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Evaluation of peripheral nerve and muscle disease

Evaluation of peripheral nerve and muscle disease
Literature review current through: Jan 2024.
This topic last updated: Oct 11, 2023.

INTRODUCTION — Neurologic conditions may present with similar but distinct constellations of symptoms and signs. The patterns of symptoms and examination findings may be used to identify the location and underlying causes of neurologic conditions.

This topic will review the findings on history and physical examination that are characteristic of nerve, muscle, and neuromuscular junction disorders as well as diagnostic tests used to establish diagnoses.

Specific peripheral nerve and muscle disorders are discussed in more detail separately.

(See "Overview of upper extremity peripheral nerve syndromes".)

(See "Overview of lower extremity peripheral nerve syndromes".)

(See "Overview of polyneuropathy".)

(See "Differential diagnosis of myasthenia gravis".)

(See "Overview of acquired peripheral neuropathies in children".)

(See "Overview of peripheral nerve and muscle disorders causing hypotonia in the newborn".)

DISTINGUISHING PERIPHERAL FROM CENTRAL NERVOUS SYSTEM DISEASE — Distinguishing whether symptoms indicate a peripheral nervous system (PNS) or a central nervous system (CNS) source is straightforward in most cases. Some symptoms such as aphasia or encephalopathy clearly indicate a CNS source. However, the distinction may be more difficult for other presentations, such as numbness or weakness in the lower extremities. In these instances, both CNS and PNS disorders must be considered.

History — It is important to ask the patient detailed questions about pain, location of symptoms, the time course of illness, and features that may localize symptoms to the CNS. Both CNS and PNS disorders can be present simultaneously; in such a situation, even detailed questioning of a patient may not identify the source.

Location of symptoms — The distribution of symptoms on the body may be used to differentiate CNS from PNS pathology. Signs or symptoms affecting the face, arm, and leg on one side of the body (eg, hemiparesis, hemisensory deficit) almost always indicate CNS pathology. Rarely, patients with PNS disease will report symptoms in the arm and leg on one side. In such cases, the condition may be generalized, but the patient may only be aware of deficits on the most severely affected side. Generally, weakness or sensory loss confined to one limb suggests a peripheral nerve source.

Localization is less clear when weakness or sensory loss is bilateral or when the symptoms are painless. For example, a patient who presents with painless sensory loss and numbness in the feet may have a polyneuropathy or a spinal cord lesion. Complaints of poor coordination or unsteady gait can be due to either primarily central or peripheral dysfunction. Bilateral leg weakness can be either central or peripheral.

Time course — Abrupt onset of symptoms (seconds) almost always indicates CNS pathology (eg, stroke, seizure) with the exception of diplopia, which may indicate CNS or PNS pathology. Acute onset of weakness or sensory loss in an awake, alert patient who is not performing an activity or maintaining an unusual posture is likely to be central in origin, while symptoms that come on after maintaining one position for a prolonged time are probably peripheral in origin. Examples of the latter include hand paresthesias while driving in a patient with carpal tunnel syndrome and penile numbness after prolonged bicycling (secondary to compression of the pudendal nerve in the perineum). Disorders that develop over days or weeks and those with onset during sleep may be more difficult to classify.

Pain — Extremity pain in addition to neurologic complaints is suggestive of a peripheral nervous system process. However, some CNS disorders can be accompanied by pain.

Many patients develop a chronic pain syndrome several months to years after spinal cord injury. (See "Chronic complications of spinal cord injury and disease", section on 'Pain syndromes'.)

Patients with stroke can also experience pain, particularly if the stroke was localized to the brainstem, thalamus, or parietal cortex. In most cases, the pain affects the upper and lower extremities on one side. (See "Central neuropathic facial pain", section on 'Central poststroke pain' and "Neuropalliative care of stroke", section on 'Pain'.)

Pain often originates from outside the nervous system, for example due to an arthritic joint. These patients may also complain of weakness secondary to the pain induced by movement of the joint or limb.

Pain that is position-dependent or brought on with activity (such as calf or thigh pain with walking in patients with spinal stenosis) is more likely of peripheral than central origin. In addition, pain that radiates into a very discrete area is unlikely to be central. However, random or diurnal fluctuations in pain are common in many peripheral and central disorders and may not help with localization.

Features suggestive of central nervous system disease — Symptoms such as impaired consciousness, cognitive difficulties, language disturbance, behavior change, or difficulty completing complex motor tasks point to CNS pathology. Neurologic symptoms with associated nausea, vomiting, or headaches also suggest CNS disease.

Neurologic examination — The neurologic examination plays an important role in differentiating central and peripheral nervous system disease [1,2].

Cranial nerves — Many generalized neuromuscular diseases affect the cranial nerves to some extent. Mild degrees of facial or bulbar weakness can be present in myopathies and neuromuscular junction disorders. Similar findings, including eye movement abnormalities, can be identified in patients with polyradiculoneuropathies such as in Miller-Fisher syndrome, a variant of Guillain-Barré syndrome. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis", section on 'Clinical features'.)

Cranial nerve signs are often subtle (especially when symmetric) and may manifest mainly as overactivation of the frontalis muscle, mild ptosis, or subtle eye movement abnormalities or nasality to the voice. Bilateral facial weakness can escape notice. Clues include incomplete eye closure and a smooth uncreased face. Examination of the tongue for atrophy and fasciculations is also important, especially when considering the diagnosis of motor neuron disease.

Reflexes — Examination of the deep tendon reflexes is perhaps the single most important test in determining whether a condition is peripheral or central. Brisk reflexes, especially if associated with a "pathologic" sign, such as the Babinski reflex or Hoffman sign, indicate central pathology.

The Brissaud reflex is useful when the great toe is absent or is paralyzed by polyneuropathy. In this sign, stroking the sole of the foot elicits contraction of the tensor facia lata at the hip. A positive Brissaud sign indicates upper motor neuron pathology, analogous to the Babinski sign.

Hyporeflexia or areflexia points to a peripheral source. However, in rapidly evolving CNS conditions, such as spinal cord compression or infarction, reflexes can initially be absent due to spinal shock. (See "Acute traumatic spinal cord injury", section on 'Clinical presentation'.)

Motor examination — Observation of the muscles may yield useful information before examining strength. Atrophy of muscles isolated to a specific root(s) or peripheral nerve places the etiology in the peripheral nervous system. Mild disuse atrophy occurs in patients with motor lesions of the CNS, but severe reduction in muscle bulk is not typically observed with central lesions alone. Fasciculations suggest a peripheral process.

Increased tone on passive movement of the extremities suggests a CNS process. Side-to-side comparison is helpful in distinguishing subtle abnormalities. Normal or decreased tone is found in most peripheral processes.

Weakness caused by upper motor neuron (CNS) etiologies generally follows a specific pattern. For example, in patients with weakness due to stroke, the extensor muscles in the arm (deltoid, triceps, wrist, and finger extensors) and flexor muscles in the leg (iliopsoas, hamstrings, and foot dorsiflexors) are weakest. Hemiplegia is straightforward to localize, but a patient with an incomplete spinal cord lesion who has only unilateral lower extremity weakness may prove a greater diagnostic challenge.

Weakness caused by radiculopathy, plexopathy, or nerve entrapments is usually restricted to only a specific group of muscles. Rarely, however, a patient with a stroke may present with relatively isolated weakness, perhaps just of the hand.

Peripheral symptoms that cause generalized weakness often affect the neck extensor muscles prominently and may lead to a "dropped head syndrome". As examples, myasthenia gravis, amyotrophic lateral sclerosis, and Guillain-Barré syndrome can all produce marked neck extensor weakness. This pattern is very atypical in most central disorders.

Symmetric generalized weakness is more likely peripheral than central and may suggest myopathy or diffuse polyneuropathy, although cervical myelopathy or brainstem lesions can also cause generalized weakness. Symmetric proximal weakness involving both the arms and legs is usually associated with myopathy, demyelinating polyneuropathy, or neuromuscular junction disease and is unlikely to be central in etiology.

Sensory examination — Sensory loss that follows a specific nerve or root territory and can be brought on by position changes is suggestive of a peripheral process. Examples include numbness in the fingers with wrist flexion (Phalen maneuver) in patients with carpal tunnel syndrome or sensory loss over the lateral thigh with prolonged standing in patients with meralgia paresthetica.

Determining which sensory modalities are most affected is useful. A peripheral source is more likely when all modalities are affected to some extent, although peripheral processes may also present with predominant loss of only one or two modalities (eg, reduced pain and temperature sensation in patients with a polyneuropathy affecting small unmyelinated fibers). Some central processes, such as syringomyelia, also may present with one or two modalities affected, such as reduced pain and temperature sensation and preserved light touch in the arm.

Coordination — Abnormal coordination without associated weakness or sensory loss suggests a central source. A central process should also be considered if coordination is affected out of proportion to weakness or sensory deficits. However, some patients with weakness or sensory loss due to peripheral nerve disease may have a considerable degree of incoordination.

Gait — Many central disorders are accompanied by changes in gait, such as the festinating gait of a patient with Parkinson disease, the hemiplegic gait of a patient with a stroke, or the "frontal" gait in a patient with normal pressure hydrocephalus. Gait disorders are often idiopathic or multifactorial in origin, especially in older adults. (See "Approach to abnormal gait in adults".)

Peripheral disorders also occasionally have stereotypical gait abnormalities. A steppage gait, where the patient needs to lift the knees up high to overcome weakness in foot dorsiflexors, can be seen in patients with polyneuropathy such as Charcot-Marie-Tooth disease. A waddling gait is characteristic of patients with proximal muscle weakness, as with myopathy. An antalgic gait occurs when posture and walking are altered in order to avoid or reduce pain. It arises from musculoskeletal rather than neurologic problems.

Other important distinctions — A number of situations may present diagnostic dilemmas.

Bilateral numbness and tingling in the feet are suggestive of a polyneuropathy, but other causes are also possible. Lumbosacral polyradiculopathy (eg, from lumbar stenosis) commonly presents with predominant distal sensory symptoms with little back or radiating pain or discomfort. Bilateral compression neuropathies (eg, bilateral peroneal or tibial neuropathies) occasionally affect the legs and need to be considered. Spinal cord conditions, including degenerative disease or myelitis, can also present with predominantly distal lower extremity symptoms. Determining whether the symptoms are due to a central (eg, spinal cord) versus a peripheral process can usually be accomplished by neurologic examination. Hyperreflexia and increased tone suggest a central process, whereas reduced reflexes and normal tone suggest a peripheral process. Symmetric involvement (by history and examination) suggests polyneuropathy, while asymmetric findings generally suggest compression neuropathies or polyradiculopathy.

Acute onset of painless unilateral hand and finger extension weakness is suggestive of an upper motor neuron condition, although an acute radial neuropathy can produce identical signs. In radial neuropathy, however, the brachioradialis usually is also weak, as a muscle not typically affected in central processes such as a stroke. Thus, examining the strength of this muscle (and its bulk during contraction compared with the normal side) can help make the distinction between these two entities. The brachioradialis flexes the elbow with the hand midway between pronation and supination, and during contraction it can be palpated radially in the proximal forearm.

Urgency and incontinence usually suggest upper motor neuron dysfunction. Patients with bladder difficulties from lower motor neuron symptoms typically present with weak streams and overflow incontinence. Distinguishing between these complaints can be challenging since many patients simply note an increased frequency of urination. Urodynamic studies may be useful when bladder difficulties are the predominant complaint. (See "Female urinary incontinence: Evaluation".)

Fatigue is a nonspecific complaint that may be hard to sort out. It is important to clarify what the patient means by fatigue, as many individuals use fatigue as a synonym for "weakness" or "sleepy."

Generalized fatigue is usually not a symptom of peripheral nervous system disease, although it may be a sequela of polio (ie, post-polio syndrome) and Guillain-Barré syndrome [3]. The mechanism for fatigue in these disorders is uncertain.

Weakness, not fatigue per se, tends to be the hallmark of most neuromuscular junction and muscle diseases. For example, patients with myasthenia report double vision or head drop at the end of the day.

Many patients with CNS demyelination, as in multiple sclerosis, complain of fatigue.

Patients experiencing depression commonly report fatigue related to impaired sleep or anhedonia.

In patients with preexisting moderate or severe peripheral nervous system disease, a superimposed central process can be very difficult to identify. As an example, a patient with diabetes mellitus and polyneuropathy who presents with progressive leg weakness, fever, and absent reflexes in the lower extremities may lead a clinician to suspect an acute polyneuropathy. However, these symptoms may also be due to a thoracic epidural abscess. A Babinski sign was absent due to atrophy of leg muscles and loss of sensory nerve fibers from chronic diabetic polyneuropathy. As a general principle, though, if the effector organs are not working normally, a central process cannot be excluded by examination.

Even the most experienced neurologist may have difficulty correctly identifying symptoms as peripheral or central. In most acute situations, it is more important to exclude a possible central process since substantial neurologic recovery in the CNS is unlikely. As an example, excluding stroke should be prioritized above eliminating a radial neuropathy in patients with acute hand weakness.

CLINICAL DISTINCTION AMONG NERVE, MUSCLE, AND NEUROMUSCULAR JUNCTION DISEASE — For patients with symptoms that localize to the peripheral nervous system (PNS), differentiating among disorders of the peripheral nerve, muscle, or neuromuscular junction can often be made from the clinical setting. As examples:

The diagnosis of diabetic polyneuropathy in a patient with long-standing diabetes mellitus who presents with classic "stocking-glove" sensory loss is relatively straightforward. (See "Screening for diabetic polyneuropathy".)

In patients taking drugs that can interfere with muscle function (eg, antimalarial, glucocorticoid, or cholesterol-lowering medications), proximal weakness may indicate a myopathy. (See "Glucocorticoid-induced myopathy" and "Drug-induced myopathies".)

However, patients with disorders of nerves, muscle, or the neuromuscular junction can present with a similar constellation of symptoms. In addition, even when the process is localized to the nerve, it is not always clear if the origin is in the central or peripheral nervous system.

Diseases of the nerve (eg, polyneuropathy), muscle (eg, myopathy), and neuromuscular junction (eg, myasthenia gravis) may present with varying degrees of sensory loss, weakness, and pain. Nevertheless, specific patterns of the sensory and motor disturbance may help differentiate among these disorders.

History — Focal sensory loss in the absence of a known central nervous system (CNS) lesion suggests a peripheral lesion occurring somewhere along the length of the nerve between the nerve root and the most distal fibers. Identifying the distribution of sensory loss is paramount and is discussed in further detail below. The loss of certain modalities (eg, vibration or sharp/dull discrimination) may also help identify the source.

Weakness can arise from dysfunction of motor neuron, nerve, neuromuscular junction, or muscle. Weakness tends to be a difficult symptom for patients to quantify and localize. Frequently patients will complain of pain and associated weakness. However, since pain may limit the action and mobility of a joint, the finding of weakness in the setting of pain may not indicate true neurologic dysfunction. Patients who complain of painless weakness generally have significant abnormalities on examination. Similar to sensory loss, the distribution of weakness is extremely important. (See 'Motor' below.)

Cranial nerve complaints can be very useful in localizing symptoms. In the absence of CNS disease, diplopia is likely secondary to a neuromuscular junction defect. Progressive dysarthria or dysphagia without associated eye symptoms suggests motor neuron disease (eg, amyotrophic lateral sclerosis). Less frequently, myopathies or acute motor polyneuropathies (such as the Miller-Fisher variant of Guillain-Barré syndrome) can present with dysarthria and eye movement abnormalities. (See "Guillain-Barré syndrome in adults: Treatment and prognosis".)

Neurologic examination — The neurologic examination should focus upon the distribution of muscle weakness and sensory loss and the deep tendon reflexes.

Motor — The distribution of muscle weakness is an important distinguishing feature. Proximal weakness is most consistent with a myopathy or neuromuscular junction disorder. Weakness in these individuals is usually symmetric, with involvement of head extensors and flexors, although mild asymmetries are not unusual. However, some patients with myasthenia may present with or develop predominately distal weakness. Repetitive movements may increase the weakness in myasthenia gravis. (See "Clinical manifestations of myasthenia gravis".)

If the weakness involves predominantly only one extremity, it is useful to determine if the lesion is in the distribution of a single root, a region of the plexus, or a single nerve territory; this requires a detailed knowledge of the anatomy. The examination can be confounded if multiple lesions are superimposed in a single limb (eg, a simultaneous radiculopathy plus a focal mononeuropathy, or multiple mononeuropathies).

Observation of the muscles themselves is often helpful. Important features include the presence of fasciculations, whether the muscle produces a painful cramp after activation, and the presence of atrophy. Such findings may occur in amyotrophic lateral sclerosis. (See "Epidemiology and pathogenesis of amyotrophic lateral sclerosis".)

Sensory — Root lesions may cause sensory loss in a dermatomal pattern (figure 1 and figure 2 and figure 3), though the overlap of dermatomal territories usually precludes mapping the area of numbness by examination. By contrast, sensory loss due to single nerve lesion can often be mapped with pin or touch on examination. Numbness in a single nerve territory might suggest an entrapment neuropathy.

Multiple areas of numbness in different extremities point to a mononeuropathy multiplex. In axonal polyneuropathies, "glove and stocking" sensory loss is most prominent, initially affecting the feet and later the hands. (See "Overview of polyneuropathy".)

Reflexes — The loss of reflexes suggests a neuropathic lesion, generally affecting either sensory or motor fibers. Globally depressed or absent reflexes are frequently associated with Guillain-Barré syndrome (see "Guillain-Barré syndrome in adults: Treatment and prognosis"). Reflexes are generally preserved in muscle disease unless it is severe. Neuromuscular junction disorders do not follow a clear pattern: in myasthenia gravis, reflexes are generally normal; in Lambert-Eaton myasthenic syndrome, reflexes are reduced or absent. (See "Clinical manifestations of myasthenia gravis".)

Additional signs — Bulbar and ocular signs suggest CNS disease but, if fluctuating or slowly progressive, may point to a neuromuscular condition. Patients with myasthenia gravis, if presenting with limb weakness, will usually have a degree of diplopia and fatigable ptosis on examination of the extraocular muscles. Atrophy and fasciculations of the tongue may suggest amyotrophic lateral sclerosis.

Checking the Tinel test, that is, tapping over a nerve to test for reproduction of pain and paresthesia (picture 1), might be helpful. A patient with intermittent numbness of the leg and a markedly positive Tinel sign over the fibular neck may have a peroneal neuropathy. However, the sensitivity and specificity of this test is generally low (see "Carpal tunnel syndrome: Clinical manifestations and diagnosis", section on 'Provocative maneuvers'). Multiple Tinel signs can be present in patients with polyneuropathy; in one study, the sensitivity and specificity of this finding was 79 and 42 percent, respectively [4].

Skin examination — Skin findings may be subtle but can help identify the source. Distal hair loss over the feet is common in patients with polyneuropathy. A healing, painful dermatomal rash may point to a recent episode of herpes zoster (see "Postherpetic neuralgia"). Unusual color changes with pain can point to complex regional pain syndrome accompanying a peripheral nerve lesion. (See "Complex regional pain syndrome in adults: Pathogenesis, clinical manifestations, and diagnosis".)

Points of confusion — Some presenting symptoms may be difficult to interpret.

Pain is generally not a prominent symptom of myopathy. Myopathic processes are usually painless, including polymyositis, dermatomyositis, toxic myopathies, and inclusion body myositis. Generally, muscle pain is confined to patients with acute rhabdomyolysis, a few metabolic myopathies (such as McArdle disease), and myopathies associated with connective tissue disease (the pain perhaps secondary to joint involvement rather than muscle involvement itself).

Myopathies may be superimposed upon polyneuropathies. As an example, colchicine can produce a severe myopathy, usually associated with a polyneuropathy. Patients with connective tissue diseases may also have both polyneuropathy and myopathy. In a critically ill patient who develops flaccid generalized weakness, the major considerations in the differential diagnosis are critical illness myopathy and critical illness polyneuropathy or very often a combination of the two. (See "Neuromuscular weakness related to critical illness".)

Contrary to standard teaching, proximal weakness is sometimes caused by nerve conditions and distal weakness by a myopathy. As an example, patients with Guillain-Barré syndrome occasionally present with proximal weakness secondary to predominant polyradiculopathy. On the other hand, some myopathies such as inclusion body myositis or myotonic dystrophy cause more distal than proximal weakness.

Mononeuropathy multiplex, when longstanding, can produce signs and symptoms suggestive of a polyneuropathy. The multiple mononeuropathies produce confluent sensory loss and weakness. (See "Overview of polyneuropathy".)

DIAGNOSTIC TESTING — Diagnostic tests are used to augment the history and physical examination in distinguishing among neurologic disorders and to help establish a diagnosis.

Electrodiagnostic testing — Electromyography (EMG) and nerve conduction studies (NCS) are the two most common diagnostic tests for establishing a diagnosis of nerve and muscle disease after the history and examination. It is often worth performing these tests prior to ordering additional blood tests. (See "Overview of electromyography".)

Electrodiagnostic studies are tailored for patients individually; the clinician should carefully consider what they are looking for when referring a patient for these tests. The electromyographer should be given some background information, although too much data (eg, results of radiologic studies) may bias the examiner. Similarly, the referring clinician should avoid narrowing the question too much; in a patient with proximal arm pain and hand numbness, asking to rule out only carpal tunnel syndrome may cause the electromyographer to miss a plexopathy or radiculopathy. The electromyographer typically performs a brief history and physical examination, which can help tailor the study. Referral to a neurologist or neuromuscular specialist before performing EMG/NCS is useful in particularly complex or confusing cases.

NCS and EMG can identify a wide variety of neuromuscular conditions quickly and can also provide useful information about severity and prognosis. Conditions commonly diagnosed by NCS and EMG include focal neuropathies, such as carpal tunnel syndrome, ulnar neuropathy at the elbow or wrist, and peroneal neuropathy at the knee. Cervical or lumbar radiculopathies are a common electrodiagnostic finding and EMG can be very useful to differentiate root impingement from orthopedic conditions such as rotator cuff or hip pathology that can mimic root disease. NCS/EMG can identify polyneuropathies affecting large, myelinated fibers. NCS are used to support the diagnosis of Guillain-Barre’s syndrome and CIDP, and EMG is critical to the diagnosis of ALS. Repetitive stimulation studies and single-fiber EMG have great value in diagnosing neuromuscular junction disorders. EMG is also useful in the setting of muscle diseases, such as acute inflammatory myopathy.

Limitations — Superimposed processes may make interpretation of the EMG/NCS difficult. As an example, underlying diabetic neuropathy can complicate the diagnosis in a patient with radiculopathy.

Many technical factors also play a role in the accuracy and interpretability of a study.

Conduction velocity will slow and response amplitude will increase if the patient's limbs are cool. Thus, a patient may be inadvertently diagnosed with carpal tunnel syndrome or polyneuropathy if the hand is cool. Limb temperature should be monitored, and limbs warmed, if necessary.

Normal values for NCS are not firmly established in older populations; some variability in interpretation is inevitable in this population.

Obesity or peripheral edema may make certain tests more difficult to perform.

Electrical interference from pumps, ventilators, or other hardware and software problems can also interfere with results.

Needle examination is generally safe in anticoagulated patients given the small size of the needles typically used. Nevertheless, EMG of the paraspinal and certain deep other muscles is usually not performed in these individuals, to avoid the possibility of hematoma formation. This can also limit interpretation.

Routine NCS are safe in patients with pacemakers, although high-intensity proximal stimulation of nerves (for example, at Erb's point in the shoulder or stimulation at the root level) is avoided.

EMG/NCS can only evaluate large, myelinated neurons. Only a few nerves in the arms (median, radial, and ulnar) and legs (posterior tibial, deep peroneal, and sural) are routinely studied. These nerves are easily accessible to stimulation and are frequently involved in neurogenic illness. However, many diseases, especially those that are painful, affect smaller myelinated or unmyelinated nerve fibers, and EMG/NCS may therefore be entirely normal. Thus, the absence of electrophysiologic evidence for a polyneuropathy does not mean that one does not exist.

EMG/NCS is an uncomfortable test; occasionally, patients are unable to complete a study. The electromyographer must make choices between one test and another to avoid excessive procedures. In addition, evaluation of motor units may be difficult if patients are not able to provide good effort (activation) on the EMG portion of the study. Explaining the procedure ahead of time may avoid some of these difficulties.

Electromyographers may have very limited training or may perform studies infrequently, which can lead to incorrect diagnoses. One study found that repeat EMG/NCS resulted in a new diagnosis in 40 percent of cases [5].

Neuromuscular ultrasound — Ultrasound of the peripheral nerves in conjunction with standard EMG/NCS can help further establish or refine diagnoses [6]. The test can help confirm common disorders, including carpal tunnel syndrome and ulnar neuropathy at the elbow, and it can also aid in evaluating demyelinating polyneuropathy and atypical nerve compression syndromes and in identifying the presence of a nerve tumor. Ultrasound has greater sensitivity and resolution in these roles even than magnetic resonance imaging (MRI). (See "Diagnostic ultrasound in neuromuscular disease".)

Magnetic resonance imaging — MRI has taken on a greater role in the diagnosis of a number of disorders, including muscular dystrophy (assessing fatty replacement of muscle) and various forms of myositis to assist with establishing the presence of ongoing muscle inflammation and identifying a good location for biopsy [7]. MR neurography may also be used in patients with difficult to localize lesions, such as those located to the brachial or lumbosacral plexus [8].

Laboratory testing — Several standard blood tests are available to help diagnose peripheral nerve diseases. Studies can be obtained to evaluate for polyneuropathy, myopathy, and neuromuscular junction disease. (See "Overview of polyneuropathy" and "Muscle enzymes in the evaluation of neuromuscular diseases" and "Clinical manifestations of myasthenia gravis".)

Genetic testing — Improvements in the accuracy and convenience of genetic testing, including targeted next-generation sequencing, whole exome sequencing, and whole genome sequencing now allow many rare and otherwise difficult-to-diagnose neuromuscular disorders to be identified with a single sample of blood or cheek swab [9]. These tools are now being used commonly in the diagnostic evaluation of patients referred to neuromuscular clinics.

Several specific genetic diseases are sufficiently common that they demand special consideration in patients with peripheral nerve and muscle disease. These include:

Charcot-Marie-Tooth type 1 is a hereditary demyelinating polyneuropathy. The electrophysiologic features are often suggestive, but genetic testing is commercially available. A duplication of the peripheral myelin protein 22 (PMP22) gene on chromosome 17 (producing type 1A disease) is the most common cause, although pathologic variants on other chromosomes also exist (producing types 1B, 1C, etc). (See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis".)

Hereditary polyneuropathy with predisposition to pressure palsies is a hereditary disease that is localized to the same gene as Charcot-Marie-Tooth disease type 1A. Rather than a duplication of the gene, a deletion is present. These patients often have multiple entrapment neuropathies, including carpal tunnel syndrome, ulnar neuropathy at the elbow, and peroneal neuropathies at the fibular neck, superimposed upon a mild polyneuropathy. Abnormalities can be identified on EMG in asymptomatic individuals. (See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis", section on 'Hereditary neuropathy with liability to pressure palsy'.)

Approximately 5 to 10 percent of amyotrophic lateral sclerosis cases are familial. (See "Familial amyotrophic lateral sclerosis".)

Another syndrome, Kennedy disease, is an X-linked form of motor neuron disease that is often associated with prominent bulbar signs. (See "Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease", section on 'Genetic testing'.)

Myotonic dystrophy type 1 (DM1), the most common myotonic disorder, is caused by an excessively long repeat of a cytosine-thymine-guanine (CTG) sequence in a gene on chromosome 19 that likely codes for a protein kinase called myotonin. The length of the repeated CTG sequence correlates with the severity of disease. Genetic testing is also available for the less common myotonic dystrophy type 2 (DM2), which is caused by a CTG repeat expansion on chromosome 3. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis".)

Dystrophin testing of blood and muscle can be performed to identify the X-linked disorders Duchenne and Becker muscular dystrophy. (See "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis".)

In addition, several uncommon polyneuropathies and myopathic/dystrophic diseases may be identified by genetic testing. However, genetic testing often needs to be interpreted cautiously and in reference to the patient’s presenting signs, symptoms, and the results of other diagnostic testing [10].

Muscle biopsy — Muscle biopsy assists most in the accurate diagnosis of an acquired myopathy. In patients with primary neurogenic disease, muscle biopsy will show fiber-type grouping or grouped atrophy. Muscle biopsy is also useful in patients evaluated for vasculitic polyneuropathy; inflammatory changes may be present in blood vessel walls of the muscle. Muscle biopsy is being used less frequently for the assessment of a potential hereditary myopathy given the advent of next-generation genetic sequencing. However, in cases where genetic testing is inconclusive, a biopsy in conjunction with the genetic results may help confirm a specific disorder.

Nerve biopsy — Nerve biopsy is used only rarely today and typically in complex or confusing cases where rare acquired disorders are being considered such as sarcoidosis, vasculitis, or leprosy (see "Overview of polyneuropathy", section on 'Nerve biopsy'). As with muscle biopsy, nerve biopsy has been replaced with targeted next-generation sequencing and whole exome sequencing to help establish the diagnosis of a genetic disorder.

Skin biopsy — Epidermal skin biopsy is an especially useful test in the diagnosis of polyneuropathy that predominantly affects small, unmyelinated nerve fibers. Typical symptoms of small-fiber neuropathy are distal burning, pain, numbness, and paresthesia. In patients with idiopathic painful distal sensory polyneuropathies who have a normal sural nerve biopsy, skin biopsy has demonstrated degeneration and loss of terminal nerve twigs. While this test may not explain the reason for the polyneuropathy, it can at least confirm its presence. (See "Overview of polyneuropathy", section on 'Skin biopsy'.)

SUMMARY

Differentiating peripheral nerve, muscle, and neuromuscular junction symptoms – Distinguishing whether symptoms indicate a primarily central nervous system (CNS) or a primarily peripheral nervous system (PNS) source at the nerve, muscle, or neuromuscular junction is based on characteristic patterns elicited in the history and examination. (See 'Distinguishing peripheral from central nervous system disease' above and 'Clinical distinction among nerve, muscle, and neuromuscular junction disease' above.)

History – Symptoms elicited from a careful history including the location of symptoms, time course, and the presence of pain can be used to help localize and identify the etiology. (See 'History' above.)

Weakness or sensory loss confined to one limb generally suggests a peripheral nerve source. (See 'Location of symptoms' above.)

Symptoms that come on after maintaining one position for a prolonged time are usually peripheral in origin. (See 'Time course' above.)

Extremity pain in addition to neurologic complaints is suggestive of a peripheral nervous system process. Important exceptions include chronic spinal cord injury and thalamic stroke. (See 'Pain' above.)

Neurologic examination – The neurologic examination should focus upon the distribution of muscle weakness, sensory loss, and pathologic deep tendon reflexes. Proximal weakness often, but not always, points to a myopathy or neuromuscular junction disorder. Focal sensory loss in the absence of a known central nervous system (CNS) lesion suggests a peripheral source. The loss of reflexes suggests a neuropathic lesion, generally affecting either sensory or motor fibers. (See 'Neurologic examination' above.)

Diagnostic testing – Diagnostic tests are used to augment the history and physical examination in distinguishing among neurologic disorders and to help establish a diagnosis.

Electrodiagnostic testing – Electromyography (EMG) and nerve conduction studies (NCS) are among the most informative diagnostic tests for nerve and muscle disease. (See 'Electrodiagnostic testing' above.)

Laboratory testing – Laboratory testing is used to evaluate for several conditions including polyneuropathy, myopathy, and neuromuscular junction diseases. (See 'Laboratory testing' above.)

Imaging – Ultrasound and magnetic resonance imaging are sometimes useful to help confirm diagnoses, especially in the diagnosis of localized conditions impacting nerve or muscle. (See 'Neuromuscular ultrasound' above.)

Genetic testing – Genetic testing, including next-generation and whole exome sequencing, is the test of choice for many primary muscle and nerve disorders without a clear etiology. (See 'Genetic testing' above.)

Tissue biopsies – Muscle biopsy can still assist in the accurate diagnosis of myopathy that otherwise eludes diagnosis. For patients with polyneuropathy, nerve biopsy is occasionally helpful to define whether the process is predominantly axonal or demyelinating. Epidermal skin biopsy is a useful test in the diagnosis of polyneuropathy that predominantly affects small, unmyelinated nerve fibers. (See 'Muscle biopsy' above and 'Nerve biopsy' above and 'Skin biopsy' above.)

Topic 5277 Version 20.0

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