Immune Mediated Brachial Plexopathy

Definition

Immune mediated brachial plexopathy (INA) is characterized by acute severe attacks of neuropathic pain followed by multifocal weakness, atrophy and sensory changes of the affected shoulder or arm.¹ INA is often preceded by a traumatic event or immunologic insult such as a viral infection or immunization. INA was first reported in 1948 by Parsonage and Turner and has eponymously been called Parsonage Turner Syndrome (PTS).² It is also known as neuralgic amyotrophy (NA) which is considered the most descriptive and preferred term to describes the pathology.²

Etiology

To date, the etiology of INA is not clearly understood. The cause is likely multifactorial. NA may be precipitated by a biomechanical traumatic event or by an iatrogenic or infectious insult, which may be followed by an inflammatory autoimmune pathophysiologic process.^2,3,4 Certain forms of NA such as hereditary neuralagia amyotrophy (HNA) may be caused by genetic susceptibility.

NA has been associated with activities of repetition such as sports and manual labor. Traumatic insults from minor trauma, childbirth, gunshot wounds, and burns have also been described. Various types of surgical interventions associated with NA have been described. A non-exhaustive list including laparoscopic surgeries, knee surgery, tonsillectomy and thyroidectomy have all been described.^2,5,6 Surgical interventions of the head, neck and shoulder girdle region as well as distant surgical sites have all been reported due to improper positioning during surgery resulting in excessive neuronal traction.^2,5,6,7

Some reports of up to approximately 15% of cases occur after immunization.⁸

Genetic susceptibility: HNA has been well described and involves an autosomal dominant inheritance pattern associated with a mutation of septin 9 gene (SEPT9) on chromosome 17q23. Ten percent of patients with NA have a positive family history. Attacks occur more frequently in HNA and often involve peripheral nerves.⁷

Epidemiology including risk factors and primary prevention

NA considered to be rare with an estimated incidence of approximately 2-4 per 100,000 persons a year.⁴ More recent data suggests NA is not as rare as previously thought and is often a missed diagnosis.^8,9,10 A prospective cohort study estimated the incidence rate to be 1 in 1000.^11,12

The recurrence rate of NA is approximately 26.1% and as high as 75% in HNA. Recurrent attacks are a common feature of NA and may involve the same nerve(s) or may recur in an entirely different neuropathic pattern. Currently, there are no clinical diagnostic tools to predict or prevent recurrent attacks.^4,12

There is a 3:2 predominance of men over women with the highest incidence occurring between the third and seventh decade of life.⁴ The median age is 40 years in INA and 25 years in HNA.⁴

Patho-anatomy/physiology

The exact pathophysiology is unknown and is thought to be multifactorial. An autoimmune pathogenic model has been described, although no distinct immunologic trigger has been identified. Nearly half of patients with NA will have preceding events associated with an immune response such as a viral or bacterial infection, child birth, emotional or physical stress or immunization. It is theorized an immune-mediated response may be triggered by an event.^7,8 Approximately 10 percent of cases have associated hepatitis E infection found at symptom onset.^7,9,10

Autoantibodies targeting the nervous system have been detected in patients with neurologic symptoms such as paresthesias, weakness, and twitching. Humoral autoimmunity has been suggested by reports of multifocal mononuclear inflammatory cell infiltrates in brachial plexus biopsies, increased compliment factor as well as CD20⁺ B-lymphocyte germinal centers around dorsal ganglions.^10,11,12 More recently, findings of the seroprevalence of antiganglioside antibodies have been found. Gangliosides are glycosphingolipids found throughout membrane components of the nervous system. Antiganglioside antibodies are thought to cause complement-dependent nerve damage. In another study, complement fixing antibodies to peripheral nerve myelin were found to be increased in the acute phase of the condition.^4,7,13 High titers of anti-GA1 (asialo-GM1 ganglioside) antibodies have been associated with a variety of motor syndromes such as guillain-Barré, multifocal motor neuropathy and motor neuron disease.¹³

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Long term prognosis is variable depending on severity and hence the rate of recovery also varies. Reports of good recovery after 2-3 years was previously reported to be 80-90%, however, some studies have showed less positive outcomes. A large cohort study found only 10% full recovery after >3 years and 25% of patients were unable to work due to NA.⁷

A large proportion of patients have persistence of both neuropathic and musculoskeletal pain, fatigue and impaired activities of daily living. Reports of residual paresis and exercise intolerance are variable and as high as 70% in some studies.^3,7,14,15

Neuralgic amyotrophy disease progression is classically categorized into three phases: Acute, Subacute, chronic/Stable. Hallmark findings of NA are characterized as an initial episode of pain followed by weakness. In the later stages amyotrophy and sensory disturbances are seen.^2,3,16

The acute phase is characterized by constant and intense sharp pain localized around the shoulder or scapular region related to the portion of the plexus affected.¹⁷ Upper brachial plexus with or without the involvement of the long thoracic nerve is the most common pattern.^3,4 Pain duration on average lasts 1-2 weeks and is highly variable lasting from several hours to months. Lingering pain beyond the acute episode is not uncommon.^4,18

The subacute phase can occur days to weeks after onset, weakness may develop with motor deficits predominating. Paresthesia and hypoesthesia can also develop in the subacute stage.^4,18

In the later stages of recovery and chronic/stable phase pain and autonomic dysfunction including vegetative and trophic skin and nail changes, edema, and temperature dysregulation and contractures have been reported.^2,4,18

Specific secondary or associated conditions and complications

Any peripheral nerve may be affected, although the upper trunk of the brachial plexus is most common.³ In cases of HNA and INA extra-brachial involvement of peripheral nerves can be seen. Lumbo-sacral plexus, phrenic nerve and recurrent laryngeal nerve involvement have all been described.^14,19

Autonomic symptoms have been described and occurs more commonly in brachial plexus lesions to the posterior cord and lower trunk.¹²

More than 75% of patients can develop an additional type of pain due to the hypersensitivity of the damaged nerves.¹²

History

The presentation of NA is highly variable. The hallmark presentation is acute onset severe pain lasing for days to weeks followed by weakness and muscle atrophy. These symptoms are often preceded by an antecedent event such as trauma, surgery, immunization, sports or work injury prior to the onset of symptoms.^2,14

Pain is the presenting symptom in 90-95% of patients. A key feature of NA is a patchy distribution of pain not necessarily coinciding with a single neurologic source and often involves multiple muscles and dermatomal regions.^4,17 Pain involvement can vary and can be quite severe. NA Pain is typically not positional and can commonly be worse at night and affect sleep.^14,16

NA pain is often located in the upper extremities, neck, trunk or shoulder girdlelast up to 4 weeks with pain dissipating in 5% of the cases in 24 hours. In 10% it can last greater than 2 months.¹ Pain may be bilateral in 28.5% of patients.^4,9

Nerve distribution is often patchy and may involve any nerve in the brachial plexus as well as nerves outside of the brachial plexus.¹⁴ Commonly involved sites include the upper and middle trunk distribution^14,16 and long thoracic and/or suprascapular nerve occurred most frequently (71.1%).¹⁴The most commonly affected nerve root patterns are C5 and C6; C4 and C7 are involved less frequently.¹⁴

Involvement of nerves outside the brachial plexus occurs more commonly in HNA. Nerves involved include the lumbo-sacral plexus (32.6%), phrenic nerve (14%), recurrent laryngeal nerve (18.6%) or other (7%).¹⁴ While extra-brachial nerve involvement is seen less in INA with recent findings of 8.2%, lumbosacral plexus; 6.6%, phrenic nerve; 2%, recurrent laryngeal nerve; 2.6%, other).¹⁴

Similar to motor findings, anatomical distribution of sensory symptoms is also variable. Sensory disturbances are most commonly found over the deltoid and lateral upper arm (48.9%) which correlates with the predominant involvement of the upper trunk.^14,15,16

Although less common, autonomic symptoms have been described, including edema of the involved extremity, trophic changes of the skin and temperature dysregulation.

Physical examination

On inspection, abnormal symmetry of the shoulder girdle may be seen. Medial or lateral scapular winging may be present. If presenting in the chronic phase, atrophy of the involved muscles may be visualized.

Weakness results in dysfunction of coordinated shoulder girdle movement resulting in scapular dyskinesis.⁴ As NA is a patchy disorder, essentially any muscle can be involved. Van Alfen et al in 2006 found the infraspinatus (72%) and serratus anterior muscle (70%) to be more effected with the sternocleidomastoid (7.2%) or neck extensors (1.5%) infrequently involved.^14,16

Sensory abnormalities, most commonly seen over the deltoid and lateral indicating upper trunk involvement of the brachial plexus. Dysasthesias may also be present.^14,16 Reflexes may be absent or normal and there should be no upper motor neuron findings such as hyper reflexia or increased tone.

HNA may have additional findings of mild dysmorphic features, including up slanting palpebral fissures, long nasal bridge, and hypotelorism.¹⁷

Functional assessment

Patients may have difficulty with proximal muscle movements that can interfere with daily activities. Such activities include the following: grooming, hygiene, self-feeding, and bathing. Referral to occupational or physical therapy for upper limb functional assessment may be beneficial.

Laboratory studies

The diagnosis of NA remains a clinical diagnosis. Electrodiagnostic evaluation may demonstrate brachial plexopathy and is also useful in ruling out other causes of symptoms such as cervical radiculopathy or a mononeuropathy of the median or ulnar nerves.

All laboratory studies are typically normal. Occasionally, elevation in liver function tests can be seen in associated viral infections.

Monocular inflammatory infiltrates have been noted on brachial plexus biopsy and complement-fixing antibodies to peripheral nerve myelin though biopsy is not typically pursued.¹⁰

Routine Cerebral spinal fluid (CSF) analysis may show seroprevalence of antimyelin and antiganglioside antibodies and disruption of the blood-brain barrier, however CSF analysis may not have a relevant role in NA as its findings are typically non-specific.^19,20

Imaging

Imaging has been useful to exclude other diagnoses, such as cervical and rotator cuff disease, that may be in the differential diagnosis. MRI or computed tomography can be used to rule out a Pancoast tumor. Although Pancoast tumors usually involve the lower trunk of the brachial plexus and are not commonly seen in NA, it is important to rule out as they may cause compression of vital structures such as the brachiocephalic vein, subclavian artery and phrenic nerve. A hemidiaphragm can be detected in 10% of patients with NA on MRI suggesting phrenic nerve involvement.²¹

MRI may detect abnormalities including dennervated muscles on MRI. In the subacute or chronic phase, T1-weighted images may demonstrate atrophy and fatty infiltration. Magnetic resonance neurography (MRN) has been used and may demonstrate hyperintense thickening of the involved areas of the brachial plexus.^4,8

More recently, high resolution ultrasound has been explored as a diagnostic tool in NA, however, to date there are no systematic studies of ultrasound findings in NA. Several case studies have shown focal nerve swellings that mostly seem to affect the perineural compartment surrounding the fascicles as typically seen in other inflammatory neuropathies such as mutifocal motor neuropathy. In advanced NA, focal constrictions and torsion can be seen.^4,21,22

Supplemental assessment tools

Electrodiagnostic (EDX) testing is the most useful tool in assessing NA. Localization of the lesion in NA is possible with EDX and the most common pattern of NA appears to be either a single or multiple mononeuropathy affecting the suprascapular, long thoracic, phrenic, or axillary nerves on EDX.¹⁷ In particular, EDX findings can be seen in the distribution of the plexus, the upper and middle plexus, and/or in combination of peripheral nerves. When sensory abnormalities are involved, the lateral antebrachial cutaneous nerve is most commonly affected.⁸ Needle electromyography of the affected muscles demonstrates fibrillation potentials and positive sharp waves.^4,17 The electrophysiologic evidence suggest that the neural insults are multifocal as well as bilateral.¹⁷ Sensory nerve and compound muscle action potentials studies are important for localization, determining the degree of axonal loss, and prognosis; side-to-side comparison is often useful in more mild cases.¹⁷

Early predictions of outcomes

Multiple attacks of NA, seen more frequently in HNA, may lead to a poor recovery. Additionally, the prognosis for recovery is affected by the severity of axonal involvement. The more axonal involvement the longer recovery period.² With partial nerve lesion, reinnervation can take up to 6 to 12 months. Whereas with more severe lesions the recovery process can be delayed 1 to 3 years or longer.^2,14

Social role and social support system

Some patients may require assistance with their activities of daily living, and if they are severely affected they may need caregivers to help with mobility and impairments in daily living. In addition, patients may have difficulties with maintaining their occupational functions and if unable to return to work may benefit from resources provided by the American’s with disability act (ADA).

Professional Issues

Given the hypothesis of an autoimmune etiology, patients have been treated with high dose steroids and/or intravenous immunoglobuin (IVIG). These treatments have not been approved by the U.S. Food and Drug Administration, thus could be considered an “off label” use of these agents.

Available or current treatment guidelines

A 2009 Cochran review identified 1 open-label, retrospective series suggesting that oral methylprednisolone during the first month of an attack could shorten the duration of painful symptoms.²³

Focus of rehabilitation includes addressing the altered biomechanics and functional deficits of the affected limb with physical and occupational therapy to prevent joint contractures, protect the limb from subluxation, and address activity of daily living issues. Splinting may be useful. Edema control may be necessary.

At different disease stages

Most patients are treated with a multidisciplinary approach including physical and occupational therapy, pharmacologic treatment and bracing.² Surgical referral may also be considered.^4,14

Treatment is an ongoing area of research and strategies vary depending on the phase. Oral corticosteroids in the acute phase has been shown in some studies to shorten the duration of painful symptoms.^4,14,23  

Pain is usually self limiting in the first two weeks from symptom onset. Prolongation of pain symptoms occurring less frequently.^14,16 In cases of severe pain, a short course of opioids may be used. In the chronic phase, pain relief may be provided by acetaminophen, nonsteroidal medications, gabapentin or pregabalin, tricyclic antidepressants. Topical analgesics or a course of transcutaneous electrical stimulation (TENS) may be used.

Physicians may need to consider immobilized rehabilitation measures for these patients: skin breakdown prevention, venous thromboembolism treatment, and prevention of contractures.

Surgical treatment options in cases refractory to pharmacologic and nonpharmacolgic treatments include neurolysis, nerve grafts and nerve transfers. Tendon and muscle transfers may facilitate function in cases of severe weakness.⁴

Coordination of care

Requires the integrated management of a team that may include a physiatrist, electrodiagnostician, pediatrician, neurologist, physical and occupational therapist, and/or pain specialist. Referral to surgery may be indicated in certain cases.

Patient & family education

Patients and families need to be educated on the etiology, signs and symptoms, treatment, and prognosis of the disorder. Prevention of complications needs to be addressed with the patients and their caregivers. In particular, patient’s with HNA are at increased risk for recurrence and should be counseled on avoidance of precipitating causes. If initial presentation follows vaccination, a discussion on the risks and benefits of vaccination is crucial.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

NA should be included in the differential diagnosis of acute upper-limb pain in the brachial plexus distribution followed by weakness in muscles innervated by the brachial plexus. High suspicion for NA should also arise if in addition to these these symptoms there are precipitating factors such as trauma, surgery, infection, immunizations.

Routine laboratory studies are likely to be normal.

Electrodiagnosis may demonstrate single or multiple mononeuropathy or brachial plexopathy with motor and sensory abnormalities and may involve a very proximal nerve, including the long thoracic or phrenic nerves and nerve roots.

Rate of recovery is highly variable depending on severity. More recent data suggests ~25% unable to return to work after three years.^3,5,17

Gaps in the evidence-based knowledge

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