We described a cervical cancer patient who received successful radiation treatment but developed a substantial radiotherapy-related long-term complication—RILP. The most remarkable aspect of this case is the occurrence of the RILP 36 years after the therapeutic radiotherapy. To the best of our knowledge, this is the longest time between irradiation and the development of RILP described in the literature.
This example demonstrates that patients presenting with lower extremity weakness, hypoesthesia, or pain more than 30 years after radiation therapy delivered to the pelvis should be evaluated for radiation-induced plexopathy.
Radiation-induced plexopathy is a rare consequence of cancer therapy that may be difficult to diagnose and cure. According to the literature, it is characterised by a dormant interval between radiation exposure and the onset of symptoms . Several cases of delayed manifestation of radiation damage to the lumbosacral plexus have been described in the literature [2, 4, 6, 7, 11].
Numerous risk factors associated with radiotherapy have been identified: large total dose (> 50 Gy to plexus), large dose per fraction (2.5 Gy), heterogeneous high-dose distribution, hot spot high dose, and using an intracavitary radium source [1, 3, 12]. Low-energy devices operated in the 1970s used a close source-to-skin distance, alternating treated fields with steep dosage gradients inside the body .
Even though our case did not exceed the dose constraints to the plexus, as the total dose of external beam radiotherapy to the pelvis was 40 Gy, numerous risk factors were involved, including the use of an older generation radiation source (betatron) and the intracavitary radium source.
Radiation-induced adverse effects on the nerve cells may be categorised into early and late stages. Early effects manifest as bioelectrical abnormalities, enzyme modifications, aberrant microtubule assembly, and altered vascular permeability during irradiation. The late effects manifest anytime between one year and decades after irradiation and may be divided into two phases. The first phase is characterised by alterations in the electrophysiology and histochemistry of neurons and glial cells; the second phase is characterised by fibrosis of the nerve-supporting tissue [11, 13]. Recent studies also suggest that compression of nerves produced by severe indirect radiation-induced fibrosis is another essential factor . Thus, the pathogenesis of RILP has not been fully explained; it is a kind of delayed local nerve tissue damage that is partially caused by early microvascular injury followed by radiation-induced fibrosis . In our case, retroperitoneal fibrosis was also present. Its contribution to RILP could be questioned, but it clearly resulted in complications other than neurological, such as uretrohydronephrosis.
The onset of RILP neurological symptoms is typically gradual, with the majority of nerve damage being motor-related. The initial symptoms of RILP are diminished muscular strength. Sensory impairments together with neuropathic pain are typically discovered later. Symptoms are usually bilateral and asymmetric, with initial unilateral damage [1, 3, 14]. Our case fits this description; the disease manifested initially as bilateral and asymmetric lower extremity weakness, followed by sensory impairment and neuropathic pain.
The diagnosis of RILP is established by the exclusion of other conditions. Differential diagnoses include particularly metastasis and local tumour growth that result in direct compression or infiltration of the lumbosacral plexus or lumbosacral roots, neuroinfection, connective tissue diseases, systemic vasculitis,polyneuropathy, spondylogenic disorders especially lumbar spinal stenosis with compression of lumbosacral roots. Minimal workup should include laboratory studies, cerebrospinal fluid analysis, NCS/needle EMG, and radiological imaging, preferably MRI, of the pelvis and lumbar spine [15, 16].
The initial examination thus usually includes radiological imaging of the lumbar spine and pelvis, which is crucial to rule out tumour invasion and spondylogenic compression of the lumbosacral roots in the lumbar spinal canal. Although cerebrospinal fluid analysis is critical for ruling out malignant cells or infection, it may detect elevated cerebrospinal fluid protein level in some RILP patients but does not reveal any specific findings [1, 3, 10]. The NCS/needle EMG of the lower extremities is used to determine the location, phase and severity of plexus injury .
Three criteria for determining the diagnosis of RILP have been established: 1) there is a history of radiotherapy that includes the plexus, 2) the primary neurologic lesion is contained within the radiotherapy-exposed segments, 3) metastatic and other disorders of the plexus have been ruled out . Our patient met these three criteria. Initially, however, the diagnosis of RILP was not considered because the lower extremity NCS/needle EMG was misinterpreted, and spondylosis of the lumbar spine was overestimated.
In contemporary clinical practice, there is no definitive treatment for RILP. The therapeutic modalities should be aimed at relieving pain, paraesthesia, psychological distress, strengthening the muscles, and preserving the range of motion in joints of the lower extremity. Once the severe weakness is established, it is extremely unlikely to recover regardless of treatment due to severe axonal damage [1, 3, 10, 17].
Neuropathic pain is the main type of pain in RILP patients. Several recommendations and guidelines for neuropathic pain pharmacotherapy have been proposed [18, 19]. In light of these recommendations, tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitor (SNRI) antidepressants, pregabalin, and gabapentin are the most suitable for the treatment of neuropathic pain . However, the treatment of neuropathic pain should be comprehensive, and rehabilitation is also recommended (in the form of a tailored rehabilitation programme and physical therapy), as are neurostimulation techniques (e.g. transcutaneous electrical nerve stimulation, high-frequency repetitive transcranial magnetic stimulation of the motor cortex) [19, 20]. Psychotherapy is an integral part of neuropathic pain treatment (cognitive behavioural therapy and mindfulness), recommended as a second-line therapy, as an add-on to other therapies . Rehabilitation of RILP patients assists not only in pain relief but also in strengthening the muscles and avoiding joint contractures.
In our case, pregabalin was used because of its tolerability, effectiveness in alleviating neuropathic pain, and ability to improve mood states in patients with radiotherapy-related neuropathic pain with great effect . Even though the pregabalin dose was low (25 mg once every two days) due to severe renal insufficiency and lower extremity oedema, the effect on neuropathic pain was excellent because pain intensity as assessed by the NRS was reduced by 83% with pregabalin administration.
Two years after the initial admission to our clinic, the patient’s lower extremity neuropathic pain was well tolerated on pregabalin and the neurological deficit remained stable, so sensory impairment and pareses of the lower extremities remained unchanged. Even though the pareses have not worsened over the last two years and the neuropathic pain has been manageable, there is no expectation that patient’s motor deficit would be completely recovered. However, all used therapeutic modalities have aimed to preserve the patient’s quality of life and ability to participate in activities of daily living.
As a result of the lack of a curative method, the optimal approach is prevention. When radiotherapy to the small pelvis is chosen as the treatment modality, the optimal strategy is to avoid exceeding dose-volume constraints to pertinent at-risk organs by employing state-of-the-art radiotherapy technologies (for example volumetric modulated arc therapy) .