disorders. Mitochondrial Diseases. Skeletal Muscle Storage Diseases: Myopathies Resulting from Errors in Carbohydrate and Fatty Acid Metabolism. Inflammatory Myopathies. Endocrine Myopathies. Drug-Induced, Toxic and Nutritional Myopathies. The Pathology of Malignant Hyperthermia. Neurogenic Disorders. Pathology of the Neuromuscular Junction. Pathology of Intramuscular Nerves and Nerve Terminals. Pathology of the Muscle Spindle. Circulatory Disorders and Pathology of Intramuscular Blood Vessels. Tumours of Skeletal Muscle. Muscle Trauma. Disuse, Cachexia and Ageing. Myosetes Ossificans, Myosclerosis and Other Miscellaneous Disorders. Index

Serum enzyme studies in muscle disease: Part III Serum creatine kinase activity in relatives of patients with the Duchenne type of muscular dystrophy

In recent years it has been established that the measurement of serum enzymes is of value in the diagnosis of muscular dystrophy (Dreyfus, Schapira, and Schapira, 1958, Dreyfus, Schapira, and Demos, 1960; Aebi, Richterich, Stillhart, Colombo, and Rossi, 1961; Pearce, Pennington, and Walton, 1964b). The magnitude of the elevations found in serum enzymes when related to the clinical and genetic findings is of additional value in distinguishing between the various types of muscular dystrophy and in separating them from the acquired myopathies (Pearce et al., 1964b). Recent family studies (Pearson, 1962 a and b) have shown that studies of serum enzyme levels may be helpful in the detection of both early and preclinical cases of muscular dystrophy, enabling the subsequent development of the clinical disease to be predicted in infancy. The value of such studies in the detection of the carrier state is a controversial point. Leyburn, Thomson, and Walton (1961) were unable to identify the female carrier by means of estimations of serum aldolase and transaminases. Dreyfus and his co-workers (Dreyfus et al., 1960, 1962b) have demonstrated increased activity of serum creatine kinase in some of the mothers of children suffering from the Duchenne type of muscular dystrophy. However, Okinaka, Kumagai, Ebashi, Sugita, Momoi, Toyokura, and Fujie (1961) found normal serum creatine kinase activity in the parents but increased activity in some female sibs of five cases of muscular dystrophy in childhood. More recently the results of serum aldolase and serum creatine kinase estimations have been reported (Hughes, 1962, 1963) in known carriers and in possible carriers. The first of these studies has shown that seven of eight known carriers exhibited high serum creatine kinase levels, and that 50% of possible carriers showed raised serum enzyme activity.

THE INHERITANCE OF MUSCULAR DYSTROPHY: FURTHER OBSERVATIONS

The results are reported of a survey of the mode of inheritance of muscular dystrophy as determined from a series of sixty‐seven cases occurring in seventeen families.

Serum enzyme studies in muscle disease: Part II Serum creatine kinase activity in muscular dystrophy and in other myopathic and neuropathic disorders

It has been established that the levels of certain enzymes are elevated in the serum of patients suffering from muscular dystrophy. Previous studies (Pearson, 1957; Dreyfus, Schapira, and Demos, 1958; Thompson and Vignos, 1959; Schapira, Dreyfus, Schapira, and Demos, 1960; Thomson, Leyburn, and Walton, 1960; Pearson, Chowdhury, Fowler, Jones, and Griffith, 1961) have indicated that a number of different serum enzymes, including aldolase, transaminases, lactate dehydrogenase, and phosphohexoseisomerase, may be found to have abnormally high activity in such cases. Comparative studies in affected patients have shown that the serum creatine kinase is more satisfactory than the other enzymes mentioned above for diagnostic purposes in cases of clinical and preclinical muscular dystrophy, and is also useful in discriminating other forms of dystrophy from the Duchenne type (Chung, Morton, and Peters, 1960; Aebi, Richterich, Colombo, and Rossi, 1962; Dreyfus and Schapira, 1962; Hughes, 1962; Richterich, Rosin, Aebi, and Rossi, 1964). Most recent reports have been confined to relatively small numbers of patients, and deal mainly with the Duchenne variety of muscular dystrophy. Physiological variations in serum creatine kinase activity have recently been described in normal subjects (Pearce, Pennington, and Walton, 1964). Against this background, the present paper gives our findings in a series of patients suffering from the more common varieties of muscular dystrophy and in patients with non-hereditary myopathic disorders, as well as in a number of patients with muscular weakness and wasting of neuropathic origin, in order to delineate more precisely the diagnostic value of serum creatine kinase estimations in these conditions.

Superficial haemosiderosis of the central nervous system

In 1940 Noetzel reported two cases of slowly progressive neurological illness in which, at necropsy, the meninges overlying the brain and spinal cord and the peripheral areas of the brain, cerebellum, and spinal cord were found to be rust-brown in colour. Iron pigment was found in the meninges, glial cells, within mesodermal cells and around blood vessels in the cortex, and in the lining of the cerebral ventricles, and the pigmented cerebellar convolutions were disorganized. The author concluded that this condition was due to the diffusion of blood pigment into the marginal zone of the central nervous system and suggested that the condition was probably the result of chronic subarachnoid bleeding. Subsequently, however, additional cases were reported by Lewey and Govons (1942), Cammermeyer (1947), Neumann (1948, 1956), Garcin and Lapresle (1957), Rosenthal (1958), and McGee, van Patter, Morotta, and Olszewski (1962). Neumann (1948, 1956) concluded that the pathological changes in the central nervous system which she observed in her two cases were the result of haemochromatosis of the central nervous system. Others, however, have pointed out that the pigment deposits consist of haemosiderin and suggest that in most, if not all, cases this disorder results from repeated or long-continued bleeding into the subarachnoid space. In all, 11 cases of this type have now been reported in the world literature. They have shown a remarkably consistent clinical picture characterized particularly by progressive dementia, nerve deafness, and cerebellar ataxia, and the pathological changes in the reported cases have also been strikingly uniform in character. Table I summarizes details of the cases reported to date and we give below detailed clinical and pathological observations in the first case of this type to be reported from Great Britain.

Serum enzyme studies in muscle disease: Part I Variations in serum creatine kinase activity in normal individuals

It has been recognized for many years that in patients with muscular dystrophy there are substantial increases in the activity of certain enzymes, e.g., aldolase and the transaminases, in the serum. Extensive surveys by several workers have shown that the changes are particularly striking in cases of the Duchenne type muscular dystrophy (decreasing as the disease progresses), smaller in the limb-girdle and facio-scapulo-humeral types of dystrophy, and slight or absent in cases of neurogenic muscular weakness and wasting (Dreyfus and Schapira, 1955; Dreyfus, Schapira, and Schapira, 1954, 1958; Schapira, Dreyfus, Schapira, and Demos, 1960; Thomson, Leyburn, and Walton, 1960; Hughes, 1962). Hence they are of value in helping to distinguish conditions of the latter group from the muscular dystrophies. Of the enzymes studied, creatine kinase (A.T. P.: creatine phospho transferase) appears to display the largest increase. Recent studies (Chung, Morton, and Peters, 1960; Schapira et al., 1960; Aebi, Richterich, Colombo, and Rossi, 1962; Hughes, 1962; Walton, Pearce, Pennington, and Barwick, 1962) have shown that there is an elevation of serum creatine kinase in some of the female relatives of patients with the Duchenne type muscular dystrophy. The results indicate that many, but not all, the known carriers of this sex-linked recessive gene display a level of serum enzyme activity above the normal range. The importance of being able to establish whether or not a woman is a carrier is evident. In order that the maximum use may be made of the serum creatine kinase level as a criterion for detecting carriers it is important to possess adequate data concerning variations occurring in normal individuals under a wide variety of physiological conditions. The main reason why this is necessary is that wide variations in levels of serum enzyme activity, e.g., of aldolase, have been shown by Thomson (1962) to occur in relation to physical exercise and parturition. Minor elevations of enzyme activity occurring under varying physiological circumstances could conceivably make it difficult to detect carriers in whom the increase is usually small. We have therefore undertaken a study of the influence of various factors upon the activity of the enzyme in healthy individuals. The use of estimations of the serum creatine kinase in the diagnosis of the carrier state, of preclinical muscular dystrophy, and of other hereditary and nonhereditary myopathies will be the subject of subsequent publications (Pearce, Pennington, and Walton, 1964).

MUSCULAR DYSTROPHY: SOME RECENT ADVANCES IN KNOWLEDGE.

FIG. 3.-Electron micrograph, X 15,550, transverse section of muscle FIG. 4.-Electron micrograph, X 19,430, of muscle section from patient outained by biopsy from patient with muscular dystrophy of Duchenne with muscular dystrophy of Duchenne type, showing excessive numbers type. There is widespread loss of myofilaments with disorganization of of bodies, provisionally identified as lysosomes, lying between the myomitochondria and of the sarcotubular system. (From Pearce, 1964.) fibrils. (From Pearce, 1964.) A=Myofibrils. B=Z-band. C=SarcoA= Relatively normal nmyofilaments. B= Area of myofilament loss. C= tubule. D= Lysosomes. E= Mitochondrion. Mitochondria. D= Collagen fibrils outside the sarcolemma. E =Sarcolemma. F= Sarcotubule.

L-Dopa in Parkinsonism and the Influence of Previous Thalamotomy

A double-blind cross-over trial over 24 weeks (10 weeks on the active remedy, 4 weeks off treatment, and 10 weeks on placebo) of the effect of L-dopa on idiopathic Parkinsonism (paralysis agitans) has shown no difference in the response obtained in patients who had undergone previous stereotaxic ventrolateral thalamotomy and in those who had not. Of the 34 patients (18 men and 16 women) in the trial 18 had been operated on (nine unilateral, nine bilateral operations) and 16 had not. All patients entering the trial were taking anticholinergic drugs in stable dosage and these were continued throughout. The only factor which seemed to limit the response to treatment was pre-existing hypertension. Of 31 patients who completed the 10-week treatment period, 12 showed marked improvement, 15 moderate improvement, and 4 and mild or negligible change. It seems that previous ventrolateral thalamotomy affords some protection against the development of L-dopa-induced involuntary limb movements on the side contralateral to the operation. As found by others, maximum benefit was seen in bradykinesia and rigidity and related features but a significant reduction in tremor was also noted during treatment. Side effects (nausea, hypotension, and involuntary movements) were common but rarely limited the therapeutic response.

Clinical and pathological study of a case of congenital muscular dystrophy

The classification of disorders giving rise to generalized hypotonia of the skeletal musculature in infancy has been discussed previously by Walton (1956, 1957) who suggested that these cases can be separated into three categories, namely, infantile spinal muscular atrophy, symptomatic hypotonia, and benign congenital hypotonia. Congenital muscular dystrophy is one of the least common causes of symptomatic hypotonia in infancy and a review of the literature by Short (1963) revealed seven reported cases with necropsy information, to which a further case presenting with congenital hypotonia was added. Banker, Victor, and Adams (1957) have described the clinico-pathological findings in two male sibs with congenital muscular dystrophy: the initial clinical picture in one of them was of arthrogryposis multiplex congenita, whereas the other had hypotonic flaccid weakness without contracture at birth. Greenfield, Cornman, and Shy (1958) listed congenital or early infantile muscular dystrophy of Batten amongst the different conditions of muscle which can produce the clinical syndrome of weakness and hypotonia at birth or in the early weeks of life. The following case report with biochemical, histological, and electron microscopic findings is of a 5i-year-old child with congenital hypotonia and weakness who also showed multiple contractures giving the appearance of arthrogryposis multiplex and in whom muscle biopsy has shown the histological changes of progressive muscular dystrophy. It is thought worthy of record because of the apparent rarity of this condition.

The electroencephalogram in pernicious anaemia and subacute combined degeneration of the cord.

Abstract Eighty cases of pernicious anaemia in relapse, of which 24 had subacute combined degeneration of the cord (one with optic atrophy), 41 mild neurological involvement and 15 none, have been studied by means of the EEG. Seven cases showed mild organic reactions and in all of these the pre-treatment record was abnormal. The pre-treatment record was also abnormal in 60 per cent of the remaining patients who showed no significant mental abnormality. In some cases abnormality was severe (delta activity, generalised, paroxysmal or focal), in some slight (slight or moderate excess of theta activity), but the degree of abnormality bore no relationship to the severity of the anaemia, the age of the patient or the degree of neurological involvement. Ten cases of anaemia of miscellaneous type were also studied before treatment; although in 3 of these the haemoglobin level was less than 40 per cent, only in one case did the EEG show a significant abnormality and this patient had severe hypertension and atherosclerosis. Seventy-six of the cases of pernicious anaemia were re-examined after treatment with vitamin B 12 . In 14 of the 29 cases which gave normal records before treatment there was a significant increase in mean frequency of the alpha rhythm and diminution in overall amplitude. Forty-two of the remaining 47 cases in which the initial record was abnormal s showed a satisfactory clinical response to treatment and in 31 (74 per cent) the EEG returned to normal, so that 60 of the 76 cases (79 per cent) eventually gave normal records. Improvement in the record began as a rule 7–10 days after the beginning of treatment and was often complete within a month, although some cases showed further improvement after intervals varying from 3–16 months. In the other 11 cases (26 per cent) who responded, persisting abnormalities consisted of a slight excess of generalised theta activity, a finding which in some could possibly be accounted for by age or constitution. Another 50 cases of pernicious anaemia (including 37 with subacute combined degeneration of the cord, 8 with mild neurological involvement and one with optic atrophy) were first studied after treatment had been in progress for between 3 months and 8 years (average 18 months). Excluding 5 cases showing epileptic discharges, 38 (84 per cent) of the other 45 patients had normal records; the remaining 7 cases (16 per cent) were restudied and in all EEG showed further improvement 5 months to 3 years after the beginning of treatment. The final total of normal records was 42 (93 per cent). Eight (6 per cent) of the 130 cases of pernicious anaemia studied gave records showing epileptic discharges (usually temporal spikes or sharp waves) and of these 4 (3 per cent) gave a personal or family history of fits or faints. It is suggested that the EEG changes in pernicious anaemia are due not to the anaemia but to a specific defect in cerebral metabolism, presumably related to the deficiency state responsible for the anaemia. Though not as sensitive as studies of cerebral metabolism by the blood flow method, the EEG is a useful tool in the investigation of these cases and reveals that maximum improvement may be delayed for up to 3 years after treatment has begun. The possible relationship of the EEG changes to alterations in glucose and pyruvate metabolism is discussed.