In addition to inherited or acquired neuromuscular disorders, muscle weakness and alterations in muscle bulk can occur in association with several underlying conditions and as a consequence of ageing. Hormone imbalances, vitamin deficiencies, malignancies and ageing are the most common causes, and, although the muscle pathology is often non-specific, the pathologist should be aware of their effects.
Endocrine Disorders
Many hormones have an important role in maintaining normal muscle function. Myopathies have been described in association with several endocrine disorders, either an excess or deficiency, in particular those affecting thyroid, parathyroid, glucocorticoid, growth hormone and insulin levels. In most cases the muscle involvement is an incidental feature of the disorder, and may even be subclinical and only revealed by special investigations, such as serum enzyme levels, electromyography and biopsy, in the course of study of these disorders. In other instances, the muscle symptoms may be the presenting features and may lead to the diagnosis of the underlying disorder, e.g. thyrotoxicosis. In many cases the muscle weakness is disproportionate to the degree of muscle wasting.
There have been relatively few recent detailed histochemical or electron microscopic studies on the muscles in these various disorders, and estimation of the hormone levels is the primary diagnostic tool. Many of the reported studies from the pioneering days of muscle pathology show that, in general, only non-specific myopathic changes accompany changes in hormone levels: these relate mainly to changes in fibre size (atrophy or hypertrophy) and fibre type proportions.
Disorders of the Thyroid
Thyroid dysfunction is frequently associated with neurological manifestations ( ); several of these involve the neuromuscular system ( ).
Hyperthyroidism
There are four different muscle disorders associated with hyperthyroidism:
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thyrotoxic myopathy;
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myasthenia gravis;
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thyrotoxic periodic paralysis;
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exophthalmic ophthalmoplegia.
Thyrotoxic Myopathy
The most common myopathy in association with thyrotoxicosis is a chronic form, which may be generalized or confined mainly to proximal muscles. Although commonly seen in females, particularly after the age of 50 years, males can also be affected ( ). At times, it may precede other signs of thyrotoxicosis and in otherwise subclinical hyperthyroidism ( ). The electromyogram shows abnormality, usually of a myopathic type, in about 90% of cases of hyperthyroidism, but histological changes occur in only about 50% ( ).
The muscle biopsy may show no abnormality on light microscopy or varying degrees of fibre atrophy ( ) and fatty infiltration. Ultrastructural studies have revealed a number of relatively non-specific changes ( ). These include mitochondrial hypertrophy, focal loss of mitochondria, focal myofibrillar degeneration beginning at the Z line, focal dilatations of the transverse tubular system, subsarcolemmal glycogen deposits and papillary projections of the surface of the muscle fibres, probably resulting from fibre atrophy. Thyroid hormone influences many metabolic pathways in muscle ( ), and hyperthyroidism induces a shift in myosin heavy-chain synthesis favouring fast isoforms, which are expressed in type 2, glycolytic muscle fibres ( ), a change that is reversible after treatment and similar to what has been found in rat models. It should be noted that treatment of hyperthyroidism may result in myopathy by rapid reduction of thyroid hormone, which may induce a relative hypothyroidism (see later) ( ).
Acute thyrotoxic myopathy may involve bulbar and extraocular muscles and is probably due to associated myasthenia rather than being a separate entity.
Myasthenia Gravis
The association of myasthenia and thyrotoxicosis is well documented (see Ch. 21 ; ). The incidence of hyperthyroidism in the course of myasthenia is in the region of 5–8%, whereas that of myasthenia in the course of hyperthyroidism is much lower, being less than 0.5% ( ). The association of the two diseases is perhaps not surprising since both are recognized to have an autoimmune origin.
Thyrotoxic Periodic Paralysis
The clinical pattern of the paralytic attacks is very similar to the idiopathic type of hypokalaemic periodic paralysis. The attacks may be the presenting feature of thyrotoxicosis ( ) and usually subside after treatment of the hyperthyroidism. The condition appears to be more common in Asian races but is increasingly seen in Western countries ( ), and there is a marked preponderance of affected males.
The biopsy may show vacuolation, as in idiopathic hypokalaemic periodic paralysis, but at times may be almost normal in appearance ( ).
A mutation in the potassium channel Ki2.6 encoded by KCNJI8 has been found in up to one-third of patients with thyrotoxic periodic paralysis ( ), indicating that genetic variants in ion channels may increase the susceptibility to develop thyrotoxic periodic paralysis ( ).
Exophthalmic Ophthalmoplegia
Although usually looked upon as a complication of thyrotoxicosis, many cases do not have associated hyperthyroidism at the time of its development. Overproduction of thyroid-stimulating hormone, long-acting thyroid stimulator or a specific exophthalmos-producing factor has been invoked, but the mechanism still remains unknown ( ). suggested a delayed hypersensitivity response directed against the orbital contents as a result of the development of antibodies to thyroglobulin. Some patients may also develop a compressive optic neuropathy ( ).
Hypothyroidism
Muscle cramps, stiffness or aching is common in hypothyroidism, and there may be associated weakness ( ). Movements, as well as reflexes, tend to be sluggish (‘myotonic reflexes’). Some cases may show ridging of the muscle on percussion (myoedema); there may be increased muscle bulk, but others have muscle atrophy. In childhood, hypothyroidism may cause hypertrophy in association with slowness of movements, fatigability and myotonic tendon reflexes. The creatine kinase (CK) is usually elevated, even in the absence of overt muscle weakness. In addition, there is delayed myelination of the peripheral nerves, with slow nerve conduction velocity ( ). Hypothyroidism may present with respiratory muscle weakness ( ) or rhabdomyolysis ( ).
The rare syndrome of ‘hypertrophia musculorum vera’ in children was first described by Kocher in 1892 and the term was popularized by , who stressed the relation with hypothyroidism. This Kocher–Debré–Sémélaigne syndrome has been described in congenital cases and in children of all ages with hypothyroidism, and also following surgical or radioactive ablation of the thyroid. The hypertrophy is completely reversible by treatment of the hypothyroidism.
The so-called Hoffmann syndrome occurring in adults is another form of hypothyroid myopathy with muscle weakness, myotonia-like features and muscle hypertrophy ( ).
Muscle biopsy in hypothyroid patients has revealed relatively non-specific changes such as fibre atrophy or enlargement, type 1 fibre predominance, increased internal nuclei, glycogen and mitochondrial aggregates, dilated sarcoplasmic reticulum and proliferating T-system profiles and focal myofibrillar loss ( ). studied needle biopsies before and several months after treatment in 11 adult hypothyroid patients aged between 51 and 71 years old with associated muscle weakness. Abnormalities were found in 8 of the 11 biopsies, the commonest being type 2 fibre atrophy. After treatment, resolution of the changes was slow and 50% of the patients had persistent abnormalities.
Hypothyroidism during pregnancy can affect the expression of myosin isoforms and fibre typing in the fetus ( ).
Disorders of the Pituitary and Adrenals
Acromegaly
In acromegaly there is a general hypertrophy of muscle, especially in the early phases, but later there may be muscle weakness ( ). studied a group of 48 patients with acromegaly and found increased muscle mass and increased proximal muscle strength, but reduced handgrip strength. These parameters had normalized at follow-up 1 year after treatment. In a study of 8 cases, detected electromyogram (EMG) changes of a myopathic nature (small polyphasic potentials), but the muscle histology in six cases biopsied was apparently normal. However, no histographic analysis of fibre diameter and no histochemical studies were performed. found mild proximal weakness in 6 of their 11 cases of acromegaly and elevation of serum CK in five. EMG in all of them showed a shorter mean action potential duration than controls, and there was histological abnormality in five of the biopsies taken. These comprised segmental necrosis of single muscle fibres and proliferation of sarcolemmal nuclei. The histochemical pattern was normal, but there was an increase in size of both type 1 and 2 fibres. There was no apparent correlation of histological change with clinical weakness. In a more detailed analysis of the muscle biopsies from nine of these patients, found hypertrophy of type 1 and 2 fibres in two subjects, hypertrophy of type 1 fibres only in two subjects, atrophy of both fibre types in two and atrophy of type 2 fibres only in four. Isolated fibre necrosis or vacuolar degeneration was present in three biopsies and an increase in internal nuclei in five.
found clinical and EMG evidence of myopathy in 9 of their 17 acromegaly cases and a frequently associated carpal tunnel syndrome but no abnormalities in the muscle biopsies from three patients.
In a detailed histographic analysis of needle biopsies of the quadriceps from 18 cases, found that the most frequent changes were hypertrophy of type 1 fibres (nine cases) and atrophy of type 2 fibres (2A and/or 2B, nine patients). Only two showed atrophy of type 1 fibres and four had hypertrophy of type 2A and/or 2B fibres. There was no apparent direct correlation of the degree of change with the level of growth hormone.
The two cases of pituitary gigantism reported by had an associated peripheral neuropathy. However, the muscle biopsy done in one of them showed a marked variation in fibre size and proliferation of connective tissue, thought to be ‘myopathic’ in appearance, in addition to some group atrophy and selective type 2 fibre atrophy.
Hypopituitarism
In children with hypopituitarism there is poor muscle development and reduced muscle mass in parallel with the deficit in skeletal growth, but no evidence of any associated myopathy.
Cushing Syndrome and Steroid Myopathy
Proximal weakness, especially of the lower limbs, is a well-recognized complication of Cushing syndrome ( ) and probably occurs in more than 50% of cases.
Myopathy as a result of steroid therapy was first documented in the same year as Cushing myopathy ( ) and many reports have followed, especially since the introduction of the 9α-fluorosteroids (dexamethasone, triamcinolone), which appear to be even more toxic to muscle than the non-fluorinated drugs (cortisone, prednisone). The exact mechanism is not known ( ), but a relative androgen deficiency has been demonstrated in patients treated with dexamethasone and may contribute to steroid-induced myopathy ( ).
The onset of steroid-induced myopathy is partly dependent on the dosage and the duration, but there is considerable variation in individual susceptibility and the onset may occur within weeks rather than months ( ). In Cushing syndrome itself, the onset is usually insidious.
While the diagnosis of steroid myopathy may be readily apparent in the steroid treatment of conditions that are not associated with muscle weakness, it can be extremely difficult in muscle disorders such as dermatomyositis that are being treated with steroids. Moreover, the superadded steroid myopathy in some of these cases may be more responsible for the patient’s disability than the underlying myositis ( ).
The most consistent change in the muscle biopsies, both from Cushing syndrome ( ) as well as in steroid myopathy, is selective type 2 fibre atrophy, usually the 2B fibres (see Ch. 4 ). This has also been produced in some of the experimental studies in animals. On electron microscopy, enlargement, proliferation and degeneration of mitochondria, dilatation of the sarcoplasmic reticulum, thickening of the basal lamina, loss of myofibrils and increase in lipid droplets and subsarcolemmal glycogen have been described ( ).
Because of non-specific findings and lack of clear definition of steroid myopathy, a diagnostic workup for steroid myopathy was suggested to include a multidisciplinary approach with combined assessments of muscle mass, strength and performance ( ).
A special form of myopathy in which steroid treatment is thought to be an important player is critical illness myopathy or acute quadriplegic myopathy (AQM) seen in intensive care units (see Ch. 23 ; ).
Abuse of anabolic steroids may be a cause of necrotizing myopathy ( ).
Glucocorticoid Deficiency
Muscle weakness is a common symptom in Addison disease and other diseases associated with glucocorticoid deficiency, but underlying myopathy has rarely been reported ( ). The weakness probably has a biochemical basis in relation to the fluid and electrolyte changes and responds rapidly to treatment of the disorder.
Hyperaldosteronism
When first described primary aldosteronism, he drew attention to the associated periodic attacks of weakness, presumably related to the hypokalaemia, which is due to renal loss of potassium, but increased Na + -K + ATPase activity in skeletal muscle may also be involved ( ). In a subsequent review of 145 cases ( ), muscular weakness was one of the most common presenting features, occurring in 73% of their cases. documented a case, including detailed studies of a muscle biopsy. There was necrosis of isolated muscle fibres and also the presence of small angulated fibres, strongly reactive with reduced nicotinamide adenine dinucleotide-tetrazolium reductase (NADH-TR), similar to those associated with denervation. also documented a myopathy in association with primary aldosteronism in two adult patients. There was necrosis and vacuolation of muscle fibres on light microscopy, and at the electron microscopic level the necrotic areas were characterized by dissolution of myofilaments and degenerative vacuoles.
Insulin-Associated Disorders
Primary muscle weakness is not a feature of diabetes or hypoglycaemia but may result secondarily from a neuropathy. This is painful and asymmetrical and may be accompanied by muscle tenderness and swelling. Muscle biopsies show no distinctive features, but thickening of capillary basal lamina may be seen with electron microscopy, even in prediabetics (see Ch. 5 ).
Muscle pain, cramps and fatigue, without weakness, may be associated with insulin-resistant diabetes.
Disorders of the Parathyroids, Osteomalacia and Vitamin Deficiencies
Muscle weakness can occur in the course of primary and secondary hyperparathyroidism and in osteomalacia. Disorders which lead to osteomalacia, such as vitamin D deficiency, renal tubular acidosis and chronic renal failure, are associated with secondary hyperparathyroidism.
drew attention to myopathy affecting mainly the proximal muscles, with associated pain and fatigability, a waddling gait and hyper-reflexia, in two cases of primary hyperparathyroidism and one of osteomalacia associated with renal tubular acidosis. This association of myopathy with primary or secondary hyperparathyroidism has been well substantiated in many subsequent reports ( ). Muscle biopsy in many of these patients showed relatively minor changes, even in the face of fairly severe clinical weakness. These have included non-specific fibre atrophy, selective type 2 fibre atrophy, minor vacuolar changes and degeneration of isolated fibres.
Myopathy is a common feature of osteomalacia and a prominent symptom of vitamin D deficiency ( ). Parathormone levels may be normal or increased. Severely impaired muscle function may be present even before biochemical signs of bone disease develop ( ).
Treatment of the underlying cause, particularly in primary hyperparathyroidism, has led to resolution of the associated neuromuscular involvement.
Myopathy is not a feature of hypoparathyroidism, the main manifestations of which are tetany and carpopedal spasms.
Vitamin E Deficiency
Vitamin E comprises a group of lipid-soluble compounds, tocopherols and tocotrienols, of which α-tocopherol has the highest biological activity. Vitamin E deficiency may be acquired or inherited. Chronic intestinal fat malabsorption may give rise to vitamin E deficiency, which causes spinocerebellar ataxia, dysmetria, areflexia and loss of vibratory sensation ( ). A similar neurological syndrome, ascribed as ataxia with isolated vitamin E deficiency (AVED), is caused by mutations in the α-tocopherol transfer protein gene TTPA ( ) and is sometimes accompanied by retinitis pigmentosa and macular degeneration ( ). In animals, and less often in humans, vitamin E deficiency may also cause a myopathy ( ). This is described as a reversible myopathy with occasional necrotic muscle fibres and typical electron-dense membrane-limited inclusions between myofibrils, although the membrane is not always clear. These inclusions may be numerous and are distributed throughout the fibre. They are positive for acid phosphatase, have esterase activity and are autofluorescent; with electron microscopy, they appear as dense bodies ( Fig. 19.1 ).
Selenium Deficiency
Selenium is an essential trace element and a component of numerous selenoproteins, many of which are enzymes. Selenium deficiency, especially in combination with vitamin E deficiency, is a well-known cause of myopathy in animals, but in humans it is less well documented. Selenium deficiency may be caused by insufficient intake in areas with low soil selenium content, by malabsorption or parenteral/enteral nutrition, or in chronic disorders with oxidative stress such as alcoholism and HIV infection ( ). Muscle symptoms associated with selenium deficiency include myalgia, muscle tenderness and weakness. Serum CK may be elevated or normal. The symptoms are usually reversible by selenium supplementation. Muscle biopsy may show type 2 fibre atrophy, and mitochondrial alterations were described in one report ( ).
Malignancy
Malignant disease can be associated with various neurological manifestations involving the central nervous system, peripheral nerves, neuromuscular junctions or muscle ( ; e.g. Lambert–Eaton syndrome; see Ch. 21 ). Paraneoplastic manifestations are secondary manifestations not directly caused by the malignancy or the treatment. Immunological or endocrine mechanisms are believed to play a major role in paraneoplastic manifestations, which frequently present before the malignancy has been diagnosed. Type 2 fibre atrophy, frequently as a part of cancer-induced cachexia ( ), is a common but non-specific manifestation of various types of malignancies. Inflammatory myopathies, especially dermatomyositis, are sometimes associated with malignancy, especially pulmonary, gastrointestinal, ovarian and nasopharyngeal carcinomas ( ; see Ch. 22 ). Paraneoplastic necrotizing myopathy is a rare proximal, symmetrical and rapidly progressing myopathy with widespread muscle fibre necrosis and regeneration associated with various types of malignancies ( ; see Ch. 22 ).
Amyloidosis
Amyloid is a pathological proteinaceous substance. With Congo red it shows a specific staining pattern: under ordinary light it shows a pink or red colour and green birefringence when observed by polarizing microscopy ( Fig. 19.2b, c ). Rhodamine or Texas red fluorescence optics show enhanced fluorescence at the sites of amyloid deposition in Congo red-stained sections ( Fig. 19.2d ). Amyloid may be formed by aggregation of many different proteins and be deposited intra- as well as extracellularly in various clinical settings It is largely made up of fibrillar structures measuring 7.5–10 nm in diameter ( Fig. 19.3 ) and with a characteristic β-pleated sheet conformation.
