Clinical manifestations

Presentation and course

For several reasons, including the presence or absence of a trigger, the time variation between the trigger and disease onset, and the varied distribution of the lesions, individuals with neuralgic amyotrophy present in a large number of ways. Despite this great variation, when present, a distinctive triad: (1) trigger, (2) forequarter region pain, and (3) forequarter region muscle weakness and wasting permits easy diagnosis. Even when the triad is incomplete, the disorder is can still be easily recognized by its two most important clinical features (severe pain and muscle weakness and atrophy). In our series of 281 patients with sporadic neuralgic amyotrophy, a complete triad was noted in over 90%, forequarter region pain was present in 92% (8% of the bouts were painless), and forequarter muscle weakness and wasting were present in 98.4% (1.6% did not manifest muscle weakness or atrophy) (16). In our series, among those patients lacking one of the two key features, a trigger was always present, and all had neuralgic amyotrophy previously and, thus, sought medical attention with this diagnosis in mind.

Although most patients report focal pain (this is the primary chief complaint), they uncommonly report focal sensory loss; even when present, focal sensory loss tends to be minor in degree. Consequently, the neurologic examination abnormalities seen with neuralgic amyotrophy primarily involve the motor system (16).

Trigger (antecedent event). According to the medical literature, triggers are identified in at least 50% of bouts of neuralgic amyotrophy. The most common trigger is an upper respiratory infection or flu-like illness, including Coxsackie B virus; cytomegalovirus; Epstein-Barr virus; hepatitis viruses (B, C, and E); herpes simplex virus; HIV; varicella virus; and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (08). In addition to infection, other common triggers include medical and surgical procedures, childbirth, immunizations, and vaccinations (including herpes zoster, human papillomavirus, influenza, tetanus toxoid and antitoxin, and COVID-19 vaccinations) (31), autoimmune disorders, unaccustomed strenuous activity, and trauma, including trivial trauma. These triggers presumably activate the immune system in genetically susceptible individuals. This pathogenesis is supported by the occurrence of neuralgic amyotrophy following graft-versus-host disease, a disorder known to be associated with immune system activation (32).

In our series, a trigger was identified more frequently, likely because we collected our data prospectively at the time of diagnosis using a preprinted form listing all of the recognized triggers (15). With this approach, a trigger was identified in 73% of our patient population. In our series, the most common was a surgical or medical procedure (29%), followed by an upper respiratory illness or nondescript flulike illness (24%), excessive or unaccustomed strenuous exercise (17%), closed trauma (10%), childbirth (7%), a dental procedure (6%), vaccination (5%), and open trauma (2%).

In addition to the above-listed triggers, neuralgic amyotrophy has been associated with the administration of various medications, including those affecting the immune system, such as immune checkpoint inhibitors (29). Botulinum toxin has also been reported as a trigger (05).

A latency period separates the trigger and the symptom onset time. In the literature, this period is typically defined as lasting 4 to 6 weeks. In our series, the latency period ranged from several hours to 28 days and, in 67%, the pain started during the first week (15).

Pain. Neuralgic amyotrophy is typically heralded by severe pain most frequently located at the lateral aspect of the shoulder, followed by the posterior aspect of the shoulder. There may also be pain in the region of the involved nerve, either in addition to the shoulder pain or, less frequently, in isolation. Examples include the superolateral aspect of the chest wall with long thoracic nerve involvement, the dorsal aspect of the shoulder with suprascapular nerve involvement, the lateral aspect of the shoulder with axillary nerve involvement, the lateral aspect of the arm or forearm with musculocutaneous nerve involvement, and the distal aspect of the biceps or antecubital fossa region with anterior interosseous nerve involvement. In the setting of motor nerve branch involvement, the pain often overlies the involved motor nerve branch (eg, the volar aspect of the distal forearm with involvement of the motor nerve branch to the flexor pollicis longus muscle).

The pain is usually sudden in onset and typically either awakens the patient from sleep or is the first thing noted on awakening. The pain quickly intensifies (usually within several hours) and, because of its severity, causes patients to seek immediate medical attention. The pain is exacerbated by shoulder or upper extremity movement, not by head or neck movement (this differentiates it from an acute onset radiculopathy). The severe pain usually persists for 1 to 2 weeks and then either resolves or is replaced by a dull aching pain.

Infrequently, the pain is mild to moderate in intensity or absent. In our series (n = 281), pain was absent in 8% of the 322 bouts (14). Interestingly, in our series, the individuals with painless neuralgic amyotrophy had previously experienced painful neuralgic amyotrophy (ie, it was not their first bout of neuralgic amyotrophy), allowing them to recognize the recurrence and present for medical attention.

Whenever painless neuralgic amyotrophy is suspected (eg, because of unexplained severe forequarter muscle weakness and wasting) but preceding pain is denied, it is important to ask about more remote shoulder pain because they may have had typical painful neuralgic amyotrophy and failed to recognize the associated muscle weakness and wasting. The presence of a triggering event should also be queried.

Despite significant pain, cutaneous sensory axon involvement producing numbness is infrequent. When it is present, it is typically not pronounced. In our experience, when sensory loss is identified, it most commonly involves the cutaneous distribution of the axillary nerve (for example, the superior lateral brachial cutaneous nerve) or of the musculocutaneous nerve (the lateral antebrachial cutaneous nerve distribution).

Weakness and wasting. Forequarter muscle weakness and wasting follow the pain and are typically recognized when the pain is subsiding and the patient begins to use the affected limb. On occasion, the weakness is not initially recognized and, instead, the muscle atrophy is the initially recognized feature. Muscle atrophy typically is noted within a few weeks of the onset of the pain. On rare occasions, weakness and wasting are absent. In our series, this occurred 1.6% of the time. In these cases, similar to the painless neuralgic amyotrophy cases, the individuals had experienced a previous bout of neuralgic amyotrophy associated with the full triad, and, based on that experience, when the severe shoulder pain developed, they suspected a recurrence and sought medical care. Interestingly, all of these patients reported the same trigger as in their previous bout. Despite careful neurologic examinations at that time and at follow-up, focal muscle weakness or wasting was never noted.

There are several reasons that muscle weakness and wasting might go unnoticed by patients or even their healthcare providers. First, in the early stage, when pain limits effort, mild weakness may not be appreciable. Second, when synergistic muscles mask the weakness (eg, isolated involvement of the brachialis muscle may go unrecognized when the biceps muscle is spared). Third, when an overlying muscle masks the underlying muscle wasting, such as when the trapezius muscle masks the supraspinatus muscle wasting or when the biceps muscle masks the brachialis muscle wasting.

Lesion distribution. The distribution of the lesions associated with neuralgic amyotrophy has been unnecessarily controversial. The muscles involved in neuralgic amyotrophy lie in the forequarter region of the body (the ipsilateral bulbar, neck, chest, and upper extremity). Because of the high incidence of shoulder girdle muscle involvement and their intermediate innervation via the upper trunk (ie, after exiting the spinal cord, the motor axons innervating these muscles traverse the upper trunk), neuralgic amyotrophy was initially considered an upper trunk brachial plexopathy. However, because the clinical and electrodiagnostic examinations of many of these patients did not always support such a localization, many authorities concluded that at least some of the time, multiple mononeuropathies must be responsible. Eventually, either a mononeuropathy or a multiple mononeuropathy distribution was shown to represent the overwhelming majority (699 of 703) of these lesions (16). The authors suggested that the upper trunk brachial plexopathy-like presentation might reflect a predilection for motor axons.

Expected distribution if there is a predilection for motor axons. In the setting of motor axon predisposition, nerves composed solely of motor axons should have the highest incidence of involvement, followed by nerves with an axon composition that is composed predominantly of motor axons (ie, with minimal cutaneous axons). Nerves with a more balanced composition of motor axons and cutaneous sensory axons should have an even lower incidence of involvement. And, finally, nerves composed solely of cutaneous sensory axons should have the lowest incidence of involvement. Although all motor nerves contain sensory afferents from the muscle spindles and the Golgi tendon organs, only cutaneous sensory axons are being referred to, such as those composing the lateral antebrachial cutaneous nerve.

In our series, the suprascapular nerve and the long thoracic nerve (both are pure motor nerves) were the two most commonly affected nerves. Other examples of pure motor nerves include the anterior and posterior interosseous nerves, the motor nerve branches to individual muscles, the phrenic nerve, and certain cranial nerves (eg, facial, glossopharyngeal, vagus, recurrent laryngeal, spinal accessory, and hypoglossal). Examples of predominant motor nerves are the axillary and musculocutaneous nerves. The cutaneous sensory axons contained within these nerves represent a minority of the total number of axons. These cutaneous axons innervate the lateral aspect of the shoulder via the superior lateral brachial cutaneous nerve branch of the axillary nerve and the lateral aspect of the forearm via the lateral antebrachial cutaneous nerve branch of the musculocutaneous nerve. These two nerves are also commonly affected by neuralgic amyotrophy, and their cutaneous distributions are the most reported sites to have sensory symptoms. Examples of more evenly mixed nerves include the median, ulnar, and radial nerves. Examples of nerves composed solely of cutaneous sensory axons include the lateral antebrachial cutaneous nerve, the medial antebrachial cutaneous nerve, the superficial radial nerve, and smaller cutaneous branches, such as the common palmar digital nerve branches of the median and ulnar nerves.

Cranial nerve involvement. The incidence of cranial nerve involvement varies from 0% to 10% and is more common among patients with the hereditary form of neuralgic amyotrophy than those with the sporadic form (41). In our series of 281 patients with sporadic neuralgic amyotrophy, the spinal accessory nerve was the most frequently involved cranial nerve, accounting for approximately 2% of the total lesions (16).

It is possible that many cranial neuropathies related to neuralgic amyotrophy are not recognized as such. For example, when the cranial nerve affected is known to be commonly involved by neuralgic amyotrophy (eg, the spinal accessory nerve) or when a cranial nerve is affected along with another nerve known to be commonly affected by neuralgic amyotrophy (eg, the suprascapular nerve), disease recognition is more likely. Conversely, when an individual with neuralgic amyotrophy presents with an isolated cranial neuropathy, especially when the involved cranial nerve is one that is uncommonly associated with neuralgic amyotrophy (eg, the hypoglossal nerve), the diagnostic challenge is much greater, and neuralgic amyotrophy may not be identified. As with any mononeuropathy related to neuralgic amyotrophy, the presence of a trigger, a 1- to 2-week history of severe shoulder pain, and significant weakness and wasting in the forequarter region, all help to identify neuralgic amyotrophy as the responsible disorder.

Phrenic nerve involvement. Phrenic nerve involvement by neuralgic amyotrophy may be unilateral or bilateral. When unilateral, it frequently goes unnoticed because the associated symptoms may be nonspecific, the patients may be asymptomatic, or, when symptomatic, the symptoms may be mild and short-lived (eg, mild, transient dyspnea). When the symptoms are associated with an antecedent event or with severe shoulder pain, neuralgic amyotrophy is more likely to be recognized. In addition, as with cranial neuropathies, when unilateral phrenic neuropathies are associated with other neuropathies known to have a high incidence of involvement with neuralgic amyotrophy (eg, suprascapular neuropathy), their relationship to neuralgic amyotrophy is more obvious. In one study of phrenic neuropathies from neuralgic amyotrophy, the majority (10 of the 17) were isolated (37). Of the 10 individuals with isolated phrenic neuropathies, five reported characteristic preceding pain, and 10 identified an antecedent event. When diaphragm involvement from neuralgic amyotrophy goes unrecognized, proper management cannot be offered. For this reason, when confronted by an individual with a unilateral phrenic neuropathy of unclear etiology, the clinical features of neuralgic amyotrophy must be sought so that appropriate management can be provided. This includes regular monitoring of diaphragm function during the recovery period and the use of nocturnal noninvasive ventilation when indicated (10).

The distribution of lesions based on electrodiagnostic assessment. We reported the distribution of lesions among 281 patients with sporadic neuralgic amyotrophy, all of whom underwent extensive electrodiagnostic assessment (16). Due to recurrences, which occurred in 12% of our 281 patients, 322 bouts were studied in total. Of these, 265 bouts were unilateral (involved only one limb) and 57 were bilateral (involved two limbs) for a total of 379 affected limbs (265 + 114 = 379). Of these 379 limbs, 46% (174 of 379) involved a single nerve and, as expected, these patients presented with a mononeuropathy. As predicted by the motor axon predilection of neuralgic amyotrophy discussed above, the three nerves with the greatest incidence were pure motor nerves: 58 long thoracic mononeuropathies, 56 suprascapular mononeuropathies, and 22 anterior interosseous mononeuropathies. Together, these three nerves accounted for nearly 80% of the mononeuropathies in our series (136 of 174 mononeuropathy presentations). The remaining 54% (205 of 379) had multifocal involvement, the overwhelming majority of which showed involvement of two or more individual nerves. A focal plexus lesion was rare (4 of 703 lesions).

In total, 703 lesions were identified. Of these, the majority (162 of 703; 23%) involved the suprascapular nerve, followed by the long thoracic nerve (117 of 703; 17%). Although the incidence of long thoracic mononeuropathies exceeded the incidence of suprascapular mononeuropathies by two (58 vs. 56), the incidence of suprascapular nerve lesions significantly exceeded the incidence of long thoracic nerve lesions overall (162 vs.117). The suprascapular nerve was also the most affected nerve among individuals with multiple mononeuropathies in the original series reported by Parsonage and Turner in 1948. One explanation for this incidence difference in the mononeuropathy group is that suprascapular mononeuropathies may go unrecognized.

Motor nerve branches to individual muscles are commonly involved with neuralgic amyotrophy. In one series, these neuropathies were the third most frequent lesion site (102 of 703; 15%) (16). The distribution of motor branch neuropathies in this study, in decreasing order, was pronator teres/flexor carpi radialis complex (82), flexor pollicis longus (9), recurrent median nerve (4), lateral triceps head/anconeus complex (2), brachioradialis (2), biceps (1), brachialis (1), and pronator quadratus (1). Because the median nerve often innervates the pronator teres and flexor carpi radialis muscles through a common motor nerve branch, we grouped these two muscles together and included involvement of either one of them or both in this group. A similar approach was used for the lateral head of the triceps muscle and the anconeus muscle, as well as for the two spinatus muscles and the three thenar eminence muscles.

The incidence and distribution of pure sensory nerves in our study were as follows: the lateral antebrachial cutaneous nerve (15), the medial antebrachial cutaneous nerve (1), the superficial radial nerve (1), and the common digital branch to the long finger (1). Thus, by far, the lateral antebrachial cutaneous nerve was the most frequently involved pure sensory nerve on electrodiagnostic testing.

Imaging study distributions. Several imaging studies have reported focal and multifocal lesions occurring outside of the brachial plexus in the setting of neuralgic amyotrophy. One of these imaging studies, which used high-resolution magnetic resonance imaging (MRI) to assess the brachial plexuses of 27 patients with neuralgic amyotrophy, reported the presence of 38 lesions (focal nerve enlargement and signal hyperintensity in all 38 and severe focal constrictions in 32), all of which were extraplexal in location (34). Although the brachial plexus showed signal changes in three of the 27 patients, the responsible lesion was actually extraplexal, involving the axillary nerve (n = 1) or the suprascapular nerve (n =2). In these three cases, there was extension of signal from the extraplexal nerve lesion into the brachial plexus, into the axillary nerve bundle of the posterior cord or into the upper trunk, respectively.

Arguments against a plexus localization. Although some authorities argue that a proximally located fascicular lesion involving the brachial plexus could account for an anterior interosseous neuropathy or a motor branch neuropathy, for a number of reasons, this position makes little sense. First, it would not explain the quick reinnervation times and, especially, the distally located severe pain associated with motor nerve branch lesions. For example, when a patient presents with sudden-onset, severe pain at the volar aspect of the distal forearm and isolated severe weakness of distal thumb tip flexion, the lesion likely involves the motor nerve branch to the flexor pollicis longus muscle or to a more proximally located fascicular lesion involving the median nerve or the plexus is less likely because a severe lesion could not significantly recover through distal collateral sprouting. Instead, it would require proximodistal axonal advancement, which would require a significant amount of time (discussed below). Although a focal demyelinating conduction block would appear similarly, this pathophysiology is rarely encountered among patients with neuralgic amyotrophy and would not be associated with significant muscle atrophy.

The main argument against a fascicular lesion of the brachial plexus affecting an individual muscle is that the distal aggregation of motor axons destined to innervate an individual muscle or muscle head does not occur until the motor axons are within several centimeters of their exit site from the parent nerve. Regarding fascicular anatomy: (1) the number of fascicles contained within a nerve varies along the length of the nerve; (2) the motor axons move from one fascicle to the other with distal advancement down the nerve; and (3) at the plexus level, the motor axons innervating an individual muscle are distributed among many (and possibly all) of the fascicles of the plexus element.

Lower extremity involvement. Although the literature reports that lower extremity muscles may occasionally be affected by a bout of hereditary neuralgic amyotrophy, we did not note lower extremity muscle involvement in any of our 281 patients with the sporadic form of neuralgic amyotrophy (16). Also, when the bouts of lower extremity muscle involvement do not occur coincident with the bouts of forequarter region weakness, there is no guarantee that they represent the same disorder. Thus, although lumbosacral radiculoplexus neuropathy and neuralgic amyotrophy share the same two major clinical features (severe pain and muscle weakness and atrophy) and the same pathology (perivascular inflammation and microvasculitis), there are enough differences (eg, persistent pain and prolonged recovery) that we continue to treat them as separate entities.

Prognosis and complications

Reinnervation. The degree of recovery from severe pain, sensory loss, and weakness varies. The severe pain associated with neuralgic amyotrophy typically resolves over 1 to 2 weeks, and most of the associated sensory loss typically recovers over time. Thus, the most important component of recovery is motor recovery based on the likelihood of muscle fiber reinnervation. Although generalized statements have been made regarding the rate of recovery among patients with neuralgic amyotrophy, some of which were more positive (36% of patients recover within 1 year, 75% within 2 years, and 89% within 3 years) and some of which were more negative (only 11 of 83 individuals showed complete recovery over a 17-year follow-up period), in our experience, we find it more helpful to determine the likelihood of recovery for each individual lesion independent any other lesions (ie, in the setting of a multiple mononeuropathy, prognostication is applied to each neuropathy independently) using the basic rules of reinnervation.

Still, even with good reinnervation, patients may be left with some disability, including early muscle fatigue (due to an increased innervation ratio related to reinnervation through distal collateral sprouting), persistent weakness (due to incomplete reinnervation or to a mechanical disadvantage related to an anatomical distortion of the musculoskeletal system), and prolonged discomfort (also frequently due to musculoskeletal distortions arising from weakened muscles). Anatomical distortions in the spatial orientation of the bones, ligaments, tendons, and muscles not only impair performance but also render patients more susceptible to subsequent injury.

Regarding motor recovery, denervated muscle fibers are reinnervated in two basic ways: (1) via distal sprouting from unaffected intramuscular motor axons (ie, termed distal collateral sprouting) and (2) via proximal sprouting of motor axon collaterals from the proximal axon stumps at the lesion site with subsequent axonal advancement (termed proximal collateral sprouting or proximodistal axonal advancement). When impediments to axon advancement are not present, axonal advancement proceeds at a rate slightly faster than 1 inch per month (12). Thus, we use 1 inch per month to establish the point in time at which a denervated muscle should demonstrate evidence of reinnervation through this mechanism. Because denervated muscle fibers not reinnervated within about 20 months undergo degeneration, the maximum successful reinnervation distance is approximately 20 inches, using the 1-inch-per-month rate of axonal growth. For reinnervation distances exceeding 20 inches, reinnervation by this mechanism is not less likely (requires faster rates of axon advancement). In addition to reinnervation distance, one must also consider the completeness of the lesion because distal collateral sprouting only occurs with incomplete lesions, given that the distal collateral sprouts are generated by the unaffected intramuscular motor axons. When the lesion is complete, there are no unaffected motor axons from which distal sprouting can occur. In summary, incomplete lesions with short reinnervation distances have the best prognosis, whereas complete lesions located more distant than 20 inches from the denervated muscle fibers have the worst prognosis.

Another major factor in determining the likelihood of reinnervation via proximal sprouting is the degree of connective tissue proliferation, which, when present, impedes axonal advancement. Unfortunately, this cannot be determined clinically (requires histopathological assessment), although this limitation is lessening as high-resolution MRI and ultrasound techniques continue to advance. Because of this lack of predictability, ideally, whenever moderate or more severe nerve lesions are encountered, it is in the best interest of the patient to involve a neurosurgeon with expertise in peripheral nerve surgery early in the course so that potential surgical interventions can be considered. In general, when surgical intervention is required, delays exceeding 12 months do not result in good muscle recovery.

Prognostication. In the acute to subacute timeframe (ie, prior to reinnervation by collateral sprouting), the degree of severity of each lesion is estimated using the motor nerve conduction studies by comparing the amplitude value of the distal motor response (compound muscle action potential; CMAP) from the affected muscle with that recorded from the homologous muscle on the unaffected side using the following formula:

1 – [distal CMAP amplitude(affected side) / distal CMAP amplitude(unaffected side)] x 100%

For example, prior to distal collateral sprouting, if the amplitude value of the musculocutaneous motor response recorded from the biceps on the affected side is 1.2 millivolts and the amplitude value from the contralateral side is 4.8 millivolts, then the degree of involvement is 75%: (1 – 1.2/4.8) x 100% = (1 – 0.25) x 100% = 0.75 x 100% = 75%. Again, this equation is only accurate in the time period prior to reinnervation via collateral sprouting.

In the setting of bilateral disease, when the contralateral response is also affected, the contralateral motor response cannot be used for comparison. In this setting, both responses must be compared to the age-specific normal values for the motor nerve conduction study technique being used by the EMG laboratory.

With more severe disease, even when reinnervation through distal collateral sprouting is successful, the increased innervation ratio causes early muscle fatigue, limiting patient endurance.

When reinnervation is incomplete, agonist-antagonist imbalance across the joint may result, with one side weaker than the other. This causes one muscle group to be lengthened (the weaker of the two) and the other muscle group to be shortened (the stronger of the two), which, in turn, changes the relationship of the bones, ligaments, tendons, and muscles. As stated above, this may result in long-term discomfort and susceptibility to injury.

Clinical vignette

A 53-year-old right-hand-dominant female dentist was referred for EDX assessment of right shoulder pain that started four weeks earlier. According to the patient, she awoke with severe right shoulder pain. It involved the dorsal aspect of the shoulder to a greater extent than the lateral aspect of the shoulder. The pain caused her to seek immediate medical help. The pain persisted for approximately 2 weeks and then resolved. She also reported a flu-like illness 2 weeks before the onset of the shoulder pain. She did not recognize the weakness until the pain lessened and she began to use her limb. On examination, there is profound weakness of right shoulder abduction, external humeral rotation, and forearm flexion. There is obvious bicep and deltoid atrophy. She has sensory complaints along the lateral aspect of the right forearm (ie, in the lateral antebrachial cutaneous nerve distribution). Based on the neurologic examination features, we expect the responsible lesion to be severe in degree.

The screening sensory nerve conduction studies are performed on the right. Given that the weakness is in the distribution of the upper plexus, the LABC and median-D1 sensory nerve conduction studies will be added bilaterally.

Screening sensory nerve conduction studies

The screening sensory nerve conduction studies are normal and argue against a significant axon loss process involving the median nerve, ulnar nerve, superficial radial nerve, radial nerve, posterior cord, medial cord, lateral cord, or lower plexus.

As stated above, to better assess the upper plexus, the LABC and median-D1 sensory nerve conduction studies are required, both ipsilaterally and, for comparison purposes, contralaterally (to avoid missing a relative abnormality).

Additional sensory nerve conduction studies

The LABC response is absent, indicating an axon loss lesion that localizes to the LABC nerve, the musculocutaneous nerve, the lateral cord, or the upper plexus. As discussed earlier, sparing of the median-D1 strongly argues against a median nerve, lateral cord, or upper plexus lesion. Thus, the most likely explanation is that the lesion producing the LABC sensory response abnormality involves the musculocutaneous nerve. Although this localization would also account for the forearm flexion weakness (ie, the musculocutaneous nerve innervates the biceps muscle), it does not explain the external humerus rotation weakness (the infraspinatus and teres minor muscles perform this function) or the shoulder abduction weakness (the supraspinatus and deltoid muscles perform this function). The weakness can be further addressed during the motor nerve conduction studies. What we know at this point is shown here:

The motor nerve conduction studies are now performed. In addition to the screening motor nerve conduction studies, the musculocutaneous nerve-recording biceps, axillary nerve-recording deltoid, and suprascapular nerve-recording infraspinatus are added bilaterally (bilateral studies permit severity to be determined).

Motor nerve conduction studies

The amplitude values of the right musculocutaneous, axillary, and suprascapular motor responses are severely to very severely reduced, indicating severe axon loss. Thus, the lesion localizes to multiple nerves (ie, it is a multiple mononeuropathy) and not to the upper plexus. What we know at this point is shown here:

Involvement of the musculocutaneous sensory and motor axons indicates that the lesion is proximal to the departure site of the LABC nerve from the parent musculocutaneous nerve. The location of the lesion along the suprascapular and axillary nerves is unclear.

The needle EMG study

The needle EMG study is consistent with an axon loss process involving the musculocutaneous, axillary, and suprascapular nerves.

EDX study conclusion. Multiple mononeuropathies – neuralgic amyotrophy: the above lesions are axon loss in nature, involve the musculocutaneous, axillary, and suprascapular nerves, and are very severe in degree. The sensory and motor nerve conduction study abnormalities exclude an upper plexus localization and indicate multiple mononeuropathies. The distribution of muscle involvement noted on the needle EMG study also indicates a multiple mononeuropathy distribution. The needle EMG study did not show any features of distal collateral sprouting, consistent with the timeframe reported by the patient (4 weeks).

The pattern of severe involvement of the infraspinatus muscle with sparing of the supraspinatus muscle suggests involvement of the motor nerve branch to the infraspinatus muscle rather than a fascicular lesion of the parent suprascapular nerve.

Important points. The patient demonstrates the full triad of neuralgic amyotrophy (flulike illness, severe right shoulder pain, severe muscle atrophy). The distribution of the sensory and motor examination abnormalities suggested an upper plexus lesion or multiple mononeuropathies receiving intermediate innervation via axons traversing the upper plexus. The discordance of the lateral antebrachial cutaneous and median-D1 sensory nerve conduction studies (ie, an absent lateral antebrachial cutaneous response coupled with a normal median-D1 response) essentially excludes an upper plexus localization. In our brachial plexus study, which included 26 upper plexus lesions, concordance of the lateral antebrachial cutaneous and median-D1 sensory nerve conduction studies was noted in all 26 patients (they were either both abnormal [25 of 26] or they were both normal [1 of 26]) (13).

Biological basis

Etiology and pathogenesis

Evidence for an underlying immune-mediated pathophysiology includes: sudden onset; monophasic course; association with preceding viral illnesses, serum sickness, vaccinations, and the use of immunomodulating agents; involvement of both the humoral and the cellular immune systems; the presence of focal chronic inflammatory infiltrates, edema, and onion bulb formation; mononuclear inflammatory infiltrates surrounding endoneurial and epineurial vessels without features of necrotizing vasculitis; altered lymphocyte subsets (decreased CD3 values and increased CD4/CD8 ratios due to decreased CD8 values); oligoclonal bands in the CSF; lymphocyte sensitization to brachial plexus axons; and the presence of antiganglioside and antiperipheral nerve myelin antibodies and terminal complement activation products in the sera of patients with neuralgic amyotrophy.

Genetics. The sporadic form of neuralgic amyotrophy is much more common than the hereditary form. To date, the hereditary form has only been described in approximately 200 families worldwide. Overall, the hereditary form constitutes about 10% of the total, although in some series this value is significantly higher. For example, in the series of 246 patients with neuralgic amyotrophy discussed earlier, 19% had a family history (47 individuals from 36 families) (41). Conversely, in our series, we had so few patients with the hereditary form that we limited the study to the sporadic form (16).

Individuals with the hereditary form demonstrate many of the same clinical features as those with the sporadic form (ie, antecedent event, severe pain, muscle weakness and wasting). Differences include the age at presentation, the frequency of recurrences, and the presence of dysmorphic features.

Regarding inheritance, individuals with the hereditary form of neuralgic amyotrophy pass the genetic susceptibility from one generation to the next generation in an autosomal dominant manner. The founder effect has been identified in European and North American families, accounting for the inheritance of the disease (01). In North American families, most gene mutations (approximately 55%) involve the SEPT9 gene (codes for septin 9) on chromosome 17q and show high penetrance (80% to 90%) (42). Septin 9 mediates septin microtubule binding, bundling, and neurite growth. Microtubules are cytoskeletal polymers composed of tubulin dimers that switch between shortening and growing phases (termed dynamic instability). The genetic abnormality causing neuralgic amyotrophy in the other 45% of these families is unknown, indicating that hereditary neuralgic amyotrophy is a genetically heterogeneous syndrome. Although individuals with the sporadic form of neuralgic amyotrophy do not pass the disorder from generation to generation, there is still likely to be an underlying genetic predisposition that renders them susceptible to the antecedent event.

Pathology and pathophysiology. Pathologic studies of patients with neuralgic amyotrophy are limited. Brachial plexus and superficial radial nerve biopsies have demonstrated perivascular mononuclear T-cell infiltration of the epineurium, multifocal axonal degeneration without vessel wall inflammation or necrosis (ie, arguing against a vasculitis), and perineurial thickening. Hourglass-like constrictions are focal constrictions of the involved nerve (or portion of it), typically with thickening proximal and distal to the site of constriction, involving the perineurium, and associated with marked edema (18). These constrictions are often associated with fascicular torsion. The pathological mechanisms underlying these changes remain unclear. One proposal is that early inflammation produces nerve enlargement and, as the associated edema subsides, adhesion formation and local fascicle fixation occurs, resulting in hourglass-like constrictions and an increased likelihood of nerve torsion (33). Pathological specimens taken from patients with hourglass-like fascicular constrictions who underwent interfascicular neurolysis have revealed perineurial thickening with inflammatory infiltrates (CD8-positive T lymphocyte infiltrates) (28).

Although pathological data are limited, electrodiagnostic data indicate that the primary pathophysiology associated with both forms of neuralgic amyotrophy is conduction failure (ie, action potentials cannot propagate along the affected axons) due to axon disruption with resultant Wallerian degeneration (ie, the pathology is axon loss). Electrodiagnostically, this is evidenced by fibrillation potentials (in the acute and subacute settings) and features indicative of reinnervation via distal collateral sprouting (in more chronic settings). Clinically, the presence of early muscle wasting and long recovery periods is also consistent with an axon loss pathology.

Rarely (in our experience, less than 1% of patients), the weakness is due to a focal demyelinating conduction block. In this setting, because the axon does not undergo Wallerian degeneration, the motor axon remains in contact with the muscle tissue. As a result, muscle wasting does not occur. Moreover, because recovery occurs via remyelination, which usually occurs over a period of a few weeks to a few months, the recovery period tends to be much shorter and is typically complete. Consequently, patients demonstrating demyelinating conduction block have much better prognoses.

Epidemiology

Neuralgic amyotrophy has previously been considered a rare disorder, with an annual incidence estimated at 1.64 cases per 100,000 population. However, because it is significantly underrecognized, the actual incidence is likely much higher. In a retrospective analysis performed by a German health insurance company, the incidence among 26 million insured individuals was estimated to be 7.7 to 12.8 per 100,000 people (20). Although this value is higher than historical values, its accuracy requires an accurate diagnosis in the billing statements. Thus, it must also be an underestimate. In one prospective study, the incidence rate was estimated at 100 cases per 100,000 population (40).

Neuralgic amyotrophy comes in two major forms – sporadic and hereditary. The sporadic form is much more common, affects individuals of every age and both genders and is primarily a disease of young to middle-aged adults (its mean age of onset is approximately 40 years). Its male-to-female ratio has been reported to slightly exceed two. In our series of 281 patients with sporadic neuralgic amyotrophy, males accounted for 70% of the cohort, which yields a male-to-female ratio of 2.3, consistent with the literature. Regarding the hereditary form, the mean age of onset is approximately 15 years earlier (41).

The term familial neuralgic amyotrophy refers to the nearly simultaneous onset of neuralgic amyotrophy among multiple family members without evidence of transmission between generations. In one report, a 15-year-old boy developed an acute influenza-like illness, followed one week later by severe left shoulder pain and subsequent left shoulder abduction weakness. His mother and, a few days later, his brother both developed a similar febrile illness followed by left shoulder pain (26). Familial neuralgic amyotrophy most likely represents a genetic predisposition within the family.

There have been two reports of epidemics of neuralgic amyotrophy, the largest of which involved 265 individuals who presented over a 4-year period (1949-1953) and in whom the outbreak was ultimately attributed to a coxsackie virus (type A2)-contaminated water supply (03).

In addition to the age and gender data discussed above, most bouts of sporadic neuralgic amyotrophy are unilateral, involve the dominant limb, and infrequently recur. In our series, 82.3% (265 of 322) of bouts were unilateral, and 17.7% (57 of 322) were bilateral (14). Of the unilateral bouts, 60% involved the dominant limb. Regarding the bilateral bouts, the overwhelming majority were sequential in onset rather than simultaneous. We identified recurrences in 12% of our patient population (26 individuals with two bouts, six individuals with three bouts, and one individual with four bouts) (33 of 281 patients).

Prevention

Given its rarity, it is not the standard of care to inform patients in the preoperative or preprocedural setting that they are at risk of developing neuralgic amyotrophy. Although most patients with neuralgic amyotrophy (73% in our large series) report an antecedent event, subsequent trigger avoidance (eg, future infections or medical procedures) is impractical. Thus, when neuralgic amyotrophy is triggered by a vaccination, it is not recommended that further vaccinations be avoided. In our experience, when a woman has had two bouts of neuralgic amyotrophy triggered by childbirth, the likelihood of a third bout of neuralgic amyotrophy with a subsequent childbirth is much higher.

Differential diagnosis

Confusing conditions

The differential diagnosis for individuals manifesting the full triad or the two quintessential features is limited, especially when there is a documented delay between the antecedent event and the onset of the severe pain. There may also be a delay between the onset of pain and the onset of muscle weakness. However, this delay likely represents a lack of awareness of the weakness (due to the lack of limb usage during the period of severe pain and the time required for muscle atrophy to develop). Other clinical features strongly supporting neuralgic amyotrophy are when the severe pain is monophasic (typically resolving after 1 to 2 weeks) and when the weakness is in the muscle domain of one or more pure or predominantly motor nerves.

When one of these two quintessential features is absent –neuralgic amyotrophy without pain or neuralgic amyotrophy without muscle weakness or wasting – the diagnosis is much more challenging. Interestingly, in our experience, those individuals with painless neuralgic amyotrophy and those without muscle weakness or wasting have had a previous bout of typical neuralgic amyotrophy (full triad) and were able to recognize the recurrence and, therefore, seek medical advice with this diagnosis already in mind. When one of the quintessential features is absent, and there has not been a previous episode, the diagnosis may go unrecognized.

Another diagnostic challenge occurs at the onset of neuralgic amyotrophy, when the patient initially presents with severe shoulder pain. At this point, the muscle weakness may be attributed to pain, the muscle atrophy has not yet developed, and it is too early to appreciate the monophasic nature of the severe shoulder pain. In this setting, the differential diagnosis includes neoplastic processes and various orthopedic disorders, both of which may present with severe shoulder pain. The shoulder pain associated with neoplastic disease is often in the cutaneous distribution of the axillary nerve, is frequently worse in the recumbent position, and is relentless (rather than monophasic). Orthopedic problems presenting with shoulder pain include rotator cuff tears, acromioclavicular joint dislocations, and other injuries. With orthopedic disease, the motor and sensory examinations are normal (although the associated pain may limit strength assessment). Suprascapular nerve entrapment is another possible orthopedic consideration (discussed below).

Patients with cervical radiculopathies, especially C5 and C6 radiculopathies involving the shoulder girdle muscles, may present with shoulder or periscapular pain. When present, the following five help to identify cervical radiculopathies: (1) neck pain more pronounced than shoulder pain; (2) neck pain radiating distally along the limb; (3) neck pain worsened by head and neck movements rather than by shoulder and limb movements; (4) myotomal pattern of weakness; and (5) the sensory loss has a dermatomal distribution and is usually more pronounced distally (eg, the distal aspect of the thumb with C6 radiculopathies). When MRI of the cervical spine is ordered to address patients presenting with severe shoulder pain, to avoid unnecessary surgical procedures, it is important to be aware of the high prevalence of degenerative changes among asymptomatic individuals, including young persons.

When neuralgic amyotrophy is painless, the diagnosis is much more challenging. In this case, the differential diagnosis includes other painless, focal, and multifocal disorders of nerves, such as tomaculous neuropathy (ie, hereditary neuropathy with liability to pressure palsies) and multifocal motor neuropathy (previously termed multifocal motor neuropathy with demyelinating conduction block) as well as painless disorders involving the upper plexus (eg, rucksack palsy, classic postoperative paralysis) or the cervical spinal cord segments (eg, Hirayama disease, amyotrophic lateral sclerosis). Fortunately, these disorders are easily differentiated from painless neuralgic amyotrophy. With tomaculous neuropathy, there is typically a family history (autosomal dominant), the nerve lesions occur at common entrapment sites, lower extremity nerves may also be involved, and the pathophysiology is demyelinating conduction block. With multifocal motor neuropathy, at least initially, the primary pathophysiology is demyelinating conduction block, and there is no muscle atrophy. With rucksack palsy, there is a history of rucksack usage, the lesion involves the upper plexus, and the primary pathophysiology is demyelinating conduction block. With amyotrophic lateral sclerosis, the muscle weakness and wasting have a myotomal distribution, lower extremity and bulbar muscles may be involved, there is slow and contiguous progression, fasciculation potentials are typically observed, and the neurologic examination may show upper motor neuron features (eg, pseudobulbar affect, hyperreflexia, hypertonia).

When patients with neuralgic amyotrophy present with a mononeuropathy, entrapment neuropathies are usually considered. With entrapment neuropathies, the onset of symptoms is not sudden, severe pain is atypical (especially at onset), and the lesion localizes to a common entrapment site. However, there is one exception, suprascapular nerve entrapment, which is the most challenging mononeuropathy to differentiate from neuralgic amyotrophy involving the suprascapular nerve. With both entities, there is typically severe, dorsal scapular region pain. Time will differentiate them – the severe pain of neuralgic amyotrophy is transient and is followed by severe muscle wasting, which is often restricted to a single spinatus muscle, either the supraspinatus or the infraspinatus muscle. The recognition of a preceding antecedent event also supports neuralgic amyotrophy. Imaging may be helpful (eg, to identify a ganglion cyst in the suprascapular notch). When in doubt, it may be possible to treat the patient for pain and follow the clinical course rather than to surgically release a nerve that is not entrapped. This decision must be made individually. The best approach is to educate emergency room physicians and orthopedic surgeons about neuralgic amyotrophy and its predilection for the suprascapular nerve. This is important not only for neuralgic amyotrophy patients presenting with a suprascapular mononeuropathy, but emergency department and urgent care center providers need to be made aware of neuralgic amyotrophy in general. In one report, the majority of neuralgic amyotrophy patients presenting to an emergency department or urgent care center received an incorrect diagnosis (04).

When the time between the antecedent event and the onset of the pain is short, a cause-and-effect relationship between the trigger and the symptoms may be erroneously assumed. A common example of this occurs when a patient complains of severe shoulder pain in the recovery room following a surgical procedure. When neuralgic amyotrophy goes unrecognized, and the surgery was in the shoulder region, the surgeon may be inappropriately blamed, whereas when the surgery was not in the shoulder region, the anesthesiologist may be inappropriately blamed. Unfortunately, because of the significant pain and the severity of the muscle weakness and wasting, bouts of neuralgic amyotrophy following a medical procedure often enter the legal arena. When the involved surgeons and anesthesiologists are themselves unaware of neuralgic amyotrophy, they may not be able to offer an acceptable defense and, as a result, they may not prevail despite their innocence. When ordered, consultation with a neuromuscular specialist and electrodiagnostic testing typically easily identify the responsible party (ie, the immune system of the patient). Injuries involving multiple nerves at different sites are extremely unlikely to be due to a surgical error or to an error related to positioning. In this setting, it is extremely important to perform extensive electrodiagnostic testing (including contralateral studies) as cases like these often go to trial. Patient education may also serve to clear the surgical team of any wrongdoing.

Neoplastic infiltration of the brachial plexus can present in an episodic manner. In one report, recurrent and painful attacks involving the brachial plexus occurred with large B-cell lymphoma (27).

Associated or underlying disorders

Currently, there are no disorders that are biologically associated with neuralgic amyotrophy. Disorders that are in anatomic proximity to the lesion sites associated with neuralgic amyotrophy can be categorized based on the presence or absence of the triad of clinical features associated with this entity, the distribution of the weakness, and the timing of the visit.

Diagnostic workup

The diagnosis of neuralgic amyotrophy is clinical and based on the typical history and neurologic examination findings. Although genetic studies can be used to confirm hereditary neuralgic amyotrophy, there are no blood, urine, or CSF tests available to confirm sporadic neuralgic amyotrophy. Thus, the most important issue is clinical recognition. When neuralgic amyotrophy goes unrecognized, unnecessary, expensive, and often invasive testing (eg, nerve and muscle biopsies) may be performed.

Electrodiagnostic testing typically is extremely useful through its ability to localize and characterize lesions of the peripheral nervous system, thereby identifying patterns of abnormalities that are typical of neuralgic amyotrophy, such as mononeuropathies and multiple mononeuropathies involving pure or predominantly motor nerves, as well as mononeuropathies in which one muscle is severely involved and another is spared or relatively spared despite being innervated by the same nerve (indicates a motor branch neuropathy). It is especially useful for excluding an upper plexus lesion. Regarding mononeuropathies, except for the long thoracic nerve, the commonly involved nerves are easily studied by motor nerve conduction studies.

Also, even when neuralgic amyotrophy is clinically unrecognized, when electrodiagnostic testing is ordered (or when referral is made to a neuromuscular medicine specialist), the features associated with neuralgic amyotrophy are usually recognized.

Because of the spinal cord segment derivation of the motor axons composing these nerves – suprascapular (C5,6), long thoracic (C5,6,7), axillary (C5,6), and musculocutaneous (C5,6) – the distribution of the resultant weakness and wasting is predominantly C5 and C6, which gives the appearance of an upper plexus lesion. However, with an upper plexopathy, sensory abnormalities are present on the clinical examination, and sensory response abnormalities are present on the electrodiagnostic examination (11). With neuralgic amyotrophy, because the lesions are overwhelmingly extraplexal and favor pure or predominantly motor nerves, sensory abnormalities on clinical examination and sensory response abnormalities on electrodiagnostic testing are much less common.

In the early stages, when the diagnosis of neuralgic amyotrophy is less obvious, imaging studies are typically obtained to exclude alternative diagnoses. However, due to improvements in technology, these studies have more than exclusionary value. Advanced imaging modalities, such as high-resolution MRI (3 Tesla imaging and magnetic resonance neurography) and high-resolution ultrasound studies can identify the lesions associated with neuralgic amyotrophy, thereby potentially providing additional confirmation when neuralgic amyotrophy is suspected (25; 02; 34; 43).

The choice between magnetic resonance neurography and ultrasonic imaging depends on the specific situation because these two studies have specific advantages and limitations. High-resolution ultrasound provides dynamic evaluation, identifies muscle atrophy and fibrofatty muscle replacement, and generates detailed images of the internal architecture of superficial nerves, whereas magnetic resonance neurography offers greater contrast resolution, assesses the musculature for atrophy and denervation edema, and has the ability to assess deeper nerves, in addition to superficial ones (17).

Focal features described in these studies include hourglass-like constrictions, pre- and post-lesion dilations, and bullseye changes. In an MRI study, hourglass-like constrictions were identified in 90.2% of 123 neuralgic amyotrophy patients (35). An affected nerve may demonstrate more than one hourglass-like constriction. In an imaging study assessing hourglass-like constrictions among neuralgic amyotrophy patients with suprascapular neuropathies, a mean number of 2.1 hourglass-like constrictions (range 1 to 4) was reported, all of which involved the suprascapular nerve between its takeoff site from the upper trunk of the brachial plexus and the suprascapular notch (22). In one MRI study, the imaging abnormalities were classified into one of four types: incomplete focal, complete focal (hourglass), multifocal (string of pearls), and segmental (06). In one review, an excellent correlation was found between hourglass-like constrictions (on MRI and high-resolution ultrasound), denervation edema (on MRN), and fibrillation potentials (on EMG) (30), and hourglass-like constrictions on MRI are common among patients with neuralgic amyotrophy (35). Although ultrasound is less useful for brachial plexus imaging than is MRI, it is much more useful for extraplexal imaging due to its ability to follow nerves and fascicles along their courses. Because most lesions associated with neuralgic amyotrophy are extraplexal, this gives ultrasonic imaging an advantage over MRI. Other advantages of ultrasonic imaging over MRI include better spatial resolution, lower cost, ease of side-to-side comparisons, and real-time assessment (25). Ultrasonic imaging is also useful for identifying phrenic neuropathy, for assessing diaphragm movement, and to direct the needle EMG electrode into the diaphragm when needle EMG is needed. The pathological findings observed with high-resolution ultrasound can be grouped into four categories, which may represent a continuum: nerve swelling, swelling with incomplete constriction, swelling with complete constriction, and fascicular entwinement (07). Because ultrasound is operator-dependent, especially for smaller-caliber nerves (suprascapular nerve, long thoracic nerve), false-negative studies may occur (43). At this time, because the sensitivity and specificity values of these higher-resolution imaging studies remain unclear and because they may not be available at many diagnostic imaging centers, electrodiagnostic testing remains the most useful diagnostic study.

Management

Disease recognition. The first and most important step in the management of neuralgic amyotrophy is its recognition so that unnecessary diagnostic testing and surgical intervention are avoided. Because the pain is so severe, surgeons unfamiliar with neuralgic amyotrophy may be more likely to perform an unnecessary operative procedure based on vague diagnostic testing abnormalities. When severe pain involves the dorsal aspect of the scapula and a healthcare provider with familiarity with neuralgic amyotrophy is not consulted, surgical intervention may be undertaken (eg, suprascapular nerve release) and a good outcome realized (because the natural history of neuralgic amyotrophy pain is resolution, typically within 1-2 weeks).

When neuralgic amyotrophy is considered, treatment of the pain is provided (discussed below), and watchful waiting for pain recovery and the onset of muscle weakness and wasting is undertaken. Again, education of emergency department physicians and orthopedic surgeons is important so that neuralgic amyotrophy is considered.

Drug treatment. During the acute phase of neuralgic amyotrophy, pain control is a priority. In general, over-the-counter analgesics (eg, nonsteroidal antiinflammatory drugs, NSAIDs) do not provide relief. To address the neuropathic pain associated with this disorder, we typically prescribe a neuropathic pain medication (eg, an antiepileptic drug, such as gabapentin or pregabalin, or a tricyclic agent, such as amitriptyline or nortriptyline; or an SNRI (serotonin and norepinephrine reuptake inhibitor), such as duloxetine. While ramping up the dosage and waiting for the neuropathic pain medication to become effective, in those patients without contraindications, we usually prescribe a short course of oral corticosteroids (eg, 60 mg po qd x 14 days), followed by a 6-day taper (eg, 40 mg / 40 mg / 20 mg / 20 mg / 10 mg / 10 mg). Although corticosteroids have not been shown to shorten the course of the disease or improve the prognosis, they are often used to lessen the intensity of the severe pain. With excruciating pain, intravenous corticosteroid therapy is an alternative. To lessen the likelihood of a gastroduodenal ulcer, we provide a preventive agent (proton pump inhibitor), and we advise patients to avoid concomitant NSAID usage because the risk of gastrointestinal complications is significantly increased when corticosteroids and NSAIDs are taken together. After the course of corticosteroids has been completed, we introduce NSAIDs using either a scheduled dosing regimen or a prn dosing schedule. If the pain recurs following the corticosteroid course and is NSAID-unresponsive, we discontinue the NSAID and repeat the corticosteroid course.

In addition to starting a neuropathic pain medication and corticosteroids, in the setting of severe pain, the short-term use of a narcotic may be required. Unfortunately, these efforts are often incompletely effective. Although small case series of IVIG treatment suggested that early treatment shortens the disease course, larger studies are required, given that the duration of the severe pain varies among individuals.

Physical therapy. In the acute setting, when the pain is severe and exacerbated by limb motion, immobilization is beneficial. Once the severe pain has lessened enough to permit movement, physical therapy is initiated, including range-of-motion exercises (passive initially, then active), stretching exercises, agonist muscle strengthening, and various orthotic devices. Physical therapy also helps prevent the development of adhesive capsulitis, shoulder subluxation and dislocation, chronic pain, and loss of function. The program prescribed depends on the muscles affected and the severity of the weakness. As stated earlier, changes in the spatial arrangement among the musculoskeletal elements render the affected joint more susceptible to secondary injury and, hence, care must be taken to avoid this complication. For example, during periscapular muscle strengthening, patients with long thoracic nerve involvement and significant scapular winging may benefit from lying supine on an exercise bench during exercise so that their body weight maintains the affected scapula in its normal position.

Surgical intervention. Surgical intervention is typically reserved for those patients with refractory or severe disease or for those who have failed conservative treatment. Because the natural history of neuralgic amyotrophy may not be as positive as historically reported, the duration of conservative treatment prior to considering surgical options has become less clear (39). As a result, earlier surgical intervention must be considered, especially in the setting of severe mononeuropathies. The specific surgical intervention is also unclear and may depend more on the severity of the neuropathy. In one report of neuralgic amyotrophy patients with long thoracic neuropathies, neurolysis was recommended after 9 to 12 months of conservative treatment and observation (45). In the setting of a severe long thoracic neuropathy, when there is no evidence of improvement after several months, a nerve transfer procedure (eg, using one or more intercostal nerves, a branch of the thoracodorsal nerve, or a middle trunk nerve fascicle innervating the pectoral muscles) may be beneficial (38). Nerve transfer procedures may also benefit other neuropathies, such as transferring the motor nerve branch innervating the extensor carpi brevis muscle to the anterior interosseous nerve when anterior interosseous neuropathy produces significant loss of thumb and index finger function (44; 36) or ipsilateral transfer of C7 to C5 in the setting of shoulder abduction impairment (21). In the setting of focal structural abnormalities (eg, hourglass-like constrictions), decompression or reconstruction are potential options (19). For example, among anterior interosseous neuropathies with identified fascicular constrictions, interfascicular neurolysis may be beneficial. In a retrospective review of 27 patients with anterior interosseous nerve palsy, 13 patients underwent interfascicular neurolysis after they showed no evidence of recovery at 6 months (23). Of these, 10 of the 13 who underwent surgical intervention between 6 and 8 months showed good recovery (MRC score of at least 4), whereas the three who underwent surgical intervention more than 12 months after symptom onset showed antigravity strength or less. One study of 24 neuralgic amyotrophy patients who demonstrated hourglass-like constrictions and failure to improve treated 11 patients with microvascular epineurolysis and perineurolysis, and 13 patients nonsurgically (24). They defined failure to improve after 12 months or failure to demonstrate clinical and electrodiagnostic improvement after six months following three successive examinations at least six weeks apart. In that manuscript, they reported that 9 of 11 operative patients experienced clinical recovery as compared to three of 13 nonsurgical patients. For patients with severe and permanent weakness, tendon transfers are a consideration and do not have a time requirement for their implementation.

Among neuralgic amyotrophy patients with diaphragm involvement, regular monitoring during the recovery period (up to 2 to 3 years) with spirometry and diaphragm ultrasound should be performed for prognostic purposes and to determine whether treatment with nocturnal noninvasive ventilation is required (10).

Patient education. It is important to educate patients and to inform them that (1) the severe pain passes, typically within 14 days and typically during the first week and (2) that most patients get significantly better, although the final degree of recovery varies.

Outcomes

See the prognosis and complications section.

Special considerations

Pregnancy

Although pregnancy and childbirth are known triggers, they do not affect the clinical course or prognosis (09). Among individuals with recurrences, it is not uncommon for the inciting trigger of the first bout to also be the inciting trigger for the second bout. Of the various triggers, childbirth may have a higher incidence of recurrence. In our series, one of our patients had a bout of neuralgic amyotrophy with three of her four deliveries. Because the muscles required during childbirth are not affected by neuralgic amyotrophy, there is no preferred method of delivery (eg, vaginal vs. caesarean section). Moreover, when bouts of neuralgic amyotrophy are triggered by childbirth, they occur in the postpartum period, and, thus, also do not dictate the method of delivery.

Anesthesia

As previously stated, the most common trigger in our series was a medical or surgical procedure. There is no contraindication to surgery for patients with neuralgic amyotrophy, but when the phrenic nerve is involved, the anesthesiologist should be made aware so that the proper preoperative evaluation and choice of anesthesia can be determined.