Radiation-Induced Brachial Plexopathy

Although radiation therapy is used in the treatment of a myriad of neoplastic diseases, it has potentially adverse effects on several organs and systems that are exposed during treatment. Radiation-induced neurotoxicity can involve the central and peripheral nervous systems. Radiation-induced brachial plexopathy can occur when radiotherapy is directed at the chest, axillary region, thoracic outlet, or neck.

Results from the English National Cancer Survivorship initiative, which includes a study on the consequences of treatment in adult cancer, such as radiation-induced brachial plexopathy, suggest that patients benefit significantly when the prevention, detection, and treatment of some of these consequences are approached systematically.[1]

When treating the axillary and supraclavicular lymph nodes with radiation therapy, it is impossible to avoid irradiating normal tissues, including the brachial plexus. While dosing regimens are designed to limit damage to healthy tissue, radiation-induced neuropathy may occur. The radiation dose; treatment technique; concomitant use of chemotherapy; surgical lymph node dissection; and underlying comorbidities such as diabetes, hypertension, obesity, and vascular disease all demonstrate significant association with the development of radiation injury to the brachial plexus.[2, 3] The mechanism is believed to be a combination of failure of cellular proliferation and localized ischemia. The net result is fibrosis of the neural and perineural soft tissues secondary to microvascular insufficiency. This, in turn, leads to ischemic damage to the axons and Schwann cells.[4]

Frequency

United States

The frequency of radiation-induced brachial plexopathy has declined over the past 60 years and depends significantly on both the radiation dose and the proximity of the radiation volume to the underlying plexus. In the 1950s, the incidence was as high as 66% after 60-Gy total dosing to the axillary and supraclavicular area using 5 Gy/fraction. The current incidence is 1-2% in patients receiving a typical dose of less than 55 Gy.[5] Breast carcinoma accounts for 40-75% of reported cases, followed by lung carcinoma and lymphoma.[6, 7]

International

No satisfactory data have been reported.

Mortality/Morbidity

The natural course of radiation injury to the brachial plexus varies. Most commonly, the plexopathy develops months to years after radiation therapy and demonstrates a relatively stable course over months to years with a gradual worsening of paresthesias and pain. One third of patients deteriorate rapidly and exhibit significant weakness, lymphedema, and pain. Rarely, the disorder presents as a mild and relatively reversible set of symptoms.[8] No present studies quantify the degree of disability experienced by patients with this disorder.

Race

No sources in the literature have examined the racial or ethnic distribution of patients with radiation-induced brachial plexopathy.

Sex

Given that breast cancer often is treated with radiation therapy, women experience a greater incidence and prevalence of radiation-induced brachial plexopathy than men.[9]

Age

Advanced age may be a risk factor for the development of brachial plexopathy after radiation treatment.[10] Otherwise, the age range closely parallels that of patients with breast cancer.

The interval from the last dose of radiation to the first symptom of plexus disorder varies widely. The average interval range reported is 7.5 months to 6 years; however, symptoms may develop decades after treatment. Owing to this prolonged time interval and nonspecific symptoms, often an extensive workup is undergone prior to arriving at the diagnosis of radiation plexopathy.

Sensory symptoms, such as numbness, paresthesia, and dysesthesia, along with swelling and weakness of the arm, are the predominant presenting symptoms. These neurologic symptoms can be progressive and may lead to a weak and edematous arm.

Most radiation plexopathies are painless, but when present, pain symptoms usually are limited to the shoulder and proximal arm. Such pain usually is rated as mild to moderate in intensity. Significant pain complaints are more commonly associated with recurrent tumor than with radiation plexopathy.[4]

The physician, therefore, must ask temporally and neurologically focused questions. Address the existence, onset, and pattern of weakness, as well as the presence, quality, and distribution of any altered sensation. Explore the history if the patient also is experiencing pain in the involved extremity. The characteristics of the pain need to be investigated and documented. Also document details of any swelling in the involved extremity.

Physical examination findings for radiation-induced brachial plexopathy fall primarily into the following 2 categories:

• Neurologic findings are most prominent in the upper trunk or lateral cord distributions, as well as diminished deep tendon reflexes supplied by C5-C6.[11, 12]  (A retrospective study by Cai et al of patients with nasopharyngeal carcinoma found that clinical symptoms of radiation-induced brachial plexopathy arose primarily in the upper and middle trunk of the brachial plexus.[13] ) Myokymia is difficult to visualize by inspection or palpation.[14] The lymphatic-vascular system may reveal prominent lymphedema of the involved extremity without cyanotic or dusky features. There should be no disturbance of arterial or venous circulation in the involved extremity and no changes in the limb to suggest venous insufficiency (varicosities, stasis ulcers, or dermatitis). The Allen test should be negative. Horner syndrome is not present in patients with radiation-induced brachial plexopathy.

• The musculoskeletal examination may reveal decreased passive scapulothoracic and glenohumeral joint range of motion secondary to fibrosis of the musculoskeletal tissues from the radiotherapy or due to postsurgical scar tissue. Neurologic damage to the upper trunk of the brachial plexus may result in scapular winging, decreased shoulder external rotation, and abduction.[15] No specific joint tenderness or effusions should be encountered during the examination of the involved extremity.

Treatment technique, radiation volume,and concomitant use of chemotherapy are associated with development of radiation injury to the brachial plexus.[16, 17]

A 2009 report examined the incidence of brachial plexopathy resulting from the use of stereotactic body radiotherapy to treat apical lesions in early-stage, non–small cell lung cancer.[18] The study found that grade 2, 3, or 4 plexopathy developed in 7 out of 37 apical lesions exposed to radiotherapy. The report's authors advised that the risk of brachial plexopathy be reduced by keeping the maximum radiation dose to a brachial plexus below 26 Gy in 3 or 4 fractions.

A study by Sood et al of patients with apical lung tumors who underwent stereotactic body radiation therapy (SBRT) found that during such treatment, the radiation dose received by the brachial plexus can be much higher than the conventionally recommended limits; in some cases, the biologically effective dose in the study exceeded 100 Gy. Nonetheless, by median 17-month follow-up, no cases of brachial plexopathy had occurred.[19]

In the aforementioned study by Cai et al, the incidence of the plexopathy was increased in nasopharyngeal carcinoma patients with lower cervical lymph node metastasis who underwent corresponding radiotherapy.[13]

No laboratory studies help differentiate radiation-induced brachial plexopathy from other disorders involving the brachial plexus.

Plain radiography does not have diagnostic value for detecting radiation-induced brachial plexopathy.

Computed tomography (CT) scanning of the involved brachial plexus may reveal a diffuse infiltration of the tissue planes.

Magnetic resonance imaging (MRI) often reveals low signal intensity on T2-weighted images; minimal changes are found with gadolinium.[14, 20, 21]

All of these characteristics are in contrast to neoplastic processes, which would be identified by the presence of a focal mass. In addition, if traditional modalities demonstrate normal findings, positron emission tomography imaging may provide an additional tool for excluding suspected malignant plexopathy. Malignant etiologies of brachial plexopathy are associated with significantly increased uptake of 18-fluoro-2-deoxy-D-glucose, reflecting the increased metabolism associated with neoplastic processes.

Electrodiagnostic testing can be used to help distinguish between radiation-induced and neoplastic disorders of the brachial plexus. Generally, no significant differences between the 2 conditions are noted on sensory and motor conduction studies or late responses. However, nerve conduction studies are important to exclude other causes of paresthesias in the lateral digits, such as carpal tunnel syndrome.

Needle electromyography in radiation-induced brachial plexopathy reveals myokymia more often than in neoplastic-induced brachial plexopathy.[4] Myokymia represents spontaneous discharges accompanied by wavelike muscle quivering. The frequency may be paroxysmal motor unit action potentials or a slow continuous discharge at 1-5 Hz in motor unit action potentials.[14]

Evoked potential studies do not have any particular value for this diagnosis.

In some cases, surgical exploration and biopsy are required to distinguish between radiation-induced and tumor-induced brachial plexopathy. Nerve grafting has been attempted in animals with fair results, but data from human trials are lacking.[22, 23]

Surgical treatment options are aimed at breaking up fibrotic tissue to eliminate mechanical constriction of the plexus and its blood supply. Attempts have been made at exoneurolysis/endoneurolysis, with or without placement of an omental or latissimus dorsi flap as a source of well-perfused tissue. Unfortunately, these approaches have proven ineffective and even harmful. Indeed, dissection alone can lead to a significant worsening of symptoms. Some relief of pain may be achieved in a minority of patients, with little or no impact on other sensory or motor deficits.

Findings may include the following:

• Fibrosis of the neural elements and surrounding soft tissues

• Chronic perineurial microvascular ischemia

Physical Therapy

Therapeutic modalities should focus on pain reduction, strengthening, preservation of range of motion, and limiting lymphedema. The interventions and modalities should address underlying impairments, as follows:

• Weakness: Assign therapeutic exercise to enhance flexibility and strength of the shoulder girdle paracervical and parathoracic muscles. The glenohumeral joint may require a sling for sitting or standing activities to reduce the degree of glenohumeral joint subluxation and discomfort.

• Pain: Use caution when considering the application of heat and cold if the sensation in the extremity is impaired. Transcutaneous electrical nerve stimulation therapy may be considered for pain control.

• Lymphedema: Educate the patient. Perform manual lymphatic therapy and motorized intermittent pneumatic compression therapy; use graded pressure upper extremity garments.

• Range of motion: Emphasis should be placed on a home exercise program to preserve range of motion and strength.

Occupational Therapy

Assess basic and instrumental activities of daily living and provide appropriate adaptive equipment.

Provide fine motor skills training, if the lower plexus is involved.

Recommend sensory and motor re-education techniques.

Consider using a flexor hinge tenodesis orthosis with or without long opponens orthosis if it allows the patient to be functionally prehensile.

Recreational Therapy

Focus on enjoyable activities that help to preserve range of motion and retain or build strength while limiting pain and discomfort.

As with other conditions that produce lymphedema of the upper extremity, hygiene plays an important role in radiation-induced brachial plexopathy, and venipuncture should be avoided to obviate the risk of cellulitis/lymphangitis.

If the affected extremity is involved in trauma with skin laceration, exercise vigilance in monitoring for cellulitis or lymphangitis. Antibiotic treatment should be considered early if there is any indication of infection.

Glenohumeral joint arthrodesis rarely is indicated.

Lymphatic bypass surgery interventions to divert or to redirect lymphatic flow rarely are required.

A radiation oncologist, neuro-oncologist, neuroradiologist, and physical medicine/rehabilitation specialist can assist in diagnosis and management.

Dorsal root entry zone lesion or chemical sympathectomy can be considered for intractable cases of chronic severe pain.

Neurolysis/decompression of the first rib or clavicle and neural grafting generally are not indicated.

Hyperbaric oxygen has not shown reproducible neurologic benefit.

The goal of pharmacotherapy is to reduce morbidity and prevent complications.

Class Summary

Anticonvulsants are used to manage severe muscle spasms and provide pain relief in neuralgia.

Gabapentin (Neurontin, Gralise)

Gabapentin has anticonvulsant properties and antineuralgic effects; however, the exact mechanism of action is unknown. Gabapentin is structurally related to GABA but does not interact with GABA receptors.

Titration to effect can take place over several days (300 mg on day 1, 300 mg bid on day 2, and 300 mg tid on day 3).

Pregabalin (Lyrica)

Pregabalin is a structural derivative of GABA. The mechanism of action is unknown. It binds with high affinity to the alpha2-delta site (a calcium channel subunit). In vitro, it reduces calcium-dependent release of several neurotransmitters, possibly by modulating calcium channel function. It is FDA approved for neuropathic pain associated with diabetic peripheral neuropathy or postherpetic neuralgia and as adjunctive therapy in partial-onset seizures.

Class Summary

These agents have central and peripheral anticholinergic effects, as well as sedative effects, and block the active reuptake of norepinephrine and serotonin.

Amitriptyline

Amitriptyline is indicated as an analgesic for certain types of chronic and neuropathic pain.

Nortriptyline (Pamelor)

Nortriptyline has demonstrated effectiveness in the treatment of chronic pain. By inhibiting the reuptake of serotonin and/or norepinephrine by the presynaptic neuronal membrane, it increases synaptic concentration of these neurotransmitters in the CNS.

Class Summary

These agents are a complex group of drugs that inhibit serotonin and norepinephrine reuptake. Some drugs in this class are weak inhibitors of dopamine reuptake with sedative effects.

Duloxetine (Cymbalta)

Duloxetine is indicated for diabetic peripheral neuropathic pain. It is a potent inhibitor of neuronal serotonin and norepinephrine reuptake.

Continue to monitor the neurologic examination findings and clinical symptomatology. If unexpected changes occur, consider repeating electromyography or MRI.

Reinforce patient education regarding protection and care of the extremity with lymphedema. If lymphedema worsens, consider the aforementioned therapeutic interventions and perform an MRI to rule out metastatic disease.

For pain control, tricyclic antidepressants, anticonvulsants, or serotonin–norepinephrine reuptake inhibitors may be indicated for lancinating/neuropathic-type pain. Traditional analgesics also play a role in the treatment of neuropathic pain.

If there is evidence of neoplastic disease, the patient needs to be reevaluated by oncological services.

Use focally directed radiotherapy with doses below 55 Gy. A study by Chen et al indicated that in patients undergoing radiotherapy for head-and-neck cancer, a significant association exists between radiation dosages of more than 70 Gy over more than 10% of the brachial plexus volume and the development of brachial plexopathy symptoms. The study involved 352 disease-free patients who had finished radiotherapy for squamous cell carcinoma of the head and neck a median of 40 months prior to the study.[24]

Complications may include the following:

• Lymphangitis

• Cellulitis

• Complex regional pain syndrome, type 2

• Glenohumeral joint subluxation

• Contractures in the involved upper extremity

One third of patients experience significant progression of their radiation-induced plexopathy, whereas the remainder of patients demonstrate gradual progression. Rarely, a mild form of reversible radiation plexopathy may present.

Patients should be educated about the expected progressive course of radiation plexopathy. A home exercise program should be considered to preserve strength and range of motion. Susceptibility to trauma and infection due to altered sensation, edema, and fibrotic tissue should be discussed.