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Disease/ Disorder

Definition

Radiation-induced plexopathy (RIP) is a neurologic impairment of the peripheral nervous system and surrounding tissues at the level of the cervical,1,2 brachial or lumbosacral plexus.  Additional neurologic impairment can also occur in the submucosal and myenteric plexus within the enteric nervous system.3,4 RIP presents most commonly with nonspecific neurologic changes that can include a combination of numbness, paresthesias, neuropathic pain, vasomotor changes and weakness that can progress to complete loss of function of the affected limb.5,6,7

Etiology and Pathophysiology

The exact pathophysiology of RIP is not completely understood but several contributing mechanisms have been identified.  Radiation therapy (RT) utilizes either electromagnetic or subatomic particles to damage DNA and intracellular molecules thereby inhibiting cellular function and reproductive capability.8 RT can achieve this by either direct cellular damage or indirectly through the production of free radicals.  All cells are affected but rapidly dividing cancer cells are more susceptible.  Radiation can be delivered by an external or internal emitter.  Several techniques such as image guidance and conformal methods have been developed for external radiation delivery to maximize dose to cancerous tissue while minimizing exposure to normal tissue.  Internal radiation therapy utilizes radiopharmaceuticals delivered intravenously (i.e., radioactive iodine) or by insertion of radioactive “seeds” or plaques directly at the site of the tumor (e.g., brachytherapy).9

The harmful effects of radiation are commonly seen both acutely and chronically in the healthy tissue surrounding a treated cancer.  Because they are fully differentiated post mitotic cells, neurons are not effective at repairing radiation-induced damage and are susceptible in a dose-dependent fashion to direct and indirect damage.  Acutely radiation-induced injury is characterized by an inflammatory cascade, alteration of synaptic activity, and ultimately apoptosis.4,10,11 Chronic effects can occur weeks to years after radiation exposure and continue indefinitely.  This phenomenon is attributed to direct injury to the neuron and its supporting microvasculature.  Direct neuronal injury is caused by increased oxidative stress, imbalanced fibroblast proliferation and abnormal extra cellular matrix deposition, microvascular dysfunction, and ultimately Wallerian degeneration.12,13,14 Nerve plexuses are uniquely vulnerable to radiation due to their proximity to commonly radiated areas of the body (i.e., regional lymph nodes) and potentially increased susceptibility to vascular damage.15

Epidemiology including risk factors and primary prevention

More than 50% of cancer patients will receive radiation as a component of their treatment.16  Patients who receive radiation to the head and neck, axilla, chest wall, abdomen, or pelvis are at increased risk for developing RIP.5,17,18,19,20,21, The incidence of RIP affecting the brachial and lumbosacral plexus increases sharply with total radiation doses higher than 60 Gy,17,20,24,25 even with fractionation as low as 2 Gy.26,27 The myenteric plexus appears to be unaffected with fractionated doses up to 8 Gy.61  Unfortunately, there is no sure way to predict who will develop RIP or how to prevent it.  In fact, it was once thought that the primary tumor location with respect to the clavicle showed predilection towards upper versus lower trunk brachial plexopathy.  A recent study suggests that tumors superior/inferior to the clavicle increase the change of largely upper/lower trunk plexopathy, respectively, regardless of the mechanism of injury.64 To date, management of RIP is largely symptomatic.

Acute onset of plexopathy related symptoms

Acute onset of symptoms varies from days to several weeks11 following radiation administration.  Paresthesias are the most common presenting symptom in RIP.5,17,28,29,30 Disorders of sensation such as tingling, burning, numbness and/or pain are common findings in the upper and lower extremities and pelvis as a result of radiation-induced cervical, brachial and lumbosacral plexopathies.  Patients treated for gastrointestinal (GI) and pelvic cancers may show early signs of radiation-induced myenteric plexopathy resulting in dysregulation of the migrating motor complex (MMC) within the gastrointestinal system.  These patients commonly present with symptoms of bloating, fecal incontinence, nausea, vomiting, and delayed gastric emptying.3,62 

Subacute plexopathy related symptoms

In the weeks following the acute onset of RIP, patients’ symptoms may progress to include limb edema and worsening motor and sensory deficits.6,29,31 Within the GI system, decreased absorptive and secretory function may be associated with radiation-induced submucosal plexopathy.47,72

Chronic plexopathy related symptoms

Signs and symptoms of plexopathy can develop and progress months, years, or decades following treatment.  This phenomenon can be seen in patients in remission of any cancer treated by radiation.  Hodgkin’s lymphoma (HL) patients32 treated with now obsolete techniques (e.g., mantle field radiation), head and neck cancer patients, and even those treated with advanced techniques (e.g., involved site radiation therapy), in which the radiation beam is more focused to affected lymph nodes in an attempt to reduce the size of the treatment area, are commonly affected. These patients often develop cervical and/or brachial plexopathy leading to severe atrophy, weakness and pain in their neck and upper extremities.33,34 In addition to severe lower extremity atrophy, weakness and pain, patients treated for GI cancers, pelvic cancers or malignancy of the thoracic or lumbar spine, often experience chronic gastrointestinal and genitourinary dysfunction such as sexual dysfunction, and bowel and/or bladder incontinence. 31  

Specific secondary or associated conditions and complications

Radiation fibrosis syndrome is a common side effect of external beam radiation therapy.  It is associated with RIP and has a similar pathophysiology in that it is the result of radiation injury that triggers inflammatory pathways, resulting in the proliferation of myofibroblasts and excess production collagen and extracellular matrix.  For reasons unclear at this time, neuronal tissue in the plexuses in these affected regions may be spared or minimally effected.  However, symptoms associated with radiation fibrosis syndrome may overlap RIP and include dropped head syndrome, cervicalgia, cervical dystonia, trismus, dysphagia, dysarthria, paralysis of the affected limb(s), contracture, lymphedema, bowel or bladder incontinence, impotence, and chronic radiation enteritis.31,32,33,34,35, 55

Essentials of Assessment

History

Patients with cervical, brachial, and/or lumbosacral radiation-induced plexopathy may report paresthesias, numbness, weakness, heaviness and swelling of the upper and lower distal limb(s). 6,17,28,29,36 Pain (e.g. dysesthesias, allodynia, and hyperpathia) is generally seen later in the course of the disease and is more frequent in brachial than in lumbosacral plexopathy.31 Metastasis or local tumor recurrence should be considered in all patients presenting with signs and symptoms of RIP. 6,17,28,29,36 The clinician should document a complete oncologic treatment history including specifics of radiation, systemic therapy and surgery. Understanding the total dose, fractionation and which tissues are encompassed by the radiation field is key to elucidating the potential clinical manifestations of RIP.  Multiple neural structures including the spinal cord, nerve roots, plexus, peripheral nerve, and muscles may be damaged in head and neck cancer and HL patients.  HL patients treated with mantle field radiation, for instance, can have a myelo-radiculo-plexo-neuro-myopathy underlying cervical dystonia, dropped head syndrome, and a variety of other clinical manifestations.32 Patients with radiation-induced myenteric plexus and or submucosal plexus may report frequent loose stools, nausea, vomiting, loss of appetited, abdominal cramps and pain, mucus discharge from the rectum and hematochezia or melena.3,35,37,38

Physical examination

A comprehensive history will inform and guide the physical exam.  It is important to perform a detailed visual inspection of the patient’s anatomy to look for asymmetry, muscle atrophy, skin changes and lymphedema.  Enlarged and/or indurated and non-mobile lymph nodes may indicate cancer recurrence. A detailed and comprehensive neurological exam including strength, sensation, and reflexes is critical to diagnosing plexopathy, clarifying which components of the plexus are affected and confirming if other neural structures are involved.6   Because nerve injury occurs distal to the anterior horn cell in isolated RIP, diminished reflexes and flaccid paralysis are generally expected.  An abdominal exam and rectal exam may be necessary for patients who have received abdominal or pelvic irradiation, assessing for hyperactive or hypoactive bowel sounds, guarding, and abnormal masses.  These findings along with correlation to patient history can be used to guide further management.

Functional assessment

Functional assessment tools help objectively document the patient’s functional status and monitor their progress or deterioration in response to various interventions.

Cervical Plexus Assessment Tools

  • The Toronto Bedside Swallowing Screening Test (TOR-BSST)39
  • Gothenburg Trismus Questionnaire (GTQ)63
  • Eating Assessment Tool-10 (EAT-10)40

Brachial Plexus Assessment Tools

  • Brachial Assessment Tool (BrAT)41
  • Upper Extremity Functional Index (UEFI)42

Lumbosacral Plexus Assessment Tools

  • The Lower Extremity Functional Scale (LEFS)43
  • Get Up and Go Test44
  • Cleveland Clinic Florida (CCF)/Wexner Fecal Incontinence Score45
  • The Michigan Incontinence Symptom Index (M-ISI)46

Myenteric and Submucosal Plexus Assessment Tools

  • Cleveland Clinic Florida (CCF)/Wexner Fecal Incontinence Score45

Laboratory studies

There are no lab abnormalities that would suggest a cervical, brachial, or lumbosacral radiation-induced plexopathy.  However, electrolyte abnormalities may be present in patients with chronic enteritis, secondary myenteric and submucosal plexopathy.  Additionally, these patients may also have a positive fecal occult blood stool. 

Imaging

The only way to ensure that plexopathy is due to radiation and not cancer recurrence is with imaging and ultimately biopsy if a mass or infiltration is identified.  Magnetic resonance imaging (MRI) with and without gadolinium, preferably comparing side-to-side, is usually the initial imaging study ordered to make this determination.  Cancer mediated plexopathy typically show contrast enhancement of a non-uniform asymmetric mass. With tumor involvement of the plexus (primary or metastatic), there is usually enhancement of nerve roots and T2-weighted hyper intensity, though different tumor types will have different, characteristic enhancement patterns.17,47 If MRI is negative and suspicion is high for tumor, then positron emission tomography should be ordered.17,47 If suspicion for tumor remains high, then repeating MRI and PET in 3-4 months may be indicated.  If present, post-radiation plexopathy will typically reveal symmetric uniform swelling that may be enhanced with contrast up to several years after the last radiation treatment.48,49 Additionally, radiation fibrosis will present as low signal intensity on MRI for both T1 and T2 weighted images.

Supplemental assessment tools

Nerve conduction studies and electromyography (NCS/EMG) may be used to assess cervical, brachial plexus or lumbosacral plexus involvement.  Gastric motility studies such as gastric emptying scintigraphy, wireless pH and motility capsules, stable isotope breath tests, single photon emission computed tomography (SPECT) and functional ultrasonography are some of the tests that can be used to assess the function of the migratory motor complex, but do not directly assess the enteric nervous system.  Additionally, urodynamic studies and anorectal manometry can be used to assess the effects of the lumbosacral plexopathy on the genitourinary (GU) and gastrointestinal (GI) system, respectively.35,46,62 Video fluoroscopic swallow studies are used to evaluate swallow function.

Early predictions of outcomes

RIP is almost always progressive, but the rate and pattern of deterioration is highly variable.5,31 The structures involved are dependent on the radiation field and there may be a sharp demarcation of affected plexus structures with conformal radiation techniques.  If the entire plexus is involved, complete loss if limb function is possible.  The effects on the myenteric and submucosa plexuses have a similar prognosis but is poorly understood.

Social role and social support system

Impact on the patient’s social role will depend on the nature of impairments. Impact could include bowel and/or bladder dysfunction, occupational and physical challenges related to functional impairment, difficult to treat pain, and social isolation. Cancer support groups are valuable resources to learn about the syndrome facing the patient, therapeutic options, and are a means to voice emotions related to the burden of being a cancer patient and survivor.

Rehabilitation Management and Treatments

Available or current treatment guidelines

There is no definitive treatment to arrest RIP progression or improve neurologic function. Treatment with a combination of tocopherol and pentoxifylline has been touted as helpful in reducing radiation-induced fibrosis and possibly stabilizing neurologic symptoms, but larger randomized trials are lacking and the available data is uncompellng.50,51 Hyperbaric oxygen has not been shown convincingly to have benefit for RIP.52 Potential aggravating factors, such as diabetes, hypertension, alcohol abuse, and acute edema, should be managed aggressively to prevent synergistic neurologic damage.28,53

An interdisciplinary team approach will improve the efficacy of both the intervention and communication with the patient.  Physical therapy and occupational therapy are necessary to address weakness, myofascial restrictions, functional impairment, activities of daily living, return to work (including workplace modifications), adaptive equipment and orthotic restoration, tissue desensitization, and lymphedema management.53,54 Speech and language pathologists help to address dysphagia and apraxia. Gastroenterology, urology and nutrition specialist are necessary to support patients with severe bowel or bladder dysfunction.

Pharmacologic treatment should be tailored to its efficacy and the patient’s side effect tolerance.  Treatment options for neuropathic pain include tricyclic antidepressants (e.g., amitriptyline), serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine), nerve stabilizers (e.g., gabapentin, pregabalin, carbamazepine), tramadol, antiarrhythmics (e.g., mexiletine), narcotics, and anesthetic interventions (e.g., nerve block).28

Surgical exploration has been attempted for restoration of vascular supply with mixed results and should be undertaken with caution only when conservative measures fail and symptoms are severe.5

Coordination of care

In cancer rehabilitation, coordination of care is recognized as valuable in improving the patient’s experience during care, improving outcomes, and lessening caregiver burden.  Integrated treatment is provided by physiatrists, oncologists, pain specialists, gastroenterologists, urologists, speech and language pathologists, occupational and physical therapists, lymphedema specialists, and psychologic services.53,54

Patient & family education

Patients and their family should be made aware of potential clinical progression in RIP. They should understand that there is no definite cure and that there is no evidence that available treatment options will change the course of the disease. Family members should know and understand that their supportive role for the patient may include assistance with activities of daily living.

Translation into practice

Cancer patients who receive radiation as part of cancer treatment should be educated about potential long-term complications associated with both the disease and treatment. Providers must ensure that the patient understands why radiation is used as part of the treatment. It is important to remember that RIP can present and progress decades following radiation treatment and should be considered in patients who developed appropriate symptoms. If neurologic symptoms develop following radiation treatment, differentiation between radiation-induced and neoplastic plexopathy is critical to preserve function and life.  Primary management for RIP is supportive and directed at lessening symptoms.

Cutting Edge/ Emerging and Unique Concepts and Practice

Nerve transfer, using microsurgery, has become more widely used in recent years to provide reinnervation to the musculocutaneous nerve, and consequently return function to the elbow with mixed results.56,57 There has been one case study to show promise with managing radiation-induced enteritis with a visceral sympathetic block.  However, treatment of this condition is typically symptom control.58

Upper and lower limb exoskeletal systems and hybrid assistive limb devices 59,60 may help to bridge the gap until new medical therapies, such as tissue engineering, can prove effective at repairing peripheral nerve injury.61 Transcutaneous nerve stimulation has shown to be an effective method of managing neuropathic pain in radiation-induced plexopathy.

Gaps in the Evidence-Based Knowledge

It is known that effective postoperative radiotherapy can diminish cancer relapse and RIP is a potential complication of high dose radiation. Even though there is no cure for RIP, the consequences for not optimally treating it can be severe. Although RIP occurrence has diminished with new treatment approaches, the evidence-based therapeutic options to prevent progression of RIP and manage its symptoms are limited.

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Original Version of the Topic

Maricarmen Cruz, MD, Jesuel Padro-Guzman MD. Radiation Plexopathy. 7/25/2012.

Previous Revision(s) of the Topic

Christian Custodio, MD, Cody Christopher Andrews, MD. Radiation Plexopathy. 8/1/2017.

Author Disclosure

Noble Jones, MD
Nothing to Disclose

Michael Dean Stubblefield, MD
Nothing to Disclose