Evaluation of the Patient with Muscle Weakness AARON SAGUIL, CPT (P), MC, USA, Madigan Army Medical Center, Tacoma, Washington

Muscle weakness is a common complaint among patients presenting to family physicians. Diagnosis begins with a patient history distinguishing weakness from fatigue or asthenia, separate conditions with different etiologies that can coexist with, or be confused for, weakness. The pattern and severity of weakness, associated symptoms, medication use, and family history help the physician determine whether the cause of a patient’s weakness is infectious, neurologic, endocrine, inflammatory, rheumatologic, genetic, metabolic, electrolyte-induced, or drug-induced. In the physical examination, the physician should objectively document the patient’s loss of strength, conduct a neurologic survey, and search for patterns of weakness and extramuscular involvement. If a specific cause of weakness is suspected, the appropriate laboratory or radiologic studies should be performed. Otherwise, electromyography is indicated to confirm the presence of a myopathy or to evaluate for a neuropathy or a disease of the neuromuscular junction. If the diagnosis remains unclear, the examiner should pursue a tiered progression of laboratory studies. Physicians should begin with blood chemistries and a thyroid-stimulating hormone assay to evaluate for electrolyte and endocrine causes, then progress to creatine kinase level, erythrocyte sedimentation rate, and antinuclear antibody assays to evaluate for rheumatologic, inflammatory, genetic, and metabolic causes. Finally, many myopathies require a biopsy for diagnosis. Pathologic evaluation of the muscle tissue specimen focuses on histologic, histochemical, electron microscopic, biochemical, and genetic analyses; advances in tech- nique have made a definitive diagnosis possible for many myopathies. (Am Fam Physician 2005;71:1327-36. Copyright© 2005 American Academy of Family Physicians.)

See page 1245 for uscle weakness is a common disease.1 Because these conditions are preva- strength-of-evidence complaint among patients lent in the ambulatory population, family labels. presenting to the family phy- physicians can expect to encounter patients The online-only version of sician’s office. Although the with asthenia and fatigue more frequently this article, which offers M cause of weakness occasionally may be appar- than those with intrinsic muscle weakness.1 more detailed information on additional selected ent, often it is unclear, puzzling the physician Selected causes of asthenia and fatigue are causes of muscle weak- and frustrating the patient. A comprehen- listed in Table 1.1 ness, is available at: sive evaluation of these patients includes a Unfortunately, the distinction between http://www.aafp.org/ afp/URL. thorough examination and coordination of asthenia, fatigue, and primary weakness appropriate laboratory, radiologic, electro- often is unclear. Patients frequently con- diagnostic, and pathologic studies. fuse the terms, and the medical literature sometimes uses them interchangeably.2 In Definitions addition, a patient’s condition may cause Determining the cause of muscle weakness progression from one syndrome to another; involves distinguishing primary weakness for example, asthenia in a patient with from fatigue or asthenia, common condi- heart failure may progress to true muscle tions that differ from, but often overlap weakness through deconditioning. Further, with, muscle weakness.1 Fatigue describes the asthenia and fatigue can coexist with weak- inability to continue performing a task after ness, such as in patients with multiple scle- multiple repetitions; in contrast, a patient rosis and concomitant depression. Because with primary weakness is unable to perform depression is so prevalent, it is essential to the first repetition of the task. Asthenia is consider it as a possible cause of a patient’s a sense of weariness or exhaustion in the symptoms; diagnosis can be facilitated by absence of muscle weakness. This condi- using one of the several validated screening tion is common in people who have chronic tools designed for the outpatient setting.3,4 fatigue syndrome, sleep disorders, depres- This article discusses only intrinsic muscle sion, or chronic heart, lung, and kidney weakness in adults.

April 1, 2005 ◆ Volume 71, Number 7 www.aafp.org/afp American Family Physician 1327 Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright© 2005 American Academy of Family Physicians. For the private, noncommercial use of one individual user of the Web site. All other rights reserved. Contact [email protected] for copyright questions and/or permission requests. Strength of Recommendations

Key clinical recommendation Label References

It is essential to consider depression as a possible diagnosis; several screening A 3,4 tools for depression have been validated for use in outpatient settings. Primary muscle weakness must be distinguished from the more common C 1 conditions of fatigue and asthenia. If the diagnosis is still inconclusive after the history, physical examination, and C 41 laboratory, radiologic, and electromyographic evaluation, a muscle biopsy is required for patients who have a suspected myopathy.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, opinion, or case series. See page 1245 for more information.

Differential Diagnosis include influenza and Epstein-Barr virus Conditions that result in intrinsic weakness (Table 36,9-12). Human immunodeficiency can be divided into several main categories: virus (HIV) is a less common cause of infectious, neurologic, endocrine, inflam- muscle weakness but should be considered matory, rheumatologic, genetic, metabolic, in patients with associated risk factors or electrolyte-induced, or drug-induced. symptoms.6,9 Neurologic conditions that can In adults, medications (Table 25,6), infec- cause weakness include cerebrovascular dis- tions, and neurologic disorders are common ease (i.e., stroke, subdural/epidural hemato- causes of muscle weakness. The use of alco- mas), demyelinating disorders (i.e., multiple hol or steroids can cause proximal weakness sclerosis, Guillain-Barré syndrome), and with characteristic physical and laboratory neuromuscular disorders (i.e., myasthenia findings.5,7,8 Infectious agents that are most gravis, botulism). Localizing neurologic commonly associated with muscle weakness deficits can help the physician focus the diagnostic work-up6,10-12 (Table 36,9-12). Less common myopathies include those TABLE 1 caused by endocrine, inflammatory, rheu- Causes of Asthenia and Fatigue matologic, and electrolyte syndromes (Tables 45-8,13-26 and 56,8,15,16,18,20,24-38). Of Addison’s disease Heart disease the endocrine diseases, thyroid disease is Anemia Hypothyroidism common, but thyroid-related myopathy is Anxiety Infections (such as influenza, uncommon; parathyroid-related myopathy Chemotherapy Epstein-Barr virus, HIV, hepatitis C, should be suspected in a patient with muscle tuberculosis) Chronic fatigue syndrome weakness and chronic renal failure.14,15,32 Medications Chronic pain Inflammatory diseases typically affect older Narcotics Deconditioning/sedentary adults and include both proximal (poly- Paraneoplastic syndrome lifestyle myositis and dermatomyositis) and dis- Pregnancy/postpartum Dehydration and electrolyte tal myopathies (inclusion body myositis); disorders Pulmonary disease the proximal inflammatory myopathies Depression Renal disease respond to steroids.21-23 Rheumatologic dis- Diabetes Sleep disorders orders causing weakness, such as systemic Fibromyalgia lupus and rheumatoid arthritis, can occur 17,18 HIV = human immunodeficiency virus. in young and elderly persons. Disorders Adapted with permission from Hinshaw DB, Carnahan JM, Johnson DL. Depression, of potassium balance are among the more anxiety, and asthenia in advanced illness. J Am Coll Surg 2002;195:276. common electrolyte myopathies and may be primary (such as in hypokalemic or hyper-

1328 American Family Physician www.aafp.org/afp Volume 71, Number 7 ◆ April 1, 2005 Muscle Weakness

typically subacute, myasthenia gravis may TABLE 2 present with rapid, generalized weakness or Medications and Narcotics remain confined to a single muscle group for that Can Cause Muscle Weakness years (as in ocular myasthenia).12 Because of this variability, the pattern of Amiodarone (Cordarone) muscle weakness is crucial in differentiating Antithyroid agents: methimazole (Tapazole); the etiology. The physician should estab- propylthiouracil lish whether the loss of strength is global Antiretroviral medications: zidovudine (e.g., bilateral; may be proxi- (Retrovir); lamivudine (Epivir) mal, distal, or both) or focal. Chemotherapeutic agents The use of alcohol or ste- Focal processes (those that are Cimetidine (Tagamet) roids can cause proximal unilateral or involve specific Cocaine weakness with characteris- nerve distributions or intra- Corticosteroids cranial vascular areas) tend to tic physical and laboratory Fibric acid derivatives: gemfibrozil (Lopid) be neurologic—although not findings. Interferon all neurologic processes are Leuprolide acetate (Lupron) focal—and may require a different approach Nonsteroidal anti-inflammatory drugs than that used with global strength loss. Penicillin In patients with diffuse weakness, the Sulfonamides physician should determine whether the loss Statins of function is proximal or distal by noting Information from references 5 and 6. which physical activities muscle weakness limits. If the patient has difficulty rising from a chair (hip muscles) or combing his or her kalemic periodic paralysis) or secondary hair (shoulder girdle), the weakness is proxi- (such as in renal disease or angiotensin- mal; if the patient has difficulty standing converting enzyme inhibitor toxicity). on his or her toes (gastrocnemius/soleus) or Patients in whom these disturbances are suspected should have electrocardiography to screen for cardiac sequelae.13,27-30 TABLE 3 Rare causes of muscle weakness include Infectious and Neurologic Causes of Muscle Weakness genetic (muscular and myotonic dystrophies), metabolic (glycogenoses, lipidoses, Infectious Neurologic (continued) and mitochondrial defects), and sarcoid- Epstein-Barr virus Demyelinating disorders and amyloid-associated myopathies24-26,34-38 Human immunodeficiency Guillain-Barré syndrome (Tables 45-8,13-26 and 56,8,15,16,18,20,24-38). virus Multiple sclerosis Influenza History Neoplasm Lyme disease Neuromuscular disorders Once muscle weakness has been differenti- Meningitis (multiple agents) Botulism ated from asthenia and fatigue, the physi- Polio Lambert-Eaton myasthenic syndrome cian should ask the patient about disease Rabies Myasthenia gravis onset and progression. Acute onset may Syphilis Organophosphate intoxication indicate infection or stroke. Subacute onset Toxoplasmosis Radiculopathies may implicate drugs, electrolytes, or inflam- Neurologic Cervical spondylosis matory or rheumatologic disease. Chronic Amyotrophic lateral sclerosis Degenerative disc disease progressive weakness is the classic presenta- Cerebrovascular disease Spinal cord injury tion in genetic and metabolic myopathies. Stroke Spinal muscle atrophy Despite these generalizations, there is consid- Subdural/epidural hematomas erable variation in the time courses of different classes of myopathy, and even within the Information from references 6 and 9 through 12. individual disorders. For instance, although

April 1, 2005 ◆ Volume 71, Number 7 www.aafp.org/afp American Family Physician 1329 TABLE 4 Selected Causes of Primary Muscle Weakness

Cause Weakness Age of onset/diagnosis Systemic symptoms and findings Laboratory abnormalities Creatine kinase Electromyogram Muscle biopsy

Drugs Alcohol Proximal (may be distal) Variable Change in mental status; telangiectasia; Elevated transaminase and GGT Normal to elevated Normal Myopathic changes*; selected atrophy peripheral neuropathy levels; anemia; decreased of type II muscle fibers

vitamin B12

Endocrine Adrenal insufficiency Generalized Variable Hypotension; hypoglycemia; Hyponatremia; hyperkalemia; ACTH Normal Myotonic discharges† Diminished glycogen content bronzing of the skin assay; ACTH stimulation test Glucocorticoid excess Proximal Variable Buffalo hump; striae; osteoporosis Elevated urine-free cortisol, Normal Myopathic MUAPs‡ Selective atrophy of type II muscle dexamethasone suppression, or fibers corticotropin-releasing hormone stimulation tests Parathyroid hormone (secondary Proximal, lower extremity Variable, older adult Usually has associated comorbidities Hypocalcemia; uremia Normal Myopathic MUAPs‡ Atrophy of type II muscle fibers; hyperparathyroidism§) more than upper extremity (cardiovascular disease, diabetes) increased lipofuscin beneath cell membrane; calcium deposits in muscle

Thyroid hormone Proximal, bulbar 40 to 49 years Weight loss; tachycardia; increased Elevated T4 and T3; TSH Normal or elevated Myopathic MUAPs‡ with or Usually normal (hyperthyroidism) perspiration; tremor variable, depending on cause without fibrillation potentials|| Thyroid hormone Proximal 30 to 49 years Menorrhagia; bradycardia; goiter; delayed TSH Elevated With or without myopathic Myopathic changes*; glycogen (hypothyroidism) relaxation of deep tendon reflexes MUAPs‡ and fibrillation accumulation potentials||

Inflammatory Dermatomyositis Proximal Variable, increased Gottron papules; heliotrope rash; Elevated myoglobin; ANA positive; Greater than 10 times Myopathic MUAPs‡ with Inflammatory infiltrate with myopathic incidence with age calcinosis; interstitial lung disease; myositis autoantibodies may be normal elevations fibrillation potentials|| changes* and replacement by disordered GI motility present adipose and collagen Inclusion body myositis Distal, especially At least 50 years Dysphagia; extramuscular involvement Elevated myoglobin; positive ANA Elevated Myopathic MUAPs‡ with Inflammatory infiltrate with vacuoles forearm and hand (younger than not as common less common; myositis fibrillation potentials|| containing eosinophilic inclusions 50 years: rare) autoantibodies may be present Polymyositis Proximal Variable, increased Interstitial lung disease, disordered GI Elevated myoglobin; ANA positive; Greater than 10 times Myopathic MUAPs‡ with Inflammatory infiltrate with myopathic incidence with age motility; overlap with rheumatologic myositis autoantibodies may be normal elevations fibrillation potentials|| changes* and replacement by diseases more common present adipose and collagen

Rheumatologic Rheumatoid arthritis Focal, periarticular, or diffuse Adult Symmetric joint inflammation (especially Elevated rheumatoid factor Normal or elevated No data Atrophy of type II muscle fibers; MCP, PIP joints); dry eyes and mouth may have overlap syndrome with polymyositis Systemic lupus erythematosus Proximal Adult Malar rash; nephritis; arthritis ANA, anti-DNA antibodies, Normal to elevated No data Type II fiber atrophy; lymphocytic depressed C3 and C4¶ vasculitis; myositis

Genetic Becker muscular Hip; proximal leg and arm Late childhood to Mental retardation; cardiomyopathy None Elevated Myopathic MUAPs‡ with Myopathic changes*; decreased and dystrophy adulthood fibrillation potentials|| patchy staining of dystrophin Limb-girdle muscular Variable, usually proximal Variable Variable, may have cardiac abnormalities None Variable, normal, or Myopathic MUAPs‡ +/- Myopathic changes*; may demonstrate dystrophies** limb, pelvic, and shoulder elevated fibrillation potentials|| absence of specific protein on girdle muscles immunohistochemical staining Myotonic dystrophy Distal greater than proximal; Adolescence to Conduction abnormalities; mental None Normal to minimally Myopathic MUAPs‡; Less necrosis and remodeling than in type 1 foot drop; temporal and adulthood retardation; cataracts; insulin resistance elevated myotonic discharges|| muscular dystrophies; atrophy of masseter wasting type I muscle fibers; ring fibers

Metabolic Glycogen and lipid storage Proximal Variable Variable; exercise intolerance and Some glycogenoses associated Variable, may increase Normal or myopathic MUAPs‡ Myopathic changes* with glycogen diseases; mitochondrial disease cardiomyopathy more common with abnormal FIET†† with exercise +/- fibrillation potentials|| deposits, lipid deposits, or ragged red fibers (for glycogen, lipid, or mitochondrial disease, respectively)

GGT = gamma-glutamyltransferase; ACTH = adrenocorticotropin hormone; MUAPs = motor unit action potentials; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; GI = gastrointestinal; ANA = antinuclear antibodies; MCP = metacarpophalangeal; PIP = proximal interphalangeal; EMG = electromyogram; FIET = forearm ischemic exercise testing. *—Myopathic changes are nonspecific and include atrophy, degeneration, and regeneration of muscle fibers. †—Myotonic discharges are a type of prolonged burst of activity seen on insertion of the EMG needle. ‡—Myopathic MUAPs are shorter in duration, lower in amplitude, and polyphasic when compared to MUAPs from normal muscle. §—Secondary hyperparathyroidism usually caused by renal failure. Information from references 5 though 8 and 13 through 26. 1330 American Family Physician www.aafp.org/afp Volume 71, Number 7 ◆ April 1, 2005 TABLE 4 Selected Causes of Primary Muscle Weakness

Cause Weakness Age of onset/diagnosis Systemic symptoms and findings Laboratory abnormalities Creatine kinase Electromyogram Muscle biopsy

vitamin B12

*—Myopathic changes are nonspecific and include atrophy, degeneration, and regeneration of muscle fibers. ||—Fibrillation potentials represent spontaneous activity on the part of single muscle fibers (not usually noted with nondiseased muscle). †—Myotonic discharges are a type of prolonged burst of activity seen on insertion of the EMG needle. ¶—C3 and C4 are complement components. ‡—Myopathic MUAPs are shorter in duration, lower in amplitude, and polyphasic when compared to MUAPs from normal muscle. **—Including facioscapulohumeral dystrophy. §—Secondary hyperparathyroidism usually caused by renal failure. ††—FIET evaluates the rise of ammonia and lactate in the forearm during exertion. Information from references 5 though 8 and 13 through 26. April 1, 2005 ◆ Volume 71, Number 7 www.aafp.org/afp American Family Physician 1331 doing fine work with the hands or alcohol toxicity can present with either Focal processes tend to be (intrinsics), the muscle weak- proximal or distal weakness.5,7,39 neurologic and may require ness is distal. Although many Other areas to address in the patient’s a different approach than myopathies are associated with history are associated symptoms, family that used in patients with proximal weakness, a small history, and pharmaceutical use. Common global strength loss. number are associated predom- drugs associated with muscle weakness are inantly with distal weakness; listed in Table 2.5,6 Associated symptoms are these include myotonic dystro- found in many myopathies and can be espe- phy, inclusion body myositis, and the genetic cially helpful in narrowing the differential distal myopathies.21,34 Patients with statin diagnosis among endocrine, rheumatologic, and inflammatory disorders. For example, dysphagia may accompany weakness in TABLE 5 inclusion body myositis and systemic scle- Additional Selected Causes rosis, whereas menorrhagia may attend the of Muscle Weakness weakness that occurs in hypothyroidism. A family history, which almost always is pres- Electrolyte ent in genetic myopathies, may also be pres- Hypercalcemia ent in other causes of weakness, including Hyperkalemia/hypokalemia lupus, rheumatoid arthritis, dermatomyo- Hypermagnesemia/hypomagnesemia sitis, polymyositis, and the potassium-related Endocrine paralyses27 (Table 65,7-15,17,18,21,24-27,34,36,38). Acromegaly Primary hyperparathyroidism Physical Examination Hypopituitarism The physical examination begins with an Vitamin D deficiency (osteomalacia) objective confirmation of the subjective Rheumatologic severity and distribution of muscle weak- Polymyalgia rheumatica ness. In addition to individual muscles, the Systemic sclerosis/scleroderma physician should survey functional activities Genetic such as standing and writing to determine Distal myopathies whether the weakness is proximal, distal, or Oculopharyngeal muscular dystrophy both. Myotonic dystrophy type 2 (proximal myotonic Next, a thorough neurologic survey should myopathy) accompany motor testing. The physician Metabolic should note patterns and relations among Glycogenoses defects and narrow the differential by deter- Acid maltase deficiency mining whether the deficits are referable to Aldolase A deficiency the central or peripheral nervous system. The Brancher enzyme deficiency pattern is important. A neurologic examina- Myophosphorylase deficiency tion that shows deficits in a single nerve or Phosphofructokinase deficiency radicular distribution indicates a possible Lipidoses mononeuritis, entrapment neuropathy, or Carnitine deficiency radiculopathy, and calls for a different work- Carnitine palmitoyltransferase II deficiency up than that required for a limb paresis in a Trifunctional protein deficiency patient with cerebrovascular risk factors. Mitochondrial defects If the neurologic examination is unreveal- Miscellaneous ing, a more general physical examination, Amyloidosis searching for extramuscular signs, is war- Sarcoidosis ranted (Table 65,7-15,17,18,21,24-27,34,36,38). Mental Information from references 6, 8, 15, 16, 18, 20, and status testing may reveal changes suggestive 24 through 38. of a myopathy-inducing electrolyte disorder (calcium or magnesium) or an arrest of

1332 American Family Physician www.aafp.org/afp Volume 71, Number 7 ◆ April 1, 2005 Muscle Weakness

TABLE 6 Diagnostic Clues for Muscle Weakness

Finding Suggested diagnoses

History Abdominal pain; excessive urination; renal stones Hypercalcemia; hyperparathyroidism Acute weakness with neurologic deficit(s) Spinal cord injury; stroke Arthralgia; malaise; myalgia; respiratory symptoms Epstein-Barr virus; HIV; influenza Chronic neck or back pain, with or without sharp Cervical spondylosis; degenerative disc disease shooting pains Distal weakness Genetic distal myopathies; inclusion body myositis Dysphagia; rash around eyelids; shortness of Dermatomyositis breath Easy bruising; emotional lability; obesity Glucocorticoid excess; steroid-induced myopathy Exercise-provoked weakness Glycogen and lipid storage diseases; mitochondrial myopathies; myasthenia gravis Family history of myopathy Hyper- or hypokalemic periodic paralysis; inflammatory disease; muscular dystrophies; rheumatologic disease Heat-induced symptoms; multiple neurologic Multiple sclerosis deficits spread over space and time Legal problems; memory loss; repeated trauma; Alcoholism sexual dysfunction Positive medication history Medication-induced myopathy (esp. anti-retrovirals, statins, steroids) Sexually transmitted disease HIV; syphilis Physical examination Arthritis; malar rash; nephritis Systemic lupus erythematosus Cardiomyopathy Alcohol; amyloid; glycogen storage disease; inflammatory myopathies; muscular dystrophies; sarcoid Dry eyes and mouth; joint inflammation Rheumatoid arthritis (especially MCP, PIP joints) Facial weakness; fatigable weakness; ptosis Myasthenia gravis Neurologic deficits Focal Central Multiple sclerosis; stroke Peripheral Peripheral neuropathy; radiculopathy Diffuse Central Amyotrophic lateral sclerosis Peripheral Guillain-Barré syndrome; polyneuropathy Orthostatic hypotension; skin bronzing Hypoadrenalism

HIV = human immunodeficiency virus; MCP = metacarpophalangeal; PIP = proximal interphalangeal. Information from references 5, 7 through 15, 17, 18, 21, 24 through 27, 34, 36, and 38. mental development as occurs in genetic quence of many myopathy-inducing disor- myopathies.25,29 The cardiovascular assess- ders—or a pericarditis, as occurs with some ment may elicit changes consistent with of the infectious and rheumatologic causes a cardiomyopathy—a nonspecific conse- of muscle weakness.5,7,8,9,18,21,24,25,29,36,38

April 1, 2005 ◆ Volume 71, Number 7 www.aafp.org/afp American Family Physician 1333 Pulmonary testing may reveal the crackles cion (e.g., 24-hour urine cortisol testing of a restrictive lung defect, found in some to rule out Cushing’s disease; oral glucose inflammatory and rheumatologic myopa- load/growth hormone assay to rule out thies.17,21 Gastrointestinal examination may acromegaly; vitamin D assay to rule out reveal hepatomegaly, associated osteomalacia).8,13-15,28,29,32 In a patient whose muscle with metabolic storage diseases Next, investigations looking for inflam- 24,38 weakness is suggestive and amyloidosis. Skin find- matory, rheumatologic, or genetic myop- of neurologic disease, ings are possible in multiple athies can be performed sequentially or categories of disease (e.g., skin concurrently. Although nonspecific, the cre- early neuroimaging (for bronzing in adrenal insuffi- atine kinase (CK) level usually is normal in suspected cerebrovascular ciency; Gottron’s papules and the electrolyte and endocrine myopathies disease) or lumbar puncture heliotrope rash in dermatomyo- (notable exceptions are thyroid and potas- (for possible meningitis, sitis; and erythema nodosum sium disorder myopathies).8,16,28,29 However, encephalitis, or multiple in sarcoidosis). The skeletal the CK level may be highly elevated (10 to sclerosis) is indicated. examination may reveal the leg 100 times normal) in the inflammatory bowing and pseudofractures of myopathies and can be moderately to highly osteomalacia or the symmetric joint swelling elevated in the muscular dystrophies.16,23,25 of lupus and rheumatoid arthritis.8,17,18,21,25,35 Other conditions that can be associated with elevated CK levels include sarcoidosis, infec- Laboratory and Radiologic Evaluation tions, alcoholism, and adverse reactions to The sequence and timing of the ancillary medications. Metabolic (storage) myopa- investigations varies with the clinical sce- thies tend to be associated with only mild to nario. In a patient whose muscle weak- moderate elevations in CK levels.7,16 ness is suggestive of neurologic disease, early In addition to CK, an erythrocyte sedi- neuroimaging (for suspected cerebrovascular mentation rate (ESR) and an antinuclear disease) or lumbar puncture (for possible antibody assay (ANA) may help determine meningitis, encephalitis, or multiple sclero- if a rheumatologic myopathy exists. If either sis) is indicated. If infectious disease is sus- ESR or ANA assay is positive, additional pected, appropriate titers or cultures should studies may be obtained, including rheuma- be obtained. When a specific class or type of toid factor (rheumatoid arthritis); anti– myopathy is suspected, appropriate testing double-stranded DNA or antiphospholipid should be performed. antibodies (lupus); or anticentromere anti- If the cause of muscle weakness is unclear, bodies (scleroderma).17-19 Patients with idio- serum chemistries (electrolytes, calcium, pathic inflammatory myopathies also tend phosphate, magnesium, glucose) should be to have elevated ESR and ANA levels; many obtained, as well as a thyroid-stimulating of these same patients have overlap syn- hormone assay to evaluate for electrolyte dromes, in which an inflammatory myopa- and endocrine myopathies. If an endocri- thy and a rheumatologic disease coexist. An nopathy is suspected, more specific assays antisynthetase antibody, when positive, may can be performed based on clinical suspi- help confirm the presence of an inflammatory myopathy.23

The Author Electromyography If the presence of myopathy is uncer- AARON SAGUIL, CPT (P), MC, USA, is a faculty development fellow in the Department of Family Medicine at the Madigan Army Medical Center, Tacoma, tain, electromyography may be indicated. Wash. Dr. Saguil received his medical degree from the University of Florida Although changes seen on electromyography College of Medicine, Gainesville. He completed a family practice residency at are not pathognomonic for any specific dis- DeWitt Army Community Hospital, Fort Belvoir, Va. ease process, an abnormal electromyogram Address correspondence to Aaron Saguil, CPT (P), MC, USA, Department of can indicate if a neuropathy or neuromuscu- Family Medicine, Madigan Army Medical Center, Tacoma, WA 98431 (e-mail: lar disease is present or can help solidify the [email protected]). Reprints are not available from the author. diagnosis of a primary myopathy.

1334 American Family Physician www.aafp.org/afp Volume 71, Number 7 ◆ April 1, 2005 Muscle Weakness

Electromyography assesses several com- myopathies), noncaseating granulomas ponents of muscle electrical activity: the (sarcoidosis), and amyloid deposits (amy- muscle’s spontaneous activity; its response loidosis). Histochemical techniques assay to the insertion of a probe; the character of for specific enzymes and proteins, and the muscle’s individual motor unit action may reveal deficiencies as in disorders of potentials; and the rapidity with which addi- carbohydrate or fatty acid metabolism tional motor units are recruited in response or the muscular dystrophies. Electron to an electrical signal. Muscle inflammation, microscopy and biochemical assays may atrophy, necrosis, denervation, or neuromus- help to uncover subtle changes not detect- cular disease can alter these components, able by other techniques, further aiding giving rise to patterns that may help illu- in the diagnosis of metabolic and protein- minate the underlying pathology. Although deficiency myopathies.7,18-20,21,24,25,27,28,35,37 the procedure can cause minor discomfort, 16,24,40 The opinions and assertions contained herein are the most patients tolerate it well. private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Army Muscle Biopsy Medical Department or the U.S. Army Service at large.

If the diagnosis is still inconclusive after the The author does not have any conflicts of interest. history, physical examination, and laboratory, Sources of funding: none reported. radiologic, and electromyographic evalua- tions, a muscle biopsy is required for patients REFERENCES who have a suspected myopathy.41 The tech- nology of this method, especially regarding 1. Hinshaw DB, Carnahan JM, Johnson DL. Depression, the use of genetic markers, is advancing rap- anxiety, and asthenia in advanced illness. J Am Coll Surg 2002;195:271-7. idly, making a definitive diagnosis possible 2. Griggs RC. Episodic muscle spasms, cramps, and weak- 24,25 for a wider range of myopathies. ness. In: Harrison TR, Fauci AS, eds. Harrison’s Principles The biopsy site should be an affected mus- of internal medicine. 14th ed. New York: McGraw-Hill, cle that is not diseased to the point of necro- 1998:118-22. 3. Pignone MP, Gaynes BN, Rushton JL, Burchell CM, sis. Common biopsy sites are the vastus Orleans CT, Mulrow CD, et al. Screening for depres- lateralis of the quadriceps for proximal sion in adults: a summary of the evidence for the myopathies and the gastrocnemius for distal U.S. Preventive Services Task Force. Ann Intern Med 2002;136:765-76. myopathies; in patients without involve- 4. Kumar A, Clark S, Boudreaux ED, Camargo CA Jr. A multi- ment of these muscles, an affected group is center study of depression among emergency depart- chosen.24 The muscle biopsy can be accom- ment patients. Acad Emerg Med 2004;11:1284-9. plished as an outpatient procedure and car- 5. Bannwarth B. Drug-induced myopathies. Expert Opin ries the attendant risks of pain, bleeding, Drug Saf 2002;1:65-70. 6. Muscle weakness. In: Ferri FF, ed. Ferri’s Clinical advi- infection, and sensory loss. As with elec- sor: instant diagnosis and treatment. St. Louis: Mosby, tromyography, patients should avoid using 2003:1436. anticoagulants before the procedure, and 7. Preedy VR, Adachi J, Ueno Y, Ahmed S, Mantle D, Mul- the site chosen for biopsy should be free of latti N, et al. Alcoholic skeletal muscle myopathy: definitions, features, contribution of neuropathy, impact and overlying infection. diagnosis. Eur J Neurol 2001;8:677-87. The pathologic analysis of biopsy spec- 8. Alshekhlee A, Kaminski HJ, Ruff RL. Neuromuscular imens focuses on the histologic, histo- manifestations of endocrine disorders. Neurol Clin chemical, electron microscopic, genetic, 2002;20:35-58. and biochemical changes that are found in 9. Roos, KL. Viral infections. In: Goetz CG, ed. Textbook of clinical neurology. 2d ed. Philadelphia: Saunders, the affected muscle. Histology may show 2003:895-918. atrophic, degenerating, and regenerating 10. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshen- muscle fibers (general findings referred ker BG. Multiple sclerosis. N Engl J Med 2000;343:938- to as myopathic changes), or it may show 52. 11. Hughes RA. Peripheral neuropathy. BMJ 2002;324: more specific findings such as accumula- 466-9. tions of glycogen (glycogen storage dis- 12. Vincent A, Palace J, Hilton-Jones D. Myasthenia gravis. eases), ragged red fibers (mitochondrial Lancet 2001;357:2122-8.

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13. Ten S, New M, Maclaren N. Clinical review 130: 27. Bradley WG, Taylor R, Rice DR, Hausmanowa-Petru- Addison’s disease 2001. J Clin Endocrinol Metab 2001; zewicz I, Adelman LS, Jenkison M, et al. Progressive 86:2909-22. myopathy in hyperkalemic periodic paralysis. Arch 14. Singer PA, Cooper DS, Levy EG, Ladenson PW, Braver- Neurol 1990;47:1013-7. man LE, Daniels G, et al. Treatment guidelines for 28. Comi G, Testa D, Cornelio F, Comola M, Canal N. Potas- patients with hyperthyroidism and hypothyroidism. sium depletion myopathy: a clinical and morphological Standards of Care Committee, American Thyroid Asso- study of six cases. Muscle Nerve 1985;8:17-21. ciation. JAMA 1995;273:808-12. 29. Riggs JE. Neurologic manifestations of electrolyte dis- 15. Yew KS, DeMieri PJ. Disorders of bone mineral metabo- turbances. Neurol Clin 2002;20:227-39. lism. Clin Fam Pract 2002;4:525-65. 30. Grauer K. A practical guide to ECG interpretation. St. 16. Lacomis D. Electrodiagnostic approach to the patient Louis: Mosby, 1992. with suspected myopathy. Neurol Clin 2002;20:587- 31. Sims MH, Bell MC, Ramsey N. Electrodiagnostic eval- 603. uation of hypomagnesemia in sheep. J Anim Sci 17. Brasington RD Jr, Kahl LE, Ranganathan P, Latinis KM, 1980;50:539-46. Velazquez C, Atkinson JP. Immunologic rheumatic dis- 32. Vance ML. Hypopituitarism [published correction orders. J Allergy Clin Immunol 2003;111(2 suppl):S593- appears in N Engl J Med 1994;331:487]. N Engl J Med 601. 1994;330:1651-62. 18. Nadeau SE. Neurologic manifestations of connective 33. Hunder GG. Giant cell arteritis and polymyalgia rheu- tissue disease. Neurol Clin 2002;20:151-78. matica. Med Clin North Am 1997;81:195-219. 19. Lim KL, Abdul-Wahab R, Lowe J, Powell RJ. Muscle 34. Mastaglia FL, Laing NG. Distal myopathies: clinical and biopsy abnormalities in systemic lupus erythematosus: molecular diagnosis and classification. J Neurol Neuro- correlation with clinical and laboratory parameters. surg Psychiatry 1999;67:703-7. Ann Rheum Dis 1994;53:178-82. 35. Barnard J, Newman LS. Sarcoidosis: immunology, rheu- 20. Russell ML, Hanna WM. Ultrastructural pathology of matic involvement, and therapeutics. Curr Opin Rheu- skeletal muscle in various rheumatic diseases. J Rheu- matol 2001;13:84-91. matol 1988;15:445-53. 36. Newman LS, Rose CS, Maier LA. Sarcoidosis [published 21. Yazici Y, Kagen LJ. Clinical presentation of the idio- correction appears in N Engl J Med 1997;337:139]. pathic inflammatory myopathies. Rheum Dis Clin North N Engl J Med 1997;336:1224-34. Am 2002;28:823-32. 37. Hull K, Griffith L, Kuncl RW, Wigley FM. A deceptive case 22. Mastaglia FL, Phillips BA. Idiopathic inflammatory of amyloid myopathy: clinical and magnetic resonance myopathies: epidemiology, classification, and diagnos- imaging features. Arthritis Rheum 2001;44:1954-8. tic criteria. Rheum Dis Clin North Am 2002;28:723-41. 38. Gertz MA, Lacy MQ, Dispenzieri A. Amyloidosis. Hema- 23. Targoff IN. Laboratory testing in the diagnosis and tol Oncol Clin North Am 1999;13:1211-33. management of idiopathic inflammatory myopathies. 39. Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Rheum Dis Clin North Am 2002;28:859-90. Kimura BJ, et al. Statin-associated myopathy with normal 24. Wortmann RL, DiMauro S. Differentiating idiopathic creatine kinase levels. Ann Intern Med 2002;137:581-5. inflammatory myopathies from metabolic myopathies. 40. Preston DC, Shapiro BE. Needle electromyography. Rheum Dis Clin North Am 2002;28:759-78. Fundamentals, normal and abnormal patterns. Neurol 25. Wagner KR. Genetic diseases of muscle. Neurol Clin Clin 2002;20:361-96. 2002;20:645-78. 41. Nirmalananthan N, Holton JL, Hanna MG. Is it really 26. Pourmand R. Metabolic myopathies. A diagnostic myositis? A consideration of the differential diagnosis. evaluation. Neurol Clin 2000;18:1-13. Curr Opin Rheumatol 2004;16:684-91.

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