Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
This article includes discussion of hyperparathyroid myopathy, myopathy associated with hyperparathyroidism, myopathy with secondary hyperparathyroidism due to renal failure, myopathy associated with hypoparathyroidism, myopathy associated with pseudohypoparathyroidism, myopathy associated with osteomalacia, osteomalacic myopathy, parathyroid myopathy, vitamin D myopathy, and dropped head syndrome. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Disorders of calcium metabolism, including hyper- or hypofunction of parathyroid hormone, are frequently overlooked causes of muscle dysfunction, and presentation is often nondescript, with mild proximal weakness, muscle pain, and a normal CK. However, when identified and treated, complete resolution of the myopathy can occur, as seen with removal of an adenomatous parathyroid gland for primary hyperparathyroidism or with a subtotal parathyroidectomy for secondary hyperparathyroidism in patients on chronic hemodialysis. Despite an ever-increasing understanding of the molecular mechanism of parathyroid hormone, its action on skeletal muscle and the pathophysiology of skeletal muscle disorders produced by hyper- and hypoparathyroidism is poorly understood.
• Primary hyperparathyroidism, secondary hyperparathyroidism (due to renal failure), and osteomalacia may cause myalgia, mild proximal weakness, and normal or slightly elevated CK; the shared features suggest a similar effect on muscle metabolism due to parathyroid hormone excess and vitamin D deficiency.
• Primary hyperparathyroidism is a common cause of hypercalcemia and hypomagnesia, which can cause a nonnecrotizing proximal myopathy. It can also lead to hypophosphatemia, which can rarely result in a necrotizing myopathy associated with rhabdomyolysis.
• Myopathy (with normal or elevated CK) is rare in primary hypoparathyroidism. The most common muscle manifestation in hypoparathyroidism is due to hypocalcemia, resulting in tetany (hyperexcitability of nerve axons leading to repetitive firing) and subsequent muscle cramps or spasm (carpopedal or laryngeal).
• Management of myopathies related to parathyroid disorders requires treatment of the primary cause, eg, removal of an adenoma in primary hyperparathyroidism; vitamin D and calcium replacement in osteomalacia; removal of hyperfunctioning parathyroid glands and treatment with cholecalciferol (D3) or kidney transplant in uremia.
Muscle weakness is common in disorders of calcium and phosphorous homeostasis, including primary and secondary hyperparathyroidism, osteomalacia, hypoparathyroidism, and other abnormalities of bone metabolism. The association of myopathy with hyperparathyroidism and osteomalacia was recognized over a century ago (41; 94). Vicale reintroduced this association in the modern era, describing 3 patients with severe proximal weakness, waddling gait, and extensive bone disease (93). Patten and colleagues thought that the clinical features, electromyography, and muscle biopsies from weak patients with hyperparathyroidism reflected a neurogenic disorder (72). However, others suspected a myopathic basis for the weakness and disputed this (56; 50).
In contrast to hyperparathyroidism and osteomalacia, hypoparathyroidism has only rarely been associated with overt clinical myopathy (97; 87; 53; 98). Patients can have elevated serum creatine kinase levels and myopathic features in electrophysiologic or histologic studies, which may be secondary to tetany or seizures resulting from hypocalcemia (43; 95; 83; 50; 01; 78). However, objective weakness is uncommon (50).
The myopathy associated with primary hyperparathyroidism or osteomalacia is characterized by gradual onset of symmetric proximal weakness with atrophy (55). Pain is often a prominent comorbidity, and the combination of weakness and bone or muscle pain may be the presenting complaint in up to 50% of patients with primary hyperparathyroidism (65). Significant leg weakness leads to a waddling gait or inability to walk in some patients (Moxley 1994). In children, a Gowers sign may be present (03). The nonnecrotizing limb-girdle myopathy is associated with serum hypercalcemia and hypomagnesium in hyperparathyroidism, whereas hypophosphatemia can cause a necrotizing limb-girdle myopathy (49). Patten and colleagues reported several patients with bulbar involvement resulting in hoarseness, dysphagia, and fasciculations (72). Rarely, patients have severe neck extensor weakness (09; 81), with “dropped head” syndrome or severe respiratory muscle involvement (31; 70). Cramps and paresthesia are reported in approximately 50% of patients (90).
Besides proximal weakness and atrophy, examination of patients with hyperparathyroidism often reveals brisk muscle stretch reflexes with flexor plantar responses, and there are rare reports of spasticity and extensor plantar responses (15; 30). In addition, 29% to 57% of patients experience a stocking and glove distribution of reduced pain or vibratory sensation and decreased muscle stretch reflexes suggestive of an underlying peripheral neuropathy (72; 90). Patten and colleagues also described abnormal tongue movements reminiscent of fasciculations (72), but others have not found this feature. Finally, neurobehavioral abnormalities (memory loss, poor concentration, personality changes, inappropriate behavior, anxiety, and hallucinations) can also occur.
Older patients with primary hyperparathyroidism may have significant functional deficits, including slower repeated sit-to-stand and gait speed that may affect safety and quality of life (63). Non-neurologic presentations of primary hyperparathyroidism can include pathologic fractures, recurrent renal stones, acute pancreatitis, or a solitary bone swelling (65).
Secondary hyperparathyroidism most often can occur in patients with chronic renal failure, who can develop weakness similar to that observed in primary hyperparathyroidism and osteomalacia. Lower extremity weakness predominates early on with eventual progression to involvement of all 4 limbs. Rare cases of arterial calcification with secondary muscle necrosis and myoglobinuria have been reported in this condition (77).
Vitamin D deficiency has also been associated with muscle symptoms, including myalgia and proximal myopathy (92). This is a significant public health issue given the high prevalence of vitamin D deficiency, and the symptoms often respond favorably to replacement therapy (42). This topic is considered in greater detail in the article on Vitamin D in neurologic disorders. In 25 patients with chronic kidney disease on dialysis, there was a correlation between reduced quadriceps muscle strength and increased fall risk with low levels of 25-hydroxyvitamin D (25(OH)D) levels, but not with levels of parathyroid hormone (13). This was further supported by several metaanalyses. Stockton and colleagues concluded that muscle strength improved if supplemented with 1000 IU of vitamin D in individuals with a baseline serum 25(OH)D level of less than 25 nmol/L (88). In 2014, Beaudart and associates also found a small but statistically significant improvement in muscle strength with vitamin D supplementation (08).
Myopathy secondary to hypoparathyroidism is unusual, although perioral and distal paresthesia and tetany secondary to hypocalcemia do occur. Chvostek sign (ipsilateral facial contraction when tapping the facial nerve at the external auditory meatus) and Trousseau sign (thumb adduction, metacarpophalangeal joint flexion, and interphalangeal joint extension after temporary occlusion of the brachial artery) may be demonstrated in hypocalcemic patients. Severe tetany can cause stridor and apnea due to vocal cord involvement, as well as bronchospasm, diaphragmatic chest wall contraction (16; 58), and occasionally, tetanic seizures (54).
There are only a few reports of mild proximal weakness in patients with hypoparathyroidism (97; 87; 53; 98), and only 2 small series of cases of myopathy or myalgia with raised serum creatine kinase associated with hypocalcemia and hypoparathyroidism (89; 19). A nonnecrotizing myopathy may be a partial cause of the muscle weakness seen in some patients (21). Back pain and stiffness are often major complaints, and rare cases of hypoparathyroidism have been misdiagnosed as ankylosing spondylitis in part due to paravertebral ligamentous calcification or ossification and the presence of syndesmophytes (48).
A case of idiopathic hypoparathyroidism with proximal myopathy, high CK, low calcium, and EMG evidence of myokymia and neuromyotonia has been reported (99). There are also reports of painless myoglobinuria without objective weakness or tetany (01; 66). Patients with Kearns-Sayre syndrome, a mitochondrial encephalomyopathy due to sporadic large-scale mitochondrial DNA deletions, may also develop endocrinopathies including hypoparathyroidism (79).
Because more extensive blood chemistries are now performed routinely, hyperparathyroidism is diagnosed earlier than in the past, and patients are frequently asymptomatic or only mildly affected (50). In symptomatic patients, medical or surgical (parathyroidectomy) treatment is effective, and improvement of muscle strength is usually noticeable within a few months (72; 50; 67; 68).
A 76-year-old man was referred for a 1-year history of progressive weakness. He complained of difficulty climbing stairs, arising from chairs, and lifting objects over his head. In addition, he noted hoarseness of his voice over the past year.
Evaluation by otolaryngology was unrevealing. The patient denied weakness in his hands or feet, ptosis, diplopia or blurred vision, dysarthria, dysphagia, difficulty chewing, nasal regurgitation, fluctuation in muscle strength or voice, myalgia, numbness, or paresthesia.
Past medical history was remarkable for prostate cancer, which was treated with radical prostatectomy and bilateral orchiectomies. There was no evidence of tumor recurrence. He also had chronic renal insufficiency felt to be secondary to hypertension. There was no family history of neuromuscular disorders. He denied alcohol or tobacco use. Medications included propranolol, diltiazem, and aspirin.
Examination revealed a normal mental status. Extraocular movements were full. There was no ptosis. Face, jaw, palate, and tongue strength were normal. He had decreased muscle bulk in his shoulder and hip girdles. Fasciculations were not evident. Manual muscle-strength testing demonstrated symmetric proximal upper and lower extremity weakness.
He had the following Medical Research Council grades: orbicularis oculi 5, neck flexors 4, neck extensors 5, shoulder abductors 4, elbow flexors and extensors 4, wrist flexors and extensors 5-, hand intrinsics 5, hip flexors 4-, hip extensors 4-, hip abductors 4-, knee flexors 4, knee extensors 5, ankle dorsiflexors 4+, and plantar flexors 5. Complex motor skills were intact. He had diminished pain and vibratory sensation in his feet to the distal one third of his lower legs bilaterally. His gait was slightly wide-based, but he was able to walk on his heels and toes. Deep tendon reflexes were 1+ at his biceps, triceps, brachioradialis, and knees, but unobtainable at the ankles.
Nerve conduction studies demonstrated a mild sensorimotor polyneuropathy with unobtainable sural sensory nerve action potentials (SNAPs), borderline amplitudes, and mildly prolonged distal latencies of the median, ulnar, and radial SNAPs. He had low amplitude peroneal compound motor action potentials (CMAPs), borderline amplitude median CMAPs, but normal ulnar and posterior tibial CMAPs as well as normal distal motor latencies and conduction velocities. There was no evidence of abnormal decrement or increment on repetitive nerve stimulation. EMG of weak proximal muscles demonstrated normal insertional activity and no abnormal spontaneous activity (ie, fibrillations and fasciculations were not present).
There was a mixture of small and large motor unit potentials, but the overall size on quantitation of 20 motor unit potentials was normal.
However, the motor unit potentials did appear to recruit early.
Laboratory evaluation was remarkable for anemia (hematocrit 30%) and chronic renal insufficiency (blood urea nitrogen 32 mg/dL and creatinine 1.9 mg/dL). In addition, he had a low serum albumin level of 2.0 g/dL. Of note, the alkaline phosphatase and electrolytes were normal, including a calcium level of 8.4 mg/dL and phosphate level of 4.3 mg/dL. However, an ionized calcium level (correcting for the hypoalbuminemia) was mildly elevated at 5.52 mg/dL (normal 4.48 to 5.20 mg/dL). Intact parathyroid hormone level was elevated at 106.5 pg/mL (normal 10 to 65 pg/dL). Interestingly, his 25-hydroxy vitamin D level was low at 8.6 ng/mL (normal 16 to 74 ng/mL), and the 1,25 dihydroxy vitamin D level was not measurable. Other pertinent blood work revealed normal serum immunofixation, fasting glucose, creatine kinase, thyroid and liver function tests, erythrocyte sedimentation rate, rheumatoid factor, antinuclear antibody, B12, folate, and CSF (protein 32 mg/dL). Acetylcholine receptor antibodies were not present. Nuclear medicine scans demonstrated increased uptake in the left inferior parathyroid gland.
This patient had the unusual combination of both primary hyperparathyroidism and primary vitamin D deficiency. The patient underwent excision of the parathyroid gland and was started on vitamin D replacement. One year after treatment he had normal strength in his upper extremities but still had mild weakness in his lower extremities and hoarseness of his voice.
Primary hyperparathyroidism is most often caused by a single overactive parathyroid gland, usually an adenoma or, rarely (1%), a carcinoma. In 15% of cases, diffuse hyperplasia of all the parathyroid glands is the culprit (Potts 1998). Rare genetic disorders such as multiple endocrine neoplasia type 1 can also cause primary hyperparathyroidism (36). Effects of elevated parathyroid hormone commonly include hypercalcemia, osteopenia, and nephrolithiasis, although in modern times the most common presentation is of asymptomatic laboratory abnormalities.
Secondary hyperparathyroidism is the result of changes in renal function or deficiency of calcium and/or vitamin D and can result from resistance to the metabolic action of parathyroid hormone leading to hypocalcemia, hyperphosphatemia, and osteomalacia. Chronic renal failure is not infrequently associated with secondary hyperparathyroidism. In chronic renal failure, reduction of 1,25-dihydroxy vitamin D conversion causes decreased intestinal absorption of calcium. In addition, decreased renal phosphorus clearance causes increased serum phosphorous that binds calcium. Both lead to hypocalcemia and signal to increase parathyroid hormone secretion. Other causes of secondary hyperparathyroidism include gastrointestinal bypass surgery, severe celiac or Crohn disease, or severe vitamin D deficiency, which leads to secondary hyperparathyroidism and osteomalacia. In addition to acquired forms, there are hereditary forms of primary hyperparathyroidism (36) and of vitamin D deficiency and osteomalacia (33). Lastly, an increased incidence of usually asymptomatic secondary hyperparathyroidism associated with vitamin D deficiency has been found in up to 17.5% of patients with myotonic dystrophy type 1, which correlated with the CTG expansion size (69); only 1 of 17 patients was symptomatic and had surgery for an adenoma.
Hypoparathyroidism is seen in a number of conditions, including complications of surgery (eg, thyroidectomy, parathyroidectomy), hypomagnesemia or hypermagnesemia, irradiation, drugs, sepsis, infiltrative diseases of the parathyroid, and autoimmune, hereditary, or developmental disorders (23). Decreased parathyroid hormone results in diminished synthesis of 1,25-dihydroxy vitamin D, hypocalcemia, and hyperphosphatemia. Osteomalacia can also develop in association with hypoparathyroidism.
The accumulation of unmineralized bone matrix leads to rickets in children and osteomalacia in adults. As noted above, osteomalacia can complicate hyperparathyroidism and rarely hypoparathyroidism. Other etiologies of osteomalacia include vitamin D deficiency, inadequate nutrition, phosphate depletion, acidosis, and renal tubular disorders (33; 92). Vitamin D deficiency is common among the elderly who live in northern latitudes and need to cover their skin, and it should be evaluated in older individuals presenting with weakness and premature fatigue (73).
Calcium and phosphorus homeostasis require a complex interaction of intestinal, renal, hepatic, endocrine, skin, and skeletal functions (50). Parathyroid hormone regulates blood calcium concentration by promoting bone resorption, reducing renal clearance of calcium, and enhancing 1,25 dihydroxy vitamin D conversion. In addition, intestinal calcium absorption is increased under the influence of vitamin D. There are several forms of vitamin D: (1) vitamin D3 or cholecalciferol, which is derived from the skin; (2) vitamin D2 or ergocalciferol, which is dietary and absorbed through the intestines; and (3) 25-hydroxy vitamin D, which is made in the liver and converted to the more potent metabolite 1,25 dihydroxy vitamin D in the kidney. Increased parathyroid hormone leads to an increased synthesis of 1,25-dihydroxy vitamin D, hypercalcemia, and hypophosphatemia. Serum phosphorus levels are also determined by diet, intestinal absorption, and renal excretion. Persistently elevated parathyroid hormone results in resorption of minerals within bone and replacement by fibrous tissue, a condition termed "osteitis fibrosa" or "osteitis fibrosa cystica" in severe forms (50).
The mechanism of weakness in hyperparathyroidism and osteomalacia is not known. Some authors have suggested a neurogenic basis (04; 72; 60), but others have suspected a myopathic process (56; 50). Muscle biopsies usually demonstrate nonspecific myopathic features such as type 2 fiber atrophy. Elevated levels of parathyroid hormone (possibly related to the accompanying hypophosphatemia) are associated with impaired energy production, transfer, utilization (05; 50), and enhanced muscle proteolysis (28). The latter may be the result of cyclic AMP (cAMP) activation of calcium channels, initiated by parathyroid hormone, raising the intracellular calcium to a level sufficient to increase activation of intracellular proteases, thus, tipping the molecular homeostatic balance in favor of muscle degradation (06).
In addition, parathyroid hormone may diminish the sensitivity of contractile myofibrillary proteins to calcium and activate a cytoplasmic protease, thus, impairing the bioenergetics of muscle (91). Interestingly, calcium and phosphorus levels do not correlate well with the clinical severity of muscle weakness (25; 86; 72).
Vitamin D may also play a role in muscle weakness and has been shown to have a direct effect on muscle: it increases muscle adenosine triphosphatase concentration, accelerates amino acid incorporation into muscle proteins (12; 50), and increases the uptake of calcium by sarcoplasmic reticulum and mitochondria (18; 74). In experimental animals with vitamin D deficiency, excitation-contraction coupling is deranged, calcium uptake and storage capacity are impaired, myofibrillar ATPase activity is depressed, and protein synthesis is decreased (11). Vitamin D receptors have been demonstrated in adult mouse skeletal muscles with higher concentrations in precursor cells and younger animals (32). Other in vitro studies demonstrated 1,25(OH)2D3 increased myocyte precursor differentiation, and vitamin D deficiency accelerates muscle degradation through the ubiquitin pathway (29; 10).
The etiology of the rare myopathy associated with hypoparathyroidism is even less clear. Elevated serum creatine kinase and mild nonspecific histologic abnormalities on muscle biopsy are generally considered secondary to muscle damage from hypocalcemia, with more severe abnormalities related to the degree and duration of the hypocalcemia (19). Decreased serum calcium concentration causes a shift in the cellular activation potential toward the resting potential (14; 26; 26; 01). Therefore, less current is required to elicit an action potential. Tetany may manifest when plasma calcium plummets to about 6 mg/dL (35). By the same process, central nervous system neuronal hyperexcitability can result in seizures.
The reduced peripheral response to parathyroid hormone in pseudohypoparathyroidism is best described in families with a mutation in GNAS1, the alpha subunit of stimulatory G protein, which couples with the parathyroid hormone receptor to stimulate adenylyl cyclase (07); it was thought to be caused by either a mutation in the parathyroid hormone receptor, its G protein, or possibly adenylyl cyclase (22).
Muscle weakness is common in osteomalacia, occurring in as many as 72% of patients in some series (86). Weakness develops in only 2% to 10% of patients with hyperparathyroidism alone (86; 72; 55). Rarely is overt myopathy evident in hypoparathyroidism (50).
Because better techniques are currently available for the early diagnosis and treatment of hyperparathyroidism and osteomalacia (38), neuromuscular complications nowadays are milder (90) than those reported in earlier series (93; 86; 72; 60). No information is available on prevention of myopathy secondary to hypoparathyroidism, although a prospective study of age-related muscle loss in men ages 60 to 85 showed that in addition to low leisure physical activity, type 2 diabetes, and low testosterone, low parathyroid hormone serum concentration was associated with greater age-related acceleration of muscle loss (76).
Certain populations are clearly at a higher risk to develop hypo- or hyperparathyroid complications. These include people who underwent thyroidectomy because the parathyroids are adherent to the thyroid gland and, therefore, at risk for accidental excision (leading to hypoparathyroidism), or family members of people with multiple endocrine neoplasia, who are at increased risk for the disease themselves. Laboratory surveillance (ie, checking serum calcium levels) of such individuals mitigates the risk of developing sequelae.
The pattern of weakness (ie, proximal greater than distal weakness and legs worse than arms) is not specific for parathyroid-related myopathies and can be observed in other endocrine disorders such as hyperthyroidism and hypothyroidism and corticosteroid myopathies. History of corticosteroid use, thyroid function tests, electrolytes, and cortisol levels can help in distinguishing these endocrine myopathies. Polymyositis and dermatomyositis are associated with proximal limb weakness but, in contrast to parathyroid myopathies, serum creatine kinase levels are usually elevated, EMG demonstrates increased insertional and spontaneous activity (fibrillation potentials, complex repetitive discharges), and muscle biopsies reveal inflammation. Less common causes of proximal weakness in older individuals include limb-girdle muscular dystrophies, Lambert-Eaton syndrome, and myasthenia gravis. These disorders should readily be distinguished by clinical and family history, neuromuscular examination, electrophysiologic testing, muscle histology, and ancillary tests (eg, edrophonium test, acetylcholine receptor antibody titer, P/Q voltage gated calcium channels antibody titer, or genetic testing).
Finally, there are a few cases of hyperparathyroidism mimicking amyotrophic lateral sclerosis, characterized by spasticity, hyperreflexia, and extensor plantar responses in combination with lower motor neuron weakness (72; 15; 30). Some of these patients improved following resection of parathyroid adenomas. However, on close scrutiny, these patients never would have fulfilled criteria for amyotrophic lateral sclerosis (45). The presence of hyperparathyroidism in patients with amyotrophic lateral sclerosis appears to be coincidental, and patients do not improve following surgical resection. In 1 study, 5 patients who met El Escorial criteria for amyotrophic lateral sclerosis were found on workup to have hyperparathyroidism secondary to parathyroid adenomas (45). Resection of the adenomas failed to alter the fatal course of amyotrophic lateral sclerosis in these patients. The previously reported patients who improved with surgical resection of the parathyroid adenomas most likely had the associated myopathy, not amyotrophic lateral sclerosis.
In hyperparathyroidism, serum calcium levels are usually elevated and serum phosphate levels are low, whereas urinary excretion of calcium is low and excretion of phosphate is high. In patients with concurrent hypoalbuminemia, serum calcium levels may be normal, and in these cases, ionized calcium should be measured and is typically elevated. Increased urinary excretion of cyclic adenosine monophosphate in the presence of hypercalcemia is indicative of hyperparathyroidism. In primary hyperparathyroidism, serum parathyroid hormone levels and 1,25-dihydroxy vitamin D levels are elevated. In hyperparathyroidism secondary to renal failure, 1,25-dihydroxy vitamin D levels are low. Noninvasive imaging techniques, such as ultrasound, thallium/technetium scintigraphy, computed tomography, and magnetic resonance imaging, may be useful in localizing abnormal parathyroid glands (67).
In osteomalacia, serum calcium levels are low or normal and serum phosphate is variably low depending on the degree of secondary hyperparathyroidism. Serum vitamin D levels are also usually low. Urinary excretion of calcium is low (except in cases secondary to renal tubular acidosis), whereas excretion of phosphate is high. In addition, elevated serum alkaline phosphatase levels are present in 80% to 90% of cases and are a useful screening tool for osteomalacia (80). Roentgenography usually demonstrates a decrease in bone density associated with loss of trabeculae, blurring of trabecular margins, and variably thinned cortices (33).
Electromyography in patients with weakness secondary to hyperparathyroidism and osteomalacia can be normal or show small polyphasic motor unit potentials with early recruitment, suggestive of a myopathic process (85; 86; 25; 72; 84; 44). There are only rare reports of neurogenic features on EMG, such as fibrillation and fasciculation potentials, large polyphasic motor units, and decreased recruitment (72; 30). Rare reports of myotonic discharges on EMG have been reported (37). Ljunghall and colleagues reported increased jitter on single-fiber EMG but no significant blocking (59). Occasionally, nerve conduction studies demonstrate a superimposed axonal sensorimotor neuropathy (90). Muscle biopsies usually demonstrate nonspecific myopathic features with atrophy predominantly of type 2 fibers but occasionally also of type 1 fibers.
Hypoparathyroidism is associated with low serum parathyroid hormone and calcium levels, low serum magnesium, and high serum phosphate levels. Although serum creatine kinase is usually normal in hyperparathyroidism, in hypoparathyroidism creatine kinase levels may be elevated. Muscle biopsies may reveal nonspecific myopathic features that may reflect muscle damage secondary to episodes of tetany (50). Decreased glycogen phosphorylase activity of muscle biopsy specimens has also been described (91). Electrocardiogram should routinely be performed to monitor for prolonged QT interval. Head computed tomography may incidentally show basal ganglia calcifications; likewise, lumbar puncture is unnecessary, but when performed (eg, in the setting of a seizure), cerebrospinal fluid pressure occasionally may be elevated (22).
Parathyroidectomy is the treatment of choice of symptomatic patients with primary hyperparathyroidism (67). In patients with adenoma, the affected gland is removed, although additional glands may be biopsied. Patients with hyperplasia of all 4 glands generally have subtotal (3.5 glands) parathyroidectomies. Medical management of primary hyperparathyroidism is reserved for asymptomatic patients or those with significant perioperative risk (68). Bisphosphonates and cinacalcet can be used to treat symptomatic hyperparathyroidism (81) in patients who choose not to have surgery or are poor surgical candidates. Patients with secondary hyperparathyroidism usually improve with vitamin D and calcium replacement and lowering of phosphate levels or, if they are in end-stage renal failure, with renal transplantation (91). Cinacalcet can also be added if parathyroid hormone levels remain elevated. Occasionally, subtotal parathyroidectomy is performed in patients with secondary hyperparathyroidism. In 1 study, the outcome was similar between medical versus surgical treatment for patients with severe secondary hyperparathyroidism (62); 25% (4 of 16 patients) had improvement in their muscle weakness with a subtotal parathyroidectomy whereas 40% (2 of 5 patients) improved with a total parathyroidectomy. The myopathy associated with osteomalacia responds well to vitamin D and calcium replacement and to treatment of the underlying responsible condition (85; 86; 60; 82; 84; 44; 33; 80). The rare myopathy associated with hypoparathyroidism also improves following correction of hypocalcemia and hyperphosphatemia with vitamin D and calcium (97; 98).
Emergency treatment of hypocalcemic tetany requires intravenous infusion of calcium 15 to 20 milliequivalents per kilogram over 4 to 6 hours. When seizures occur, calcium can be given as a slow intravenous push; however, cardiac and blood pressure monitoring would be necessary (91). The target serum calcium should be between 8 and 9 mg/dL (22), with further titration based on clinical improvement. Concurrent hypomagnesemia must also be addressed with exogenous supplementation. Should stridor be present, close respiratory monitoring is mandatory, with consideration for emergency tracheostomy (a kit should be brought to the bedside) if obstruction occurs.
Chronic management with vitamin D2 (ergocalciferol, dose: 25,000 to 150,000 units daily) should begin in conjunction with oral calcium repletion when the patient can safely take oral medication. In some patients who do not respond to vitamin D2, 1,25(OH)2D3 or 1-OH-D3 may be tried (at a higher cost) as a means to circumvent impaired vitamin D activation (91).
Over 80% of 103 consecutive patients with primary hyperparathyroidism who underwent parathyroidectomy improved after surgery (17). In another large series, all of 42 patients over the age of 60 benefited from surgery (20). Fifteen of 17 patients with muscle weakness and 14 of 15 patients with premature fatigue reported significant improvement postoperatively (20). Quantitative muscle testing demonstrated mild improvement (3% to 33%) in isokinetic strength or torque in knee extensors and flexors following surgery (39; 96; 46). The increase in isokinetic strength was noted at higher angular velocities, suggesting that therapy had affected predominantly type 2 (fast-twitch) muscle fibers, which, as noted earlier, are selectively involved in the myopathy associated with hyperparathyroidism. Increases in maximal expiratory pressures have also been reported 6 to 12 months postoperatively (51). Joborn and colleagues found that postoperative improvement in strength correlated with higher preoperative calcium levels and worse muscle strength (46), but others have not observed such a correlation (39; 96; 51).
Although similar quantitative data are not available for patients with secondary hyperparathyroidism and osteomalacia, subjective and objective improvement in muscle strength also occurs in most patients with secondary hyperparathyroidism and osteomalacia following treatment of the underlying condition (24; 40; 60; 57; 50; 80). One report describes a center's 10-year experience in subtotal parathyroidectomy of hemodialysis patients. Symptoms of myopathy were present in 89% of patients before surgery and in only 15% of patients after surgery (47).
The rare myopathy associated with hypoparathyroidism improves following correction of the hypocalcemia and hyperphosphatemia with vitamin D and calcium administration (97; 98).
Primary hyperparathyroidism is rare during pregnancy (36). However, women of childbearing age account for 5% to 25% of patients with primary hyperparathyroidism (52). The most serious complications are neonatal death, stillbirth, and miscarriage. In a review of 73 reported cases of pregnant patients with primary hyperparathyroidism, 45 patients had detailed clinical histories. Twenty-two percent of them had weakness with premature fatigue or myalgias (52). Twenty-three patients underwent surgery during pregnancy and 18 of them gave birth to healthy children. Fifty women with a total of 79 pregnancies did not undergo surgery and bore 35 healthy children; complications arose in 40 births. Perinatal death occurred in 9% of the operated group and 15% of the nonoperated group. To reduce the risk of complications in both the mother and the child, the authors recommended surgery in the second trimester of pregnancy after the fetal organs have developed and the risk of postoperative miscarriage is less (52).
Primary hyperparathyroidism is uncommon in children. Of 1000 patients who underwent parathyroidectomy over a 15-year period, 2.1% were under 20 years of age and 15 were between 16 to 20 years (71). The triad of fatigue, weakness, and/or depression was about twice as common in adolescents (67%). Renal stones (52%) and hypercalcemic crisis (5%) were also more common in children, whereas osteopenia and osteoporosis, common in the adults, was not diagnosed in any of the adolescents. Children had higher presenting serum calcium level and lower parathyroid hormone concentration. Similar to adults, 86% of children had single gland disease and 95% were cured after the first operation.
The risk of complications with anesthesia and surgery in patients with myopathies related to hyperparathyroidism is considered low, with mortality less than 2% and morbidity less than 4% (17; 67). No particular anesthetic or anesthesia technique is known to produce a better outcome in patients undergoing surgery for hyperparathyroidism. Particular consideration should, however, be given when using succinylcholine or atracurium, because sensitivity to these substances have been reported in patients with hyperparathyroidism (02). This is especially pertinent when the surgeon wants to preserve the ability to test the recurrent laryngeal nerve (not routinely done by most surgeons) during surgery. Lastly, although there is general concern for cardiac dysrhythmias in patients with hypercalcemia, 1 series found no increase in intraoperative ventricular dysrhythmias in patients with calcium levels of 11.6 mg/dL (34).
Emma Ciafaloni MD FAAN
Dr. Ciafaloni of the University of Rochester received personal compensation for serving on advisory boards and/or as a consultant for Alexion, Avexis, Biogen, PTC Therapeutics, Ra Pharma, Sarepta, Strongbridge Biopharma PLC, and Wave; and for serving on a speaker’s bureau for Biogen. Dr Ciafaloni also received research and/or grant support from Orphazyme, Santhera, and Sarepta.See Profile
Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Childhood Degenerative & Metabolic Disorders
Jun. 10, 2021
X-linked myotubular (centronuclear) myopathy is a severe muscle disorder mainly affecting newborn boys, but sometimes it can also affect girls. Diagnostic
Mar. 24, 2021
Mar. 21, 2021
This article discusses pyridostigmine, the most commonly used first-line therapy for myasthenia gravis. The article addresses the pharmacology, indications, contraindications, treatment goals, dosing, special considerations, interactions, and adverse effects to be considered in the use of this cholinesterase inhibitor.
Mar. 12, 2021
Mar. 06, 2021
In this article, the author discusses caring for children with various types of chronic neuromuscular disease. The updated article includes discussion
Feb. 24, 2021
Neuromuscular syndromes of the paraspinal muscles comprise the dropped head syndrome and the bent spine syndrome (camptocormia). Although these phenotypes
Feb. 15, 2021
Myasthenia gravis (MG) is a neuromuscular disease that causes muscle weakness and fatigue, affecting the ocular, bulbar, and limb muscles. Symptoms are worsened by muscle activity and improved by rest. They are caused by an autoimmune attack on acetylcholine receptors (AChR) or other components of the neuromuscular junction (NMJ).
Feb. 15, 2021