The neuromyopathy of hypothyroidism Some new observations

Journal of the neurological Sciences 243 Elsevie~ Publishing Company, Amsterdam - Printed in The Netherlands

The Neuromyopathy of Hypothyroidism

Some New Observations

J O H N PEARCE AND HASAN AZIZ

Combined Neurological Serrice, Hull Royal In[irmary, Hull (Great Britain)

(Received 2 January, 1969)

INTRODUCTION

In addition to the general lethargy and slowness of severe hypothyroidism there is a specific myopathy associated with muscular hypertrophy. KOCHER (1892) reported that patients with sporadic cretinism or myxoedema often showed bulky musculature, diminished muscular power and sluggish movement with or without " te tany". DEBR~ AND SEMELAIGNE (1935) described cases in childhood and reviewed the literature. Since then this syndrome which in childhood may give the appearance of "an infant Hercules" has been referred to as Kocher-Debr6-Semelaigne syndrome (THOMASEN 1948).

HOEFMAN (1897) described a similar syndrome in hypothyroid adults in which the above clinical features were associated with pseudomyotonia (a failure of muscle relaxation not improving after repeated contractions) and painful muscular cramps. He noted a similarity between the pseudomyotonia and myotonia congenita (THOMASEN 1948). The two syndromes overlap, and one may develop into the other during replacement therapy (NORRIS AND PANNER 1966).

Since most cases of myxoedema are diagnosed and treated early, such complications are rarely encountered. However, myxoedema is often of extremely insidious pro- gression, and Hoffman's syndrome may be its earliest presenting manifestation (WILSON AND WALTON 1959) when other established clinical features of myxoedema may not be obvious.

The object of this paper is to review the literature with particular reference to 2 personal cases, l of which showed histological and biochemical features not previously recorded.

CASE REPORTS Case 1

S. A., a 72-year-old retired man was admitted to the Neurology unit with a history of generalised aches and pains in the muscles for the preceding few months and weakness of the legs with severe difficulty in walking. His wife had noticed that he looked older than his age, he was getting progressively deaf and his voice had changed, being hoarse and his speech had become slurred. Over the last few years he tended to be rather lethargic and had developed intolerance to cold.

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244 J. PEARCE, H. AZIZ

Fig. I. Enlargement of both calf muscles, and coarse hyperkeratot ic skin.

On examination he had classical myxcredema facies, a large tongue, slurred speech, a hoarse voicc and modera te bilateral deafness. His skin was dry with a waxy consistency. The hair was sparse and lacked the normal lustre. Examina t ion of the higher mental funct ions revealed slow cerebration. short a t tent ion span, failure to follow two- or three-step c o m m a n d s and a very poor recall. There was no abnormal i ty in the cranial nerves.

He had marked generalised hyper t rophy of the skeletal muscles, particularly of the left deltoid, both triceps, right quadr iceps and both gastrocnemii (Fig. I ). All the muscles were exceedingly firm in consistency. There was no gross proximal weakness but there was a modera te degree o f weakness in the peripheral group of muscles in the upper limbs. There was marked myoederna on percussion of the muscles, which lasted for more than 5 sec (Fig. 2). There was a gross pseudomyoton ic reaction in which there was a prolonged relaxation phase observed when eliciting the deep tendon reflexes. There was no evidence of any sensory deficit. His gait was very slow and unstable and this was associated with unsteadiness o f the t runcal muscles with a tendency to reel backwards. The degree of disability was such that he could only walk a few yards with the aid o f a stick. There was no evidence of cerebellar ataxia in the limbs.

Laboratory investigations. The haemoglobin and blood count were normal . The ESR was 23 m m in the first hour . Serum cholesterol was 302 mg,'100ml, protein bound iodine 2.6 mg/100ml. Tests for thyroid ant ibodies were negative. Radio- iodine (~aZl) uptake at 2 h was 5 % while following s t imu- lation with 5 IU of thyrotropic ho rmone (24 h previously) was 4 % at 2 h proving that this was a pr imary myxoedema. Serum aldolase was 11 m U / m L (Boehringer), se rum glutamic oxaloacetic

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THE NEUROMYOPATHY OF HYPOTHYROIDISM 245

Fig. 2. Myoedema of left biceps muscle. Arrow shows the "dimpling" or "mounding" after percussion.

transaminase (SGOT) 227 U/ml (Reitmann and Frankel), and serum glutamic pyruvic transaminase (SGPT) 88 U/ml (Cabaud), serum creatine kinase 230 U/ml (Sigma). The electrocardiogram (ECG) showed a partial right bundle branch block.

Electrophysiological studies. An electroencephalographic (EEG) record was dominated by O-activity of 6 c/s; this was symmetrical and did not respond to visual attention, suggesting a diffuse encephalo- pathy.

Nerve conduction studies were done (room temperature 70°F) in both median (terminal latency at wrist 5.4 msec), right ulnar (35 m/see) and both lateral popliteal nerves (32 m/see). The conduction velocities were at the lower limit of normal in this laboratory. These studies were not repeated after therapy.

Electromyographic studies were also done. The percussion myoedema was found to be electrically silent. The pseudomyotonia was apparent as repetitive after-discharges on percussion of the tendons. Examination of various proximal and distal muscles indicated a widespread reduced interference pattern with short duration polyphasic potentials compatible with a myopathy.

Muscle and nerve biopsy. Specimens were obtained from the right gastrocnemius muscle and left sural nerve. Histologically the muscle showed a variety of changes. Many of the fibres were large and rounded, measuring up to 120/a in diameter, and there were also a few groups of small fibres which were necrotic and with evidence of regeneration. There was a conspicuous vacuolation of the larger fibres; the vacuoles were multiple and were mostly centrally-placed in the myofibrils The vacuoles were either empty, or in places contained granular remnants and even phagocytes. In the same and in other fibres central myofibrils were coalescent, forming twisted or wavy bands staining darkly and in cross-section producing typical 3-zoned target fibres. There were no myxoedema crescents. Small areas of grouped atrophic fibres indicating denervation were seen (Fig. 3). Occasional short chains of central nuclei were found in a few small muscle fibres (Figs. 3.4 and 5).

The sural nerve showed over 50 % loss of myelinated fibres and contained many fine regenerating axons and some naked axons. With nerve dissection segmental demyelination and remyelination was conspicuous and in some fibres myelin swellings were formed as a spindle-shaped mass, in an other- wise demyelinated segment (Fig. 6).

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Fig. 3. Variation in muscle fibre size; marked vacuolation; target fibres; one small area near centre of grouped denervation atrophy.

Fig. 4. Longitudinal section of muscle showing central vacuolation and abnormal myofibrillary pattern.

Treatment and follow up. He was treated with sodium-l-thyroxine 0.05 mg daily. Within a month of starting this treatment there was subjective and objective improvement in his clinical state. He could walk about without the aid of a stick. There was slight improvement in the higher mental functions. The muscles were less tense and showed a decrease in size which at this stage was slight but significant. The serum cholesterol was 187 mg'100 ml, SGOT 20 U/ml, SGPT 21 U.'ml, serum creatinine phosphokinase 41 U/ml and serum aldolase 3 m u r a l , suggesting a marked improvement in the biochemical parameters of the myopathy.

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Fig. 5. High powered view of vacuolated muscle fibre. Note: amorphous material at periphery and central nucleation of adjacent fibres.

Fig. 6. Sural nerve showing marked reduction of the number of myelinated axons.

The dose of thyroxine was gradually increased to 0.15 mg daily. Three months after starting treatment the improvement was found to be remarkable. The impaired higher mental functions which had amounted virtually to a gross dementia had reverted to quick cerebration, with normal orientation in time and place, and normal performance of two- and three-stage commands. There was a consider- able reduction in the size of the muscles (Table !) and their consistency was now normal. The myxoedema was less severe. His gait was normal and he could walk unaided. The biochemical parameters had returned to normal (Table 1 ). The EEG had changed to one with symmetrical normal o~-activity which responded to visual attention. However there was no significant change in the ECG.

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TABLE 1

A SUMMARY OF CLINICAL AND INVESTIGATIVE FINDINGS IN CASE l

Initial 3 months after obserL, ations start o f treatment

6 months after start o f treatment

Measurements (cm) (Circumference o f limbs ) Right arm 30 29 30 Left arm 34 30 30.5 Right forearm 30 28.5 29.5 Left forearm 30 28 28 Right quadriceps 51.5 52 49 Left quadriceps 51.5 52.5 47 Right calf 41 37 35 Left calf 38 37 34

Myoedema marked, lasting less marked, 5 sec lasting 2-3 scc absent

Gait walks 20 yards walks unaided walks up to one mile with one stick

Serum cholesterol 302 mg;100ml 173 mg:100ml 185 mg:100ml Serum creatine

phosphokinase 230 Sigma U:ml 21 Sigma U 'ml 10 Sigma U ml Serum aldolase 11 m U r a l 2.1 mUra l 2.2 mU/ml SGOT 227 U/ml 22 U:ml 32 U,ml SGPT 88 U:ml 19 U ml 13 U:ml EEG generalised 0 ~- activity

activity; does not responding to normal respond to visual visual attention

attention

C o m m e n t

T h e severe def ici t o f h i g h e r m e n t a l f u n c t i o n s a m o u n t i n g to d e m e n t i a , t he s t i f fness ,

a c h i n g a n d h y p e r t r o p h y o f the musc les , a n d b i o c h e m i c a l p a r a m e t e r s o f m u s c l e

d y s f u n c t i o n h a v e b e e n s h o w n to h a v e been r eve r sed by t r e a t m e n t .

Case 2 J. L., a 54-year-old man was seen in 1964 and was admitted to hospital with the complaint of

diffuse muscular pain and stiffness in the legs and arms, a feeling of restlessness in the legs, intolerance to cold and huskiness of voice. He was troubled by insomnia, loss of energy and constipation. Eleven years before admission, he had a partial gastrectomy and later a gastrojejunostomy was performed for biliary vomiting. Since the operation he had developed persistent post-gastrectomy symptoms, loss of weight, wasting and multiple vitamin deficiencies.

On examination he had the typical facies of myxoedema, a deep voice, diffuse pigmentation and dry skin with lack of body hair. There was no abnormality in the cardiovascular system. In the nervous system there was gross pseudo-myotonia characteristic of hypothyroidism in the muscles of all four limbs, There was a prolonged relaxation phase of the ankle jerks. There was no hypertrophy or weakness of the muscles. Tests of sensation and co-ordination were normal.

lm'estigations. The haemoglobin and blood count were normal. The ESR was 45 mm in the first hour. Serum cholesterol was 144 mg/100ml, protein-bound iodine 1.8 #g; 100 ml. Studies of thyroid antibodies (haemagglutinins) were negative. The radio-iodine uptake at 24 h was 32 ~,,, The ECG showed low voltage (the sum of the height of the QRS complexes in standard leads 1, 2 and 3 being 10 ram). Other biochemical investigations disclosed marked intestinal malabsorption and multiple deficiencies of vitamins, iron and vitamin B 12.

Electromyographic studies. The ankle jerk was recorded on a moving kymograph. The total duration of the reflex was found to be 415 msec (235-395 msec being the normal range). Nerve conduction

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studies on the median and other peripheral nerves were normal suggesting that there was no peripheral neuropathy in this patient.

Treatment. He was treated with sodium-l-thyroxine 0.1 mg daily and the dose was gradually increased to 0.3 mg daily. Serial reviews after admission showed reversal of the signs of myxoedema. The muscle cramps, pain and stiffness disappeared completely. His postgastrectomy symptoms remained.

Comment

Although his condition was complicated by post-gastrectomy symptoms this man showed clear clinical and biochemical evidence of hypothyroidism with severe muscular pain and stiffness. The causal relationship between these phenomena was established by the reversal of his muscular symptoms by thyroxine.

DISCUSSION

Disorders of voluntary muscle which may complicate hypothyroidism include: (1) Pseudomyotonic syndrome. (2) Muscular hypertrophy with variable pain and weakness and prolonged con-

traction and relaxation. In infancy this syndrome is designated the Kocher-Debr6- Semelaigne syndrome, and in adults it is known as Hoffman's syndrome.

(3) Muscular cramps which may resemble tetany. (4) A rare atrophic type of myopathy. (5) A myasthenic syndrome with poor response to edrophonium (NORRIS 1966). These various syndromes may occur singly or in combination and may be seen at

any stage in the natural history of hypothyroidism. This latter feature is important since the degree of muscular involvement does not parallel the degree of overt hypothyroidism and therefore the myopathy may be the presenting feature of the illness (WILSON AND WALTON 1959).

Certain features were found in our patients which merit discussion.

Clinical aspects

The 2 patients described here show the commoner features of the myopathy seen in adult hypothyroidism (NORRIS AND PANNER 1966). The most prominent symptoms were aching and stiffness of skeletal muscles with a variable tendency to spontaneous cramp. Slowness of all volitional movement was present in both patients, it was especially marked in Case 1 who could only walk a few yards, extremely slowly, before treatment. This patient also had clear evidence of dementia which was subsequently proved to be reversible by thyroxine and this factor may have been of some importance in determining the slowness of movement, although quite clearly it was of secondary importance to the primary involvement of skeletal muscles. It was not possible to determine with certainty whether the instability of movements of the trunk, and of movements involved in walking were the result of a muscular disorder alone, or whether they were in part caused by a cerebellar degeneration (JELLINEK AND KELLY 1960). Gross muscular weakness was not seen in our patients, but slight distal weakness of the upper limbs was apparent in one of them, and whether this was caused by myopathy or by the neuropathy, subsequently demonstrated, remains uncertain. Slowness of voluntary contraction and relaxation of the muscles was present in both

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250 J. PEARCE, II. AZIZ

patients and is interpreted on the basis of pseudomyotonia. Similarly a prolonged contraction and relaxation phase seen in eliciting the deep tendon reflexes was evident in both patients, and to this phenomenon the term pseudomyotonic reflex is applied. A great deal of confusion still exists about the meaning of pseudomyotonia, but used in the above sense as a clinical phenomenon its meaning is clear.

Electromyography (EMG), however, shows that the clinical phenomenon of pseudomyotonia may have its electrical accompaniments. The interpretation and definition of the electrical phenomena are still open to debate. In Case 1 we established the occurrence after percussion of the muscle of a continuous burst of action potentials of high frequency which had a constant rate of firing and which began and terminated abruptly, lasting 15 sec. We believe that this is characteristic of the electromyographic appearance of pseudomyotonia and it should be clearly distinguished from the more prolonged and progressively-decreasing action potentials which characterise true myotonia and are associated with the classical "dive-bomber" sound. Other workers (THOMASEN 1948; PERUGINI AND PRATI 1957; WILSON AND WALTON 1959) have noted the "dimpling" of muscle in hypothyroidism on percussion. This was very striking in our cases, and we believe that this phenomenon is quite distinct from percussion myotonia. In the myopathy of hypothyroidism percussion produces an elevated ridge in the belly of the muscle, which is sustained for several seconds and then slowly declines. The appearance produced differs from the contraction of discrete muscle fascicles seen in true percussion myotonia. On clinical grounds we interpreted this sign as myoedema. This interpretation was confirmed electromyographically when a needle was inserted into the "dimple" and showed complete electrical silence.

It may be necessary in future to modify the use of the existing terminology con- cerning the above clinical and electromyographic signs, but confusion could be avoided by restricting them to certain clearly-detined patterns such as those used in this discussion.

SALICK AND PEARSON (1967) reported a similar case of electrically silent myoedema or "mounding phenomenon" in a patient with myxoedema myopathy. There is no satisfactory explanation of the electrical silence of myoedema. It has been suggested that although action potentials are necessary for an effective contraction of the muscle, local changes in the content of the sarcolemma may occur on direct percussion without producing any electrical change. This may be akin to idiomuscular contraction in a recently dead animal (SCruFF 1858). SALICK AND PEARSON (,1967) suggest that the common denominator of muscle function in myxoedema, malnutrition and cachexia is an abnormal state of muscular irritability. An external stimulus such as a blow to the muscle causes an immediate contraction which is electrically silent. This phenomenon is usually localized to the site of percussion; however, DENNY-BROWN AND PENNYBACKER (1938) mentioned that the wave of myoedema does continue in vioo to a distant point along a muscle fibre.

Biochemical f ea tures

Previous studies of serum enzymes in acquired myopathies have shown a singular lack of elevation of these enzymes in the endocrine myopathies (PEARCE et al. 1964; PEARCE 1965). In clinical practice this generalisation remains true. However, elevations

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of serum creatine kinase activity (GRAIG AND Ross 1963; GRIFFITHS 1963) have been found in hypothyroidism, and indeed have been claimed to be a useful diagnostic test for this disorder although this remains unconfirmed. The striking elevation of the activity of this enzyme in the serum of one of our patients (Case i) may be associated with the thyroid disorder per se, but in view of the elevated serum levels of aldolase and transaminase, it is likely that at least some part of the creatine kinase elevation was due to the primary myopathy. It is possible that the high transaminase and aldolase levels were due to myocardial or liver disease in our patient, but in the light of the other clinical and biochemical findings we felt this was unlikely. Although high levels of lactic dehydrogenase have been reported in the European literature on hypothyroidism, current reviews of the myopathy of hypothyroidism are notable for the absence of any reference to alterations in serum enzymes. We would suggest that this problem is investigated further, and meanwhile we attribute these changes to im- pairment of the muscle cell membrane function which allows leakage of these enzymes from the sarcoplasm into the serum.

Pathological features

There have been few detailed studies of the histology of muscles in hypothyroidism. The available reports show variable and inconclusive findings. ADAMS et al. (1963) reported that they had no personal experience of the pathology of this disorder and in considering the literature they concluded that there were no constant pathological changes in muscle biopsies. ASTROM et al. (1961) described a proximal myopathy in such cases and found areas of focal necrosis in the muscles they studied. MEVENaERG (1929) had earlier reported a mucoid degeneration. The only claim to specific muscle lesions, is that of ASBOE-HANSEN et al. (1952) who described half-moon-shaped homo- geneous masses situated beneath the sarcolemmal sheath in skeletal muscle. These were found to contain acid mucopolysaccharides. KmCHHEINER (1962) reported similar lesions in 6 out of 10 muscle biopsies in patients with myxoedema. He also found an increased number of mast cells and oedema. KIRCHnEINER postulated that these changes were associated with increased activity of thyroid-stimulating hormone (TSH) since similar lesions were found in more than half of 98 patients with pituitary- thyroid disorders. NOgRlS AND PANNER (1966) found infrequent areas of basophilia on light microscopy, but abnormalities of myofibrillar pattern, nuclear proliferation and mitochondriai changes on electron microscopy. A metabolic or enzymatic abnormality was postulated to account for these changes, but routine histochemical studies were within normal limits.

The histological study of muscle from 1 of our patients disclosed very striking findings not previously reported. The main features were hypertrophy of individual muscle fibres associated with hyaline necrosis and regeneration of other fibres. The most remarkable feature was the presence of unequivocal vacuolation in many large fibres.

A vacuolar myopathy has been previously reported in patients with periodic paraly- sis, particularly the hypokalaemic type and in systemic lupus erythematosus, chloro- quine myopathy and glycogen storage diseases of muscle, but to our knowledge has not been found in the myopathy associated with myxoedema. In addition there was

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evidence of minor denervation changes with small groups of atrophic fibres, and loss of the myelin sheath of intramuscular nerves. The histology of the sural nerve showed loss of over 50% of myelinated fibres. Nerve dissection showed segmental demyelination.

It is well known that paraesthesiae in the hands is common in myxoedema but this is usually due to compression of the median nerve in the carpal tunnel. Standard references on the subjects of peripheral neuropathy and hypothyroidism however provide sparse information about the polyneuropathy (NICKEL AND FRAME 1963; MERRITT 1967). In clinical practice it is rarely encountered and even more rarely proved by pathological evidence. The picture of segmental demyelination presented here suggests a primary disorder of Schwann cell metabolism rather than a diffuse axonal degeneration. A similar pattern is known to occur in porphyria, beriberi, diabetes and in other metabolic disorders.

It is not claimed that the changes observed have any degree of specificity for the myopathy of hypothyroidism, but they do demonstrate a definite pathological basis for the hypertrophy and pseudomyotonic changes observed clinically. At a cellular level, we are still ignorant of the electrophysiological and biochemical changes which produce the cruder clinical and EMG phenomena of this myopathy. It is possible that detailed histochemical studies might clarify these problems.

ACKNOWLEDGEMENTS

We are indebted to Prof. J. N. Walton for permission to describe Case 2. The slides and photomicrographs were kindly supplied by Dr. Dennis Harriman.

SUMMARY

The clinical, biochemical and pathological features of 2 patients with hypothyroid myopathy are described. Some new observations have been made. These include:

(l) grossly elevated levels of serum creatine kinase and aldolase in 1 case; (2) the finding of a vacuolar myopathy in muscle biopsy sections; (3) evidence of segmental denervation in a peripheral nerve biopsy from the same

case. The significance of these observations is discussed in the light of the previous

literature.

REFERENCES

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ASBOE-HANSEN, G., K. IVERSEN AND R. WICHMANN (1952) Malignant exophthalmos; muscular change~ and thyrotrophin content in serum, A cta endocr. (Kbh.), 11 : 376.

ASTROM, K. E., E. KUGELBERG AND R. MULLER (1961) Hypothyroid myopathy, Arch. Neurol. (Chic.), 5 : 472.

DEBRI', R. AND G. SEMELAIGNE (1935) Syndrome of diffuse muscular hypertrophy in infants causing athletic appearance; its connection with congenital myxoedema, Amer. J. Dis. Child., 50: 1351.

DENNY-BROWN, D. AND J. B. PENNYBACKER (1938) Fibrillation and fasciculation in voluntary muscle, Brain, 61 : 311.

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The neuromyopathy of hypothyroidism Some new observations

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