Werner & Ingbar's The Thyroid: A Fundamental & Clinical Text, 9th Edition

41.The Neuromuscular System and Brain in Thyrotoxicosis

David F. Gardner

The earliest reports of thyrotoxicosis by Graves (1) and von Basedow (2) recognized muscle weakness as an important presenting complaint, and neuromuscular symptoms continue to be prominent clinical findings in patients with thyrotoxicosis. The frequency and severity of the abnormalities that have been described in these patients have varied considerably, undoubtedly due to variations in the severity of the thyrotoxicosis and in the ways that the diagnosis was established. Most patients with thyrotoxicosis who have abnormalities in neuromuscular function have Graves' disease, but the abnormalities occur in patients with thyrotoxicosis of any cause. This chapter focuses primarily on the direct effects of thyrotoxicosis on muscle and the central nervous system, but it also addresses primary neuromuscular disorders associated with thyrotoxicosis, specifically myasthenia gravis and thyrotoxic periodic paralysis.



Symptoms or signs of muscle weakness occur in a high percentage of patients with thyrotoxicosis. In 54 consecutive patients evaluated by Ramsey, 50% gave a history of muscle weakness, and 63% had objective evidence of weakness or proximal muscle wasting (3). Similar data have been reported in numerous subsequent studies, with some variability in terms of the percentage of patients with subjective versus objective findings (4,5,6,7). A recent prospective study documented similar findings, with 67% of patients reporting weakness and 81% having decreased strength in at least one muscle group (8). In 36% of the patients in that study, muscle symptoms were the main reason for consulting a physician. Weakness is primarily proximal and often out of proportion to the degree of objective muscle wasting (3,9). Typical symptoms are similar to those in patients with other proximal myopathies and include difficulty arising from a sitting or supine position and raising the arms over the head, as well as generalized muscle aching. Distal muscle weakness is usually less prominent than proximal (3) and tends to occur later in the course of the illness (4). Myopathic symptoms usually appear after the onset of the more typical clinical symptoms of thyrotoxicosis (3,10), although muscle weakness may be the presenting complaint (5,8,9). The degree of muscle weakness correlates more with the duration of the thyrotoxicosis than its biochemical severity (4,10), and weakness appears to be more common in men with thyrotoxicosis than women (9,10).

Less commonly, patients may have bulbar and esophagopharyngeal muscle weakness (11,12,13), with dysphonia, dysphagia, and dysarthria. Reversible diaphragmatic muscle weakness has been well documented and may contribute to the common complaint of dyspnea in patients with thyrotoxicosis (14,15,16). Substantial improvement in diaphragmatic movement and muscle strength was recently demonstrated in a study of 20 patients with thyrotoxicosis caused by Graves' disease studied before and after restoration of euthyroidism with carbimazole (14).

On physical examination, objective weakness is typically out of proportion to the degree of muscle atrophy, although some patients with long-standing thyrotoxicosis may have significant loss of muscle mass, particularly in the proximal musculature of the shoulders and the pelvic girdle. Distal weakness may be evident in the wrist flexors and extensors as well as the interosseous muscles (3). A minority of patients have muscle fasciculations, but they are usually overshadowed by the fine tremor of the hands and feet that is so characteristic of thyrotoxicosis. Signs of bulbar dysfunction may include dysphagia, dysphonia, and evidence of aspiration. Sphincter function is usually maintained (4). Deep tendon reflexes may be normal or hyperactive, but there is typically shortening of the relaxation phase (17,18).

An acute thyrotoxic myopathy has been described, with a predominance of bulbar symptoms and generalized weakness, usually in patients with preexisting thyrotoxicosis (4,19). It is likely that many of these patients had myasthenia gravis in addition to thyrotoxicosis, because of the predominance of bulbar symptoms and responsiveness to neostigmine. Rhabdomyolysis with acute renal failure has been reported in a single patient with thyroid storm (20).

The pathophysiology of muscle disease in thyrotoxicosis is probably multifactorial. That excess thyroid hormone has catabolic effects on muscle has been known for many years, with negative nitrogen balance being a consistent finding in virtually all studies (21) (see Chapter 38). Although protein synthesis is increased in thyrotoxic patients, protein degradation is accelerated to a greater degree, resulting in a net loss of muscle protein. This loss of muscle mass provides a ready explanation for both the subjective and objective muscle weakness that is so common in patients with thyrotoxicosis. Even mild degrees of thyrotoxicosis induced by exogenous administration of thyroid hormone result in negative nitrogen balance and sustained loss of muscle mass (22). Additional adverse effects of excess thyroid hormone may be related to the hormone's effects on the transcription of genes controlling calcium regulatory proteins and myosin heavy chain synthesis in muscle (23,24). Evidence that β-adrenergic antagonist drugs ameliorate muscle weakness in patients with thyrotoxicosis suggests that β-adrenergic stimulation and perhaps also cyclic adenosine monophosphate activation of muscle contribute to clinical myopathy (23,25). Finally, the multiple effects of thyroid hormone on the metabolism of muscle cells may contribute to the myopathy (4,10,26,27,28). In thyrotoxicosis, glucose uptake and utilization by muscle are increased, as is glycogenolysis, and glycogen depletion is seen in muscle biopsy samples. In addition, mitochondrial oxidation is increased, with an associated increase in muscle heat production. Lipid oxidation, protein catabolism, and purine catabolism are also accelerated, and intracellular adenosine triphosphate (ATP) concentrations are low. In sum, in muscle, substrate uptake and utilization are increased, but the latter is less efficient than normal. Therefore, ATP generation and muscle contractility are decreased. The specific metabolic perturbations and exactly how they cause myopathy are not known.

Laboratory studies relating to muscle function and integrity are usually not revealing. Serum creatine kinase and myoglobin concentrations are usually normal (4,29), and a high serum concentration of either in a patient with thyrotoxicosis should raise the suspicion of a superimposed condition such as rhabdomyolysis (20) or an inflammatory myopathy (30).

Light microscopic findings on muscle biopsy may be normal or reveal mild, nonspecific changes. These include fiber atrophy (both type 1 and type 2), varying degrees of fatty infiltration, variability in the size of muscle fibers, occasional fiber necrosis, glycogen depletion, and lymphocytic infiltration (3,4,7,9,26). Electron microscopic studies usually show elongated mitochondria, an overall decrease in the number of mitochondria, swelling of transverse tubules, subsarcolemmal glycogen deposition, and papillary projections from the sarcolemma (4,31,32,33). None of these light microscopic or electron microscopic changes is specific for thyrotoxicosis.

Numerous electromyographic and nerve conduction studies have been performed on thyrotoxic patients with myopathy over the past 40 years (5,6,8,10,34,35). Motor and sensory nerve conduction is typically normal. Consistent findings on electromyography include short duration motor unit potentials and increased frequency of polyphasic potentials. Spontaneous electrical activity including fasciculations and fibrillations is uncommon. These findings are not specific for thyrotoxic myopathy, and some patients with clinical myopathy have normal electromyographic findings and others with normal strength have abnormal findings. The prevalence of electrical abnormalities is higher when the proximal rather than the distal musculature is evaluated. In older studies, a majority of patients with thyrotoxicosis had electromyographic abnormalities indicative of myopathy, but in a 2000 study only 2 of 21 patients (10%) had these abnormalities (67% complained of weakness, and 81% had objective weakness of at least one muscle group) (8). This same study found “neuropathic” changes in 24% of the patients, considerably higher than older studies.

There is no specific treatment for thyrotoxic myopathy, other than correction of the thyrotoxicosis, although some patients feel stronger when treated with a β-adrenergic antagonist drug alone (25). In the vast majority of patients with uncomplicated thyrotoxicosis, the clinical signs of myopathy and electromyographic abnormalities resolve completely within 3 to 6 months after restoration of normal thyroid function (3,6,8,36).

Myasthenia Gravis

Graves' disease and myasthenia gravis, disorders characterized by autoimmunity against the thyrotropin (TSH) and acetylcholine receptors, respectively, have been linked epidemiologically. The presence of thymic enlargement (17,21), an association with HLA-B8 and -DR3 haplotypes, and the presence of antireceptor antibodies in both disorders suggest a common autoimmune pathophysiology. The prevalence of Graves' thyrotoxicosis in patients with myasthenia gravis ranges from 3% to 10% (37,38,39,40). The prevalence of all forms of autoimmune thyroid disease in patients with myasthenia is considerably higher, ranging from 25% to 30% (41,42). In an older autopsy study of 32 patients with myasthenia gravis, 19% had histologic evidence of thyroiditis, as compared with only 0.9% of a large control group (43). On the contrary, the prevalence of myasthenia gravis in patients with autoimmune thyroid disease was less than 1% in most studies (9,19,44,45,46). In a small series of patients with Graves' ophthalmopathy, 8% had acetylcholine receptor antibodies, but none had any symptoms or signs of myasthenia during a follow-up period of 4½ years (47). Thyrotoxicosis typically develops before or simultaneously with the myasthenia gravis, but it can occur later. Both thyrotoxicosis and hypothyroidism appear to exacerbate the clinical course of myasthenia gravis (4,19).

A study of 129 patients with myasthenia gravis in Italy found an interesting association between milder forms of myasthenia, specifically ocular myasthenia, and autoimmune thyroid disease (41). In patients with both disorders, the myasthenia was clinically milder, with a particular preference for ocular involvement, and the frequency of acetylcholine receptor antibodies and thymic disease was lower, as compared with patients with myasthenia alone. In these 129 patients, the overall prevalence of autoimmune thyroid disease was 62% in patients with ocular myasthenia, and only 29% in patients with generalized myasthenia (40). Similar findings were previously reported (48).

In occasional patients, the combination of bulbar symptoms, ocular symptoms, particularly ptosis and diplopia, respiratory muscle weakness, and severe generalized muscle weakness may make the distinction between thyrotoxic myopathy and myasthenia gravis difficult (49). The diagnosis of myasthenia gravis is based on the absence of infiltrative eye signs (periorbital and conjunctival edema, proptosis, extraocular muscle enlargement), a positive response to edrophonium (Tensilon), the characteristic decrement in response to repetitive nerve stimulation, and amelioration of symptoms with anticholinesterase drug therapy.

Thyrotoxic Periodic Paralysis

Familial periodic paralysis is an autosomal-dominant disorder characterized by acute generalized muscle weakness and hypokalemia, which usually presents in adolescence and rarely after the age of 30 years (50). Thyrotoxic periodic paralysis is the most common acquired form of periodic paralysis and typically presents in men of Asian descent, although it can occur in other ethnic groups as well (51,52,53). The reported incidence of periodic paralysis in Asian men with thyrotoxicosis ranges from 2% to 24%; a reasonable estimate of the overall incidence in this ethnic group is 5% to 10%. The incidence of thyrotoxic periodic paralysis in non-Asian North Americans has been estimated to be 0.1% to 0.2% (54). The disorder is rare in women (55), with an estimated male:female ratio of 20:1 (50). Thyrotoxic periodic paralysis typically presents between the ages of 20 and 40 years, reflecting the usual age of onset of Graves' thyrotoxicosis (55,56).

The typical clinical presentation of thyrotoxic periodic paralysis is similar to that of familial periodic paralysis. The patients have recurrent episodes of muscle weakness lasting minutes to days. The weakness is symmetric and may be local or generalized. Respiratory, sphincter, and cranial muscles are usually spared, but respiratory failure has been reported (50,57). The weakness characteristically begins in the legs, but it usually spreads, and it may progress to a generalized flaccid paralysis. Proximal musculature is more severely affected than distal, and lower extremity weakness tends to be more profound than upper extremity weakness (54,56). Sensation is normal, as is the sensorium. On examination, findings are usually limited to muscle weakness, diminished deep tendon reflexes, and evidence of coexisting thyrotoxicosis. However, the clinical manifestations of thyrotoxicosis may be subtle, so much so that serum TSH should be measured in any patient with periodic paralysis.

Patients often report prodromal symptoms of muscle pain, stiffness, and cramping. Precipitating factors include a carbohydrate challenge, insulin administration, cold exposure, and rest after vigorous exercise. Many attacks occur during sleep, with patients awakening in the morning with profound weakness, including the inability to walk (51,54). Episodes rarely occur during ongoing physical activity; in fact, mild exercise may abort an attack. Attacks of thyrotoxic periodic paralysis cease when thyrotoxicosis is treated.

The most consistent laboratory abnormality during an acute attack is a low serum potassium concentration, with values as low as 1.1 mM (56); in a small series of patients, the mean serum potassium concentration was 1.69 mM (54). Serum potassium concentrations are consistently nomal between attacks, and occasional patients may be normokalemic during an attack. Some patients have high serum creatine kinase concentrations; the enzyme is entirely of skeletal muscle origin (56). Serum creatine kinase and myoglobin concentrations may increase during the recovery phase after an acute attack (58). An electrocardiogram obtained during an attack shows typical features of hypokalemia but no evidence of cardiac muscle injury or other abnormalities.

Treatment of acute episodes is straightforward, with potassium repletion by the oral route being the mainstay of therapy. Intravenous potassium should be reserved for the rare patients with nausea or vomiting or with bulbar muscle dysfunction. Intravenous glucose should be avoided because it may exacerbate hypokalemia by shifting potassium intracellularly. The hypokalemia in this disorder does not reflect a total body potassium deficit, but rather shift of potassium from the extracellular to the intracellular space, and rebound hyperkalemia during recovery has been reported (56). Thus, serum potassium should be measured and electrocardiograms done periodically during potassium therapy. In most patients, symptoms improve within 2 to 4 hours after potassium therapy is begun, and the weakness resolves completely within 24 to 36 hours.

Pending restoration of normal thyroid function, the likelihood of recurrent attacks can be minimized by avoidance of high-carbohydrate meals, vigorous exercise, prolonged cold exposure, and alcohol. Nonselective β-adrenergic antagonist drugs prevent attacks of thyrotoxic periodic paralysis while thyrotoxicosis is being corrected (51,59). The role of these drugs in the immediate treatment of weakness, however, is less clear. Several case reports suggest that the drugs have a beneficial effect (60,61,62,63); in two of these reports the patients improved rapidly after intravenous propranolol administration (61,62).

The pathophysiology of thyrotoxic periodic paralysis is not clear, although it is almost certainly a form of muscle ion-channel dysfunction or “channelopathy” (64). The intracellular potassium shifts associated with acute episodes result in progressive depolarization of the resting potential in the sarcolemma, precluding electrical excitability, and resulting in the clinical finding of muscle paralysis. Familial hypokalemic periodic paralysis has been attributed to mutations in the genes coding for calcium, sodium, and potassium channels (65). Recently, a mutation in the KCNE3 potassium channel gene was reported in a single patient with thyrotoxic periodic paralysis from Brazil (66). How thyrotoxicosis might affect the activity of the channel is not known.


With the exception of neuropsychiatric problems (see Chapter 42) and tremor, clinically important neurologic disorders are far less common in thyrotoxicosis than the muscle disorders reviewed above. In fact, it is unclear whether some of the neurologic syndromes discussed below are truly related to thyrotoxicosis, or simply coincidental findings.

Movement Disorders

The most prominent movement abnormality in thyrotoxicosis is a persistent fine tremor, both at rest and with movement. It most commonly affects the hands, but may also involve the feet, chin, lips, and tongue. In a prospective cohort study, 42 of 50 patients under 50 years of age (84%) with thyrotoxicosis had a tremor, as compared with 15 of 34 patients over 70 years of age (44%) (67). The latter value was not significantly different from the prevalence of tremor in elderly euthyroid subjects. However, there was no age-related decline in the prevalence of tremor in a group of 880 patients with thyrotoxicosis, with the rate in all age groups being approximately 70% (68).

Many patients note the tremor much of the time, but others recognize it only indirectly, for example, by deterioration in their ability to perform fine motor tasks, resulting in impaired handwriting, difficulty threading a needle, or difficulty performing other movements requiring fine muscular control. From a diagnostic perspective, the tremor caused by thyrotoxicosis is similar both clinically and electromyographically to that caused by generalized anxiety (69,70). β-adrenergic mechanisms are implicated in the pathophysiology of the tremor, on the basis of the similarity of the tremor to that in patients with catecholamine excess syndromes and emotional stress, and the often dramatic improvement in tremor with β-adrenergic blocking agents (71,72). Tremor resolves in virtually all patients with correction of thyrotoxicosis.

The other reversible movement disorder reported in association with thyrotoxicosis is choreoathetosis. This is a rare complication of thyrotoxicosis, and most reports have described only one or two patients (73,74,75,76). Common findings in these cases include development of chorea after the onset of thyrotoxicosis, age less than 40 years, response of chorea to β-adrenergic antagonist drugs, and complete resolution of the choreiform movements with correction of the thyrotoxicosis.

Corticospinal Tract Disease

Rare patients with thyrotoxicosis present with symptoms and signs suggestive of corticospinal tract disease, including weakness, spasticity, hyperreflexia, a positive Babinski's sign, and bladder spasticity (77,78,79,80). Fasciculations are usually absent, and results of electromyographic studies are normal. As with choreoathetosis, neurologic signs resolve in most patients with correction of the thyrotoxicosis. The pathophysiology of this association has not been determined.


Generalized peripheral neuropathy is also rare in patients with thyrotoxicosis. However, an acute neuropathy associated with paraplegia or quadriplegia has been described (10). This presentation has been referred to as Basedow's paraplegia, and it bears a close resemblance to the Guillain-Barré syndrome, in terms of its clinical presentation with profound lower extremity weakness and areflexia. Electrophysiologic studies in these patients reveal a mixed axonal and demyelinating sensorimotor neuropathy, and electromyographic findings are consistent with denervation (81,82). Symptoms and signs usually resolve with correction of thyrotoxicosis.

A recent prospective study of 21 patients with thyrotoxicosis found signs of a peripheral neuropathy, including depressed deep tendon reflexes and symmetric distal sensory disturbances, in a few (19%) of the patients (8). Electrophysiologic studies confirmed evidence of a peripheral neuropathy in 24% of these patients. There are a few reports of carpal tunnel syndrome in association with thyrotoxicosis that resolved with antithyroid therapy (83,84).


Seizures are a rare complication of thyrotoxicosis. However, a report of three thyrotoxic patients presenting with seizures in a 2-year period at a single institution suggested that thyrotoxic seizures were more common than generally appreciated (85). The researchers estimated that thyrotoxicosis was the cause of an initial seizure in 1.2% of all patients admitted for seizures, and that 9% of patients admitted for thyrotoxicosis had seizures. The true prevalence of seizures in patients with thyrotoxicosis is certainly much lower than these figures suggest, because the study did not address the prevalence of seizures in nonhospitalized thyrotoxic patients. A causal relationship between thyrotoxicosis and seizures is suggested in several case reports documenting resolution of seizures and electroencephalographic abnormalities with correction of thyrotoxicosis, and relapse when thyrotoxicosis recurred (85,86,87). Reported electroencephalographic abnormalities have included diffuse bilateral slowing, alpha waves, the presence of triphasic waves suggestive of a diffuse encephalopathy, high voltage, and scattered sharp waves (85,86,87,88).

Central Nervous System Manifestations

The most common mental changes in patients with thyrotoxicosis are anxiety, irritability, emotional lability, apprehension, and difficulty concentrating. Cognitive abnormalities typically include a shortened attention span, distractibility, and occasionally impaired short-term memory. Psychosis is rare, but thyrotoxic patients may present with a frank psychosis associated with paranoia and delusions (89). An increased incidence of depression has also been reported (90,91). A detailed review of the neuropsychiatric manifestations of thyrotoxicosis is found in Chapter 42. A true encephalopathy can be observed in patients with thyroid storm. These patients typically present with agitation and delirium, associated with high fever, atrial fibrillation, congestive heart failure, vomiting, and diarrhea. Coma, sometimes associated with seizures, has also been reported (79,92,93). Central nervous symptoms and signs resolve with appropriate management of thyrotoxicosis. The clinical features of thyroid storm are covered in greater detail in Chapter 43.

The observation that elderly thyrotoxic patients may present in dramatically different fashion from younger patients was first reported many years ago (94). Rather than demonstrating hyperactivity and anxiety, these patients may present with a more “apathetic” clinical picture, including depression, lethargy, and pseudodementia. Weight loss, myopathy, atrial fibrillation, and congestive heart failure often dominate the clinical presentation (95,96,97). This atypical presentation has also been described in younger patients (98,99).

From the above summary of the neuropsychiatric manifestations of thyrotoxicosis, it follows that clinicians should have a low threshold for assessing thyroid function in patients with a wide spectrum of mental disorders.


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