Progressive Muscle Weakness: More There Than Meets the Eye

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IM BOARD REVIEW CME EDUCATIONAL OBJECTIVE: Readers will identify potential causes of muscle weakness, CREDIT including endocrine causes SIWAR ALBASHIR, MD LEANN OLANSKY, MD MADHU SASIDHAR, MD Department of General Internal Medicine, Department of Endocrinology, Department of Pulmonary, Allergy, Cleveland Clinic Endocrinology and Metabolism and Critical Care Medicine, Institute, Cleveland Clinic Cleveland Clinic

Progressive muscle weakness: More there than meets the eye

ur patient, a 56-year-old woman, • No history of alcohol or intravenous Opresents with proximal muscle weakness drug use in all four limbs. It started a few months ago • Quit smoking many years ago and has gradually become severe, so that she • Coronary artery bypass surgery in 2003 now has difficulty rising from a seated posi- • One sibling with myasthenia gravis. tion and has trouble opening jars. She has fallen several times. She says she has no mus- Medications cle pain, difficulty swallowing, or difficulty • Levothyroxine breathing. • Rosuvastatin (Crestor) She sought medical attention at another • Omeprazole (Prilosec) hospital and was found to be hypothyroid, • Spironolactone with a thyrotropin (thyroid-stimulating hor- • Furosemide mone [TSH]) level of 38 μU/mL (reference • Potassium chloride range 0.4–5.5), for which she was started • Metoprolol tartrate (Lopressor) on levothyroxine (Synthroid) 100 μg daily. • Metformin (Glucophage) She has had She also had a low serum potassium level, for • Ramipril (Altace). which potassium supplements and spirono- progressive Physical examination lactone (Aldactone) were started. She was weakness She is hemodynamically stable and is not taking furosemide (Lasix) 20 mg/day at the hypertensive. Her thyroid is not enlarged. for several time. Her lungs are clear to auscultation. Her Despite the thyroid replacement therapy, months; heart sounds are normal, except for a nonra- she continued to become weaker and had diating pansystolic murmur most audible at what is the more falls. She also noticed a new, nonpainful the apex. rash on her lower abdomen. cause? Her abdomen is soft and is not distended. Review of systems Her abdominal rash has a dermatomal dis- • Night sweats tribution consistent with an L1 distribution, • Leg swelling with vesicles over an erythematous base. • Puffiness and discoloration around the Purpuric lesions are noted over her lower ex- eyes, with easy bruisability. tremities. Her leg strength is 3 on a scale of 5 on both Medical history sides; her arm strength is normal. Ankle and • Diabetes mellitus knee reflexes are absent bilaterally. • Seizures in the 1970s • Resection of a thymic tumor in 2003 (the Initial laboratory analysis exact pathology is unknown) Initial laboratory analysis (TABLE 1) indicates • Cirrhosis of unknown etiology mild renal insufficiency, hypokalemia, elevat- • No known history of hypertension ed liver enzymes, and a normal TSH level. An acetylcholine receptor antibody assay is nega- doi:10.3949/ccjm.78a.10116 tive. Her creatine kinase level is also normal.

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specific tyrosine kinase that interacts with this TABLE 1 receptor. The patient’s general biochemistry values About 15% of patients with myasthenia gravis have a thymoma thought to be involved SUBSTANCE REFERENCE RANGE VALUE in the pathogenesis of the disease. Treatments Glucose 65–100 mg/dL 154 include immune suppressive therapy and thy- mectomy. Sodium 132–148 mmol/L 145 Our patient has a history of thymic lesion Potassium 3.5–5.0 mmol/L 3.1 resection, but her antibody workup for myasthenia gravis was negative. Creatinine 0.70–1.40 mg/dL 1.64 Blood urea nitrogen 8–25 mg/dL 77 Hypothyroidism Hypothyroidism, the most common disorder Chloride 98–110 mmol/L 115 of the thyroid gland, is especially prevalent 3 Its common symptoms include fa- Carbon dioxide 23–32 mmol/L 16 in women. tigue, exercise intolerance, muscle weakness, Thyrotropin (TSH) 0.400–5.500 µU/mL 2.57 cramps, and stiffness. Both the TSH and the free thyroxine (T ) Creatine kinase 30–220 U/L 92 4 level must be measured to diagnose hypothy- Acetylcholine receptor 0.0– 0.4 nmol/L 0.0 roidism. This information can also help dif- antibody ferentiate primary hypothyroidism (ie, due to a defect in the thyroid gland) from secondary hypothyroidism (ie, due to a defect in the pituitary gland). Elevated TSH with low free

■■ PROGRESSIVE MUSCLE WEAKNESS T4 levels indicates primary thyroid failure, whereas the combination of a normal or low What are possible causes of her muscle TSH and a low free T4 usually indicates pi- Up to 10% 1weakness? tuitary failure. Subclinical hypothyroidism is of patients □□ Myasthenia gravis characterized by mildly to moderately elevated TSH, but total T and free T values are on statins □□ Hypothyroidism 4 4 □ still within the reference range. Replacement □ Dermatomyositis-polymyositis 3–6 develop □□ Drug-induced myopathy therapy is with levothyroxine. myalgia □□ Cushing syndrome Our patient has a history of hypothyroid- □□ All of the above ism, which could explain her muscle weakness, but she is currently on replacement All of these are potential causes of muscle therapy, and her TSH level on admission was weakness. normal.

Myasthenia gravis Dermatomyositis-polymyositis Myasthenia gravis, an autoimmune disease, Dermatomyositis-polymyositis is characterized can affect people of all ages and either sex. It by proximal muscle weakness, creatine kinase presents with muscle weakness and fatigabil- elevation, erythema on sun-exposed skin, he- ity, which characteristically fluctuate during liotrope rash, and Gottron papules. It occurs the day. Some patients present in crisis with mostly in women after the second decade of respiratory failure, which may require ventila- life. Some medications have been implicated tory support.1,2 in its pathogenesis, such as statins, fibrates, Myasthenia gravis is characterized by auto- hydroxyurea, penicillamine, and omeprazole antibodies against the postsynaptic membrane (Prilosec).7 of the neuromuscular junction. Most patients In a middle-aged patient, this diagnosis have antibodies to the extracellular portion should prompt a search for cancer, especially of the acetylcholine receptor; a small number of the gastrointestinal system, breast, and of patients have antibodies against a muscle- lung.8 Cancer can arise up to 3 years after the

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diagnosis of dermatomyositis or polymyositis. Antisynthetase antibody syndrome is sus- The cortisol cascade pected if the patient is positive for antisynthetase antibody and has the following manifes- Hypothalamus tations: acute onset of disease, constitutional symptoms, interstitial lung disease, inflammatory arthritis, mechanic’s hands (thickened, Corticotropin-releasing hormone cracked skin on the palmar aspect of the thumb and index finger), and Raynaud phe- Ectopic tumors nomenon.4,8,9 Anterior pituitary The diagnosis is made by a thorough clinical evaluation. Electromyography can show an inflammatory pattern of myopathy. The Corticotropin Inhibits gold standard test for this diagnosis is muscle biopsy. Our patient has a normal creatine kinase Adrenal cortex level, which excludes the diagnosis of dermatomyositis-polymyositis. Cortisol Statin-induced myopathy Up to 10% of patients taking statins develop myalgia. Rhabdomyolysis, the extreme form of FIGURE 1 myopathy, is rare. The exact mechanism of statin-induced Cushing syndrome myopathy remains unclear; mitochondrial Cushing syndrome (hypercortisolism) is one dysfunction, cholesterol composition of cell of the most challenging endocrine diseases membranes, and coenzyme Q10 deficiency to diagnose. Most of its clinical features over- have been proposed. lap with those of common diseases, and some Cushing Risk factors for statin-induced myopathy patients have an atypical clinical presenta- syndrome include female sex, older age, higher doses of tion with only isolated symptoms. Further, its statins, a family history of statin-induced my- presentation can be subtle, with weight gain, is one of the opathy, and hypothyroidism. Drugs that in- amenorrhea, muscle weakness, and easy bruis- most crease the risk include fibric acid derivatives, ability. Acne, moon facies, plethora, abdomi- challenging macrolides, and amiodarone (Cordarone). If a nal striae, and purpura are other common statin and any of the above drugs are both re- signs. It is three to 10 times more common in endocrine quired, certain statins—ie, pravastatin (Prava- women than in men. diseases chol) and rosuvastatin—are recommended, Cushing syndrome can be classified ac- since they are the statins least likely to cause cording to whether or not the excess corti- to diagnose rhabdomyolysis.5,7,10–12 sol secretion depends on corticotropin (for- The combination of fluvastatin (Lescol) merly called adrenocorticotropic hormone or and gemfibrozil (Lopid) has also been found ACTH) (FIGURE 1). In corticotropin-dependent to be safe.13 In a crossover study in 17 pa- cases, the most common cause is pituitary ad- tients, no significant difference was seen in enoma. (When Cushing syndrome is due to the area under the curve for plasma concen- excessive pituitary secretion of corticotropin, tration over time, in the maximum plasma which in turn stimulates the adrenal glands concentration, or in the time to maximum to secrete excessive amounts of cortisol, it concentration with the combination vs with is called Cushing disease). Other causes of each drug alone.13 corticotropin-dependent Cushing syndrome Our patient is taking a statin and has hy- are ectopic corticotropin-producing tumors pothyroidism, which increases the risk of such as carcinoid tumors or medullary thyroid statin-induced myopathy. However, her cre- cancers. Corticotropin-independent Cushing atine kinase level is normal. syndrome can be caused by adrenal adenomas,

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■■ HOW TO TEST FOR CUSHING SYNDROME TABLE 2 In any practice, you may meet many peri- The patient’s immunologic laboratory values 2menopausal women who have complaints TEST Reference range Value of weight gain, amenorrhea, and acne. How can you determine if this is Cushing CD3 cells 958–2388 cells/µL 122 syndrome? What are the screening tests? CD4 + CD3 cells 533–1674 cells/µL 30 □□ 24-Hour urinary cortisol excretion Natural killer cells 102–565 cells/µL 51 □□ A late-night salivary cortisol level □□ A low-dose dexamethasone suppression CD4:CD8 ratio 1.1–3.25 0.37 test □□ All of the above □□ None of the above adrenal carcinoma, and bilateral primary micronodular or macronodular adrenocortical Any of the tests listed here can be used to hyperplasia.14–17 determine whether this is truly Cushing syn- However, the most common cause of drome. Cushing syndrome is glucocorticoid therapy. 24-Hour urinary cortisol excretion has a reference range of 20 to 100 μg/24 hours. ■■ BACK TO OUR PATIENT: However, results may be falsely high in pa- HER CONDITION DETERIORATES tients who are depressed or who abuse alcohol. The late-night salivary cortisol level is Our patient’s physical condition deteriorates, another useful test.14,16,18 Patients with Cush- she develops respiratory distress, and she is ing syndrome are found to have high late- admitted to the medical intensive care unit. night salivary cortisol levels as compared with Her mental status also deteriorates, and she normal people, indicating the loss of natural becomes lethargic and unresponsive. circadian rhythm.14,16,18 The most She is intubated to protect her airway. Af- The low-dose dexamethasone suppres- common cause ter this, she develops hypotension that does sion test, as first described by Liddle in 1960,19 not respond to fluid resuscitation and that re- involved giving dexamethasone 0.5 mg by of Cushing quires vasopressors. Her condition continues mouth every 6 hours for 48 hours and measur- syndrome is to worsen as she develops acute kidney injury ing the serum cortisol level 6 hours after the and disseminated intravascular coagulation. last dose. In healthy people, this low dose of glucocorticoid Her vesicular rash becomes more widespread, dexamethasone suppresses the production of therapy involving the entire trunk. corticotropin by the pituitary gland and in A workup for sepsis is initiated, but her turn the production of cortisol, but in patients initial blood and urine cultures are nega- with Cushing syndrome the cortisol level re- tive. Chest radiography does not reveal any mains high. An alternative is the overnight infiltrates. No other source of an infection is 1-mg dexamethasone suppression test—ie, found. giving 1 mg of dexamethasone at 11:00 pm Varicella zoster is isolated on viral culture and measuring the serum cortisol level early of a specimen obtained from the rash, and a the next morning. Failure of the cortisol level polymerase chain reaction test of her blood to drop to less than 1.8 μg/dL suggests Cushing shows cytomegalovirus DNA (64,092 copies syndrome and warrants a complete evaluation per mL). Immune suppression is suspected, for it. so a CD4 count is ordered (TABLE 2). Serologic Confirmatory testing is sometimes need- tests for human immunodeficiency virus are ed if patients have mild abnormalities in negative. their screening tests. A combination low- What could have caused our patient to dose dexamethasone suppression test and have muscle weakness in addition to dissemi- corticotropin-releasing hormone test can be nated zoster with cytomegalovirus viremia? used to differentiate Cushing syndrome from The diagnosis here is Cushing syndrome. pseudo-Cushing syndrome. This is performed

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by giving dexamethasone orally 0.5 mg every 6 hours for 48 hours and then giving ovine- TABLE 3 sequence corticotropin-releasing hormone 1 The patient’s endocrine laboratory values µg/kg intravenously 2 hours after the last dose of dexamethasone. The plasma cortisol value TeST Reference range value

15 minutes after the dose of corticotropin-re- 24-Hour urine cortisol 10–100 µg/day 23,965 leasing hormone is greater than 1.4 µg/dL (38 nmol/L) in patients with Cushing syndrome 5-HIAA random urine 0.0–9.9 µg/mg 99.8 but remains low in patients with pseudo- creatinine Cushing syndrome. Corticotropin (ACTH) 8–42 pg/mL 535 Usually, two tests are needed to diagnose Cushing syndrome unless one test is highly Calcitonin < 8 pg/mL basala 213 abnormal, as seen in our patient, who had an < 90 pg/mL peak extremely high 24-hour urinary cortisol secre- DHEA-S 10–152 µg/dL 195.5 tion (TABLE 3). aIn women Is this corticotropin-dependent 5-HIAA=5-hydroxyindoleacetic acid (a breakdown product of serotonin); or corticotropin-independent? DHEA-S=dehydroepiandrosterone sulfate Once Cushing syndrome is diagnosed by one of the screening methods described above, the source of the excess glucocorticoids needs to MRI of the pituitary gland should be be determined. Measuring the serum cortico- done in patients with suspected corticotro- tropin level early in the morning would be the pin-dependent Cushing syndrome. However, next step. MRI may be negative in 50% of patients with A low corticotropin level (< 10 pg/mL) Cushing disease, and it should therefore not indicates a corticotropin-independent source, be used for screening. In addition, 10% of the most likely in the adrenal glands. Hence, population may have pituitary incidentalomas computed tomography or magnetic resonance on MRI. If corticotropin imaging (MRI) of the adrenal glands is war- Most cases of corticotropin-dependent is > 10 pg/mL, ranted. Of note: adrenal incidentalomas are Cushing syndrome are caused by microadeno- quite common, present in 5% of the general mas (smaller than 1 cm), while a few cases are find out population, and a lesion on the adrenal gland caused by macroadenomas (larger than 1 cm). whether does not prove that the patient has primary If a microadenoma is found on MRI, further it comes from adrenal disease.16,20 testing with bilateral inferior petrosal sinus sampling is recommended (described below); the pituitary ■■ IS THE EXCESS CORTICOTROPIN FROM if a macroadenoma is found, then no further or from an A PITUITARY OR AN ECTOPIC SOURCE? testing is required.21,22 In fact, patients who have biochemical findings compatible with ectopic source If the corticotropin level is elevated, how Cushing disease (ie, due to an overactive pitu- 3can you determine if it is from the pituitary itary) and who have an adenoma larger than 6 or from an ectopic source? mm do not require further evaluation.23 □□ MRI of the pituitary gland A high-dose dexamethasone suppression □□ High-dose dexamethasone suppression test involves giving 8 mg of dexamethasone in test the evening and measuring the cortisol level □□ Corticotropin-releasing hormone the next morning. If the cortisol level declines stimulation test to 50% of the baseline level after this dose, □□ Bilateral inferior petrosal sinus sampling this suggests a pituitary cause. Corticotropin-releasing hormone stimu- If the corticotropin level is high (> 10 pg/mL), lation testing. In most cases of pituitary tumors it is of paramount importance to determine and a few cases of ectopic corticotropin-se- whether the corticotropin comes from the pi- creting tumors, giving corticotropin-releasing tuitary gland or from an ectopic source. hormone leads to an increase in serum corti-

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cotropin and cortisol levels. In contrast, these corticotropin-dependent Cushing syndrome. levels do not respond to corticotropin-releas- Our patient’s elevated levels of cortisol ing hormone stimulation if the problem is in were the cause of her muscle weakness and se- the adrenal gland. The test is performed by vere immune deficiency, which in turn led to giving 1 µg/kg or 100 µg synthetic or human cytomegalovirus viremia and sepsis. Cushing corticotropin-releasing hormone. A 35% to syndrome usually causes hypertension, espe- 50% increase above baseline in corticotropin cially in cases of ectopic corticotropin produc- suggests a pituitary cause.23 tion. However, our patient was normotensive Bilateral inferior petrosal sinus sampling on admission and then developed cytomega- can be used to confirm a pituitary source, as it lovirus sepsis, which led to hypotension and is the gold standard for differentiating ectopic shock. from pituitary corticotropin production. Once Immune suppression is a well-known effect this is confirmed, a neurosurgical consult is of glucocorticoids.26–28 Kronfol et al28 found warranted.16,18 that CD4 and CD8 counts and the CD4-to- This procedure is usually done by advanc- CD8 ratio were low in patients with Cush- ing a sheath from the femoral vein to reach ing syndrome, and natural killer cell activity the inferior petrosal sinuses. Blood samples was suppressed. Opportunistic infections have are obtained from both the inferior petrosal been described in patients with Cushing syn- sinuses and from a peripheral vein to mea- drome.26,27,29 sure corticotropin levels before and after giving corticotropin-releasing hormone (1 µg/ ■■ MANAGEMENT OF CUSHING SYNDROME kg). Before corticotropin-releasing hormone is given, a gradient of central-peripheral cor- Management of Cushing syndrome should be ticotropin levels of 2.0 or greater indicates tailored after determining its source. a pituitary source. With ectopic corticotro- A neurosurgical consultation is warranted pin production, the corticotropin gradient is in cases of pituitary adenoma, with surgical re- usually less than 1.5. Corticotropin-releasing section of the adrenal source or ectopic tumor The patient hormone is given to increase the sensitivity: if feasible.25 was too ill after it is given, a gradient of 3.0 or greater is Medical management is recommended if considered indicative of Cushing disease.24 surgical resection is not possible.30,31 Several to undergo If the corticotropin level is elevated and drugs can be used to inhibit cortisol synthesis additional the above tests indicate ectopic production, in this situation.30,32 imaging the source should be sought. The most common site of ectopic corticotropin production is Adrenal-acting agents the chest. Common causes are bronchial, thy- Aminoglutethimide (Cytadren) acts by mic, and pancreatic carcinoid tumors. Other blocking the conversion of cholesterol to causes are small-cell lung cancer, medullary pregnenolone, a precursor of cortisol. The cell cancer, and pheochromocytoma.15,18,25 dosage is 250 mg twice or three times a day. This drug is no longer available in the United ■■ BACK TO OUR PATIENT States. Ketoconazole (Nizoral) inhibits side-chain Our patient’s further laboratory results are cleavage, 11-beta hydroxylase, and 17-alpha listed in TABLE 3. hydroxylase, thus inhibiting cortisol synthesis; She has elevated 24-hour urinary cortisol it also inhibits corticotropin secretion. The excretion, consistent with Cushing syndrome. dosage is 200 to 400 mg three times a day. Her corticotropin level is elevated, which Metyrapone (Metopirone) blocks 11-beta- rules out an adrenal cause. Her 5-HIAA (a hydroxylation of deoxycortisol, the reaction serotonin breakdown product) and calcitonin that produces cortisol. The dosage is 500 to levels are also elevated, suggesting either med- 750 mg three times a day. This drug can be ullary thyroid cancer or a carcinoid tumor. obtained only from the manufacturer and only She also has a mild elevation of dehydroepi- on a named-patient basis. androsterone sulfate, which is consistent with Etomidate (Amidate), an anesthetic drug,

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also blocks 11-beta-hydroxylation of deoxy- antagonist that is being investigated in the cortisol. It is given intravenously at a rate of treatment of persistent or recurrent Cush- 0.3 mg/kg per hour. ing disease. It is not yet approved by the US Food and Drug Administration for this indi- Centrally acting agents cation. Cabergoline (Dostinex). It is believed that corticotropin-producing pituitary tumors express ■■ BACK TO OUR PATIENT D2 receptors. Cabergoline is a dopamine agonist that has been used in patients with Cushing dis- The patient was too ill to undergo additional ease. The dosage is 0.5 to 7 mg/week. imaging, including octreotide scanning to Pasireotide is still investigational. It is a identify an ectopic corticotropin-secreting somatostatin receptor agonist given subcu- tumor. She was medically treated with in- taneously for 15 consecutive days to patients travenous etomidate to reduce her cortisol with Cushing disease. level.30,31 Unfortunately, our patient died of multior- Glucocorticoid receptor antagonist gan failure. The exact site of her ectopic cor- Mifepristone (Mifeprex) is a progester- ticotropin-producing tumor was never identi- one receptor and glucocorticoid II receptor fied, and no autopsy was done. ■

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