Clinical Features

Muscle involvement is common in clinical and subclinical hypothyroidism, with more than 60 percent of patients reported to have an elevated serum CK level. The level of increase correlates with the severity of hypothyroidism and corrects when thyroid function normalizes with treatment. Symptomatic muscle disease is less common. Clinical evidence of hypothyroid myopathy occurs in 30 to 80 percent of patients. A study of clinical and electrophysiologic features prior to commencement of thyroxine therapy revealed that 45 percent of patients with hypothyroidism had decreased or absent deep tendon reflexes, 30 percent had clinical muscle weakness, 15 percent had neuropathy, and 8 percent had evidence of myopathy on electromyography (EMG).

The major clinical features of hypothyroid myopathy include weakness, cramps, aching or painful muscles, sluggish movements and reflexes, and myoedema (mounding of the muscle on direct percussion). There may be a discernible increase in muscle bulk that is most obvious in the tongue, arms, and legs. The degree of weakness is usually relatively mild and tends to involve the pelvic- and shoulder-girdle muscles. The gait tends to be slow and clumsy. Occasionally, patients have been described with more severe myopathic symptoms, including the development of rhabdomyolysis and renal failure or, very rarely, respiratory insufficiency, which may respond to hormone replacement. Muscle pain, particularly during and after exertion, is a prominent feature, and hypothyroidism should be considered in patients presenting with musculoskeletal pains of uncertain cause.

Muscle pain, stiffness, cramps, and delayed relaxation of the tendon reflexes in adult hypothyroidism is sometimes referred to as Hoffmann syndrome. Kocher–Debré–Sémélaigne syndrome is the unusual association of muscle hypertrophy with childhood hypothyroidism. The patient may have the typical clinical features of CH, with the added feature of generalized muscular hypertrophy so that the child has an athletic, almost herculean appearance.

A delay in the relaxation of muscle (pseudomyotonia) is commonly observed during assessment of the tendon reflexes in hypothyroid patients. All phases of the tendon reflex are delayed, although slowing of the relaxation phase is most apparent clinically. Pseudomyotonia differs from true myotonia in that there is reduction in the speed of both the contraction and relaxation phases, and this slowness is not increased after rest or relieved by repeated muscle contractions. EMG does not show the characteristic “dive-bomber” effect seen in true myotonia. In the pseudomyotonia of hypothyroidism, there is a continuous burst of action potentials that begins and terminates abruptly, with firing at a constant rate. Percussion of the muscle commonly causes a slow prolonged mounding effect (myoedema). This event, unlike myotonia, is electrically silent and has been attributed to derangement of intracellular calcium homeostasis.

The differential diagnosis of hypothyroid myopathy includes other causes of painful stiff muscles, such as polymyalgia rheumatica and polymyositis. Attention has been directed to the frequency of neuromuscular symptoms in patients with subclinical hypothyroidism, and the suggestion has been made that such patients should be treated early not only to prevent progression to frank hypothyroidism but also to improve neuromuscular dysfunction.

Investigations

The majority of patients with hypothyroidism have an elevated serum CK level, even when the myopathic features are not clinically obvious. In symptomatic patients, the serum CK level may rise to more than 10 times the upper limit of normal. Due to the patchy nature of the myopathy, neurophysiologic assessment may show no significant abnormalities. However, in up to 30 percent of patients with hypothyroidism, “myopathic” short-duration, low-amplitude, polyphasic motor unit potentials are seen on EMG.

Pathology

In many cases of hypothyroidism, pathologic changes in muscle are subtle and nonspecific. Light microscopy may reveal increased central nuclear counts, type I fiber predominance, or type II fiber atrophy; common abnormalities on electron microscopy are the accumulation of glycogen and lipids, abnormal and increased numbers of mitochondria in perinuclear and subsarcolemmal regions, dilated sarcoplasmic reticulum, and focal myofibrillar degeneration. There may be vacuolation in many large fibers, and crescents of material containing acid mucopolysaccharides may be found beneath the sarcolemmal sheath. Often these changes resolve with thyroxine replacement therapy.

Pathophysiology

Thyroid hormone is intimately linked to carbohydrate metabolism and mitochondrial function and, possibly, to the function of the sarcoplasmic reticulum and intrinsic contractile properties of muscle. However, the structure–function relationships are still incompletely understood, although it is assumed that underlying biochemical changes in hypothyroidism lead to prolongation of the contraction and relaxation phases of muscle activity. Magnetic resonance spectroscopy of hypothyroid muscle shows a low intracellular pH in resting muscle and delayed glycogen breakdown in exercising muscle. In addition, mitochondrial oxidative capacity is reduced in hypothyroidism. Low levels of the mitochondrial transcription factor A (h-mtTFA), a proposed thyroid hormone target, occur in hypothyroid myopathy, and abnormal h-mtTFA turnover may be implicated in mitochondrial alterations in the condition. The decreased responsiveness to adrenergic stimulation and alterations in muscle carbohydrate metabolism may contribute to the impaired ischemic lactate production, weakness, exertional pain, and fatigue occurring in hypothyroidism. Hypothyroidism is associated with changes in myosin, lactate dehydrogenase, and myofibrillar ATPase activity. These changes may underlie the observed slowing of muscle contraction and relaxation. Both protein synthesis and breakdown are reduced in hypothyroidism, resulting in net protein catabolism.

Treatment and Prognosis

The only effective therapy for hypothyroid myopathy is to restore the patient to the euthyroid state. Most patients respond to thyroxine therapy with complete clinical and biochemical recovery; however, some patients require prolonged therapy with thyroxine before they recover from their muscle disorder and some may never regain full function. Serum CK levels correct rapidly with thyroxine replacement therapy. Some patients may develop increased muscle pain and weakness after starting thyroxine replacement, and the short-term addition of corticosteroid therapy may be helpful if this problem arises.

Entrapment Neuropathy

Evidence of entrapment neuropathy is found in around 35 percent of patients with hypothyroidism. The most common mononeuropathy is carpal tunnel syndrome involving compression of the median nerve at the wrist from deposition of acid mucopolysaccharides in the nerve and surrounding tissues. Surgical decompression for the median nerve entrapment is not usually required in patients with underlying hypothyroidism, as symptoms gradually resolve once euthyroidism is achieved.

Diffuse Peripheral Neuropathy

The peripheral neuropathy of hypothyroidism is usually a relatively mild, predominantly sensory axonal peripheral neuropathy. The symptoms of peripheral neuropathy in patients with hypothyroidism may be masked by more intrusive symptoms. Perhaps for this reason, the reported incidence of peripheral neuropathy has varied widely, ranging from 15 to 60 percent. Skin biopsy studies indicate that damage to small-diameter nerve fibers also occurs; indeed, a minority of patients may have only small-fiber involvement. In patients with a generalized large-fiber neuropathy, severity appears to correlate with the duration of the disease rather than the severity of the biochemical disorder. Multifocal motor neuropathy associated with elevated titers of IgM antibodies against GM1 and responsive to intravenous immunoglobulin therapy has been described in association with Hashimoto thyroiditis.

The pathologic changes described in hypothyroid neuropathy include axonal degeneration, segmental demyelination and deposition of mucopolysaccharides in the endoneurial interstitium and perineurial sheath. Opinions have varied as to whether axonal degeneration or demyelination is the primary pathologic process, but most reports favor a primary axonal pathology.

Myasthenia Gravis

An association between hypothyroidism and myasthenia gravis has been reported, although this is less common than the association with hyperthyroidism. The myasthenic symptoms can appear before, with, or after the development of hypothyroidism, and the severity of the myasthenia may or may not improve following treatment of the hypothyroidism.

Giant Cell Arteritis and Polymyalgia Rheumatica

An association of giant cell arteritis and polymyalgia rheumatica with hypothyroidism has long been appreciated. Clinicians managing such patients should be careful not to misinterpret the musculoskeletal symptoms of hypothyroidism as an exacerbation of previously diagnosed polymyalgia rheumatica.

Hypothyroidism and Anticonvulsant Therapy

Subclinical hypothyroidism may occur in children with epilepsy treated with valproate or carbamazepine therapy. Rare cases of central hypothyroidism believed to be secondary to treatment with oxcarbazepine have been reported. Phenytoin may also impact thyroid function, either by inducing hypothyroidism or by worsening preexisting hypothyroidism. Hypothyroidism also increases the risk of phenytoin toxicity.

Clinical Features

Muscle weakness and wasting in patients with thyrotoxicosis were observed in early classic descriptions of the condition. A degree of predominantly proximal muscle weakness probably occurs in almost every patient with hyperthyroidism. The muscle weakness may not always be sufficiently severe for the affected individual to be aware of it. Men appear to develop symptomatic myopathy more commonly than women. The thyroid overactivity can be relatively mild and of long duration, or may be present for only a few weeks before the onset of weakness. A prospective cohort study of patients with newly diagnosed thyroid dysfunction found that 67 percent of hyperthyroid patients had neuromuscular complaints, and 62 percent had objective muscle weakness. In addition, myalgia and elevated serum CK levels have been reported in hyperthyroid patients after commencement of therapy, suggesting that relative hypothyroidism may also contribute to musculoskeletal complaints in previously hyperthyroid patients.

Individuals with thyrotoxic myopathy characteristically complain of difficulty with activities involving use of the shoulder- and pelvic-girdle muscles, such as climbing stairs, rising from a low chair, or performing tasks that involve raising the arms above the head. Muscle pain and stiffness are common associated symptoms, and occasionally patients report severe muscle cramps. Symptomatic weakness of the bulbar musculature resulting in dysphagia and dysarthria is very uncommon in hyperthyroidism and usually follows the development of limb weakness, although there are reports of isolated bulbar dysfunction (sometimes of acute onset) attributed to hyperthyroid myopathy. Bulbar symptoms in hyperthyroid patients may not be due to bulbar myopathy but may have another cause. A large goiter or thymic hyperplasia may physically compress the esophagus, leading to mechanical dysphagia, or compress the recurrent laryngeal nerve, leading to dysphonia. Involvement of the respiratory muscles occurs rarely but may necessitate ventilatory support. Muscle wasting is commonly found on examination of patients and most notably affects proximal girdle muscles such as the deltoid, supraspinatus, and quadriceps muscles. Some patients, especially males, show gluteal muscle wasting, and in some patients winging of the scapula is noticeable. The presence of tremor may create the appearance of muscle fasciculations; this disappears if the limb is relaxed. The tendon reflexes are normal or hyperactive, with shortening of the relaxation phase. Other features of thyrotoxicosis may not be obvious or may be masked, for example, if the patient is on β-blocker therapy.

These neuromuscular features may resemble the progressive muscular atrophy variant of motor neuron disease. The severity of the muscle weakness may be marked, but most patients retain the ability to walk. Acute thyrotoxic myopathy is rare and some have doubted its existence, suggesting that most of the described cases had myasthenia gravis superimposed on the hyperthyroid state. Patients present with muscle weakness progressing rapidly over a few days; weakness may be profound, bulbar muscles are often affected, and the patient may develop respiratory failure. The tendon reflexes may be reduced or absent. Some patients develop an associated encephalopathic state.

In contrast to hypothyroid myopathy, the serum CK level in hyperthyroid myopathy is usually normal or reduced, although rhabdomyolysis and elevation of the serum CK level may occur. EMG abnormalities are found in most patients with thyrotoxicosis and include the typical features of myopathy.

Physiologic and Biochemical Changes in Skeletal Muscle

Skeletal muscle is a major target organ of the thyroid hormones so it is not surprising that the biochemistry, electrophysiology, and even structure of skeletal muscle can be profoundly affected by an excess of thyroid hormone. A detailed examination of this literature is beyond the scope of this review, and more detailed consideration of the subject can be found elsewhere.

Hyperthyroidism affects both the physiologic and the biochemical properties of skeletal muscle with a preferential effect on type I (slow) muscle fibers, shifting their characteristics towards those resembling fast muscle fibers. The speed of muscle contraction is enhanced and its duration is reduced. This effect underlies the clinical observation that the duration of muscle contraction after a deep tendon is struck with a tendon hammer is briefer than normal in the hyperthyroid state and prolonged in the hypothyroid state. The expression of isotypes of the myosin heavy chain is altered in hyperthyroidism to favor expression of MHC type IIX associated with fast-fiber characteristics, with this isoform replacing MHC type I associated with slow-fiber characteristics. These changes reverse on treatment.

The pattern of glycogen utilization and lactate production in muscle is also altered in hyperthyroidism. Using magnetic resonance spectroscopy, Erkintalo and associates found that skeletal muscle was less efficient in hyperthyroidism, requiring more energy to function. At rest, the concentration of phosphocreatine was reduced in thyrotoxic patients compared with controls; at the onset of exercise, the magnitude of glycolysis activation was significantly larger in those with thyrotoxicity, resulting in a marked decrease in pH. The energy cost of exercise was significantly higher in thyrotoxic patients, with greater activation of both anaerobic and aerobic pathways throughout 3 minutes of exercise. The authors concluded that muscle requires more energy to function in the hyperthyroid than euthyroid state. Evidence that in hyperthyroidism the mitochondrial transport chain is uncoupled supports this finding.

Pathology

There is no pathognomonic pathologic finding in hyperthyroid myopathy. Biopsy may be needed on occasion to exclude other pathologic processes. Microscopic examination may show no abnormality or varying degrees of fiber atrophy, fatty infiltration, and nerve terminal damage, with clubbing of the motor end-plate and swelling of terminal axons. Most patients show an increase in mitochondrial size and number in muscle fibers. In addition, features of an inflammatory myositis with a marked endomysial mononuclear cell infiltrate have been reported in a patient with biochemically proven hyperthyroidism and symptoms and signs of hyperthyroid myopathy.

Treatment and Prognosis

Nørrelund and associates undertook a serial study of muscle mass assessed by computed tomography (CT) and isometric muscle strength in patients with thyrotoxicosis before and after treatment. They concluded that in thyrotoxic patients muscle mass is reduced by approximately 20 percent and muscle strength by about 40 percent and that 5 to 9 months will elapse before normal muscle mass and power are restored following treatment. Mean resolution of muscle weakness in one series was 3.6 months in hyperthyroid patients compared to 6.9 months in the hypothyroid group. Dysphagia and dysarthria due to hyperthyroid myopathy also typically resolve after treatment.

Clinical Features

Except for concomitant features of thyrotoxicosis, the clinical picture of thyrotoxic periodic paralysis (TPP) is identical to that seen in familial hypokalemic periodic paralysis (FHPP). Males are affected much more commonly than females. Affected individuals develop recurrent attacks of flaccid weakness, which may be asymmetric and affect the lower more than the upper limbs, and the proximal more than the distal muscles. The attacks may be heralded by prodromal symptoms of muscle aching, stiffness, or cramps. The weakness usually develops rapidly and varies in severity from mild weakness to total paralysis. The muscles most vigorously used before an attack tend to be most severely affected. Bulbar, ocular, and respiratory muscles tend to be spared, although there have been occasional reports of respiratory compromise. Cardiac dysrhythmias occasionally accompany the paralytic attacks. Usually, the tendon reflexes are depressed or absent during an attack, but in some patients they remain normal. Weakness usually resolves within 24 hours, but in the wake of severe attacks weakness and muscle pain may persist for several days. Patients may be able to abort impending attacks by mild exercise.

Attacks may occur with or without a triggering factor; recognized precipitants include high carbohydrate intake, strenuous physical activity followed by a period of rest, trauma, cold exposure, infection, menses, and drugs, including amiodarone and corticosteroids. A seasonal pattern of attacks has been recognized, with episodes being more common in the summer months. There is also a characteristic diurnal pattern, with attacks frequently developing during the night while patients are in bed.

The cardinal biochemical abnormality during an attack of TPP is hypokalemia resulting from an intracellular shift in potassium. Although the serum potassium decreases during the attack, it may not always decline below the normal range. Urinary excretion of potassium is reduced with a low potassium–creatinine ratio. The neuromuscular symptoms resolve over a period of hours as potassium moves back to the extracellular space.

Between attacks, a long exercise test may prove a useful diagnostic aid. In this test, a preexercise compound muscle action potential (CMAP) is recorded from a selected muscle. After this, the patient performs maximal voluntary muscle contractions for 5 minutes, with relaxation for 3 to 4 seconds every 15 seconds or so to avoid muscle ischemia. The CMAP is then recorded every 2 minutes until the amplitude of the elicited potential stabilizes. The test is interpreted as positive if the decrement exceeds 40 percent.

The most consistent ultrastructural finding in muscles from patients with thyrotoxic periodic paralysis is a proliferation and focal dilatation of the sarcoplasmic reticulum and transverse tubular system, resulting in the appearance of vacuoles. The vacuoles are characteristically seen in paralyzed muscles and are less apparent between attacks.

Physiology and Pathophysiology

Attacks of weakness in TPP are clinically similar to those of FHPP, a channelopathy caused by inherited defects to genes encoding sodium and calcium channels in skeletal muscle. This phenotypic similarity led investigators to postulate that TPP might also be a channelopathy, albeit one that manifests only in the presence of excess thyroid hormone. It is thought that TPP patients have a genetic predisposition to the disease unmasked by independently occurring hyperthyroidism.

Gene sequencing in cohorts of largely Asian TPP patients has revealed no mutations in FHPP-causing genes, or in components of the sodium-potassium ATPase (Na ⁺ ,K ⁺ -ATPase) pump. Recently six different mutations to an inwardly rectifying potassium channel, Kir2.6, expressed strongly in skeletal muscle, were found in 33 percent of an unrelated cohort of TPP patients from the United States, Brazil, and France, 25 percent of a Singaporean cohort, but none of 31 patients from Thailand. The mutations discovered all had effects upon the stability of the muscle cell membrane, altering its excitability. The gene for Kir2.6 is transcriptionally regulated by thyroid hormone and levels of the channel are increased in hyperthyroidism, explaining why it is only in this circumstance that the mutation becomes manifest. A susceptibility locus has been identified near the gene for Kir2.1, which is also highly expressed in skeletal muscle and can associate with other K ⁺ channels, including Kir2.6 ; incorporation of Kir2.6 into the channel heterotetramer reduces the abundance of Kir2-type channels on the plasma membrane with consequences for membrane excitability.

Mutations in potassium channels appear to combine with other factors to produce the clinical phenotype. Thyroid hormones increase the activity of the Na ⁺ ,K ⁺ -ATPase, which drives K ⁺ into cells; catecholamines have a similar effect. The Na ⁺ ,K ⁺ -ATPase pump is also stimulated by insulin, hence attacks may be precipitated by carbohydrate-rich meals and exercise. In addition, testosterone appears to drive the Na ⁺ ,K ⁺ -ATPase pump, while estogren and progesterone reduce activity, perhaps explaining the male preponderance. Interestingly, men with TPP have higher levels of testosterone than men with a sole diagnosis of thyrotoxicosis. These effects on the Na ⁺ ,K ⁺ -ATPase pump sum together to increase the intracellular K ⁺ concentration and as the efflux usually permitted by outwardly rectifying K ⁺ channels is reduced, a paradoxic depolarization occurs inactivating Na ⁺ channels. As a result the hypokalemia seen in attacks of weakness in TPP is not due to loss of potassium, but rather to the shift of extracellular potassium into cells driven by the Na ⁺ ,K ⁺ -ATPase pump, which has direct implications for treatment.

Treatment

First, emergency treatments of the attack of weakness, hypokalemia, and any complications are required. TPP patients presenting with severe weakness are treated with potassium chloride to speed recovery. Urgent assessment of cardiac and respiratory involvement must be carried out and appropriate supportive management and monitoring instituted pending recovery. Potassium chloride may be administered orally or intravenously until weakness resolves. Mid-attack, TPP patients do not have a potassium deficit but rather an intracellular shift of their potassium. There is therefore a risk of rebound hyperkalemia on recovery as the potassium shift reverses. In one study patients given potassium recovered twice as fast as untreated patients, but 70 percent experienced rebound hyperkalemia. In practice this is rarely of clinical importance but most authorities recommend giving lower doses of potassium (<50 mEq total). Potassium chloride does not always abort an attack of weakness in TPP. In cases of refractory weakness, propranolol administered intravenously or orally may be effective.

Patients should also be educated about TPP and its precipitants in order to prevent further attacks. They should avoid food and drink with high salt or carbohydrate content as well as alcohol. Formal exercise is best halted until the patient is euthyroid. Propranolol (40 mg daily) reduces the likelihood of further attacks until the euthyroid state is regained. Finally, definitive treatment of the hyperthyroidism and return of the patient to the euthyroid state stop further attacks of weakness altogether although, depending upon the underlying cause, it may take months for the euthyroid state to be achieved.

Chorea

Chorea is an unusual complication of hyperthyroidism and its association with the condition is not universally accepted. Some authors suggest that it is simply an exaggeration of the fidgetiness seen in thyrotoxicosis whereas others believe that hyperthyroidism unmasks preexisting and subclinical basal ganglia dysfunction. The problem appears to be more common in women, and the underlying cause of the hyperthyroidism is most commonly Graves disease. Choreiform movements typically involve the limbs, with the face, neck, or tongue affected in some cases. There are case reports of hemichorea and bilateral ballism associated with thyrotoxicosis. The chorea usually resolves once hyperthyroidism has been controlled, but there are reports of it persisting long after euthyroidism has been achieved.

The pathophysiologic basis of hyperthyroid chorea is unknown. Given that most cases occur in autoimmune hyperthyroidism, many have assumed that the associated chorea also has an autoimmune basis. It has been suggested that chorea may be mediated by the sympathetic nervous system because β-blockers may help in controlling symptoms. A disruption of striatial dopamine receptors may have some role and dopamine receptor antagonists, such as haloperidol, have been effective in the treatment of hyperthyroid chorea. Cases in which chorea develops when a patient is hyperthyroid, resolves on treatment, and then recurs when the patient once more becomes hyperthyroid due to, for instance, poor compliance, lend support to the idea that the chorea is a direct effect of high levels of thyroid hormone on the function of the basal ganglia. This contention is supported by a single case report of chorea associated with iatrogenic hyperthyroidism due to overtreatment of hypothyroidism in an elderly woman.

Tremor

Tremor is almost invariably seen in hyperthyroidism, so is best considered a feature of the hyperthyroid state rather than a neurologic complication. The tremor seen in thyrotoxicosis can be considered an exaggerated physiologic tremor. It is postural, persists on movement (but is not present at rest), and has a frequency of 8 to 12 Hz. The tremor most commonly affects the outstretched hands and the tongue, but the lips and facial muscles may also be affected. Therapy with β-blockers provides relief, suggesting that increased β-adrenergic activity is likely to be responsible.

Other Movement Disorders

Case reports have described several other movement disorders in patients with hyperthyroidism including platysmal myoclonus and paroxysmal kinesogenic dyskinesia.

Clinical Features

Symptoms and signs of Graves ophthalmopathy are usually bilateral and begin within 18 months of the onset of Graves hyperthyroidism. Ophthalmopathy in Graves disease may uncommonly appear to be unilateral (5 to 14%), although in these cases orbital imaging usually identifies subclinical involvement of the clinically unaffected eye. The onset of ophthalmopathy may precede the development of hyperthyroidism and may also develop some years after Graves disease has been diagnosed and treated. Whether Graves ophthalmopathy may be induced or existing eye disease worsened by radioiodine treatment for hyperthyroidism remains contentious. Smoking is clearly an independent and modifiable risk factor, and the more cigarettes smoked, the greater is the risk. Patients with Graves hyperthyroidism who smoke carry a 7.7-fold increased risk for development of ophthalmopathy. The group at most risk appears to be patients treated with radioiodine who also smoke.

The majority of ocular symptoms and signs in Graves ophthalmopathy are the result of an increase in the amount of cushioning fat within the orbit and an enlargement of the extraocular muscles. Patients complain of a sensation of grittiness in the eyes, photophobia, and pressure or pain behind the eyes. The commonest features of Graves ophthalmopathy are periorbital and conjunctival edema and erythema (secondary to compression of orbital veins and resultant venous stasis), retraction of the upper eyelid (due to overactive sympathetic activity), and proptosis due to the increased volume of orbital contents ( Fig. 18-1 ). If proptosis is severe, ptosis may occur. Proptosis is defined as measured exophthalmos greater than 2 mm above the upper normal limit. It is found in approximately 20 to 30 percent of patients with Graves disease. Proptosis serves to decompress the orbit—visual loss due to compressive optic neuropathy occurs more often in those with little or no compensatory proptosis. Apart from any cosmetic problems associated with proptosis, failure of the eyelids to close completely may result in sight-threatening exposure keratopathy.

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