Radiation-induced plexopathy (RIP) is a neurologic impairment of the peripheral nervous system, at the level of the brachial or lumbosacral plexus, due to sequelae from radiation therapy. RIP presents most commonly with nonspecific neurologic changes that can include a combination of numbness, paresthesias, pain, and weakness.1,2
Etiology and Pathophysiology
Prior to the 1960s, nervous tissue was thought to be resistant to radiation damage. In 1966, Stoll and Andrews published a review of 117 breast cancer patients treated with radiation and showed a high incidence of delayed radiation effects to the brachial plexus, especially patients who received a higher radiation dose.3 The mechanism of injury is not completely understood, but is proposed to occur in three stages:
- Early, asymptomatic inflammation.
- Organized fibrosis and extracellular deposits.
- Late fibroatrophic phase with retractile fibrosis.4
Various potential contributors have been posited, including free radical damage and ischemia from fibroatrophic changes.4
Epidemiology including risk factors and primary prevention
Many cancer patients receive radiation therapy in conjunction with chemotherapy and/or surgery to maximize treatment benefit. Those who receive radiation to the head and neck, axilla, chest wall, or pelvis are at risk for developing RIP.1,5,6,7,8,9,10,11 RIP incidence increases sharply with total radiation doses higher than 60 Gy5,8,12,13 and fractionation higher than 3 Gy14,15 both in the brachial and lumbosacral plexus. Current Radiation Treatment Oncology Group recommendations for head and neck cancer recommend doses below 60-66 Gy for the brachial plexus.16,17,18 Before this was understood, original reports in women with breast cancer showed that the incidence of radiation-induced brachial plexopathy (RIBP) was as high as 73%,3 but over the decades has diminished to as low as 1.8-4.9% as a result of increased understanding of the dose-dependent nature of RIP and improved radiation delivery techniques.2,13,19,20,21 Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
- Onset of symptoms is variable from 10 months15 to more than 20 years22 after the last dose of radiation. Paresthesias are the most common presenting symptom in RIBP.2,4,5,19,23 Presenting symptoms for radiation-induced lumbosacral plexopathy (RILSP) is more varied and often weakness is the initial complaint.5,24,25 Preferential lower trunk has traditionally been thought to herald tumor recurrence,2,19 though this has been challenged.23
- Symptoms progress to limb edema and motor and sensory deficits worsen.2,19,26
Chronic / stable
- Atrophy, severe weakness, and pain develop.26
Specific secondary or associated conditions and complications
Associated conditions and complications include: dropped head syndrome, paralysis of the affected limb(s), bowel or bladder incontinence, lymphedema, cellulitis, complex regional pain syndrome, and contractures.
2. ESSENTIALS OF ASSESSMENT
Patients will report dysesthesias, numbness, and swelling of the limb.2,4,5,19,23 Pain is seen later in the course of the disease and is more frequent in brachial than in lumbosacral plexopathy.26 Patients may report weakness and dysfunction of the affected limb. Patients who present with pain and/or unilateral symptoms should raise concern for tumor recurrence and nerve invasion instead of RIP,2,4,5,19,23 though symptoms of RIP will often progress in later stages.
Weakness and sensory loss follow a specific neural distribution based on the portion of the plexus which is involved and can be unilateral or bilateral.2 For example, impairment of sensation in the lateral upper arm and forearm is suggestive of upper trunk/lateral cord involvement, as seen in most cases of RIBP. As nerve injury occurs distal to the anterior horn cell in RIP, diminished reflexes and flaccid paralysis are expected when motor nerves are involved.
The Late Effects Normal Tissue-Subjective, Objective, Management, Analytic (LENT-SOMA) scale is used to assess grades of the late effect of radiation.27,28
Grade 1: Mild sensory deficit, no pain.
Grade 2: Moderate sensory deficit, tolerable pain, mild arm edema.
Grade 3: Continuous paresthesias with incomplete motor paresis; pain medication is generally required.
Grade 4: Complete motor paresis, severe pain, and muscle atrophy.
Blood and cerebrospinal fluid studies are typically normal.
Magnetic resonance imaging (MRI), computed tomography, and single-photon emission computed tomography scans are useful in looking for tumor recurrence. MRI has been shown to be more sensitive in detecting tumor recurrence and is preferred when possible.29,30,31 With tumor involvement of the plexus (primary or metastatic), there is usually enhancement of nerve roots and T2-weighted hyperintensity, though different tumor types will have different, characteristic enhancement patterns.5,33 Positron emission tomography imaging may be used in detecting an active neoplasm in the area of the plexus.5,33
There are no specific MRI enhancement patterns associated with RIP.2,5,20 However, signal abnormalities of the ipsilateral scalene muscle without nodularity may suggest RIBP.32 Isolated reports suggest that gadolinium enhancement could show variable intenisty of plexus fibrosis in RIP, versus the presence of a focal mass when a neoplastic process is present.2,34 The main MRI findings in RIP, if present, are diffuse uniform thickening of the radiated segment of the plexus, with poorly demarcated fat interfaces.35
Supplemental assessment tools
Nerve conduction studies and electromyography (NCS/EMG) may be used to assess brachial plexus or lumbosacral plexus involvement. The presence of myokymic discharges on EMG is felt to be pathognomonic for radiation-induced injury and may be seen in 60% of RIP; it is unusual to find myokymia in neoplastic plexopathy.2,4,5,19,23 Prominent fasciculation potentials are also more likely to be seen in RIP than neoplastic plexopathy.23 Other NCS/EMG findings seen in both RIP as well as in neoplastic plexopathy include needle evidence of chronic partial denervation, increased duration of motor unit action potentials (MUAPs), reduced MUAP recruitment pattern, decreased amplitude of compound motor action potentials and sensory nerve action potentials. Conduction block may be seen across the clavicle.7,23
Early predictions of outcomes
Prognosis depends largely on rapidity of progression from demyelination to axonal loss. There is no effective treatment or effective means to suppress progression, leading eventually to limb dysfunction.1,26
Social role and social support system
Impact on the patient’s social role will depend on the type of impairment present. 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 and therapeutic options, and are a means to voice emotions related to the burden of being a cancer patient and survivor.
3. 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 shown to reduce radiation-induced fibrosis and possibly stabilize neurologic symptoms, but larger randomized trials are lacking.37,38 Hyperbaric oxygen has not been shown convincingly to have benefit for RIP.39 Potential aggravating factors, such as diabetes, hypertension, alcohol abuse, and acute edema, should be managed aggressively to prevent synergistic neurologic damage.4,40
An interdisciplinary team approach will improve the intervention and communication effectiveness. Physical and occupation therapy are used 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.40,41
RIP patients with LENT-SOMA scales grades 1 and 2 could benefit from pharmacologic treatment of neuropathic pain. Pharmacologic treatment options include tricyclic antidepressants (eg, amitriptyline), serotonin-norepinephrine reuptake inhbitors (eg, duloxetine), membrane stabilizers (eg, gabapentin, pregabalin, carbamazepine), tramadol, antiarrhthmics (eg, mexilitine), narcotics, and anesthetic interventions (eg, nerve block).4 Treatment should be tailored to efficacy and side effect tolerance.
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.1
Coordination of care
In cancer, coordination of care is recognized as valuable in improving the patient’s experience during care, improving outcomes, and lessening caregiver burden. Integrated treatment is given by oncologists, physiatrists, pain specialists, occupational and physical therapists, lymphedema specialists, and psychologic services.40,41
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 change the course of the disease. Family should know 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. Providers must make sure that the patient understands the reason that radiation is used as part of the treatment, as well as the potential complications that can occur as a result of the treatment. It is important to remember that RIP has been described as long as 30 years after the radiation treatment and to remain vigilant for developing neurologic symptoms. If neurologic symptoms do develop, differentiation between radiation-induced and neoplastic plexopathy should be the first step. Primary management for RIP is supportive and directed at lessening symptoms.
4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
Cutting edge concepts and practice
Nerve transfer, using microsurgery, has been reported as an innovative approach to provide reinnervation to the musculocutaneous nerve, and consequently return function to the elbow.43,44
5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE
Gaps in the evidence-based knowledge
It is known that effective postoperative radiotherapy can diminish cancer relapse and RIP is a complication of high dose radiation. Even though there is no cure for RIP, the consequences for not properly treating cancer are generally not acceptable. Although RIP occurrence has diminished with new treatment approaches, the evidence-based therapeutic options to prevent progression of RIP and manage symptoms is limited.
- Schierle C, Winograd JM. Radiation-induced brachial plexopathy: review. Complications without a care. J Reconstr Microsurg. 2004; 20: 149-152.
- Jaeckle KA. Neurologic manifestation of neoplastic and radiation-induced plexopathies. Semin Neurol. 2010; 30: 254-262.
- Stoll BA, Andrews JT. Radiation-induced peripheral neuropathy. British Medical Journal 1966; 1: 834-837.
- Delanian S, Lefaix JL, Pradat PF. Radiation-induced neuropathy in cancer survivors. Radiotherapy and Oncology 2012; 105: 273-383.
- Dropcho EJ. Neurotoxicity of Radiation Therapy. Neurol Clin. 2010; 28: 217-234.
- Pettigrew LC, Glass JP, Maor M. Diagnosis and treatment of lumbosacral plexopathies in patient with cancer. Arch Neurol. 1984; 41: 1282-1285.
- Mondrup K, Olsen NK, Pfeiffer P, Rose C. Clinical and electrodiagnostic findings in breast cancer patients with radiation-induced brachial plexus neuropathy. Acta Neurol Scand. 1990; 81: 153-158.
- Chen AM, Hall WH, Li J, et al. Brachial Plexus-Associated Neuropathy After High-Dose Radiation Therapy for Head-and-Neck Cancer. Int J Radiation Oncology Biol Phys. 2012; 84: 165-169.
- Metcalfe E, Etiz D. Early transient radiation-induced brachial plexopathy in locally advanced head and neck cancer. Contemp Oncol. 2016; 20(1): 67-72.
- Cai Z, Li Y, Hu Z, et al. Radiation-induced brachial plexopathy in patients with nasopharyngeal carcinoma: a retrospective study. Oncotarget. 2016; 7(14): 18887-18895.
- Olsen NK, Pfeiffer P, Mondrup K, Rose C. Radiation-induced brachial plexus neuropathy in breast cancer patients. Acta oncolgica. 1990; 29(7): 885-890.
- Tunio M, Al Asiri M, Bayoumi Y, et al. Lumbosacral plexus delineation, dose distribution and its correlation with radiation-induced lumbosacral plexopathy in cervical cancer patients. OncoTargets and Therapy. 2015; 8: 21-27.
- Emami MD, et al. Tolerance of normal tissue to therapeutic irradiation. Int. J. Radiation Oncology Biol. Phys. 1991; 21: 109-122.
- Johansson S, Svensson H, Denekamp J. Dose response and latency for radiation-induced fibrosis, and neuropathy in breast cancer patients. Int. J. Radiation Oncology Biol. Phys. 2002; 52: 1207-1219.
- Powell S, Cooke J, and Parsons C. Radiation-induced brachial plexus injury: follow-up of two different fractionation schedules. Radiotherapy and Oncology. 1990; 18: 213-220.
- Truong, MT, Nadgir NR. Brachial Plexus Contouring with CT and MR Imaging in Radiation Therapy Planning for Head and Neck Cancer. RadioGraphics. 2010; 30: 1095-1103.
- Yi SK, Hall WH, Mathai M, et al. Validating the RTOG-endorsed brachial plexus contouring atlas: an evaluation of the reproducibility among patients treated by intensity-modulated radiotherapy for head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2012; 82: 1060-1064.
- Grégoire V, Levendag P, Ang KK, et al. CT-based delineation of lymph node levels and related CTVs in the node-negative neck: DAHANCA, EORTC, GORTEC, NCIC, RTOG consensus guidelines. Radiother Oncol. 2003; 69: 227-236.
- Gosk J, Rutowski R, Reichert P, Rabczyński J. Radiation-induced brachial plexus neuropathy – aetiopathogenesis, risk factors, differential diagnostics, symptoms and treatment. Folia Neuropathol. 2007; 45(1): 26-30.
- Wouter van Es H, Engelen AM, Witkamp TD. Radiation-induced brachial plexopathy: MR imaging. Skeletal Radiol. 1997; 26: 284-288.
- Wadd NJ, Lucraft, HH. Brachial plexus neuropathy following mantle radioatherapy. Clin Oncol. 1998; 10: 399-400.
- Bajrovic A, Rades D, Fehlauer F, et al. Is there a life-long risk of brachial plexopathy after radiotherapy of supraclavicular lymph nodes in breast cancer patients? Radiotherapy and Oncology. 2004; 71: 297-301.
- Harper CM, Thomas JE, Cascino TL, Litchy WJ. Distinction between neoplastic and radiation-induced brachial plexopathy, with emphasis on the role of EMG. Neurology 1989; 39: 502-506.
- Bourhafour I, Benoulaid M, El Kacemi H, et al. Lumbosacral plexopathy: A rare long term complication of concomitant chemo-radiation for cervical cancer. Gynecologic Oncology Research and Practice. 2015; 2(12):
- Georgiou A, Grigsby PW, Perez CA. Radiation induced lumbosacral plexopathy in gynecologic tumors: clinical findings and dosimetric analysis. Int J Radiation Oncology Biol Phys. 1993; 26: 479-482.
- Fathers E, Thrush D, Huson SM, Norman A. Radiation-induced brachial plexopathy in women treated for carcinoma of the breast. Clin Rehabil. 2002; 16: 160-165.
- Rubin P, Constine LS, Fajardo LF, et al. Overview: late effects of normal tissues (LENT) scoring system. Int J Radiation Oncology Biol Phys. 1995; 31(5): 1041-1042.
- Pavy JJ, Denekamp J, Letschert J, et al. Late effects toxicity scoring: the SOMA scale. Int J Radiation Oncology Biol Phys. 1995; 31(5): 1043-1047.
- Taylor BV, Kimmel DW, Krecke KN, Cascino TL. Magnetic resonance imaging in cancer-related lumbosacral plexopathy. Mayo Clin Proc. 1997; 72(9): 823-829.
- Qayyam A, MacVicar AD, Padhani AR, et al. Symptomatic brachial plexopathy following treatment for breast cancer: utility of MR imaging with surface-coil techniques. Radiology. 2000; 214(3): 837-842.
- Thyagarajan D, Cascino T, Harms G. Magnetic resonance imaging in brachial plexopathy of cancer. Neurology. 1995; 45(3 Pt 1): 421-427.
- Bowen BC, Verma A, Brandon AH, Fiedler JA. Radiation-induced brachial plexopathy: MR and clinical findings. AJNR Am J Neuroradiol. 1996; 17: 1932-1936.
- Todd MT, Shah GV, Mukherji SK. MR Imaging of Brachial Plexus. Top Magn Reson Imaging. 2004; 15(2): 113-125.
- Ahmad A, Barrington S, Maisey M, Rubens RD. Use of positron emission tomography in evaluation of brachial plexopathy in breast cancer patients. Br J Cancer. 1999; 79(3-4): 478-482.
- Boulanger X, Ledoux JB, Brun AL, Beigelman C. Imaging of the non-traumatic brachial plexus. Diag Interv Imaging. 2013; 94: 945-956.
- Stubblefield MD, O’Dell MW. Cancer Rehabilitation Principles and Practice. New York, NY: Demos Medical Publishing; 2009.
- Delanian S, Balla-Mekias S, Lefaix JL. Striking regression of chronic radiotherapy damage in a clinical trial of combined pentoxifylline and tocopherol. J Clin Oncol. 1999; 17: 3283-3290.
- Williamson R, Kondziolka D, Kanaan H, et al. Adverse Radiation Effects after Radiosurgery May Benefit from Oral Vitamin E and Pentoxifylline Therapy: A Pilot Study. Stereotact Funct Neurosurg. 2008; 86: 359-366.
- Pritchard J, Anand P, Broome J. Double-blind randomized phase II study of hyperbaric oxygen in patients with radiation-induced bracial plexopathy. Radiother Oncol. 2001; 58: 279-286.
- Delanian S, Lefaix JL. Current Management for Late Normal Tissue Injury: Radiation-Induced Fibrosis and Necrosis. Semin Radiat Oncol. 17: 99-107.
- Stubblefield MD. Radiation fibrosis syndrome: neuromuscular and musculoskeletal complications in cancer survivors. PM&R. 2011; 3: 1041-1054.
- Stubblefield MD. Clinical Evaluation and Management of Radiation Fibrosis Syncrome. Phys Med Rehabil Clin N Am. 2017; 28: 89-100.
- Tung TH, Liu DZ, Mackinnon SE. Nerve transfer for elbow flexion in radiation-induced brachial plexopathy: a case report. Hand. 2009; 4: 123-128.
- Nicoson MC, Franco MJ, Tung TH. Donor nerve sources in free functional gracilis muscle transfer for elbow flexion in adult brachial plexus injury. Microsurgery. 2016; 1-6.
Original Version of the Topic
Maricarmen Cruz, MD, Jesuel Padro-Guzman MD. Radiation Plexopathy. 07/25/2012.
Christian Custodio, MD
Nothing to Disclose
Cody Christopher Andrews, MD
Nothing to Disclose