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Home , Muscle weakness, Myopathy

Brent W. Smith, MD; Jason C. McCarthy, MD; Suspect ? Take Courtney A. Dawley, DO Travis Air Force Base Family Residency, Travis this approach to the work-up Air Force Base, Calif. This practical guide, with handy reference tools, will [email protected] The authors reported no help you to distinguish between myopathy and potential conflict of interest nonmyopathic and further refine your diagnosis. relevant to this article. The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Medical Department of the US CASE u Marie C, a 75-year-old Asian woman, reports Air Force or the US Air Force at large. Practice in her legs and arms with unsteadiness when walking. She has recommendations a vague but persistent ache in her large muscles. Her symptoms › Categorize patients with have developed slowly over the past 3 months. She denies re- muscle complaints into cent signs or symptoms of infection or other illness. Her medical suspected myositic, history includes hypertension, hyperlipidemia, osteopenia, and intrinsic, or toxic obesity. Ms. C takes lisinopril 10 mg/d and , which myopathy to help guide was recently increased from 10 to 20 mg/d. subsequent work-up. C What would your next steps be in caring for this patient? › Look for diffusely painful, swollen, or atients who experience muscle-related symptoms such boggy-feeling muscles—as as , , or weakness often seek help from their well as weakness and pain family physician (FP). The list of possible causes of these with exertion—in patients P complaints can be lengthy and vary greatly, from nonmyo- you suspect may have viral myopathy. C pathic conditions such as to worrisome forms of myopathy such as inclusion body or . › Consider electromyogra- This article will help you to quickly identify which patients with phy and for muscle-related complaints should be evaluated for myopathy patients you suspect may and what your work-up should include. have . C

Strength of recommendation (SOR) A Good-quality patient-oriented Myopathy or not? evidence Distinguishing between myopathy and nonmyopathic muscle B Inconsistent or limited-quality patient-oriented evidence pain or weakness is the first step in evaluating patients with C Consensus, usual practice, muscle-related complaints. Many conditions share muscle- opinion, disease-oriented evidence, case series related symptoms, but actual muscle damage is not always present (eg, fibromyalgia, chronic pain, and chronic fatigue syndromes).1 While there is some overlap in presentation be- tween patients with myopathy and nonmyopathic conditions, there are important differences in symptoms, physical exam findings, and lab test results TABLE( 11-4). Notably, in myopathic disease, patients’ symptoms are usually progressive, vital signs are abnormal, and weakness is common, whereas patients with nonmyopathic disease typically have remitting and re- lapsing symptoms, normal vital signs, and no weakness. continued

jfponline.com Vol 63, No 11 | novemBER 2014 | The Journal of Family Practice 631 TABLE 1 How to distinguish myopathy from nonmyopathic disease

Myopathic disease Nonmyopathic disease

Symptoms Acute to chronic Chronic Usually progressive Remitting and relapsing Commonly associated with systemic Nonprogressive symptoms2-4 Minimal systemic symptoms May have concomitant anxiety/ depression1 Physical Vital signs may be abnormal Vital signs are normal Weakness is common Strength is preserved Atrophy present in advanced disease2-4 Atrophy is absent1 Lab results , aldolase are often Lab work most often is normal1 increased Lab abnormalities are suggestive of a primary disorder, such as infection or an Patients with endocrine or disturbance2-4 a viral myositis often report prodromal symptoms such Myopathy itself is divided into 3 catego- rial and fungal myositides are relatively rare. as fever, upper ries—myositic, intrinsic, and toxic—which Both most often occur as the result of pen- respiratory reflect the condition, or medication, that etrating trauma or immunocompromise, and illness, or GI brought on the muscle damage (TABLE 22,4-15). are generally not subtle.2 Parasitic myopa- distress one to Placing patients into one of these catego- thy can occur from the invasion of skeletal 2 weeks before ries based on their risk factors, history, and muscle by trichinella after ingesting under- the onset of physical exam findings can help to focus the cooked, infected meat.2 Although previously muscle diagnostic work-up on areas most likely to a more common problem, currently only 10 complaints. provide useful information. to 20 cases of trichinellosis are reported in the United States each year.17 Due to their rarity, bacterial, fungal, and parasitic myositides are Myositic myopathy can be caused not reviewed here. by infection or Patients with a viral myositis often report Myositic result in inflammatory prodromal symptoms such as fever, upper re- destruction of muscle tissue. Patients with spiratory illness, or gastrointestinal distress myositic myopathy often exhibit fever, mal- one to 2 weeks before the onset of muscle aise, weight loss, and general fatigue. Though complaints. Muscle pain is usually multifo- weakness and pain are common, both can cal, involving larger, bilateral muscle groups, be variable or even absent in myositic my- and may be associated with swelling. opathy.2,5 Myositic myopathy can be caused Patients with viral myositis may exhibit by infectious agents or can develop from an diffusely painful, swollen, or boggy-feeling auto­immune disease. muscles as well as weakness and pain with z Infectious myositic myopathy is one exertion. Other signs of viral infection such of the more common types of myopathy that as rash, fever, upper respiratory symptoms, or FPs will encounter.2 Viruses such as influ- meningeal signs may be present. Severe signs enza, parainfluenza, coxsackievirus, human include arrhythmia or respiratory failure due immunodeficiency virus, cytomegalovirus, to or diaphragm involvement, echovirus, adenovirus, Epstein-Barr, and or signs of renal failure due to precipitation hepatitis C are common causes.2,4,16 Bacte- of myoglobin in the renal system (ie, rhabdo-

632 The Journal of Family Practice | novemBER 2014 | Vol 63, No 11 suspect myopathy?

TABLE 2 Diagnosing myopathy: Key symptoms and lab tests

Condition Symptoms Lab tests Myositic myopathy Infectious myositis Acute or subacute pain predominates, CBC, CK, CRP, ESR, LFTs. preceded by viral prodrome, fever, chills, Hepatitis C, HIV, HSV, influenza2,4 malaise. May include cardiac symptoms2,4

Autoimmune (polymyositis/dermatomyositis) Typical patient is female, African American, Aldolase, ANA, CBC, CK, CRP, and 20-50 years of age. Subacute or chronic EMG, ESR, LFTs, LDH, muscle symmetric/proximal weakness predominates. biopsy5 Weight loss, fatigue, shortness of breath, heartburn; heliotrope rash may be present with dermatomyositis5

Autoimmune () Typical patient is male, Caucasian, and over Aldolase, ANA, CBC, CK, CRP, 50 years of age. Indolent course over months/ EMG, ESR, LFTs, LDH, muscle years. Similar to polymyositis, but weakness biopsy.5 CK is often normal or may be primarily distal6 mildly elevated6 Intrinsic myopathy Electrolyte imbalance Generalized weakness7 CK, CMP, EKG, UA7 Endocrine Proximal weakness/pain8,9 CK, vitamin D, TSH8-10 Metabolic Associated with intolerance, fasting, CMP. Consider serum carnitine, or illness7 acylcarnitine, urine dicarboxylic acids, and urine acylglycines in persistent cases without obvious cause7 Toxic myopathy Medication-related No signs/symptoms of underlying disease11-14 CK, UA, LFTs, urine myoglobin13-15

ANA, antinuclear antibodies; CBC, complete blood count; CK, creatine kinase; CMP, complete metabolic panel; CRP, C-reactive protein; EKG, electrocardiogram; EMG, electromyography; ESR, erythrocyte sedimentation rate; HIV, human immunodeficiency virus; HSV, herpes simplex virus; LDH, lactate dehydrogenase; LFTs, liver function tests; TSH, thyroid-stimulating hormone; UA, urinalysis.

myolysis).2 If the infection affects the heart, confusing cases, but in most cases such test- patients may develop palpitations, pleuritic ing is unnecessary. Muscle biopsy is not rec- chest pain, or shortness of breath.2 ommended except in persistent cases, where Diagnosis of viral myositis relies heav- definitive identification of the causative agent ily on clinical suspicion in patients with a might alter treatment or when nonviral infec- fitting history and physical exam findings. tion is suspected.2 Helpful lab tests include a complete blood z Autoimmune myositic myopathy. count (CBC), erythrocyte sedimentation rate Unlike infectious myopathies, autoimmune (ESR), C-reactive protein (CRP), creatine ki- myopathies are usually chronic, subtle, and nase (CK), and liver function tests (LFTs), all relatively rare. The 3 most common autoim- of which can be abnormal in viral myositis. mune myopathies—polymyositis, dermato- Viral polymerase chain reaction, culture, or myositis, and inclusion body myositis—have antigen testing may be helpful in severe or a combined prevalence of approximately

jfponline.com Vol 63, No 11 | novemBER 2014 | The Journal of Family Practice 633 10:100,000.6 Although these types of myopa- , weakness, or pain. TABLE 3 re- thies are uncommon, FPs will likely be the views other signs and symptoms of electrolyte first to evaluate a patient with one of them. abnormalities that may be helpful in estab- Patients with an autoimmune myopathy lishing a diagnosis in a patient with muscle typically complain of weakness and mild to complaints. moderate muscle pain, although pain may be Ordering a complete metabolic panel absent. Compared to infectious myopathies, (CMP), CK, and urinalysis (UA) can help rule autoimmune myopathies usually exhibit out electrolyte disorders. If electrolyte dis- a more indolent course. Patients with ad- orders are detected, an electrocardiogram vanced disease may report fever, weight loss, is useful to evaluate for cardiac dysfunction. shortness of breath from , Once an electrolyte disorder is identified, heartburn from a weakened lower esopha- investigate its underlying cause. Correcting geal sphincter, and/or a rash.5 the electrolyte disorder should help improve Physical examination may reveal sym- symptoms of myopathy. metric, proximal . Atrophy z Endocrine myopathy can be associ- is typically not seen until late in the disease. ated with hypothyroidism, , Skin exam usually is normal in patients with parathyroid disease, vitamin D deficiency, inclusion body myositis and polymyositis. or Cushing syndrome.8-10,18,19 Although less The typical rash of dermatomyositis is a he- common than some other causes, identify- A patient liotrope (blue-purple) discoloration on the ing endocrine myopathy is crucial because with mild upper eyelids and a raised, violaceous, scaly correcting the underlying disease will often to moderate eruption on the knuckles (Gottron’s papules). improve multiple aspects of the patient’s electrolyte Laboratory tests that can be helpful in- health. problems may clude CK, lactate dehydrogenase (LDH), al- The presentation of endocrine myopathy complain of dolase, and LFTs (reflecting muscle injury, may be subtle. Patients with hypothyroidism muscle fatigue, not liver involvement). For polymyositis and may experience muscle pain or weakness, weakness, dermatomyositis, CK is the most sensitive lab fatigue, cold sensitivity, constipation, and or pain. test and often exhibits the highest elevation dry skin.20 Muscle-related symptoms may above normal.6 Conversely, CK is often nor- be the only sign of endocrine myopathy in a mal or only mildly elevated in inclusion body patient who would otherwise be considered myositis. Up to 80% of patients with autoim- to have subclinical hypothyroidism.8,18 Hy- mune myopathy will have antinuclear anti- perthyroidism can present with weight loss, bodies.3,5 ESR and CRP levels are also often heat intolerance, frequent bowel movements, elevated. tachycardia, and muscle weakness.21 Both electromyography (EMG) and mus- Patients with parathyroid disease— cle biopsy may be required to diagnose auto- especially patients with chronic renal immune myopathy, but these are typically failure—may report proximal muscle done under the direction of a rheumatologist weakness, often in the lower extremities.19 after an FP’s initial work-up is inconclusive. Complaints of muscle weakness or pain can occur with severe vitamin D deficiency.10 Pa- tients with Cushing syndrome often experi- Intrinsic myopathy: Suspect ence proximal weakness and weight gain.9 electrolyte problems, other causes Patients with a personal or family his- Intrinsic myopathy occurs in patients with tory of endocrine disorders, previous thyroid electrolyte disorders, of the en- , or those taking medications that docrine system, or underlying metabolic can impair thyroid function, such as , dysfunction. amiodarone, or interferon, are at risk for en- z Electrolyte disorders. Muscle-related docrine myopathy.18-20 Suspect hyperpara- symptoms are unlikely to be the chief com- thyroidism in patients with chronic kidney plaint of patients with severe electrolyte disease who complain of weakness. imbalance. However, a patient with mild to Vitamin D deficiency is relatively com- moderate electrolyte problems may develop mon, with at minimum 20% of elderly adults

634 The Journal of Family Practice | novemBER 2014 | Vol 63, No 11 suspect myopathy?

TABLE 3 Is an electrolyte imbalance to blame for those muscle symptoms?

Electrolyte abnormality Signs/symptoms Exam findings Generalized muscle weakness Weakness Impaired cardiac conduction Paralysis

Hypokalemia Generalized muscle weakness Weakness Ileus Ascending paralysis (severe) EKG abnormalities Respiratory depression (severe)

Hypercalcemia Impaired concentration Hypertension Confusion Weakness Fatigue Polyuria Polydipsia Muscle weakness The symptoms GI complaints of drug-induced Mood disorders toxic myopathy are usually more Abdominal pain insidious and lab Constipation abnormalities Anorexia are usually more Hypocalcemia Paresthesias Chvostek’s sign subtle than for Numbness Trousseau’s sign other forms of myopathy. Muscle Hypotension Muscle stiffness Dry, coarse skin Hypermagnesemia Hypotension Hypoactive deep tendon reflexes Nausea Paralysis (severe) Vomiting Respiratory depression (severe) Facial flushing Urinary retention Ileus

Hypomagnesemia Paresthesias Hyperreflexia Weakness Fasciculation Tremors Seizures Altered mental status EKG, electrocardiogram; GI, gastrointestinal. Adapted from: Carey WD. Current Clinical Medicine. 2nd ed. Philadelphia, PA: Elsevier/Saunders; 2010 and Goldman L, Schafer AI. Goldman’s Cecil Medicine. 24th ed. Philadelphia, PA: Elsevier/Saunders; 2012. estimated to be deficient.10 Patients at risk which can increase their risk of myopathy, for Cushing disease are most likely receiv- or to have ectopic adrenocorticotropic hor- ing pharmacologic doses of , mone secretion. continued

jfponline.com Vol 63, No 11 | novemBER 2014 | The Journal of Family Practice 635 TABLE 4 Is your patient’s medication causing myopathy?

Medications that can cause myopathy Presentation Risk factors/notes Cholesterol-lowering medications: or weakness in large muscle Higher doses and drug combinations , fibric acid derivatives, niacin, groups. Symptoms resolve 4-8 weeks (especially +)11 after drug cessation11,12,22,23 Glucocorticoids Muscle weakness without pain. CK Higher dose, chronic use, elderly, cancer normal/mildly elevated13 patients.13 (Up to 60% of patients on long-term glucocorticoids experience myopathy) Chloroquine Slow, progressive, painless proximal Chronic use, higher doses14 muscle weakness and atrophy—typically in the arms more than in the legs; may be secondary to a concomitant neuromyopathy14 Amiodarone Case reports of myopathy with severe Kidney disease, simultaneous use of proximal and distal muscle weakness and and/or statins. distal sensory loss (Use amiodarone with caution with statins. Myopathy is rare with typical use of the drug24) Colchicine Myopathy with slow, gradual onset Kidney disease, age over 5015 during chronic use or acute intoxication; progressive proximal muscle weakness with elevated CK15 Insidious onset of progressive proximal Simultaneous use of colchicine and/or muscle weakness and myalgias, statins. (Can be difficult to differentiate prominent atrophy with normal or from HIV myopathy25) slightly elevated CK25 CK, creatine kinase; HIV, human immunodeficiency virus.

z results from a thy, retinopathy, ataxia, hearing loss, or other lack of sufficient energy production in the systemic manifestations.7 muscle. The 3 main groups of metabolic my- Basic labs for investigating suspected opathy are impaired muscle glycogenoses, metabolic myopathy include serum electro- disorders of fatty acid oxidation, and mito- lytes, , LFTs, CK (which may or may chondrial myopathies.7 not be elevated), lactate, ammonia, and UA Because metabolic myopathy can occur for . More advanced labs, such at any age, a thorough history and physical is as serum total carnitine and acylcarnitine as crucial for diagnosis. Proximal weakness in well as urinary levels of dicarboxylic acids metabolic myopathy is often associated with and acylglycines, may be needed if a meta- exercise intolerance, stressful illness, or fast- bolic disorder is strongly suspected.7 Muscle ing. Patients often present with dynamic ab- biopsy, EMG, and genetic testing can also normalities such as fatigue, muscle cramping, prove helpful in diagnosis. Definitive diag- and even during exertion.7 nosis and treatment of metabolic myopathy When evaluating patients you suspect usually requires a multidisciplinary team of may have metabolic myopathy, a physical providers, including subspecialty referral. exam may reveal muscle , mus- cle swelling, or proximal muscle weakness. Patients with certain types of fatty acid oxi- Toxic myopathy dation disorders or mitochondrial disorders Toxic myopathy refers to muscle damage may also exhibit cardiomyopathy, neuropa- caused by an exogenous chemical agent,

636 The Journal of Family Practice | novemBER 2014 | Vol 63, No 11 suspect myopathy?

most often a drug. The mechanism of toxic- and mild weakness, except for the most severe ity is not always clear and may result from the or advanced cases. Most patients will not have activation of inflammatory responses simi- physical signs that suggest an underlying ill- lar to autoimmune myopathy.22 Toxic my- ness. CK levels and LFTs should be obtained. opathies may result from several commonly Basic chemistry and UA may also be helpful in used medications; cholesterol-lowering patients with risk factors for renal disease. medications are a common culprit.13-15,23-25 Drug-induced myopathies vary in frequency CASE u Ms. C has been taking a statin for more and severity. For instance, in patients taking than 10 years, and the dose was recently in- statins, the rate of myalgias is 6%, while the creased. You are aware that statin-related mus- incidence of rhabdomyolysis is estimated to cle injury can develop even after years of use, be 4 per 100,000, and is found most often in and suspect the statin may be causing her my- patients taking concomitant .23 opathy. You order a CK test, which is mildly ele- Drug-induced toxic myopathy differs vated. You recommend discontinuing the statin. from previously discussed myopathies in that After 8 weeks off her statin, Ms. C’s symptoms symptoms are usually more insidious, find- do not improve. Given her lack of systemic com- ings on exam are more often mixed muscu- plaints, myositic myopathy from an infectious or lar and neurologic, and lab abnormalities are rheumatologic cause seems unlikely. You begin usually more subtle.11,12 Symptoms of myopa- to consider an intrinsic cause of myopathy, and thy typically occur weeks or months after ini- order the following tests: a CMP, UA, thyroid- Cholesterol- tiating a drug and usually improve or resolve stimulating hormone, repeat CK, and vitamin D lowering within weeks after discontinuing the offend- level. This testing reveals a vitamin D deficiency medications such ing agent. Knowing the patient’s medication at 17 ng/ml (normal range: 30-74 ng/ml). You as statins are a list and which medications cause certain pat- recommend vitamin D, 50,000 IU per week for common cause terns of myopathy symptoms can help guide 8 weeks. At follow-up, Ms. C's vitamin D level of toxic the differential diagnosis TABLE( 411-15,22-25). is 40. She says she feels better and her muscle myopathy. Risk factors for most medication-related complaints have resolved. JFP myopathies are polypharmacy, renal or liver disease, and age over 50 years13-15,23-25 The physi- cal exam for patients with drug- or toxin-related CORRESPONDENCE Brent W. Smith, MD, Travis Air Force Base Family Medicine myopathy will most often reveal relatively mi- Residency, 101 Bodin Circle, Travis Air Force Base, CA 94535; nor abnormalities such as muscle tenderness [email protected]

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jfponline.com Vol 63, No 11 | novemBER 2014 | The Journal of Family Practice 637 on the diagnosis and management of primary hyperparathyroid- 22. Mammen AL, Amato AA. Statin myopathy: a review of recent ism. Endocr Pract. 2005;11:49-54. progress. Curr Opin Rheumatol. 2010;22:644-650. 20. Garber JR, Cobin RH, Gharib H, et al; American Association of 23. Buettner C, Davis RB, Leveille SG, et al. Prevalence of mus- Clinical Endocrinologists and American Thyroid Association culoskeletal pain and statin use. J Gen Intern Med. 2008;23: Taskforce on Hypothyroidism in Adults. Clinical practice guide- 1182-1186. lines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thy- 24. Marot A, Morelle J, Chouinard VA, et al. Concomitant use of roid Association. Endocrine Pract. 2012;18:988-1028. simvastatin and amiodarone resulting in severe rhabdomy- olysis: a case report and review of the literature. Acta Clin Belg. 21. Bahn Chair RS, Burch HB, Cooper DS, et al; American Thyroid 2011;66:134-136. Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management 25. Peters BS, Winer J, Landon DN, et al. guidelines of the American Thyroid Association and American As- associated with chronic zidovudine therapy in AIDS. Q J Med. sociation of Clinical Endocrinologists. Thyroid. 2011;21:593-646. 1993;86:5-15.

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