Approach to the patient with muscle weakness

INTRODUCTION — The approach to evaluating a person with muscle weakness is a rewarding and challenging practice, integrating various aspects of the medical history with a multisystem physical examination and the judicious use of ancillary testing. Most often, muscle weakness is due to a reduction in the amount of force that muscles are able to elicit. However, a loss of force is not specific for muscle disorders (ie, myopathies), as this may also be observed in other conditions such as nerve or neuromuscular junction disorders; other neurologic diseases, such as multiple sclerosis or a history of stroke; and nonneurologic conditions, such as pain-limited effort or degenerative changes of the musculoskeletal system.

The clinical evaluation of muscle weakness should integrate the medical history and physical examination to develop a list of likely etiologies that may be further evaluated by laboratory studies. Hopefully, this will reveal a treatable entity, which will return the patient back to normal strength. Unfortunately, not all causes of muscle weakness will have treatments besides that of supportive care. Even when that is the case, there is benefit to the patient and family or caregivers to have a clear understanding as to the cause of weakness and what to expect in the future.

This overview is intended to guide the approach to the evaluation and diagnosis of patients who are suspected to have weakness from a muscle disorder (algorithm 1).

HISTORY

Distinguishing true weakness from other conditions — Asking about the impact of weakness on routine activities can help determine whether there is true muscle weakness versus decreased effort due to other limitations [1]. Patients with true weakness will typically complain about trouble performing specific tasks.

It is important to determine what patients mean when they complain of weakness to have an accurate understanding of their experience. A variety of nonmyopathic conditions can result in a complaint of weakness. These include:

●Pain-limited weakness due to structural disease of a joint or other source of nociceptive pain

●Neuropathic pain disorders

●Fibromyalgia

●Functional neurologic disorders

Note that a perception of fatigue or lack of endurance may occur with myopathic and nonmyopathic etiologies; the latter include physical limitations due to cardiopulmonary disease, anemia, malignancy, infectious disease, depression, multiple sclerosis, medications, and substance use (table 1). (See "Approach to the adult patient with fatigue".)

In many cases, the motor examination is required to help determine if there is true muscle weakness versus decreased effort from pain, fatigue, or other limitations. (See 'Assessment of effort' below.)

Pattern of weakness — Different forms of nervous system pathology result in different patterns of weakness. It is important to ascertain from the history how weakness is impacting function, which can point to a specific pattern of weakness. This information may increase confidence for a causative underlying muscle disorder or may suggest an alternative neurologic cause, such as a neuromuscular junction or neurogenic disorder.

The pathophysiology of weakness from a muscle disorder most often is related to myofiber dysfunction or loss, causing a decreased ability to elicit force. As weakness progresses, there is greater difficulty with performing normal activities, which the patient may report voluntarily or in response to directed questions.

●Proximal weakness – Most often, people with muscle disorders will have proximal, symmetric weakness in the hip and shoulder girdles. This pattern is seen with most myopathies, muscular dystrophies, and periodic paralyses. Hip girdle weakness results in problems with getting up from a low-lying position, such as a floor or chair; with stepping up on a curb; and with climbing a ladder or stairs. Shoulder girdle muscle weakness will result in difficulty raising a heavy object above the head.

Neuromuscular junction disorders, such as acetylcholine receptor antibody myasthenia gravis and Lambert-Eaton myasthenic syndrome (LEMS), may also result in a similar pattern of proximal, symmetric weakness, though in association with a greater degree of cranial nerve symptoms such as diplopia, ptosis, dysarthria, and dysphagia that can vary significantly over time.

Proximal predominant weakness also occurs with spinal muscular atrophy, spinobulbar muscular atrophy, and some neuropathies including acute intermittent porphyria [1].

●More distal weakness – Some muscle disorders may cause more distal weakness of the upper or lower extremities. Examples include inclusion body myositis (IBM), myotonic dystrophy type 1, and rare distal myopathies (table 2). Symptoms can involve hand movements, such as finger flexion declaring itself with grip weakness; quadriceps weakness resulting in knee instability with sporadic falls and difficulty with descending stairs; and distal leg weakness with poor toe clearance during the swing phase of gait, resulting in repeated tripping and potential falls as well as ankle instability.

Neurogenic disorders such as amyotrophic lateral sclerosis most often present with distal weakness and are more often asymmetric than muscle disorders. Neurogenic disorders that result in weakness often involve sensory nerve fibers, which may result in sensory symptoms. Therefore, the presence of sensory symptoms would suggest a nonmyopathic cause of weakness, though patients may rarely have a neuromyopathy (ie, a disorder that involves both nerve and muscle, with etiologies that include toxins, vasculitis, and amyloid).

●Combined proximal and distal weakness – This pattern is seen in some late-stage muscular dystrophies [1]. Nonmyopathic disorders with proximal and distal weakness include late-stage amyotrophic lateral sclerosis, botulism, Guillain-Barré syndrome (GBS), and typical chronic inflammatory demyelinating polyneuropathy (CIDP).

●Ocular and bulbar weakness – Some muscle disorders may present with weakness of muscle innervated by cranial nerves that can result in eye movement restriction, ptosis, dysphagia, and dysarthria. Examples include chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome, oculopharyngeal muscular dystrophy, myotubular myopathy, myotonic dystrophy type 1, and nemaline myopathy [1].

Presynaptic disorders, such as LEMS and botulism, often have associated autonomic symptoms. (See "Lambert-Eaton myasthenic syndrome: Clinical features and diagnosis" and "Botulism".)

●Asymmetric weakness – Among muscle disorders, asymmetric weakness occurs with IBM and fascioscapulohumeral muscular dystrophy [1]. With neuromuscular junction disorders, this pattern is frequently seen with ocular myasthenia gravis and early-stage amyotrophic lateral sclerosis. Asymmetric weakness is a hallmark of many nerve disorders including entrapment neuropathies, plexopathies, radiculopathies, vasculitic neuropathies, and multifocal motor neuropathy.

There may be clinical overlap among different patterns of weakness. As examples, a patient with IBM may be suspected of having amyotrophic lateral sclerosis due to hand weakness and muscle atrophy, and a patient with ptosis and dysarthria may be diagnosed with autoimmune myasthenia gravis when they actually have oculopharyngeal muscular dystrophy. (See "Clinical manifestations and diagnosis of inclusion body myositis".)

Tempo of progression — The history should include questions about the onset and progression of weakness and associated symptoms. Muscle weakness may be caused by a wide variety of different etiologies, which are often associated with different rates of progression. An accurate timeline of symptoms can help guide the evaluation of muscle weakness.

●Acute – Acute presentations (over hours to days) of muscle weakness may be seen with rhabdomyolysis. Rhabdomyolysis can occur in the setting of a depressed mental status that leads to prolonged muscle compression resulting in ischemia and necrosis; other causes of rhabdomyolysis include prolonged, strenuous, or unaccustomed activity. At times, rhabdomyolysis is accompanied by darkly pigmented urine. (See "Rhabdomyolysis: Clinical manifestations and diagnosis".)

Recurrent episodes of rhabdomyolysis suggest the possibility of a genetic disorder, such as a metabolic myopathy or a genetic muscle disorder (eg, RYR1 gene defect) (see "Approach to the metabolic myopathies"). With recurrent episodes, trying to determine the type of physical activity that elicits symptoms may suggest a particular cause. As an example, rhabdomyolysis with high-intensity physical activity is more suggestive of a glycolytic defect, like myophosphorylase deficiency, as compared with a lipid metabolism defect (eg, carnitine palmitoyltransferase 2deficiency).

Other causes for acute muscle weakness include medication toxicity. Electrolyte disturbances, such as hypokalemia or hypomagnesemia, can be a source of rapid muscle weakness. Also, viral infections can result in an acute presentation of muscle weakness. (See "Overview of viral myositis".).

Muscle channel disorders are a less common cause of acute episodic muscle weakness. (See "Hypokalemic periodic paralysis" and "Thyrotoxic periodic paralysis" and "Hyperkalemic periodic paralysis".)

●Subacute – Subacute (over weeks) muscle weakness can be caused by idiopathic inflammatory myopathies (see "Overview of and approach to the idiopathic inflammatory myopathies"), immune-mediated necrotizing myopathy (see "Clinical manifestations and diagnosis of immune-mediated necrotizing myopathy"), medication toxicity (see "Drug-induced myopathies"), and endocrine disorders such as hyperthyroid myopathy, hyperparathyroid myopathy, and Cushing syndrome (see "Myopathies of systemic disease"). Muscle infections from bacterial and parasitic infections can be a cause of muscle pain and weakness and often are associated with a multisystem presentation.

●Chronic – Chronic (over months) muscle disorders are often genetic conditions (see "Limb-girdle muscular dystrophy"). Nongenetic causes for chronic muscle weakness include acquired disorders such as IBM. People who are on chronic glucocorticoids can also develop chronic muscle weakness.

●Progressive versus episodic weakness – Most muscle disorders result in myofiber dysfunction and loss, resulting in progressive weakness over time. By contrast, episodic muscle weakness is suggestive of recurrent rhabdomyolysis (due to an inherited cause such as a metabolic myopathy), muscle channelopathy (hyperkalemic periodic paralysis, hypokalemic periodic paralysis, and Andersen-Tawil syndrome), or other genetic myopathy [1]. Episodic or fluctuating weakness is also seen with neuromuscular junction disorders (myasthenia gravis, congenital myasthenic syndromes, and LEMS) and certain neuropathies including acute intermittent porphyria and relapsing CIDP.

Comorbid conditions — The history should elicit the presence or absence of comorbid medical complaints and conditions. Muscle weakness may be a consequence of disorders that involve other organ systems in addition to muscle (table 3). As an example, dermatomyositis may cause skin changes (eg, Gottron papules, heliotropic eruption), interstitial lung disease, and/or myocarditis.

Systemic disorders may negatively impact the function of muscle and should be considered when a patient presents with muscle weakness. These include endocrine myopathies (eg, disorders of thyroid and parathyroid function, endogenous Cushing syndrome), myopathies associated with malabsorption, hypokalemic myopathy, critical illness weakness, and myopathies associated with rheumatic disease (amyloid myopathy, inflammatory myopathies, polymyalgia rheumatica, and skeletal muscle vasculitis) (table 4). Often there will be other signs and symptoms that would suggest these causes. (See "Myopathies of systemic disease".)

Medication and substance use — A review of all medications and a screen for substance use is appropriate, since muscle dysfunction can be due to commonly used medications, recreational drugs, and supplements [2] (see "Drug-induced myopathies"). Common associations include weakness from statin medications and glucocorticoids. Also, incorrect dosing of thyroid medications may cause muscle weakness. Other medications may cause weakness in association with a neuropathy, such as amiodarone and colchicine. It can be helpful to ask about medication changes relative to the onset of symptoms and to inquire about the development of other disorders or changes in other medications that may impact drug pharmacokinetics.

While most drug-induced myopathies occur due to a direct toxic effect on muscles that will improve with drug cessation, an immune-mediated necrotizing myopathy may occur with the use of certain medications (eg, statins, immune checkpoint inhibitors, tumor necrosis factor inhibitors, interferon alpha, and D-penicillamine); patients continue to have weakness after stopping the offending medication, with the exception of myopathy associated with D-penicillamine.

Family history — Most chronic to very chronic myopathies are due to a genetic cause, and so an exploration of the family history is often important. Family members with weakness may have an unrecognized muscle disorder and at times may be given an incorrect diagnosis. Therefore, asking about any family members with functional limitations may be more illuminating than asking for muscle weakness itself.

The genetics associated with muscle disorders are highly varied, and so the family history can be X-linked, autosomal dominant, autosomal recessive, or maternal. Since sporadic mutations can occur, the lack of a family history does not always exclude a genetic cause. There may be phenotypic variability within a family as well as variable penetrance. Different systems may be more severely impacted than that of extremity muscles, such as prominent respiratory symptoms in acid maltase deficiency, or cardiomyopathy in a female who is a manifesting carrier of a dystrophin gene defect.

Genetic disorders may also involve the immune system, so asking about a personal and family history of immune-based disorders can be helpful when considering an immune-based myopathy for the patient.

Historical elements not typically associated with muscle weakness — Historical features such as fasciculations and prominent sensory or autonomic symptoms argue against a muscle disorder as being the primary cause of weakness. However, these symptoms may be present when muscle weakness is part of a multisystem disorder.

PHYSICAL EXAMINATION — After the history, the second most important aspect of the clinical evaluation for muscle weakness is the physical examination. While the ideal examination should be consistent and systematic, it should also be hypothesis driven, where information is being actively integrated to help guide it as it is performed. This not only includes the performance of a detailed neurologic examination but will often include a directed medical examination. (See "The detailed neurologic examination in adults".)

Strength — When muscle weakness is the primary complaint, it is important to broadly evaluate the patient for their ability to elicit force. Though it is not efficient, practical, or required to test all muscle movement for every patient, it is important to be familiar with testing most muscles. Also, evaluating muscle weakness is dependent upon the experience of the evaluator.

Common muscles to test

●Cranial nerve-innervated muscles – Muscles innervated by cranial nerves can be tested by evaluating eyelid and mouth closure, eye movement, and tongue strength. Palatal weakness may be noted in association with a nasal dysarthria; weakness of the levator palpebrae will result in eyelid ptosis. Phonation of labial, lingual, and guttural sounds can be used to further appreciate facial, tongue, and pharyngeal weakness, respectively.

Cranial nerve-innervated muscles may be more selectively involved in neuromuscular junction disorders, so incorporating an evaluation for motor fatigue (prolonged up-gaze resulting in increased ptosis, loss of binocular fusion with sustained lateral gaze, dysarthria that quickly becomes increasingly severe) can direct the clinical concern away from a primary muscle disorder.

●Proximal muscles – Evaluation of the proximal muscles is essential because muscle disorders often have proximal muscle weakness. Common movements to test include neck flexion and extension, shoulder abduction, and hip flexion. It is also important to evaluate for scapular winging, as this can be associated with a muscle disorder (eg, facioscapulohumeral muscular dystrophy or limb-girdle muscular dystrophy) and may narrow the focus of evaluation.

The proximal lower extremity muscles can be tested by asking the patient to stand up from a chair without the aid of their arms, or to stand up from a kneeling position. Hip abduction weakness may be revealed by asking the patient to stand on one leg to see if there is a downward pelvic tilt toward the unaffected side due to gluteal muscle weakness on the affected side (figure 1), or by the presence of a Trendelenburg gait, where there is a downward pelvic tilt toward the unaffected side when stepping on the affected side.

●Mid-distance muscles – Elbow and knee flexion and extension should be evaluated, as weakness of these movements is associated with certain disorders such as facioscapulohumeral muscular dystrophy or inclusion body myositis (IBM). (See "Facioscapulohumeral muscular dystrophy" and "Clinical manifestations and diagnosis of inclusion body myositis".)

●Distal muscles – Most often, distal weakness is associated with a neurogenic cause of weakness, but there are muscle disorders that are well known to cause distal weakness, such as facioscapulohumeral muscular dystrophy, myotonic dystrophy type 1, and IBM. (See "Facioscapulohumeral muscular dystrophy" and "Myotonic dystrophy: Etiology, clinical features, and diagnosis" and "Clinical manifestations and diagnosis of inclusion body myositis".)

Distal upper-extremity groups involve the muscles of the forearm and the intrinsic muscles of the hand. Disorders of forearm muscles may result in weakness of the wrist and digits of the hand (wrist extension/flexion as well as digit extension and flexion), while involvement of hand intrinsic muscles will involve other digit movements, such as finger abduction. Therefore, it may not be adequate to use grip strength alone as a marker of upper extremity distal weakness.

Distal muscles of the lower extremities include the tibialis anterior (producing dorsiflexion) and the gastrocnemius-soleus complex (producing plantar flexion). The gastrocnemius-soleus complex tends to be very strong, even in those with muscle weakness, such that plantar flexion cannot be overcome with manual muscle testing. Functional assessments such as having a patient walk on their heels (assessing dorsiflexion) or the balls of their feet (assessing plantar flexion) as well as having them support their full body weight on the ball of one foot can help demonstrate weakness that would otherwise be difficult to recognize.

Assessment of symmetry — Muscle disorders often result in symmetric weakness, so side-to-side comparison is important. The presence of asymmetric weakness may suggest a neurogenic etiology, but certain muscle disorders may present with asymmetry, including facioscapulohumeral muscular dystrophy and IBM. Alternatively, a patient with a known cause of symmetric muscle weakness who has asymmetric weakness on examination should be suspected of having a second superimposed process causing the weakness and should be evaluated for this possibility.

Assessment of effort — The strength examination is dependent upon the full cooperation of the patient. Therefore, if full effort is not being provided, it is difficult to develop an accurate assessment of their weakness, limiting the interpretation of the examination. At times, this can be overcome with encouragement and clear instruction to the patient.

Decreased effort because of pain, fatigue, functional neurological symptom disorder (conversion disorder), or malingering may be identified by "give-way" weakness, in which there is initially a full effort followed by the abrupt loss of strength against resistance; this type of response does not occur in the truly weak individual. If intentionally decreased cooperation is suspected, observing the patient performing simple functional tasks such as sitting up from a supine position or toe or heel walking may reveal a discrepancy compared with the patient's performance on directed muscle strength testing.

Muscle bulk — The examination should include an assessment of muscle bulk. People with muscle disorders presenting with weakness may have normal muscle bulk, pathologic atrophy, and/or hypertrophy of muscles.

In most instances, decreased muscle bulk from a primary muscle disorder may start at the beginning of life, such as in a congenital myopathy, or it may develop slowly as part of chronic muscle weakness, such as in a muscular dystrophy or IBM. Rapid development of muscle atrophy, in weeks to months, is most often suggestive of a neurogenic disorder. Exceptions to this include rapid cachexia as well as critical illness-acquired weakness, with the former associated with relatively preserved weakness and the latter associated with potentially profound weakness. Increased muscle bulk can be associated with normal strength but also weakness. An example of the former would be a patient with a muscle channelopathy such as myotonia congenita from a CLCN1 pathogenic variant.

Increased muscle bulk with decreased strength can be seen with pseudohypertrophy of muscles (due to infiltration of fat or connective tissue), as seen in a patient with Duchenne muscular dystrophy as well as other muscular dystrophies, but it may also be seen in other disorders such as an amyloid myopathy (ie, macroglossia) and hypothyroidism. Also, a patient with a lipodystrophy may have the accentuated appearance of increased muscle bulk due to loss of fat tissue, such as in the setting of a human immunodeficiency virus (HIV) infection; muscle hypertrophy can also be seen with lipodystrophy with some LMNA pathogenic variants.

Abnormal muscle movements — Abnormal involuntary muscle movements may accompany different neuromuscular disorders.

Myotonia is a slowed muscle relaxation following a normal muscle contraction due to abnormal membrane depolarization that persists despite no neural activation. This can often be elicited by testing for difficulty with opening the hands after strongly gripping the hand, as well as with eyelid closure. It can be observed with percussing various muscles, most classically the abductor pollicis brevis, the extensor digiti minimi, as well as the tongue. With repetitive testing, the myotonia can improve (warm-up phenomena), while if it becomes increasingly severe with repetition, the patient may have paramyotonia (paroxysmal myotonia). These findings most often suggest a particular set of genetic disorders of muscle such as myotonic dystrophy, myotonia congenita, and paramyotonia congenita.

Muscle rippling is a rare finding of a wave-like activation of the muscle and is associated with caveolin mutations [3] but also myasthenia gravis [4].

Fasciculations and myokymia are abnormal muscle movements but are not associated with muscle weakness. Fasciculations are due to neurogenic activation of the myofibers of a motor unit that result in a focal movement often perceived as a muscle twitch. Myokymia represent grouped fasciculations. These findings suggest a cause of weakness related to nerve and not muscle.

Muscle cramping is a very common symptom and may be a benign finding reported by healthy people, or it may occur with systemic disease or with disorders of the central and peripheral nervous system [5,6]. Because of the nonspecific nature of cramping, its presence is often not helpful to clarify the source of weakness.

Reflexes — Most patients with muscle disorders have normal reflexes; however, as the muscle weakness becomes increasingly severe, there is increasing loss of the terminal component of the reflex arc, resulting in decreasing movement. Usually, the degree of reflex loss is commensurate with the degree of weakness of the muscle being tested. Exceptions to this include patients with myotonic dystrophy type 1, where areflexia or hyporeflexia may be present despite normal strength. Also, the cause of muscle weakness may influence the reflex findings, as decreased or delayed reflexes can be seen in hypothyroidism and accentuated reflexes can be seen in hyperthyroidism; hyperreflexia can be seen with stroke, myelopathy, amyotrophic lateral sclerosis, or other upper motor neuron causes.

Medical examination — As different organ systems may be involved when a patient has muscle weakness, it is important to assess the eyes, skin, heart, and lungs. Cardiac arrhythmias may occur in immune-mediated myopathy, electrolyte disorders, or genetic conditions, while interstitial lung disease may develop in the setting of an immune-mediated myopathy (table 3).

Findings that suggest an alternative cause for weakness

●Sensory loss – Prominent sensory loss is perhaps the clearest examination finding indicating that a muscle disorder is not the cause of weakness. Sensory loss argues for a disorder of the peripheral nerve or higher-level structure (nerve root, spinal cord, or brain).

●Pattern of weakness – The distribution of weakness reported by the patient and revealed on the physical examination may suggest an alternative cause of weakness. Examples of this include weakness of the legs with sparing of the arms suggesting a myelopathic process; hemiparesis suggesting unilateral corticospinal tract dysfunction; and isolated weakness of the limb suggesting a disorder of neve root, plexus, or mononeuropathy. Familiarity with peripheral neuroanatomy can be helpful for this part of the evaluation.

●Reflex change – While there are instances where the reflexes are disproportionately increased or decreased in the setting of muscle weakness, most often the reflexes are normal or reduced in proportion with the weakness of the muscles involved in the reflex loop. Therefore, if reflexes are disproportionately increased or reduced, consideration should be made for alternative causes of weakness. When there are disproportionately increased reflexes for the degree of weakness, a corticospinal tract lesion should be well considered. This is especially true in association with other signs of corticospinal tract dysfunction such as spasticity or other pathologic reflexes such as the presence of an abnormal Babinski response. Acetylcholine receptor antibody myasthenia gravis can also have disproportionately increased reflexes relative to the patient's severity of weakness.

Disproportionately reduced reflexes to the degree of weakness can be due to primarily demyelinating neuropathies that may be acquired (eg, Guillain-Barré syndrome [GBS] and chronic inflammatory demyelinating polyneuropathy [CIDP]) as well as genetic (some forms of Charcot-Marie-Tooth [CMT] disease). Also, Lamberton-Eaton myasthenic syndrome (LEMS) can cause disproportionately decreased reflexes that can improve with repeated activation of the muscle being tested.

●Fluctuating weakness during the examination – Muscle weakness is most often sufficiently static such that the strength examination does not vary during the clinical visit. Neuromuscular junction disorders such as myasthenia gravis can result in increased weakness while evaluating the patient at the bedside, while LEMS can have improved strength with repeated muscle activation. Therefore, the presence of variable weakness during the examination, assuming full participation and effort of the patient, should cause careful consideration for a neuromuscular junction disorder as the cause of weakness.

DIAGNOSTIC INVESTIGATIONS — After consideration of the history and examination, further diagnostic testing can be performed to evaluate and characterize the muscle weakness as well as to possibly determine the specific cause for weakness.

Laboratory studies

●Muscle enzymes – For patients with muscle weakness or myalgias, the most important muscle enzymes to measure are creatine kinase (CK) and aldolase. Elevated serum levels of these enzymes are markers of muscle injury and are important for diagnosis and for monitoring the course and response to therapy of certain muscle disorders.

Other enzymes that may be elevated in myopathies include lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). However, their role is more limited as they may be abnormal due to other etiologies and are therefore less specific for muscle injury.

With myofiber damage, there is leakage of cellular contents that can result in elevations of CK, aldolase, AST, ALT, and LDH. Most often, the CK level is used as a marker of myofiber damage, but this test can be influenced by specific characteristics of the individual being tested such as their age, sex, ethnicity, and medical comorbidities such as renal insufficiency. Also, the CK can be modestly elevated with genetic and acquired neuropathies. There are times where a person may have a normal CK while the aldolase is elevated [7,8]. The utility of AST, ALT, and LDH is often confounded by other disorders that may also cause an elevation of these enzymes.

While CK is often used as a marker of a muscle disorder, a normal CK level may be present in patients with muscle weakness. Often this is due to a slowly progressive process, such as a congenital myopathy or indolent dystrophy; a process not associated with myofiber damage, such as a glucocorticoid-induced myopathy; an inflammatory myopathy not causing myofiber damage; or an inflammatory myopathy with perimysial pathology. In some cases, the muscle disorder may cause profound myofiber loss such that there are insufficient myofibers to result in an elevated CK.

●Testing for systemic disorders – Testing for endocrine abnormalities, thyroid and parathyroid abnormalities, and electrolyte disturbances may be warranted in association with muscle enzyme testing if there is clinical suspicion for one or more of these conditions.

●Inflammatory muscle disorder testing – When there is suspicion for inflammatory muscle disorders, panel testing for myositis-associated and myositis-specific antibodies can be useful to confirm the diagnosis, help determine the risk of an underlying malignancy, inform about the risk of other associated disorders such as interstitial lung disease, and help guide treatment [9,10]. Testing for the HMGCR and NT5C1A (cN1a) antibodies is usually not part of all commercially available myositis panels and should be pursued when appropriate. (See "Overview of and approach to the idiopathic inflammatory myopathies".)

●Genetic testing – Genetic testing can be helpful to identify the underlying etiology of weakness when there is suspicion for a genetic cause of muscle weakness (see "Genetic testing" and "Limb-girdle muscular dystrophy") but there is no one genetic panel that addresses all causes. Therefore, genetic testing should be guided by the suspected genetic cause. Examples of this include myotonic dystrophy and facioscapulohumeral muscular dystrophy; both are common genetic muscle disorders but are not part of common genetic testing panels.

The online Genetic Testing Registry is a very useful international resource where specific genetic tests may be found. With the advent of broad genetic testing with panels that may include hundreds of genes or more, discussing possible outcomes (such as variants of unknown significance) and the expected utility and sensitivity of genetic testing prior to the actual test is very helpful [11,12].

Electrodiagnostic testing — Electrodiagnostic testing should be considered if the cause of muscle weakness is uncertain from the history, physical examination, and targeted laboratory investigations [13,14]. This includes performing nerve conduction studies (NCS) and electromyography (EMG).

●Nerve conduction studies – NCS involve activating nerve fibers to propagate an action potential and either recording the summated action potential directly from the nerve (sensory NCS) or recording the summated action potentials from muscle fibers (motor NCS). With muscle disorders, there is usually preservation of the somatosensory system so that sensory studies are normal. While a motor response can be recorded from many muscles, the study is most often performed recording from distal muscles of the hand and foot. Myopathies most often affect myofibers in proximal muscles, while the motor NCS evaluate distal muscles where myofibers are most often preserved. Because of this, standard motor NCS are typically normal in patients with a myopathy. More diffuse disorders, such as intensive care unit (ICU)-acquired muscle weakness (critical illness myopathy) or chronic progressive muscle disorders that have resulted in distal myofiber loss, can result in reduced-amplitude motor responses. (See "Overview of nerve conduction studies".)

Special NCS may be performed to further evaluate the cause of muscle weakness. Slow repetitive stimulation can be used to stress the safety factor of the neuromuscular junction to help diagnose a patient with myasthenia gravis. Fast repetitive stimulation can be used to increase calcium content in the motor nerve terminus by which the physiologic consequences of presynaptic disorders such as Lambert-Eaton myasthenic syndrome (LEMS) and botulism can be overcome. Therefore, an abnormal repetitive stimulation is most often indicative of a neuromuscular junction disorder as the cause of weakness. (See "Diagnosis of myasthenia gravis" and "Lambert-Eaton myasthenic syndrome: Clinical features and diagnosis".)

●Electromyography – EMG involves placing an electrode in the muscle to evaluate motor unit morphology and recruitment as well as to further characterize the presence of abnormal insertional and spontaneous activity.

In muscle disorders, there is often a loss of functional myofibers, and the remaining functional myofibers have variable size, which will result in small-amplitude, shorter-duration, and polyphasic motor unit action potentials (MUAPs). Due to the lesser force elicited by these motor units, increasing muscle activation requires more activated motor units than would normally be needed for the amount of force generated. This is often reported as either rapid or early recruitment. As muscle disorders become more advanced, myofiber loss may be sufficiently severe such that no adjacent myofibers are available to recruit from other motor units, resulting in a rapidly firing motor unit (reduced recruitment). Therefore, while reduced recruitment typically occurs with neurogenic disorders, it can be seen in advanced muscle disorders. Also, some muscle disorders (such as inclusion body myositis [IBM]) can provide more "neurogenic"-appearing MUAPs with higher amplitude, longer duration, and more complex morphology. (See "Overview of electromyography".)

Clinical EMG primarily evaluates type 1 (slow twitch) muscle fiber groups, which are the first motor units recruited with voluntary activation of the muscle. Disorders that primarily affect type 2B fibers (eg, glucocorticoid myopathy and cachexia) will not be easily recognized on EMG.

Abnormal spontaneous activity during EMG in a resting muscle can be seen in myopathic or neuropathic disorders. Myotonia occurs in hereditary myopathies including myotonic dystrophy, myotonia congenita, paramyotonia congenita, Schwartz-Jampel syndrome, hyperkalemic periodic paralysis, metabolic myopathies, and myofibrillar myopathies. Fibrillation potentials, positive sharp waves, complex repetitive discharges, and increased or decreased insertional activity are nonspecific and can be seen in myopathic and neuropathic disorders. Other findings, such as fasciculations, myokymia, and neuromyotonia indicate a nerve disorder.

Acetylcholine receptor myasthenia gravis and botulism can result in myopathic-appearing motor units, though this is most often associated with severe presentations. Therapeutic botulinum toxin injections can also result in similar findings when evaluating muscles near the injection site.

Imaging — Over time there has been an increasingly established role in using neuromuscular imaging as part of the evaluation of the patient. Magnetic resonance imaging (MRI) is the imaging modality of choice to evaluate for a myopathy. Imaging can also be performed with computed tomography (CT) and ultrasound modalities. Each modality has its own characteristics that influence the choice of study, including cost, radiation exposure, depth of field of observation, local expertise, and availability. In general, CT is infrequently used as it does not provide as much information compared with MRI. Ultrasound also has limited utility compared with MRI; use is most often restricted to centers that regularly perform neuromuscular ultrasound.

Imaging can be used to help confirm abnormality of muscle and provide guidance as to which muscle to consider for biopsy to increase the diagnostic yield [15]. While imaging has been supplanted to a degree by the increasing ease of obtaining genetic testing, imaging can often distinguish different patterns of muscle abnormality that may suggest a specific diagnosis and narrow genetic testing [16]. Muscle abnormality on MRI can be used as a helpful adjunct to help determine the etiology of muscle weakness [17]. It can also be used as a marker of inflammation and of treatment effect [18].

Muscle biopsy — Muscle biopsy is typically reserved for patients with unexplained muscle weakness despite a thorough noninvasive evaluation. As genetic testing has become more readily available, a diagnosis may be made without the use of muscle biopsy. However, muscle biopsy may still be considered when genetic testing is normal or reveals variants of unknown significance.

To increase the diagnostic yield, the biopsy should sample a muscle that is weak (eg, one with 4 out of 5 strength on the Medical Research Council [MRC] scale), but not so weak that the findings show only nondiagnostic end-stage changes. Muscle imaging and EMG can also be used to guide the biopsy, though EMG would be used to select a biopsy of the contralateral muscle (assuming symmetry of muscle involvement) to avoid any artifactual findings from the trauma of the needle electrode [15]. Factors that increase the diagnostic yield include a myopathic pattern of muscle weakness, an elevated CK, and an EMG with myopathic abnormality [19]. Some centers will perform two-site biopsy to increase the diagnostic yield or pursue a second biopsy in select patients [20-22].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Weakness (The Basics)" and "Patient education: Dermatomyositis (The Basics)" and "Patient education: Polymyositis (The Basics)" and "Patient education: Rhabdomyolysis (The Basics)" and "Patient education: Muscular dystrophy (The Basics)")

●Beyond the Basics topics (see "Patient education: Overview of muscular dystrophies (Beyond the Basics)" and "Patient education: Polymyositis, dermatomyositis, and other forms of idiopathic inflammatory myopathy (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●History – For patients complaining of weakness, the history should attempt to distinguish whether true muscle weakness is present and how the weakness impacts normal activities and function, which can help determine the pattern of weakness and therefore narrow the focus of possible causes. The history should include questions about the onset and progression of weakness and associated symptoms, the presence or absence of comorbid medical complaints and conditions, medication and substance use, and family history. (See 'History' above.)

•Pattern of weakness – Proximal, symmetric weakness in the hip and shoulder girdles is the pattern seen with most myopathies. Other patterns (distal weakness, combined proximal and distal weakness, ocular and bulbar weakness, asymmetric weakness) can occur with some muscle disorders but may also point to alternative causes. (See 'Pattern of weakness' above.)

•Tempo of progression – Causes of acute muscle weakness include rhabdomyolysis, medication toxicity, and electrolyte disturbances. Subacute muscle weakness may include inflammatory myopathies, medication toxicity, and systemic myopathies. Chronic muscle disorders are often caused by genetic conditions. (See 'Tempo of progression' above.)

•Comorbid conditions – Myopathies may be associated with endocrine disease, malabsorption, electrolyte disturbance, critical illness, and rheumatic disease. (See "Myopathies of systemic disease".)

•Medications and toxins – Muscle dysfunction can be due to commonly used medications, recreational drugs, and supplements. (See "Drug-induced myopathies".)

•Family history – Since most chronic myopathies are due to a genetic cause, the family history is important; asking about any family members with functional limitations may be more illuminating than asking about muscle weakness itself. (See 'Family history' above.)

●Examination – While the ideal examination should be consistent and systematic, it should also be hypothesis driven, with information being actively integrated to help guide the examination as it is performed. (See 'Physical examination' above.)

•Strength testing – The motor examination should test the strength of cranial nerve-innervated muscles and proximal, mid-distance, and distal muscles, as described above. Testing should assess symmetry with side-by-side comparison of strength and should assess whether the patient is able to give full effort with testing. (See 'Strength' above.)

•Muscle bulk, abnormal movements, and reflexes – The examination should include an assessment of muscle bulk, observation for abnormal involuntary muscle movements, and reflex testing. (See 'Muscle bulk' above and 'Abnormal muscle movements' above and 'Reflexes' above.)

•Medical examination – For patients with muscle weakness, it is important to assess other organ systems as they may be part of the overall disorder causing weakness. This includes an examination of the eyes, skin, heart, and lungs. (See 'Medical examination' above.)

●Diagnostic investigations – Diagnostic testing can help characterize the muscle weakness and may determine the specific cause. (See 'Diagnostic investigations' above.)

•Muscle enzyme testing – We check markers of muscle injury including creatine kinase (CK) and aldolase for patients presenting with weakness or myalgias. Additional laboratory testing (eg, for systemic disorders, inflammatory muscle disorders, and/or genetic conditions) may be added depending upon clinical suspicion. (See 'Laboratory studies' above.)

•Electrodiagnostic testing – Nerve conduction studies (NCS) and electromyography (EMG) should be performed if the cause of muscle weakness is uncertain from the history, physical examination, and targeted laboratory investigations. (See 'Electrodiagnostic testing' above.)

•Imaging and biopsy – In select cases, muscle imaging may suggest a specific diagnosis and help to target genetic testing and/or biopsy. Muscle biopsy is typically reserved for patients with unexplained muscle weakness despite a thorough noninvasive evaluation. (See 'Imaging' above and 'Muscle biopsy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marc L Miller, MD, who contributed to earlier versions of this topic review.