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Endocrine myopathies
Abstract
This chapter discusses rarer myopathies that are associated with growth hormone, insulin, parathormone, epinephrine, insulin, and testosterone. Most endocrine disorders are now detected and treated at an early stage, and muscle abnormalities are more rarely troublesome or severe. Muscle weakness in hyperthyroidism is well-recognized, with clinical evidence of weakness in up to around 75% of patients. It is more common in females than males. Up to 40% of patients with hypothyroidism have been claimed to have clinical evidence of muscle weakness. Typical symptoms include muscle stiffness, pain, and cramps, especially related to exercise or cold weather. In adults, an extreme presentation of hypothyroidism is Hoffmann's syndrome. The periodic paralysis of thyrotoxicosis is clinically similar to hypokalemic periodic paralysis. Cushing's disease, ectopic production of adrenocorticotrophic hormone (ACTH), and corticosteroid administration, all produced similar myopathic features in patients. The clinical features are typically a painless symmetrical proximal myopathy. This usually affects the legs more than the arms. There may be additional marked muscle wasting, and the more general systemic features of glucocorticoid excess. Around 50% of patients with increased growth hormones and acromegaly have proximal muscle weakness with pain and reduced exercise tolerance. Diabetic amyotrophy is primarily a neuropathy. Ischemic infarction of the thigh muscles may occur in poorly controlled diabetes mellitus. A myopathy has been associated with medullary carcinoma of the thyroid with hypercalcitoninemia.
... Historic association of AT exists with thyroid, parathyroid and adrenal dysfunction, sometimes mediated by electrolyte derangements. Recognition is important, as diagnosis is relatively straightforward, and treatment is often effective [52]. Muscle fatigue is more common than true weakness. ...
... Muscle fatigue is more common than true weakness. Normal CK and disproportionality with the degree of muscle wasting emphasizes the energetic component to the symptom [52,53]. Severe hypo-or hyperthyroidism may present with AT and bulbar and respiratory involvement is possible. ...
... Distinguishing features are rhabdomyolysis with elevated CK in hypothyroidism and brisk reflexes in thyrotoxicosis. The latter may also be a cause of periodic paralysis [51,52]. Hypokalaemia below 3.0 mEq/L often causes acute painless proximal or generalized weakness that can induce an acute necrotizing myopathy in severe cases. ...
Introduction
Potentially life-threatening disorders may present in the emergency department with acute tetraparesis, and their recognition is crucial for an appropriate management and timely treatment. Our review aims to systematize the differential diagnosis of acute non-traumatic tetraparesis.
Results
Causes of tetraparesis can be classified based on the site of defect: upper motor neuron (UMN), peripheral nerve, neuromuscular junction or muscle. History of present illness should include the distribution of weakness (symmetric/asymmetric or distal/proximal/diffuse) and associated clinical features (pain, sensory findings, dysautonomia, and cranial nerve abnormalities such as diplopia and dysphagia). Neurological examination, particularly tendon reflexes, helps further in the localization of nerve lesions and distinction between UMN and lower motor neuron. Ancillary studies include blood and cerebral spinal fluid analysis, neuroaxis imaging, electromyography, muscle magnetic resonance and muscle biopsy.
Conclusions
Acute tetraparesis is still a debilitating and potentially serious neurological condition. Despite all the supplementary ancillary tests, the neurological examination is the key to achieve a correct diagnosis. The identification of life-threatening neurologic disorders is pivotal, since failing to identify patients at risk of complications, such as acute respiratory failure, may have catastrophic results.
... Previous studies have suggested that thyroid hormone affects intestinal motility by regulating the intestinal nervous system and changing smooth muscle function and gastrointestinal transit complex movement in the interdigestive period. However, many studies have shown that hypothyroidism is related to delayed gastric emptying, decreased intestinal peristalsis frequency and prolonged oral blindness time (34,35), and these symptoms precisely point to the most common gastrointestinal symptom of hypothyroidism, namely constipation. Lauritano et al. found that patients with hypothyroidism are more likely to have abdominal distension when SIBO is positive, but they did not observe differences in constipation symptoms. ...
Objective
To evaluate the small intestinal bacterial overgrowth (SIBO) of subclinical hypothyroidism of pregnant women, and explore their possible relevance.
Methods
In total, 224 pregnant women with subclinical hypothyroidism during pregnancy (study group) and 196 pregnant women whose thyroid function was normal (control group) were enrolled in this study. Lactulose-based hydrogen and methane breath test was performed to evaluate the growth of intestinal bacteria. The serum-free thyroid hormone (FT4), thyroid-stimulating hormone (TSH), thyroid peroxidase antibody (TPOAb), body mass index (BMI) and gastrointestinal symptoms were detected and recorded.
Results
The positive rates of SIBO were 56.7% and 31.6% in study group and control group, respectively. The levels of C response protein (CRP), abdominal distension and constipation in study group were higher than those in the control group. The risk of abdominal distension and constipation in SIBO-positive pregnant women were higher than that in SIBO-negative pregnant women, and the BMI of SIBO-positive patients in the two groups was lower than that of SIBO-negative patients in each group. In addition, the TPOAb-positive rate and TSH levels were higher but the FT4 level was lower in SIBO-positive patients compared to SIBO-negative patients in study group.
Conclusion
The occurrence of subclinical hypothyroidism is related to SIBO, and the excessive growth of small intestinal bacteria may affect gastrointestinal symptoms.
Clinical Trial
http://www.chictr.org.cn/index.aspx, identifier ChiCTR1900026326.
Endocrine disorders may sometimes present with neurological symptoms due to involvement of either the central or peripheral nervous system. Neurological manifestations of endocrine disorders are highly variable, may be serious, and occasionally cause a medical emergency. The initial symptoms of an endocrine disorder can be exclusively neurological, and, therefore, prompt referral to a neurologist can ensure an early diagnosis. As most endocrine disorders are treatable, their associated neurological manifestations are potentially reversible. An awareness of the neurological manifestations associated with endocrine disorders can facilitate early diagnosis and the implementation of specific treatment, often enabling resolution of the neurological complications without permanent sequelae. This chapter focuses on the neurological manifestations of endocrine disorders including obesity, diabetes mellitus, and disorders of pituitary gland, thyroid gland, parathyroid gland, adrenal glands, and gonads.
A 28-year-old man on thyroid hormone replacement following treatment with radioactive iodine for Graves' disease developed an episode of acute exertional rhabdomyolysis. He was found to be hypothyroid and had no rise in serum lactic acid following an ischemic exercise test. With additional thyroid replacement, his ischemic exercise test normalized and his muscle symptoms resolved. This observation suggests that rhabdomyolysis in hypothyroidism may be due to a reversible defect in glycogenolysis and that hypothyroidism should be excluded in patients with rhabdomyolysis and/or myoglobinuria.
This study investigates effects of chronic low frequency stimulation (CLFS) on myosin heavy (MHC) and light chain (MLC) expression in fast-twitch muscles in hypothyroid, euthyroid, and hyperthyroid rats. The changes at both the mRNA and protein level indicated antagonistic effects of thyroid hormone and CLFS: under euthyroid conditions, CLFS mainly elicited a MHCIIb----MCHIId----MHCIIa transition. Whereas CLFS did not induce the slow MHCI in the euthyroid state, this isoform was present in the hypothyroid state and was further enhanced with CLFS indicating the suppressive effect of thyroid hormone to be stronger than the inductive influence of CLFS. Hyperthyroidism alone suppressed the expression MHCIIa and enhanced a MHCIId to MHCIIb transition. This shift to the faster MHC isoforms was only partially counteracted by CLFS. Thus, it appeared that thyroid hormone had a graded suppressive effect on the expression of MHC isoforms in the order MHCIId less than MHCIIa less than MHCI. Elevated neuromuscular activity partially counteracted these hormone effects. Changes in MLC mRNAs were consistent with those in the MHC pattern, i.e. increases or decreases in MHCIIb led to corresponding changes in the expression of MLC3f. A similar relationship existed for the slow MHCI and the slow MLC isoforms.
A group of eleven patients in end-stage renal failure who developed proximal weakness is described. The muscle weakness in all cases was shown to be myopathic in nature by quantitative electromyography. Four of the patients presented with muscle dysfunction and were found to have severe osteomalacia secondary to renal disease. In these patients vitamin D in high doses produced some improvement in muscle weakness. In the other patients who were on maintenance dialysis, muscle weakness improved dramatically after renal transplantation or dialysis with deionized water. There were no quantitative differences between the two groups as far as muscle weakness was concerned. However it is suggested that metabolic bone disease may be one pathogenic factor in the first group and that some aspect of renal failure per se (or its treatment by dialysis) may predominate in the second and contribute to the first.
We describe a patient with bilateral orbital myositis, multiple cranial neuropathies, a sensory polyneuropathy, serum and cerebrospinal fluid paraproteins, and high-grade non-Hodgkin's lymphoma. Neurologic symptoms began more than 1 year before diagnosis of the lymphoma. Results of extraocular muscle biopsy showed extensive destruction of myofibers and granulomatous features, with no evidence of direct tumor involvement. The cranial neuropathies and orbital myositis improved with immunosuppressive therapy, while the patient's tumor progressed. We believe the orbital myositis and the multiple neurologic abnormalities were paraneoplastic effects of the lymphoma. To our knowledge, this is the first case of orbital myositis identified as a paraneoplastic syndrome.
Thyrotoxic periodic paralysis (TPP) is a rare complication of hyperthyroidism mainly seen in patients of Oriental origin and is rarely encountered in Western countries. TPP clinically resembles familial periodic paralysis with recurrent episodes of weakness or flaccid paralysis of especially the legs. Transient hypokalaemia is regularly observed during attacks and remission can be achieved by administration of potassium salts. The definitive treatment of TPP is to restore euthyroidism. This case describes a thyrotoxic patient who initially presented with periodic paralysis.
Thyrotoxic periodic paralysis (TPP) is an uncommon disorder characterized by simultaneous thyrotoxicosis, hypokalaemia, and paralysis and is the most common acquired form of periodic paralysis. It is usually associated with low plasma potassium levels and is often precipitated by physical activity or ingestion of carbohydrates. We reported two the cases with hyperthyroidism who applied to the emergency department with episode of flaccid quadriparalyis and the literature on this subject. In the both cases, physical and laboratory examination revealed the low serum potassium levels, sinus tachycardia and ST segment depression, diffuse goiter, flaccid quadriparalysis. Potassium chloride was applied via parenteral and oral. Meanwhile antithyroid treatment (propylthiouracil and propranolol) were given to they. In first patient, it was determined that intake of high dose diclophenac sodium was the probable precipitating factor. In the both cases, paralysis began to improve in 30 minutes and had completely resolved within about 8-10 hours of admission. Thyrotoxic periodic paralysis should be taken into consideration in the differential diagnosis of all acute episodes of motor paralysis especially in young patients. Thyrothoxic periodic paralysis is treated with cautious replacement of potassium and achievement of an euthyroid state. Early diagnosis is important for planning antithyroid treatment, protecting the patient from further episodes of paralysis and avoidance of precipitating factors.
In 1925, we had the honor of showing to the Pediatric Society of Paris¹ a baby 10 months old whose appearance seemed interesting. He presented a syndrome unknown to the pediatricians at the time. Eight years later we had the opportunity of seeing another child with symptoms of the same type.
In 1934, in the American Journal of Diseases of Children, Dr. Cornelia de Lange² published a very interesting article on "congenital hypertrophy of the muscles, extrapyramidal motor disturbances and mental deficiency."
In the present article we give a full history of our two observations of this syndrome, with photographs.
OBSERVATION 1 On Oct. 5, 1925, Claire B., aged 10 months, was admitted to the Crêche of the Hospital des Enfants Malades for treatment for stationary weight and prolapse of the rectum (fig. 1). At birth, the baby was slightly premature, weighing less than 2,000 Gm. She was
• A group of 17 patients had proximal diabetic neuropathy characterized by abrupt onset of asymmetric pain and weakness. Fourteen patients had unilateral onset that later involved the other extremity in 3 days to 8 months. All patients reported stepwise or steady progression during 2 to 18 months that was documented during serial examinations. In 16 patients, both proximal and distal muscles were involved. Sural nerve biopsy specimens demonstrated multifocal variability in nerve fiber density manifesting as nonrandom fiber loss between and within fascicles compared with age-matched controls. These findings demonstrate that patients may have a rapidly evolving course of proximal diabetic neuropathy followed by continued progression for many months and emphasize the overlap between proximal diabetic neuropathies of presumed different types. Our cases and others cast doubt on notions supporting two distinct types of proximal diabetic neuropathies represented by the rapid evolution of asymmetric weakness on an ischemic basis, in contrast to a more slowly progressive condition of metabolic pathogenesis.
• Idiopathic orbital myositis, a subgroup of inflammatory orbital pseudotumor, occurred in six patients with acuteonset periorbital pain, diplopia, and, in most cases, eyelid swelling. Proptosis, ductional restrictions, and responsiveness to oral prednisone administration were characteristic. Computed tomography and orbital ultrasonography showed enlargement of one or more extraocular muscles, with sparing of other orbital soft tissues. One patient had involvement of all recti muscles in both orbits. The distinction of orbital myositis from Graves' ophthalmopathy is made on clinical grounds, with acute orbital pain and corticosteroid responsiveness being uncharacteristic of the latter. The possibility of orbital myositis being an immune-mediated process is discussed.
IN CONTRAST to the situation in women, where the menopause marks the end of the fertile period, in men fertility persists into old age. Nevertheless old age in men is accompanied by clinical signs, such as a decrease in muscle and bone mass, decrease in sexual hair growth, and decreased libido and sexual activity, suggesting decreased virility. These clinical signs are supported by histological evidence for a decreased Leydig mass and function.
Evidence for decreased plasma testosterone in elderly men
As to biochemical evidence for decreased androgenicity in elderly men, 25 yr ago the blood production rate of testosterone was reported to be decreased, which at least partially is caused by a decrease of the metabolic clearance. Whether or not aging is also associated with a decrease in plasma testosterone concentrations has long been highly controversial. Indeed, a large series of publications in the 1960s and early 1970s reporting decreased plasma testosterone concentrations in elderly
Extensive studies have evaluated the risks, benefits, and indications for progestins and estrogens, but androgens have received minimal attention. Currently, physicians prescribe testosterone as replacement therapy for hypogonadism, and athletes often receive pharmacological amounts of androgens without medical supervision. Androgen use is prevalent and likely to increase. Concerns about the risks and benefits of androgen therapy thus led to a workshop conference on current knowledge and to target key areas for future study. This workshop conference was attended by over 180 experts in the field. This report summarizes the consensus that was developed.1 The conference was sponsored by the Contraceptive Research and Development Program of the Eastern Virginia Medical School (Norfolk, VA), the Special Progamme of Research Development and Research Training in Human Reproduction of the World Health Organization, the U.S. Food and Drug Administration, and the National Institute of Child Health and Human Develop...
This communication is based on a review of the clinical histories of 100 patients with proved pheochromocytoma seen at the Mayo Clinic between 1945 and 1965. The tumor was identified at operation in 97 patients and at autopsy in three. In 85% of cases only one adrenal gland was involved. Symptoms occurred almost always paroxysmally, the commonest symptom combination being headache, perspiration, palpitation, and pallor. The attacks were sudden in onset, generally less than one hour in duration, and of variable frequency. Basal metabolic rate and sugar concentration in the blood were increased in more than half of the patients. The neurological conditions most likely to be confused with pheochromocytoma include vasodilating headache, intracranial tumor, diencephalic-autonomic epilepsy, hypertensive encephalopathy, focal arterial brain disease, and anxiety state.
The present study investigates 14 patients on intermittent haemodialysis. Pre-dialysis blood and muscle samples were taken for determining plasma free- and acetylcarnitine levels. The tissue fragments were used for light and electron microscopy studies. Our results support the findings of other investigators that patients on haemodialysis generally display decreased free- and acetylcarnitine levels both in plasma and skeletal muscle when compared with control values. Muscle carnitine deficiency was apparently more severe in the longer-term haemodialysis patients. Moreover, a significant correlation (p < 0.05) between plasma and muscle free-carnitine values was found. Morphologically no pathological alterations were observed in the muscle fibres in 13 of the patients. Light and electron microscopic studies of the muscle fibre of the 14th patient showed a typical nemaline myopathy with rod bodies in the cytoplasm. The muscle free-carnitine concentration in this patient was among the lowest of the group.
Immunosuppressive treatment of thyroid-associated ophthalmopathy with high doses of oral prednisone has a response rate of 65% at the expense of major side effects. Retrobulbar irradiation is almost devoid of side effects and has an identical response rate of 65%. Newer treatment modalities have a similar response rate, except cyclosporin A which is effective in only 22% of patients. Intravenous pulses of methylprednisolone might be useful in optic neuropathy. Intravenous immunoglobulin and subcutaneous octreotide, although reasonably well tolerated, are laborious and expensive. Consequently, retrobulbar irradiation is still the treatment of choice in moderately severe cases; it is contra-indicated in diabetes mellitus. The efficacy of immunosuppression can be increased by combination therapy (e.g., prednisone + irradiation). Another way of increasing efficacy is restriction of immunosuppression to those patients who are likely to respond, i.e., patients with active eye disease. Disease activity can be assessed by the clinical activity score and various imaging techniques like orbital octreoscan and magnetic resonance. The accuracy of these methods in predicting outcome of immunosuppression still has to be determined in prospective studies in a sufficient number of patients.
With the passage of time the clinical characteristics of primary aldosteronism have been clearly defined. The condition is an easily recognized and fascinating form of curable hypertension. A small number of cases of primary aldosteronism with severe secondary renal damage will present difficulties in diagnosis. This should not distract attention from the cases in which the diagnosis is simple and straightforward. In three quarters of these cases a dramatic cure is produced by surgical removal of a small adrenal cortical adenoma. In the remainder significant improvement can be expected following surgery. Pitfalls in diagnosis have been charted.
We describe two women with acquired partial lipodystrophy, one with significant myopathic symptoms and signs. Muscle biopsy of deltoid and quadriceps was performed in each case. The light microscopy findings were of type 1 and type 2 fibre hypertrophy, with an increase in intracytoplasmic fat in both cases. Electron microscopy showed normal fibres, with accumulations of electron-lucent fat droplets between the myofibrils. The cause of the lipodystrophies is uncertain, but myopathy may be a feature, and muscle biopsy studies may help in further defining the syndrome.
An aminopeptidase was purified from bovine skeletal muscle by ammonium sulfate fractionation and by successive chromatographies of DEAE-cellulose, Sehacryl S-200, phenyl-sepharose CL-4B, hydroxyapatite and Hi-Trap chelating HP columns. The aminopeptidase was purified about 14-fold over the crude extract with a yield of 1.0% activity. The molecular mass of the enzyme was found to be 58 kDa on SDS-PAGE. The enzyme activity was enhanced by the addition of some anions, such as Cl−, NO3− and SCN−, which is the most unique property of this enzyme. While, the activity was strongly inhibited by bestatin, PMSF and puromycin, suggesting that it was a serine protease. In addition, this enzyme was identical with leukotriene (LT) A4 hydrolase, converting LTA4 to LTB4.
CROSS-INNERVATION experiments have convincingly demonstrated the importance of the nerve in determining the differential properties of skeletal muscle myosin. The role of hormones in deciding the phenotypic character of muscle myosin has received considerably less attention than that of the neural factors. Recent studies have shown that short-term alterations in thyroid status results in significant changes in cardiac muscle myosin1-4. In contrast, some of those investigations also used skeletal muscle, but no apparent effects on skeletal muscle myosin were detected2,4. But the greater half-life of skeletal muscle myosin would require a longer time than cardiac myosin to manifest these changes5. We have studied the effects of longer term hypothyroidism and hyperthyroidism on skeletal muscle myosin. We report here that alterations in thyroid status influence the quality of skeletal muscle myosin. Our observations suggest possible thyroidal involvement, along with or through neural trophic factors, in determining the phenotypic properties of skeletal muscle myosin.
Drug-induced diseases constitute up to 5% of hospital admissions,a figure which almost certainly understates the total morbidity due to drugs1. Sever drug-induced myopathies are uncommon, but milder forms may be more prevalent than is generally appreciated, since skeletal muscle constitutes some 45% of total body-weight and has a major metabolic role in addition to its mechanical function2. Knowledge of possible effects of drugs on the neuromuscular system is of increasing importance both because the range of therapeutic agents continues to expand and because the resulting syndromes, through usually reversible at the outset, may progress and lead to grave consequences if the drug responsible is not stopped. Drug-induced neuropathies3 will not be considered here, but it will be appreciated that muscle weakness may also be feature of such disorders and that some drugs may cause both a neuropathy and a myopathy. The features of the main drug-induced syndromes are summarised in the table. To these one could justifiably add the unwanted effects of srugs given for the treatment of central-nervous-system or neuromuscular disorders per se-e.g., the cholinergic block which may be produced by anticholinesterases alone or with corticosteroids in the myasthenic,4 and the profound weakness which may supervene after relief of spasticity with dantrolene sodium5.
Thyroid hormones may participate in the regulation of beta-adrenergic receptors in skeletal muscle sarcolemmal membrane. Since skeletal muscles are not innervated by sympathetic nerve endings, the biochemical mechanism involved in the control of beta-adrenergic receptors by thyroid hormones appears to be mediated by thyroid-induced regulation of serum levels of catecholamines.
Changes in the electromyograms and motor nerve conduction velocities in 12 patients with diabetic amyotrophy suggested mild distal and moderate proximal neuropathy in the lower limbs. Histological and histochemical findings in the vastus medialis muscles were consistent with denervation. Electron microscopical examination of the vastus medialis muscles in 6 patients revealed myofibrillar degeneration. One patient had abnormal mitochondria and tubular aggregates. The basement membranes of the intramuscular capillaries were thickened in all but 1 patient. Histochemical staining of the myoneural junctions showed changes consistent with degeneration and regeneration. We conclude that diabetic amyotrophy is a distinct clinical entity and is secondary to metabolic derangement rather than diabetic microangiopathy.
1. Quadriceps strength, relaxation rate, fibre-type composition and energy-turnover rate during a submaximal contraction have been measured in hypo- and hyper-thyroid patients and compared with findings in normal subjects.
2. Six out of eight hypothyroid patients had normal strength whereas four out of five hyperthyroid patients were weak.
3. Relaxation rate was decreased in all the hypothyroid patients but increased in only three out of five hyperthyroid patients.
4. In hypothyroidism there was a marked reduction in the percentage contributed by type II fibres to muscle cross-section, partly due to type II atrophy but also due to a decrease in the relative frequency of type II fibres. In hyperthyroidism both fibre types tended to atrophy.
5. The rate of ATP turnover during submaximal contraction held to fatigue was reduced in hypothyroidism. This was probably due to decreased ATP utilization rather than an impaired supply of energy-supplying substrates. In hyperthyroidism the rate of ATP turnover was increased.
6. Altered relaxation rate and ATP-turnover rate may be explained on the basis of changes in myosin ATPase activity with thyroid status. Changes in muscle-fibre-type composition, as determined histochemically, could not per se account for the functional abnormalities.
The clinical entity of chronic thyrotoxic myopathy was considered rare by Waldenström in 1945. Forty eight consecutive patients with thyrotoxicosis were studied clinically and by electromyography for muscle involvement. Quantitative electromyographic techniques were used to analyse both the electromyographic activity of the muscle at a standard tension and also the single motor potential obtained in isolation at minimal effort. The interference pattern was described in simple numerical terms such as the number of potential changes/s and the mean amplitude. All cases that were thyrotoxic (both clinically and on thyroid function tests) showed the changes of myopathy on electromyography, though only 68% of the cases showed clinical myopathy consisting of muscle weakness and/or atrophy.
A patient with subclinical hypothyroidism who presented with true myotonia is described. There was no evidence that either he or members of his family had dystrophia myotonica or myotonia congenita. Treatment with thyroxine resolved his symptoms completely.
Patients with congenital generalized lipodystrophy are extremely insulin resistant. To ascertain whether this resistance is due to an insulin receptor defect, we tested four young patients with congenital generalized lipodystrophy and seven healthy persons of comparable age for the binding of 125I insulin to mononuclear leukocytes isolated from peripheral blood. Mononuclear leukocytes from patients with congenital generalized lipodystrophy bound significantly less insulin than cells from normal subjects (P less than 0.01). When patients with lipodystrophy fasted for 60 hours, the insulin binding increased. Altered insulin receptors may be responsible for the pronounced insulin resistance and the decreased synthesis of triglycerides in congenital generalized lipodystrophy.
The carbohydrate metabolism in hypothyroid patients was investigated. After an overnight fast, the blood glucose level was 24% lower and the blood lactate level was 35% lower in the untreated hypothyroid patients than that observed in the treated hypothyroid patients or in the normal subjects. There was no difference in the blood alanine or plasma free fatty acid values between the subject groups. Skeletal muscle biopsied from two hypothyroid patients with marked myopathy showed normal glycogen content, 0.83%-0.86% (normal 1.06%), but reduced activity of acid maltase, 32-50 nmoles/min/g (normal 97). Forearm ischemic stimulation applied to hypothyroid patients failed to elevate the level of lactate. The results are compatible with impaired glycogenolysis from the skeletal muscle, which may be a contributory factor in the myopathy in hypothyroidism.
Polyneuropathy is a rare but possible manifestation of severe hyperthyroidism. The patient reported here developed a polyneuropathy affecting mostly leg muscles (Basedow's paraplegia) during the course of severe thyrotoxicosis. The polyneuropathy was confirmed with sequential electrophysiological studies of nerves and muscles and by muscle biopsy. The involvement of the proximal leg muscle is also interpreted as a neuropathic or nerve-mediated process rather than a concomitant thyrotoxic myopathy.
This chapter presents the studies on the pathogenesis of Graves' opthalmopathy. The ophthalmopathy associated with thyroid disease has constituted a diagnostic and therapeutic enigma for physicians for more than a century. Most often, the condition is associated with thyroid hyperfunction accompanying diffuse goiter Graves' disease, but the severity of the eye disease often neither parallel the degree of clinical toxicity nor laboratory parameters of thyroid function. Thus, some patients with severe thyrotoxicosis appear to have no eye involvement clinically, while in others, ophthalmopathy develops or worsens while the patient is in a euthyroid state. The clinical manifestations of ophthalmopathy offer additional puzzling variations. The manifestation may be unilateral, bilateral, symmetrical, or asymmetrical. Occasionally, a unilateral ophthalmopathy precedes later bilateral involvement. Accompanying ophthalmic symptoms may include excessive lacrimation, photophobia, burning, gritty or pulling sensations, diplopia, pain because of corneal abrasion, and loss of visual acuity. In cases with diplopia, the eye muscles lying at the bottom of the orbit, that is, the inferior rectus and inferior oblique tend to be preferentially affected, and the associated muscle dysfunction causes downward rotation of the globe or inability to rotate the eyes upward and upward-outward.
A 29-year-old female with type I diabetes mellitus developed pain, focal tenderness, and swelling in the posterior left thigh. Subsequent evaluation included a muscle biopsy, which revealed large confluent areas of necrosis and edema, compatible with a diagnosis of diabetic muscle infarction (DMI). Diabetic muscle infarction (DMI) is an unusual neuromuscular complication of diabetes mellitus. DMI begins with the acute onset of focal pain and swelling in the thigh. The anterior compartment (quadriceps muscle group) or posterior compartment (hamstring muscle group) are most frequently involved. The focal region of muscle damage can be noninvasively viewed by magnetic resonance imaging and radionuclide scans. Muscle biopsy demonstrates large confluent regions of muscle necrosis and edema. DMI needs to be differentiated from other processes that can cause leg pain in a diabetic patient.
A female patient with acanthosis nigricans, insulin resistant diabetes, and generalized lipoatrophy is reported. The patient developed skin pigmentation and acanthosis nigricans around the age of 34. Arthralgia, muscle weakness, and peripheral neuropathy were also present when she first visited us at 36 years of age. Dermatomyositis, systemic sclerosis, and internal malignancy were ruled out, and the diagnosis of acanthosis nigricans and insulin resistant diabetes was made. Her diabetes gradually worsened and, since the age of 39, she has been treated with an oral anti-diabetic drug. Around the age of 47, generalized lipoatrophy became prominent. Insulin receptor studies ruled out insulin resistant diabetes type A and B. At this point, we diagnosed this patient as having lipoatrophic diabetes, which is a syndrome characterized by insulin resistant diabetes, acanthosis nigricans, generalized lipoatrophy, and other metabolic disturbances. The control of her diabetes has been poor, and diabetic neuropathy and lipoatrophy-induced painful skin lesions such as clavus and tylosis have been persistent. The present case indicates the importance of careful skin examinations in the diagnosis of this syndrome.
A group of 17 patients had proximal diabetic neuropathy characterized by abrupt onset of asymmetric pain and weakness. Fourteen patients had unilateral onset that later involved the other extremity in 3 days to 8 months. All patients reported stepwise or steady progression during 2 to 18 months that was documented during serial examinations. In 16 patients, both proximal and distal muscles were involved. Sural nerve biopsy specimens demonstrated multifocal variability in nerve fiber density manifesting as nonrandom fiber loss between and within fascicles compared with age-matched controls. These findings demonstrate that patients may have a rapidly evolving course of proximal diabetic neuropathy followed by continued progression for many months and emphasize the overlap between proximal diabetic neuropathies of presumed different types. Our cases and others cast doubt on notions supporting two distinct types of proximal diabetic neuropathies represented by the rapid evolution of asymmetric weakness on an ischemic basis, in contrast to a more slowly progressive condition of metabolic pathogenesis.
The density of calcium ATPase was measured in the terminal cisternae of extensor digitorum longus (EDL) and soleus muscles from normal and thyrotoxic rats. The experiments tested the hypothesis that the rate of relaxation of these muscles following contraction, at temperatures above 22 C, is correlated with the density of calcium ATPase in the sarcoplasmic reticular membrane. In soleus fibres there was a progressive increase in calcium ATPase density, measured with immuno-electronmicroscopic techniques, of more than two-fold after 3 weeks of daily injections with triiodothyronine (T3). There was a parallel decrease in the relaxation time (from 80% to 20% of peak tension) of the tetanus: the parameters were closely correlated (r = 0.998) during the 3-week period. The rate of relaxation of the twitch also doubled and was correlated with the increase in gold particle density at the end of the 3-week injection period. However, twitch relaxation slowed during the 1st week of T3 injection and was not correlated with gold particle density at that time. The changes in calcium ATPase density and relaxation times in EDL fibres were small and largely insignificant. In contrast to relaxation, an increase in the rate of rise of tension is soleus was complete after only 2 weeks of T3 injection. The results show that the relaxation of tetanic tension is closely correlated with the calcium uptake capacity of the sarcoplasmic reticulum and that thyroid hormone acts more rapidly on factors regulating the rate of rise of tension than on those regulating tension relaxation and the density of calcium ATPase in the terminal cisternae.
We investigated the effects of growth hormone and thyroid hormone on the synthesis of Na(+)-K+ pumps in rat soleus muscle. Hypophysectomized rats were treated for 11 days with saline, human growth hormone (hGH; 140 micrograms/day), thyroxine (T4; 3 micrograms/day), or hGH plus T4. Age-matched nonhypophysectomized control rats received no treatment. The concentration of Na(+)-K+ pumps was reduced by 75% in the hypophysectomized rats. Treatment with hGH alone or combined with T4 restored the growth rate, whereas T4 alone did not stimulate growth. In contrast, the synthesis of Na(+)-K+ pumps was only responsive to T4 treatment when given alone or in combination with hGH. The concentration of Na(+)-K+ pumps increased around threefold in the T4-treated groups and showed full normalization to the control level after 11 days of treatment. It is concluded that growth hormone does not play any major role in the de novo synthesis of Na(+)-K+ pumps in skeletal muscle. More important, thyroid hormone, also at physiological doses, seems to be the major endocrine factor determining the concentration of Na(+)-K+ pumps in skeletal muscle.
In one hospital over a 15-month period, four out of nine patients ventilated for acute severe asthma developed acute hydrocortisone myopathy. All patients had received less than 1.0 g day-1 hydrocortisone. Affected patients had severe generalized weakness which recovered over 1-6 weeks. When myopathic and unaffected subjects were compared, there was no clearcut difference with respect to age, sex, types of drug used, serum potassium levels, duration of ventilation and muscle paralysis, total dose of vecuronium bromide, or mean daily doses of hydrocortisone. The main difference between the two groups was in the total doses of hydrocortisone. The myopathic patients all received greater than 5.0 g hydrocortisone (range 5.4-10.2 g) and the others less than 4.0 g (range 0.9-3.5 g). The possibility that neuromuscular blockade might predispose to the development of myopathy is discussed. Hydrocortisone myopathy can occur when less than 1.0 g day-1 is used, and even with as little as 5.4 g given over 6 days.
Transitions from embryonic and neonatal to adult-type-II isomyosins are known to be related to the increase in the thyroid hormone plasma concentration during postnatal development. These transitions have been shown, however, to occur at different times, depending on the muscle, suggesting that each muscle responds differently to the thyroid hormone. We have investigated quantitatively the effects of experimental hypothyroidism and hyperthyroidism on isomyosin transitions from birth until the 45th postnatal day in eight rat muscles: diaphragm, intercostals, gastrocnemius medialis, soleus, plantar muscles of the foot, tongue muscle, levator ani and bulbocavernosus complex, and masseter.
Hypothyroidism delayed the isomyosin transitions in all the muscles examined, particularly in the sexually dimorphic muscles (levator ani and bulbocavernosus complex and masseter). However, it did not eventually inhibit isomyosin transitions, indicating that the thyroid hormone was not an absolute requirement for these to occur.
Hyperthyroidism had only a slight effect on isomyosin transition in the diaphragm, and accelerated such transitions in the other muscles. The transition curves of all the muscles investigated, except those of the sexually dimorphic muscles, became similar to that of the diaphragm, demonstrating that the various muscles did not display the same sensitivity to the thyroid hormone but were regulated by it in the same way. The isomyosin transitions in the sexually dimorphic muscles remained late in comparison to that in the diaphragm, which suggests a more complex regulation. The effect of hyperthyroidism was not permanent and could be reversed, by interruption of the treatment, to a greater or lesser extent depending on the muscle.
In all muscles containing slow-type-I isomyosin, hypothyroidism had no effect on this isomyosin synthesis, whereas hyperthyroidism inhibited it. This inhibition ceased rapidly after the interruption of the treatment.
Exercise has been shown to be effective in preventing glucocorticoid-induced atrophy in muscles containing high proportions of type II or fast-twitch fibers. This investigation was undertaken to further evaluate this response in type IIa and IIb fibers, determined by histochemical staining for myofibrillar adenosinetriphosphatase with alkaline and acid preincubation. Steroid [cortisol acetate (CA), 100 mg/kg body wt] and exercise (running 90 min/day, 29 m/min) treatments were initiated simultaneously for 11 consecutive days in female rats. Fiber distribution and area measurements were performed in a deep and superficial region of plantaris muscle. The exercise regimen spared approximately 40% of the CA-induced plantaris muscle atrophy. In the deep region, the fiber population, which contained approximately 13% type I (slow-twitch), 24% type IIa, and 63% IIb fibers, was not affected by either treatment. In the superficial section, which consisted solely of type II fibers, the proportion of type IIa fibers was higher (27 vs. 9%, P less than 0.01) in the steroid- than in the vehicle-treated groups. Within each region, type IIa fibers were less susceptible to atrophy than type IIb fibers, and within each fiber type, the deep region had less atrophy than the superficial region. Type I fibers were unchanged by steroid treatment. For type IIa fibers, exercise prevented 100% of the atrophy in the deep region and 50% in the superficial region. For type IIb fibers, the activity spared 67 and 40% of the atrophy in these same regions, respectively. These results show that glucocorticoids are capable of changing the myosin phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)
Twenty-two apparently euthyroid patients with endocrine ophthalmopathy not associated with goiter, antithyroid microsomal or antithyroglobulin antibodies, or overt thyroid disease (so-called ophthalmic Graves' disease) were tested for subclinical hyperthyroidism or hypothyroidism. We measured 131I uptake and scan, serum T3 (by RIA), and serum TSH using a sensitive (by immunoradiometric assay) assay. Three patients were found to be hyperthyroid, and 1 was hypothyroid. The remaining 18 patients, who remained euthyroid throughout the study period, were investigated for evidence for antibody-mediated immunity against thyroid antigens. We measured antibody-dependent cell-mediated cytotoxicity against fresh thyroid cells using a 51chromium release assay, thyroid membrane-reactive antibodies in an enzyme-linked immunosorbent assay incorporating solubilized thyroid membranes, and TSH receptor-binding antibodies using a RRA and carried out sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting with patient sera for antibodies reactive with 64 and 110 kDa (thyroid peroxidase) membrane proteins. Bands were demonstrated, on SDS-PAGE, at 64 or 110 kDa in 13 patients, antibody-dependent cell-mediated cytotoxicity tests were positive in 7 patients, and enzyme-linked immunosorbent assay was positive in 4 of the 17 patients tested. In addition, TSH receptor antibody tests were positive in 5 patients, none of whom had other evidence for hyperthyroidism. Finally, significant lymphocyte infiltration was demonstrated on aspiration biopsy in 3 patients. All 18 patients had positive tests in at least 1 of the immunological assays. We believe that these data support the hypothesis that endocrine ophthalmopathy always occurs in patients with overt or subclinical Graves' hyperthyroidism, Hashimoto's thyroiditis, or thyroid immunological abnormalities. Those patients previously described as having euthyroid Graves' disease should, thus, be considered to have associated thyroid immunological abnormalities even though histological confirmation (from aspiration needle biopsy) may be obtained in only a minority of the patients. The possibility that the mechanism for this close association is cross-reactivity of cytotoxic antibodies against a thyroid/eye muscle cell surface shared antigen is discussed in the context of recent evidence from the authors' laboratory.
Azathioprine is used in the treatment of thyroid-associated ophthalmopathy, but its effectiveness has not been evaluated. In the present study 20 patients with moderately severe ophthalmopathy were recruited; 10 patients received azathioprine and the other 10 matched patients served as controls. During the treatment period (lasting 1 year) and 1 year later, no changes were detected in exophthalmometer readings, visual acuity or measurement of palpebral aperture. Differential intraocular pressure fell with time in both groups. Azathioprine treatment did not significantly influence these parameters, although it did induce significant decrease in thyroid microsomal antibodies and in thyroid-stimulating hormone binding inhibiting immunoglobulin index. The study demonstrates that thyroid-associated ophthalmopathy of moderate severity, often improves with time without treatment. Azathioprine is not an effective treatment for patients with moderately severe thyroid-associated ophthalmopathy. The study emphasises the necessity for an adequately matched control population in the evaluation of therapy.
We report the case of a 62-year old man presenting with generalized muscular weakness, amyotrophy, dysarthria and dysphagia. Neurological examination showed bilateral pyramidal signs and lingual fasciculations. The clinical diagnosis was amyotrophic lateral sclerosis, since only shivers and weight loss pointed to hyperthyroidism. However, after several months the patient developed typical manifestations of hyperthyroidism. After treatment of hyperthyroidism, the neurological symptoms disappeared. Although this association is extremely rare, one must have in mind the possibility of thyroid dysfunction when studying patients with amyotrophic lateral sclerosis.
Dyspnea on exertion is a frequently reported symptom of thyrotoxicosis. In the majority of cases, there is no obvious cause of dyspnea, but as skeletal myopathy is also common in thyrotoxic patients, it has been postulated that increased dyspnea could be secondary to respiratory muscle weakness. We sought to determine whether thyrotoxic patients were in fact more dyspneic on exertion than age- and sex-matched controls, and if so, whether the increased dyspnea was secondary to respiratory muscle weakness. The study group consisted of 12 thyrotoxic patients and 12 control subjects matched for age and gender. We measured lung volumes, compliance, elastic recoil, respiratory muscle strength, maximal exercise performance, and the intensity of breathlessness (modified Borg scale) at various levels of exercise in all subjects. The respiratory muscles were weaker in patients than controls. This weakness improved in treated patients (p less than 0.05) with concomitant increases in VC, IC, and TLC (all p less than 0.05). Despite this, we found no differences in breathlessness intensity scores between patients and controls or in patients before and after successful antithyroid therapy.
The immunological mechanisms involved in Graves' ophthalmopathy are not known. To explore the pathophysiology of this disorder, we used an enzyme-linked immunosorbent assay to detect antibodies that bound to the 100,000 X g sediment fraction of porcine eye muscle. Serum from patients with Graves' ophthalmopathy had enhanced immunoglobulin binding to porcine eye muscle compared to serum from control subjects (P less than 0.0001); however, several individual normal serum samples also had elevated binding activity. Incubation of serum from some Graves' patients with skeletal muscle or liver tissue resulted in reduction in immunoglobulin binding to porcine eye muscle. Thyroglobulin and TSH reduced binding only at high concentrations. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed some obvious differences in protein bands between porcine eye muscle and skeletal muscle. Serum from many normal subjects and patients with autoimmune thyroid disease formed bands with skeletal muscle protein fractions on immunoblotting, and no specific bands were found using serum from Graves' ophthalmopathy patients. Immunoblots of Graves' patients' serum after reaction with either porcine skeletal or eye muscle showed no reactivity with thyroglobulin (200K and 320K) or thyroid microsomal antigen (105K). Instead, immunoblots of eye muscle and serum from Graves' patients, with or without eye disease, showed two bands at 64K and 73K, which were shared by serum from normal subjects. In addition, several unique eye muscle determinants were detected in serum from 6 of 13 Graves' disease patients analyzed. These unique bands usually had mol wt of less than 50K, and 5 of the 6 patients whose serum reacted with these determinants had significant ophthalmopathy. Our findings support the presence of potential antigenic differences between eye muscle and skeletal muscle accounting for the immunological specificity of eye muscle as a target in Graves' ophthalmopathy.
Sodium currents were recorded in rat fast and slow twitch muscle fibers. Changes in the membrane potential around the resting potential produced slow changes in the sodium current amplitude due to alterations of the slow inactivation process that was increased by steady depolarization and removed by prolonged hyperpolarization. In contrast, classical fast inactivation was not operative around the resting potential, and depolarizations of greater than 20 mV were required to close half of the channels by fast inactivation. Because slow inactivation is operative around the resting potential of mammalian muscle fibers, it may partially explain why small depolarizations, such as those that occur in some patients with periodic paralysis, can reduce excitability.