David F. Gardner
Hypothyroidism may result in a wide spectrum of reversible abnormalities in neuromuscular function in adults. In infants and young children, however, hypothyroidism has devastating effects on the developing nervous system that are irreversible. The focus of this chapter will be a review of the muscular and neurologic sequelae of hypothyroidism in adult patients. The frequency and severity of the abnormalities that have been described have varied considerably, undoubtedly due to variations in the severity of hypothyroidism and the ways it was identified. The effects of thyroid hormone deficiency on children and newborns are discussed in detail in Chapter 49 and the section on congenital hypothyroidism in Chapter 75.
Muscle-related symptoms are common in patients with hypothyroidism. Typical symptoms include weakness, which is usually proximal, stiffness, cramps, myalgia, and muscle fatigue. The prevalence of these symptoms has varied in different series, but they appear to be common, ranging from 79% to 100% in studies published over the past 50 years (1,2,3,4,5,6). Most patients with myopathic symptoms also report the more typical symptoms of hypothyroidism such as lethargy, constipation, weight gain, and cold intolerance. However, myopathy may be the sole clinical manifestation of hypothyroidism (7), suggesting that all patients with unexplained muscular symptoms should be screened for thyroid dysfunction.
Although muscle weakness may be severe, objective findings on physical examination are often unimpressive. In a recent series in which 79% of patients reported symptoms suggestive of myopathy, only 37% had decreased strength on manual muscle testing (6). This may be because many patients perceive fatigue and lack of energy as muscle weakness. Physical examination may reveal evidence of proximal muscle weakness, hypokinesis, and delayed relaxation of the deep tendon reflexes. The pathophysiology of the delayed deep tendon reflex appears to be related to underlying muscle disease rather than slowing of nerve conduction, because there is no difference in the latency from the tapping of the tendon to the onset of muscle contraction in hyperthyroid, euthyroid, and hypothyroid patients (8,9). Slow relaxation of tendon reflexes is not unique to hypothyroidism; it also occurs in normal older people, pregnant women, patients with diabetes mellitus, and patients receiving a β-adrenergic antagonist drug (10,11). Rare patients have muscle atrophy (4), and other, rarer patients have frank muscle enlargement; this is actually pseudohypertrophy (see later discussion on Hoffman's and Kocher-Debré-Sémélaigne syndromes). Patients with severe hypothyroidism may have myoedema, a focal contraction and mounding of muscle tissue occurring after the muscle is tapped with a reflex hammer. The mounding is typically followed by slow relaxation, which may last from seconds to minutes (12,13). This phenomenon also occurs in occasional normal subjects and patients with muscle wasting associated with malnutrition or cancer (14,15).
In the late 1800s, Hoffman and Kocher described hypothyroid patients with enlarged, apparently hypertrophied muscles, weakness, muscle stiffness, and slow movements (16,17). Debré and Sémélaigne described similar findings in infants with cretinism in 1935 (18). Today, the term “Hoffman's syndrome” is applied to adults with hypothyroidism who have increased muscle mass, severe muscle stiffness, varying degrees of weakness, and often painful muscle cramps (19,20). The increased muscle mass is not associated with increased muscle strength, and therefore is referred to as pseudohypertrophy. The gastrocnemius, deltoid, and trapezius muscles are typically involved. On examination, involved muscles are firm to palpation, usually weak, and contract slowly. The Kocher-Debré-Sémélaigne or Hercules syndrome is a similar syndrome described in children with cretinism, although it differs clinically in that painful muscle cramps are typically absent (21). Transition from the Kocher-Debré-Sémélaigne syndrome to Hoffman's syndrome has been described, and the only difference between these syndromes may be the age of the patient (13,20). In both children and adults the findings of pseudohypertrophy resolve with correction of hypothyroidism, although resolution may take many months (19). The pathophysiology of pseudohypertrophy remains unexplained; most studies have not revealed any increase in the size or number of muscle fibers, or an increase in mucinous deposits or the amount of connective tissue present in muscle.
The most common laboratory abnormality indicative of muscle dysfunction in patients with hypothyroidism is a high serum creatine kinase concentration. However, the concentrations also are high in as many as 70% to 90% of patients with hypothyroidism who have no clinical evidence of muscle involvement (22,23,24,25). The increase is almost invariably in the MM isoenzyme of skeletal muscle origin (22,26). Occasional patients have strikingly high serum creatine kinase concentrations, occasionally more than 100 times the upper limit of normal (27,28,29); the severity of symptoms associated with these markedly high values varies tremendously, from virtually no symptoms to substantial muscle weakness, muscle cramps, and myalgia (29). In most, but not all (30), studies there was little correlation between the magnitude of the elevation in serum creatine kinase concentration and the severity of hypothyroidism, as determined by measurements of either serum thyroxine (T4) or thyrotropin (TSH). The mechanism underlying the high serum creatine kinase concentrations is not clear; possibilities include muscle fiber degeneration (29), altered muscle energy metabolism (31), and decreased clearance of creatine kinase from the circulation (32). High serum myoglobin concentrations have also been reported in hypothyroid patients, but the degree of elevation is considerably less than that of creatine kinase (33).
The histopathologic changes in muscle in patients with hypothyroidism are variable and nonspecific. The most consistent findings are atrophy or loss of type 2 muscle fibers, resulting in predominance of type 1 muscle fibers, and increased numbers of central nuclei (3,13,15,21,34,35,36). Additional findings have included sporadic areas of muscle fiber necrosis and regeneration, glycogen accumulation, and mitochondrial disruption. A clinical and pathologic study of 13 patients with hypothyroid myopathy revealed inflammatory changes, consistent with an underlying myositis, in 5 patients (35). The researchers emphasized the importance of considering other causes of myopathy in hypothyroid patients, particularly those who do not improve in response to thyroid hormone replacement therapy. Reported ultrastructural changes have included myofibrillar disorganization and fragmentation evidenced by the presence of “corelike” structures, increased numbers of mitochondria in the sarcolemmic region, glycogen accumulation, vacuolization, lipid accumulation, and proliferation of sarcoplasmic reticulum and T tubules (5,13,21,34,35,36).
The prevalence of electromyographic abnormalities in hypothyroid myopathy has varied substantially in different studies, ranging from 7% to 88%, undoubtedly due to varying methods of recruitment (e.g., all patients encountered, or only those with definite muscle weakness) (13,21). The most common abnormalities are low-amplitude, short-duration polyphasic motor unit action potentials, consistent with a nonspecific myopathy. In a recent study of 19 hypothyroid patients, one third had these “myopathic” abnormalities (6). Other changes have included increased insertional activity and repetitive positive waves (37). Muscle fasciculations or fibrillations are extremely rare, and probably related to coincident neuropathy rather than intrinsic muscle disease (21). Perhaps the most unique electromyographic abnormality is the “electrical silence” associated with myoedema (14,38). Overall, electromyography is not very revealing in patients with hypothyroidism, and should be done only in patients in whom the clinical findings are atypical and who may have a treatable myopathy unrelated to hypothyroidism.
Acute rhabdomyolysis has been described in a few patients with hypothyroidism, including one patient who developed acute renal failure (39,40,41,42,43). Most of the patients have had severe hypothyroidism of recent onset; possible precipitating factors have included exercise (40,44), hypolipidemic drug therapy (41), and preexisting renal failure (45). In virtually all patients, the muscle injury resolved with correction of hypothyroidism.
Although most of the preceding discussion relates to patients with overt hypothyroidism, patients with subclinical hypothyroidism may have similar, although usually less severe, findings (see Chapter 78) (30,31,46,47,48). The prevalence of muscle symptoms in these patients has ranged from 26% to 75%, and in one study muscle weakness was more prevalent in patients with subclinical hypothyroidism than in those with overt hypothyroidism (48). As in overt hypothyroidism, symptoms resolve in most patients with correction of the thyroid dysfunction.
The mechanisms underlying abnormal muscle function in hypothyroidism are not known. Possibilities include impaired glycogenolysis (49,50), alterations in myosin heavy chain gene expression (51), and reduced mitochondrial activity, with a decrease in production of adenosine triphosphate (52,53). A recent study in patients with subclinical hypothyroidism documented increased lactate production during exercise, as compared with normal subjects, findings consistent with impaired mitochondrial oxidative function (31).
Neuropathic symptoms including paresthesias and painful dysesthesias have been reported in patients with hypothyroidism. The patients may have symptoms and signs of a mononeuropathy, polyneuropathy, or cranial nerve neuropathy. Older series suggest a prevalence of neuropathic complaints in 40% to 60% of patients (1,54,55), but these patients undoubtedly had more severe hypothyroidism than do patients today (56). In a recent study of 19 patients with overt hypothyroidism, only 29% had symptoms of sensory nerve dysfunction (6).
The most common mononeuropathy encountered in hypothyroid patients is the carpal tunnel syndrome associated with median nerve compression as it traverses the volar aspect of the wrist. Typical symptoms include tingling, numbness, and pain in the sensory distribution of the distal median nerve, affecting the first, second, and third digits; other findings are wrist pain, nocturnal worsening of symptoms, and occasionally clumsiness of the hand and fingers (56). On examination there may be loss of sensation over the first three digits, weakness and atrophy of thenar muscles, and positive Tinel's and Phalen's signs. The symptoms and signs are identical to those in any patient with the carpal tunnel syndrome, and typically resolve with correction of the hypothyroidism (8). The pathophysiology of this disorder appears to be mechanical compression of the median nerve caused by edema and myxedema of perineural, endoneural, and synovial tissue within the carpal tunnel (2,57). Electrophysiologic studies document delayed distal median sensory nerve conduction, and less often delayed distal motor nerve conduction. The prevalence of the carpal tunnel syndrome in patients with hypothyroidism varies considerably; in three older series of unselected patients it varied from 27% to 45% (55,58,59), and in two more recent series it was 25% and 26% (6,60).
Other mononeuropathies that have been reported in association with hypothyroidism include the tarsal tunnel syndrome (61) and meralgia paresthetica (62), secondary to compression of the posterior tibial nerve and lateral femoral cutaneous nerves, respectively.
Generalized peripheral neuropathy is far less common than entrapment mononeuropathies in hypothyroid patients, although many patients have symptoms suggestive of a polyneuropathy. Distal paresthesias and pain were present in 48% to 100% of patients in three older series (2,54,55), but in a recent study distal sensory symptoms were present in only 29% of patients, nearly all of whom had the carpal tunnel syndrome rather than a more generalized sensorimotor polyneuropathy (6). Findings on examination that suggest peripheral neuropathy vary considerably; most often there is distal sensory loss and diminished deep tendon reflexes (6,8,56). A recent study of 19 hypothyroid patients documented distal sensory disturbances in the limbs or depressed deep tendon reflexes in 42%, although there was no significant symptomatology associated with these findings (6). Nerve conduction study results may be abnormal; they typically reveal decreased nerve conduction velocity, as well as diminished amplitude or complete absence of sensory nerve action potentials (6,54,58,63,64,65,66). Pathologic findings have varied, with some showing segmental demyelination (64,65) and others suggesting axonal degeneration as the primary process (63,67). Although polyneuropathy has clearly been described in case reports and small groups of patients with hypothyroidism, it is rarely an important clinical problem. In a recent study of 16 patients, 44% had the carpal tunnel syndrome, but none had polyneuropathy (68). The absence of any recent case series suggests that polyneuropathy may occur only in patients with much more severe hypothyroidism than is less usually encountered in clinical practice now. Although most studies have focused on the peripheral nervous system, there are several studies that document abnormalities in nerve conduction in the central nervous system. The findings were usually prolongation of the latencies of visual evoked potentials and brainstem auditory evoked potentials (60,69). The clinical consequences of these findings are not known, and not all studies have confirmed the findings (70).
Isolated mononeuropathies involving cranial nerves II, V, VII, and VIII have been reported, but with the exception of hearing loss, these syndromes are extremely rare (1,2,13). Hearing loss has been reported in 31% to 85% of patients with hypothyroidism (1,71,72) and tinnitus in 7% to 29% (1,72); on the other hand one group found no evidence of hearing loss when hypothyroid patients were compared with age and sex-matched normal subjects (73). However, an etiologic role for hypothyroidism in causing deafness, at least in some patients, is strongly suggested by studies documenting improvement in hearing during thyroid hormone therapy (71). Hearing loss appears to be sensorineural rather than conductive, but its anatomic basis is not known.
In a report published by the Committee of the Clinical Society of London in 1888, more than one third of hypothyroid patients were found to have gait unsteadiness (74). Since that initial description there have been numerous descriptions of gait ataxia and poor coordination of the extremities, suggesting cerebellar dysfunction, in patients with hypothyroidism (1,75,76,77,78). Typical findings on examination have included gait unsteadiness with impaired tandem walking, generalized incoordination of the extremities, dysmetria, and rarely, dysarthric speech. In a single study of 24 patients with hypothyroidism and ataxia, prompt and almost complete clearing of symptoms occurred in the majority of patients after the initiation of thyroid hormone therapy (76). Proposed mechanisms for this syndrome include degenerative changes in the cerebellum, impaired cerebellar blood flow, deposition of glycogen within the cerebellum, and primary muscle dysfunction. A recent report described six euthyroid patients with chronic autoimmune thyroiditis who developed progressive nonfamilial adult-onset cerebellar degeneration (79). Posterior fossa magnetic resonance imaging (MRI) revealed cerebellar degeneration in all six patients, and all had a strong family history of autoimmune disease, suggesting an immune-mediated process for the cerebellar changes.
Mental Status Changes
Neurocognitive impairment may be a prominent feature of hypothyroidism, particularly in elderly patients. Slowness in comprehension, diminished attention span, poor recent memory, difficulty with word fluency, and impaired abstract thinking may all be present (80,81,82), and indeed may be among the patients' more prominent symptoms. Most patients improve substantially when treated with thyroid hormone, but resolution may be slow or incomplete (82). Hypothyroidism is often considered a cause of reversible dementia in the elderly, and thyroid function is often routinely assessed in the evaluation of patients with cognitive impairment. The incidence of hypothyroidism in demented patients is actually low, ranging from 1.5% to 4.2%, even when patients with subclinical hypothyroidism are included (83,84,85). Consistent improvement in cognitive function in patients with dementia after correction of hypothyroidism has not been demonstrated, suggesting that other factors are contributing to mental impairment in these patients (82,83,84).
Alterations in cognition have been reported in patients with subclinical hypothyroidism as well as those with overt hypothyroidism (see Chapter 78). In a study of 19 women with subclinical hypothyroidism (mean serum TSH concentration 12.0 mU/L), there was evidence of memory impairment that improved significantly during thyroid hormone therapy (86).
The behavioral and psychiatric abnormalities associated with hypothyroidism are reviewed in detail in Chapter 64.
Since an initial case report in 1966 (87), about 100 patients have been described with an encephalopathy associated with high serum antithyroid antibody concentrations, responsiveness to glucocorticoid therapy, and no other definable neurologic disorder. The term “Hashimoto's encephalopathy” has been applied to these patients. A recent review of the literature identified 85 patients who met strict criteria for this diagnosis (encephalopathy, high serum concentrations of either antithyroid peroxidase or antithyroglobulin antibodies, and no other neurologic disorder); they had the following clinical findings: stroke-like signs (27%), psychosis (38%), seizures (66%), high cerebrospinal fluid protein concentrations (78%), and abnormal electroencephalograms (98%) (88). The clinical course of the disorder is characterized by remissions and relapses, generalized and focal seizures, focal and often transient neurologic deficits, and a variety of psychiatric manifestations, including hallucinations, dementia, and acute psychosis (89,90).
The diagnosis is based on the characteristic neurologic findings reviewed above, high serum antithyroid antibody concentrations, and exclusion of other causes of encephalopathy. Thyroid function varies; among the 85 patients referred to above, 30% had normal serum free T4 and TSH concentrations, 55% had either overt or subclinical hypothyroidism, and the remainder had biochemical evidence of hyperthyroidism (88). The neurologic presentation does not appear to be influenced by the patient's thyroid status. Cerebrospinal fluid protein levels are typically high, but most patients do not have pleocytosis. Brain imaging studies (MRI and computed tomography) are normal or show nonspecific findings. Electroencephalography typically reveals diffuse abnormalities with excess slow wave activity (89).
A high percentage of patients appear to respond to glucocorticoid therapy (88), and some researchers have suggested that an underlying vasculitis is responsible for this encephalopathy. However, there is no compelling clinical or pathologic evidence to support a diagnosis of vasculitis, and the pathophysiology of this disorder is not known. The high serum antithyroid antibody concentrations, part of the definition of the disorder, suggest the possibility of an immune-mediated central nervous system process, but there is no evidence that any antithyroid antibody reacts with neural or meningeal tissue, and antineuronal antibodies have not been detected.
Miscellaneous Neurologic Abnormalities
Seizures are a rare neurologic complication of hypothyroidism, and when they do occur it is almost always in patients who have myxedema coma or Hashimoto's encephalopathy. The few isolated case reports of seizures in hypothyroidism suggest that this may be a coincidental rather than an etiologic association, although in three reported patients seizures did not recur after thyroid hormone therapy had been initiated (91,92,93). In a study of 23 hypothyroid patients without seizures, 35% had electroencephalographic abnormalities; the most common abnormality was diffuse slowing of background activity, and epileptiform foci were not recorded (60).
A high cerebrospinal fluid protein concentration has been a consistent finding in studies of hypothyroid patients (1,2,8). In a study of nine patients with overt hypothyroidism, all had high cerebrospinal fluid albumin and immunoglobulin G concentrations that returned to normal during thyroid hormone therapy (94). The high protein concentrations are not related to thyroid autoimmunity per se; patients with subclinical hypothyroidism and high serum antithyroid antibody concentrations do not have high cerebrospinal albumin or immunoglobulin G concentrations. Presumably, hypothyroidism results in increased permeability of the blood–brain barrier.
The clinical features of myxedema coma are reviewed in detail in Chapter 65.
1. Nickel SN, Frame B. Neurologic manifestations of myxedema. Neurology 1958;8:511.
2. Nickel SN, Frame B, Bebin J, et al. Myxedema neuropathy and myopathy: a clinical and pathologic study. Neurology 1961;11: 125.
3. McKeran RO, Slavin G, Ward P, et al. Hypothyroid myopathy: a clinical and pathological study. J Pathol 1980;132:35.
4. Khaleeli AA, Griffith DF, Edwards RHT. The clinical presentation of hypothyroid myopathy and its relationship to abnormalities in structure and function of skeletal muscle. Clin Endocrinol (Oxf) 1983;19:365.
5. Modi G. Cores in hypothyroid myopathy: a clinical, histological, and immunofluorescence study. J Neurol Sci 2000;175:28.
6. Duyff RF, Van den Bosch J, Laman DM. Neuromuscular findings in thyroid dysfunction: a prospective clinical and electrodiagnostic study. J Neurol Neurosurg Psychiatry 2000;68:750.
7. Rodolico C, Toscano A, Benvenga S, et al. Myopathy as the persistently isolated symptomatology of primary autoimmune hypothyroidism. Thyroid 1998;8:1033.
8. Laureno R. Neurologic manifestations of thyroid disease. Endocrinologist 1996;6:467.
9. Lambert EH, Underdahl LO, Beckett S, et al. A study of the ankle jerk in myxedema. J Clin Endocrinol 1951;11:1186.
10. Wise MP, Blunt S, Lane RJ. Neurologic presentations of hypothyroidism: the importance of slow relaxing reflexes. J R Soc Med 1995;88:272.
11. Reinfrank RF, Kaufman RP, Wetstone HJ, et al. Observations of the Achilles reflex test. JAMA 1967;199:59.
12. Swanson JW, Kelly JJ, McConahey WM. Neurologic aspects of thyroid dysfunction. Mayo Clin Proc 1981;56:504.
13. Laycock MA, Pascuzzi RM. The neuromuscular effects of hypothyroidism. Semin Neurol 1991;11:288.
14. Salick AI, Pearson CM. Electrical silence of myoedema. Neurology 1967;17:899.
15. Salick AI, Colachis SC, Pearson CM. Myxedema myopathy: clinical, electrodiagnostic, and pathologic findings in an advanced case. Arch Phys Med Rehabil 1968;49:230.
16. Hoffman J. Weitere Beitrag zur Lehre von der Tetanie. Deutsche Z Nervenheilk 1897;9:278.
17. Kocher T. Zur Verhutung der Cretinismus und cretinoider Zustande nach neuen Forschungen. Deutsch Z Chir 1892;26:556.
18. Debre F, Semelaigne G. Syndrome of diffuse muscular hypertrophy in infants causing athletic appearance: its connection with congenital myxedema. Am J Dis Child 1935;50:1351.
19. Klein I, Parker M, Shebert R, et al. Hypothyroidism presenting as muscle stiffness and pseuohypertrophy: Hoffman's syndrome. Am J Med 1981;70:891.
20. Norris FH, Panner BJ. Hypothyroid myopathy: clinical, electromyographical, and ultrastructural observations. Arch Neurol 1966;14:574.
21. Kaminski HJ, Ruff RL. Endocrine myopathies (hyper- and hypofunction of adrenal, thyroid, pituitary, and parathyroid glands and iatrogenic corticosteroid myopathy). In: Engel AG, Franzini-Armstrong C, eds. Myology: basic and clinical, 2nd ed., Vol. 2. New York: McGraw-Hill, 1994:1726.
22. Burnett JR, Crooke MJ, Delahunt JW, et al. Serum enzymes in hypothyroidism. N Z Med J 1994;107:355.
23. Graig FA, Smith JC. Serum creatine phosphokinase activity in altered thyroid states. J Clin Endocrinol Metab 1965;25:723.
24. Fleisher GA, McConahey WM, Pankow M. Serum creatine kinase, lactic dehydrogenase, and glutamic-oxaloacetic transaminase in thyroid diseases and pregnancy. Mayo Clin Proc 1965;40: 300.
25. Giampietro O, Clerico A, Buzzigoli G, et al. Detection of hypothyroid myopathy by measurements of various serum muscle markers—myoglobin, creatine kinase, lactic dehydrogenase, and their isoenzymes. Horm Res 1984;19:232.
26. Goti I. Serum creatine phosphokinase isoenzymes in hypothyroidism, convulsions, myocardial infarction, and other diseases. Clin Chim Acta 1974;52:27.
27. Goldman J, Matz R, Mortimer R, et al. High elevations of creatine phosphokinase in hypothyroidism: an isoenzyme analysis. JAMA 1977; 238:325.
28. Finsterer J, Stollberger C, Grossegger C, et al. Hypothyroid myopathy with unusually high serum creatine kinase values. Horm Res 1999;52:205.
29. Scott KR, Simmons Z, Boyer PJ. Hypothyroid myopathy with a strikingly elevated creatine kinase level. Muscle Nerve 2002; 26:141.
30. Beyer IW, Karmali R, Demeester-Mirkine N, et al. Serum creatine kinase levels in overt and subclinical hypothyroidism. Thyroid 1998;8:1029.
31. Monzani F, Caraccio N, Siciliano G, et al. Clinical and biochemical features of muscle dysfunction in subclinical hypothyroidism. J Clin Endocrinol Metab 1997;82:3315.
32. Karlsberg RP, Roberts R. Effect of altered thyroid function on plasma creatine kinase clearance in the dog. Am J Physiol 1978; 235:E614.
33. Karlsson FA, Dahlberg PA, Venge P, et al. Serum myoglobin in thyroid disease. Acta Endocrinol (Copenh) 1980;94:184.
34. Khaleeli AA, Gohil K, McPhail G, et al. Muscle morphology and metabolism in hypothyroid myopathy. J Clin Pathol 1983;36:519.
35. Mastaglia FL, Ojeda VJ, Sarnat HB, et al. Myopathies associated with hypothyroidism: a review based upon 13 cases. Aust N Z J Med 1988;18:799.
36. Ono S, Inouye K, Mannen T. Myopathology of hypothyroid myopathy. J Neurol Sci 1987;77:237.
37. Klein I, Levey GS. Unusual manifestations of hypothyroidism. Arch Intern Med 1984;144:123.
38. Mizusawa H, Takagi A, Sugita H, et al. Mounding phenomenon: an experimental study in vitro. Neurology 1983;33:90.
39. Halverson PB, Kozin F, Ryan LM, et al. Rhabdomyolysis and renal failure in hypothyroidism. Ann Intern Med 1979;91:57.
40. Riggs JE. Acute exertional rhabdomyolysis in hypothyroidism: the result of a reversible defect in glycogenolysis? Milit Med 1990;155:171.
41. Clouatre Y, Lebland M, Quimet D, et al. Fenofibrate-induced rhabdomyolysis in two dialysis patients with hypothyroidism. Nephrol Dial Transplant 1999;14:1047.
42. Barahona MJ, Mauri A, Sucunza N, et al. Hypothyroidism as a cause of rhabdomyolysis. Endocr J 2002;49:621.
43. Kisakol G, Tunc R, Kaya A. Rhabdomyolysis in a patient with hypothyroidism. Endocr J 2003;50:221.
44. Nelso SR, Phillips AO, Hendry BM. Hypothyroidism and rhabdomyolysis in a marathon runner. Nephrol Dial Transplant 1993; 8:375.
45. Leonetti F, Dussol B, Berland Y. Rhabdomyolyse et insuffisance renale au cours d'une hypothyroidie. Presse Med 1992;21:31.
46. Rodolico C, Toscano A, Benvenga S, et al. Skeletal muscle disturbances may precede clinical and laboratory evidence of autoimmune hypothyroidism. J Neurol 1998;245:555.
47. Monzani F, Caraccio N, Del Guerra P, et al. Neuromuscular symptoms and dysfunction in subclinical hypothyroid patients: beneficial effect of L-T4replacement therapy. Clin Endocrinol (Oxf) 1999;51:237.
48. Hartl E, Finsterer J, Grossegger C, et al. Relationship between thyroid function and skeletal muscle involvement in subclinical and overt hypothyroidism. Endocrinologist 2001;11:217.
49. McDaniel HG, Pittman CS, Oh SJ, et al. Carbohydrate metabolism in hypothyroid myopathy. Metabolism 1977;26:867.
50. Taylor DJ, Rajagopalan B, Radda GK. Cellular energetics in hypothyroid muscle. Eur J Clin Invest 1992;22:358.
51. Caiozzo VJ, Baker MJ, Baldwin KM. Novel transformation in MHC isoforms: separate and combined effects of thyroid hormone and mechanical unloading. J Appl Physiol 1998;85:2237.
52. Kaminsky P, Robin-Lherbier B, Brunotte F, et al. Energetic metabolism in hypothyroid skeletal muscle, as studied by phosphorus magnetic resonance spectroscopy. J Clin Endocrinol Metab 1992;74:124.
53. Argov Z, Renshaw PF, Boden B, et al. Effects of thyroid hormones on skeletal muscle bioenergetics: in vivo phosphorus-31 magnetic resonance spectroscopy study of humans and rats. J Clin Invest 1988;81:1695.
54. Crevasse LE, Logue RB. Peripheral neuropathy in myxedema. Ann Intern Med 1959;50:1433.
55. Rao SN, Katiyar BC, Nair KRP, et al. Neuromuscular studies in hypothyroidism. Acta Neurol Scand 1980;61:167.
56. Crum BA, Bolton CF. Peripheral neuropathy in systemic disease. In: Brown WF, Bolton CF, Aminoff MJ, eds. Neuromuscular function and disease: basic, clinical and electrodiagnostic aspects. Vol. 2. Philadelphia: WB Saunders, 2002:1081.
57. Purnell DC, Daly D, Lipscomb PR. Carpal tunnel syndrome associated with myxedema. Arch Intern Med 1961;108:751.
58. Fincham RW, Cape CA. Neuropathy in myxedema: a study of sensory nerve conduction in the upper extremities. Arch Neurol 1968;19:464.
59. Murray IPC, Simpson JA. Acroparesthesias in myxoedema: a clinical and electromyographic study. Lancet 1958;1:1360.
60. Khedr EM, El Toony LF, Tarkhan MN, et al. Peripheral and central nervous system alterations in hypothyroidism: electrophysiological findings. Neuropsychobiology 2000;41:88.
61. Schwartz MS, Mackworth-Young CG, McKeran R. The tarsal tunnel syndrome in hypothyroidism. J Neurol Neurosurg Psychiatry 1983;46:440.
62. Suarez G, Sabin TD. Meralgia paresthetica and hypothyroidism [Letter]. Ann Intern Med 1990;112:149.
63. Pollard JD, McLeod JG, Honnibal TGA, et al. Hypothyroid polyneuropathy: clinical, electrophysiological, and nerve biopsy findings in two cases. J Neurol Sci 1982;53:461.
64. Dyck PJ, Lambert ED. Polyneuropathy associated with hypothyroidism. J Neuropathol Exp Neurol 1970;29:631.
65. Shirabe T, Tawara S, Terao A, et al. Myedematous polyneuropathy: a light and electron microscopic study of the peripheral nerve and muscle. J Neurol Neurosurg Psychiatry 1975;38:241.
66. Nemni R, Bottacchi E, Fazio R, et al. Polyneuropathy in hypothyroidism: clinical, electrophysiological, and morphological findings in four cases. J Neurol Neurosurg Psychiatry 1987;50:1454.
67. Meier C, Bischoff A. Polyneuropathy in hypothyroidism: clinical and nerve biopsy study of four cases. J Neurol 1977;215: 103.
68. Cruz MW, Tendrich M, Vaisman M, et al. Electroneuromyography and neuromuscular findings in 16 primary hypothyroidism patients. Arq Neuropsiquiatr 1996;54:12.
69. Huang TS, Chang YC, Lee SH, et al. Visual, brainstem auditory and somatosensory evoked potential abnormalities in thyroid disease. Thyroidology 1989;1:137.
70. Vanesse M, Fischer C, Berthezene F, et al. Normal brainstem evoked potential in adult hypothyroidism. Laryngoscope 1989; 99:302.
71. Van't Hoff W, Stuart DW. Deafness in myxoedema. Q J M 1979;48:361.
72. Bhatia PL, Gupta DP, Agrawal MK, et al. Audiological and vestibular function tests in hypothyroidism. Laryngoscope 1977;87: 2082.
73. Parving A, Ostri B, Hansen JM, et al. Audiological and temporal bone findings in myxedema. Ann Otol Rhinol Laryngol 1986;95: 278.
74. Clinical Society of London. Report on myxoedema. Trans Clin Soc Lond 1888;21(suppl):1–215.
75. Jellinek EH, Kelly RE. Cerebellar syndrome in myxedema. Lancet 1960;2:225.
76. Cremer GM, Goldstein NP, Paris J. Myxedema and ataxia. Neurology 1969;19:37.
77. Blume WT, Grabow JD. The “cerebellar” signs of myxedema. Dis Nerv Syst 1969;30:55.
78. Westphal SA. Unusual presentations of hypothyroidism. Am J Med Sci 1997;314:333.
79. Selim M, Drachman DA. Ataxia associated with Hashimoto's disease: progressive non-familial adult onset cerebellar degeneration with autoimmune thyroiditis. J Neurol Neurosurg Psychiatry 2001;71:81.
80. Kornstein SG, Sholar EF, Gardner DF. Endocrine disorders. In: Stoudemire A, Fogel BS, Greenberg DB, eds. Psychiatric care of the medical patient, 2nd ed. New York: Oxford University Press, 2000:801.
81. Osterweil D, Syndulko K, Cohen SN, et al. Cognitive function in non-demented older adults with hypothyroidism. J Am Geriatr Soc 1992;40:325.
82. Dugbartey AT. Neurocognitive aspects of hypothyroidism. Arch Intern Med 1998;158:1413.
83. Larson EB, Reifler BV, Featherstone HJ, et al. Dementia in elderly outpatients: a prospective study. Ann Intern Med 1984; 100:417.
84. Larson EB, Reifler, Sumi SM, et al. Diagnostic evaluation of 200 elderly outpatients with suspected dementia. J Gerontol 1985; 40:536.
85. D'Angelo R, Fogato E, Balzaretti M, et al. Screening for hypothyroidism in institutionalized elderly people with cognitive and functional impairment. J Endocrinol Invest 1999;22(suppl 10):42.
86. Baldini IM, Vita A, Mauri MC, et al. Psychopathological and cognitive features in subclinical hypothyroidism. Prog Neuropsychopharmacol Biol Psychiatry 1997;21:925.
87. Brain L, Jellinek EH, Ball K. Hashimoto's disease and encephalopathy. Lancet 1966;2:512.
88. Chong JY, Rowland LP, Utiger RD. Hashimoto encephalopathy: syndrome or myth? Arch Neurol 2003;60:164.
89. Shaw PJ, Walls TJ, Newman PK, et al. Hashimoto's encephalopathy: a steroid responsive disorder associated with high antithyroid antibody titers—report of five cases. Neurology 1991;41: 228.
90. Kothbauer-Margreiter I, Sturzenegger M, Komor J, et al. Encephalopathy associated with Hashimoto thyroiditis: diagnosis and treatment. J Neurol 1996;243:585.
91. Evans EC. Neurologic complications of myxedema: convulsions. Ann Intern Med 1960;52:434.
92. Rowell NP, Clarke SW. Myxoedema presenting as epilepsy. Postgrad Med J 1984;60:605.
93. Bryce GM, Poyner F. Myxoedema presenting with seizures. Postgrad Med J 1992;68:35.
94. Nystrom E, Hamberger A, Linstedt G, et al. Cerebrospinal fluid proteins in subclinical and overt hypothyroidism. Acta Neurol Scand 1997;95:311.