Radiation-Induced Lumbosacral Plexopathy

The effects of radiation are correlated with the dose, technique, and concomitant use of chemotherapy.[5] Risk particularly increases with intracavitary radiation.[6] The mechanism may be related to a combination of localized ischemia and subsequent soft-tissue fibrosis due to microvascular insufficiency. With doses above 1000 cGy, pathologic changes can be seen in Schwann cells, endoneurial fibroblasts, vascular cells, and perineural cells. Injury to anterior and posterior nerve roots in rodents has been shown with doses of 3500 Gy. However, combined modality therapy may alter predicted tolerability and potential for late effects.

Radiation-induced lumbosacral plexopathy is particularly noted with uterine, cervical, ovarian, rectal, and testicular cancers, as well as with lymphomas.[7, 8]

Frequency

United States

Radiation-induced lumbosacral plexopathy is rare (0.3-1.3% of patients treated with radiation). It was noted in 1.3% of patients after abdominal irradiation and in 0.32% of patients after pelvic irradiation.

International

The international incidence of radiation-induced lumbosacral plexopathy is unknown.

Mortality/Morbidity

Generally, the symptoms of radiation-induced lumbosacral plexopathy progress gradually and with variable rapidity. Clinical manifestations of the condition have appeared 3 months to 22 years after the completion of radiation therapy.[9] Jaeckle and colleagues found that 20% of patients developed moderate or even severe weakness over 6 months.[10] Others were found to have mild weakness at 4-5 years following the onset of neurologic symptoms.

Race

No race predilection for radiation-induced lumbosacral plexopathy has been reported.

Sex

The male-to-female ratio is 1:1.2.

Age

Age at the time of presentation ranges from 34-68 years, with a median age of 47.5 years.

With prior radiation treatment and initial symptoms, a recurrent tumor may need to be distinguished from radiation plexopathy. The median symptom-free interval for radiation-induced lumbosacral plexopathy, from treatment to the initial neurologic symptom, is 5 years, with a range of 1-31 years.[9]

• Patients with radiation-induced lumbosacral plexopathy most commonly present with painless weakness in 1 or both legs. Pain is present initially in only 10% of patients, although ultimately it is noted in as many as 50% of patients. The incidence of initial pain is lower than that of brachial plexopathy. This pain is described in varying terms, such as aching, burning, pulling, cramping, and lancinating; however, pain rarely is a major problem.

• Weakness is asymmetrical. At the height of illness, the ratio of bilateral to unilateral illness is 5:1. Acute lower extremity paralysis has been noted in a patient with cervical cancer 10 weeks after completion of radiation treatment.[11]

• Sensory loss occurs in 50-75% of patients and is more severe with greater motor impairment, which can add significantly to disability.

• Bladder or bowel incontinence may occur.[12]

Studies by Skolka et al indicated that in patients with early onset radiation-induced neuropathies, a painful, monophasic course is common. The reports included individuals with brachial and lumbosacral plexopathies, radiculopathies, and mononeuropathies, with post-radiation neuropathic onset averaging about 2 months. The patients’ responsiveness to steroids and the presence of microvasculitis suggested that an inflammatory-immune mechanism is associated with early onset radiation-induced neuropathies.[13, 14]  

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• In radiation-induced lumbosacral plexopathy, motor deficits in the lower extremities commonly are bilateral (80%) and asymmetrical. Diffuse limb weakness with distal predominance in L5-S1 distribution is relatively common (55% of patients). Exclusive proximal paresis in the distribution of L2-L4 is less common (10% of patients), as is femoral neuropathy (5% of patients). Moderate weakness is present in 50% of patients, with equal distribution of mild and severe weakness.

• Deep tendon reflexes (DTRs) almost always are abnormal at the knees and/or ankles and usually are present bilaterally.

• Sensory impairments are present in most patients (75%) and more often are bilateral. No specific sensory modality is favored. The distal lower extremities are affected more commonly than are the proximal lower extremities. Impaired deep sensation occurs with severe, superficial sensory loss.

• Skin changes may be present in areas of radiation portals.

Radiation dosage, treatment technique, and concomitant use of chemotherapy are associated with development of radiation-induced lumbosacral plexopathy.

Routine spine and pelvis radiographs and myelograms are unremarkable in lumbosacral plexopathy.

The diagnosis of radiation plexopathy can be supported by diagnostic studies, such as computed tomography (CT) scanning and magnetic resonance imaging (MRI) of the pelvis. MRI is more sensitive than is CT scanning in detecting tumor recurrence.[3, 4] Enhancement of nerve roots and T2-weighted hyperintensity usually suggests tumor. Unfortunately, differentiation from tumor recurrence remains difficult. Generally, radiation plexopathy does not produce nerve enhancement. Positron emission tomography (PET) scanning with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) may be helpful in diagnosing recurrent tumor.

Although PET/CT scanning can aid in differentiating tumor recurrence from radiation plexitis in oncology patients, it offers only limited resolution of the brachial or lumbosacral plexus.[19]

Electromyography (EMG) reveals myokymic discharges in most patients (57%) with radiation-induced lumbosacral plexopathy. Such changes occur over years; however, the absence of myokymia does not exclude radiation injury. EMG in clinically weak muscles also may reveal fibrillation potentials (ie, chronic, neurogenic motor unit changes with decreased recruitment). Paraspinal involvement occurs in 50% of cases. Compound muscle action potential (CMAP) of motor nerves may be low.[20, 21]

Physical Therapy

Strengthening of lower extremity muscles, use of assistive devices for ambulation (eg, cane, walker), and gait training should be prescribed for patients with weakness and proprioceptive feedback loss. Use of orthotics also may be beneficial in certain individuals with lumbosacral plexopathy.

Occupational Therapy

The patient's ability to perform activities of daily living (ADL) should be assessed, and appropriate assistive device(s) should be prescribed as needed. In particular, safety with standing transfers may be impaired with more distal involvement. With more proximal involvement, sit-to-stand transfers also may be affected. Strengthening exercises, along with sensory reeducation techniques, may be employed.

Treatment of radiation plexopathy is symptomatic. For issues of pain, consider the use of nonopiate pharmacologic medications, such as tricyclic antidepressants or antiepileptic agents (eg, gabapentin, carbamazepine). The use of steroids and opiates, including methadone, can also be assessed.

Nonpharmacologic measures, such as transcutaneous electrical nerve stimulation (TENS), may be used for pain.

While not studied in patients with radiation-induced lumbosacral plexopathy, hyperbaric oxygen therapy has not led to the slowing or reversal of radiation-induced brachial plexopathy symptoms, although improvement was noted in warm sensory threshold.[22]

In a small population, partial recovery of motor function was noted in few patients treated with anticoagulant therapy for a period of 3-6 months.

A study by Tunio et al indicated that radiation-induced lumbosacral plexopathy can be reduced by delineating the lumbosacral plexus through imaging and administering intensity-modulated radiotherapy (IMRT) so that radiation dosages of 40, 50, 55, and 60 Gy are absorbed by less than 55%, 30%, 5%, and 0.5% of the lumbosacral plexus volume, respectively. The study involved 50 patients with cervical cancer who underwent IMRT and high-dose-rate brachytherapy. Four patients had developed grade 2/3 radiation-induced lumbosacral plexopathy by 60-month follow-up.[23]

In a placebo-controlled, double-blind study of adults with radiation-induced upper or lower limb plexopathy, Delanian et al found no significant benefit to PENTOCLO (pentoxifylline 800 mg, tocopherol 1000 mg, clodronate 1600 mg 5 days per week) treatment, with regard to pain and paresthesia. Evaluation was made via the Subjective Objective Management Analytic (SOMA) score.[24, 25]

Tricyclic antidepressants (TCAs), such as amitriptyline, may be used in lower doses. The use of antiepileptics may be helpful.

Class Summary

TCAs have central and peripheral anticholinergic effects, as well as sedative effects, and block the active reuptake of norepinephrine and serotonin. The multifactorial mechanism of analgesia may include improved sleep, an altered perception of pain, and an increase in pain threshold. The efficacy of these drugs can be potentiated with the concomitant use of opiates and nonsteroidal anti-inflammatory drugs (NSAIDs). Rarely should these drugs be used in the treatment of acute pain, since a few weeks may be required for them to become effective.

Amitriptyline (Elavil)

Analgesic for certain chronic and neuropathic pain. Amitriptyline has the most anticholinergic side effects of all drugs in this category.

Class Summary

These drugs stabilize neuronal membranes and reduce neuronal hyperexcitability. The analgesic effect may be due to such stabilization and control of hyperexcitability, because aberrant electrical activity has been recorded with neuropathic pain.

Gabapentin (Neurontin)

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.

Carbamazepine (Tegretol)

Used typically for generalized tonic-clonic seizures and partial seizures, as well as for trigeminal neuralgia. Plasma levels are between 4-12 mcg/mL for analgesic and antiseizure response.

Valproic acid (Depakene)

Generally indicated for absence seizures and generalized tonic-clonic seizures. Some relief may be noted with neuropathic pain, especially the lancinating type.

Class Summary

Glucocorticoids have anti-inflammatory, hormonal, and metabolic effects. Inflammation is suppressed with the blockage of phospholipase A2, which inhibits the formation of arachidonic acid and, thus, the prostaglandins. The analgesic effect may be due to the anti-inflammatory activity, with a decrease in edema.

Dexamethasone (Decadron, AK-Dex)

For various allergic and inflammatory diseases. Dexamethasone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and by reducing capillary permeability.

Class Summary

These drugs are generally used for short-term, acute pain that is moderate to severe in nature, as well as for chronic pain (eg, cancer). They provide analgesia without antipyretic or anti-inflammatory action. The mechanism of action is the inhibition of nociceptive impulses at the dorsal horn of the spinal cord and at supraspinal sites due to interaction with opiate receptors. Structural derivatives of GABA are also used in the management of neuropathic pain.

Pregabalin (Lyrica)

Structural derivative of GABA. Pregabalin's mechanism of action is unknown. This agent binds with high affinity to the alpha2 -delta site (a calcium channel subunit). In vitro, pregabalin reduces the 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 an adjunctive therapy in partial-onset seizures.

Methadone (Dolophine)

Used in the management of severe pain. Methadone inhibits ascending pain pathways, diminishing the perception of and response to pain.

Morphine sulfate (Duramorph, MS Contin, Astramorph)

Available in immediate (3-4 h duration) and extended release preparation (12 h). Switch over to long-acting preparations (MS Contin) once pain is controlled with short-acting preparation (MS IR). Morphine can produce drug dependence and has the potential for being abused. Tolerance may develop with repeated exposure. Abrupt cessation or sudden reduction in dose with prolonged use may result in withdrawal symptoms. Physical dependence is not of paramount importance in terminally ill patients.

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• After radiation-induced lumbosacral plexopathy has been diagnosed, follow up with patients on functional issues. Address issues of pain in a timely fashion.

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• Inpatient care for radiation-induced lumbosacral plexopathy is not required.

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• Radiation-induced lumbosacral plexopathy may result in pain and decreased functional status.

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• Gradual, rather than stepwise, progression of radiation-induced lumbosacral plexopathy is the rule. Eventually, patients may have significant or severe disability. Spontaneous recovery is less common.[26]

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• Educate patients about the effects of radiation and the reason for altered function, pain, and sensory deficits.