Early Onset Post-Radiation Neuropathy

By Norman Latov, MD, PhD

Professor of Neurology, Weill Cornell Medicine

SYNOPSIS: Biopsy studies of early onset neuropathies seen after radiation therapy consistently show evidence of microvasculitis and other signs of inflammation. Early and rapid treatment with anti-inflammatory medications may be effective in stopping the progression and speeding up recovery.

SOURCE: Skolka M, Shelly S, Pinto MV, et al. Clinical, neurophysiologic, and pathologic features in patients with early-onset postradiation neuropathy. Neurology 2023;101:e1455-e1460.

Skolka and colleagues reviewed the clinical, neurophysiologic, and pathologic features of peripheral neuropathies with onset of less than six months after cancer radiation treatment. They identified 28 such patients, 16 men and 12 women, with a mean age of 63.8 years seen at the Mayo Clinic between 1999 and 2022.

Onsets averaged two months (range 0-5). The most frequent presentations were lumbosacral plexopathies (12 patients) or radiculopathies (10 patients), with four patients presenting with cervical plexopathy and two patients presenting with mononeuropathy. Nine patients had electromyography evidence for myokymia. Twenty-five patients had painful paresthesia, 25 patients had weakness, and two patients had autonomic symptoms. The clinical courses were subacute monophasic with incomplete recovery in 14 patients, chronic progressive course in eight patients, static course in one patient, and five patients did not have follow-up evaluations. Thirteen of 25 patients had abnormal magnetic resonance imaging, including 10 patients with nerve T2 hyperintensity. Eight of nine patients treated with a course of corticosteroids had a monophasic course, and one patient was lost to follow-up.

Eight of the patients had nerve biopsies; seven patients had sural nerve biopsy and one patient had sciatic fascicular biopsy. All had evidence for axonal loss, and all but one patient had evidence of inflammation and multifocal nerve fiber loss, including two of the patients with microvasculitis. The data suggest that radiation can cause neuropathy by triggering an inflammatory ischemic process and that early treatment with corticosteroids might help ameliorate the inflammation or development of neuropathy.

COMMENTARY

Early onset radiation-induced neuropathy differs from the chronic or delayed onset post-radiation neuropathy in that the latter typically begins at an average of 20 years post-radiation, has a chronic progressive course, is predominately motor, and has no treatment. It is not known whether the chronic neuropathy is triggered by the same mechanisms as the early onset neuropathy, but both are associated with microvascular injury and fibrosis, and both exhibit myokymic discharges from hyperexcitable motor axons, indicating similar structural and electrophysiologic alterations.¹ However, the inflammatory changes are not characteristic of the delayed onset neuropathy.

Radiation can induce cell death by several different mechanisms, including apoptosis, necrosis, autophagy, pyroptosis, ferroptosis, and immunogenic cell death.² Immunogenic cell death is mediated by activation of the adaptive immune responses to cellular antigens that are expressed by dead or damaged cells, explaining the inflammatory changes seen in the nerve biopsies. The immunological reaction adds to the anti-tumor effects of the radiation but also can induce immune reactivity to normal tissues that share some of the same antigens. Inflammation also can trigger fibrosis, possibly explaining some of the pathological changes in the more chronic neuropathies.³ Of interest, the inflammatory changes noted by the authors were seen in nerve segments distal to the sites of irradiation, so that they appear to be propagated along the course of the nerves, probably via axonal loss and microglial activation.

However, radiation injury also can trigger fibrosis by non-inflammatory mechanisms, such as abnormal activation of myofibroblasts with excessive accumulation of extracellular matrix.⁴ The delayed onset that is seen in chronic post-radiation neuropathy draws parallels to the post-polio syndrome, where there is delayed failure of axonal regeneration or an inability to maintain axonal sprouts by the previously injured nerve cells.⁵ Radiation also can induce endothelial cell premature senescence, which can present with delayed symptomatology.⁶

The monophasic or more limited disease observed in patients who were treated with corticosteroids suggests that the inflammatory changes are responsible for the early onset neuropathy, and that treatment with anti-inflammatory agents post-radiation may prevent or ameliorate the neuropathy. An intriguing parallel is the recently Food and Drug Administration-approved use of low-dose colchicine for prevention of cardiovascular events in patients with atherosclerosis, also by inhibition of the inflammatory changes that can contribute to ischemic vasculopathy.^7,8 Either agent would be an attractive therapeutic candidate that could be tested in prospective controlled trials in patients with radiation-induced neuropathy.

REFERENCES

1. Delanian S, Lefaix JL, Pradat PF. Radiation-induced neuropathy in cancer survivors. Radiother Oncol 2012;105:273-282.
2. Jiao Y, Cao F, Liu H. Radiation-induced cell death and its mechanisms. Health Phys 2022;123:376-386.
3. Mack M. Inflammation and fibrosis. Matrix Biol 2018;68-69:106-121.
4. Yu Z, Xu C, Song B, et al. Tissue fibrosis induced by radiotherapy: Current understanding of the molecular mechanisms, diagnosis and therapeutic advances. J Transl Med 2023;21:708.
5. Dalakas MC. Pathogenetic mechanisms of post-polio syndrome: Morphological, electrophysiological, virological, and immunological correlations. Ann N Y Acad Sci 1995;753:167-185.
6. Wang Y, Boerma M, Zhou D. Ionizing radiation-induced endothelial cell senescence and cardiovascular diseases. Radiat Res 2016;186:153-161.
7. Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in patients with chronic coronary disease. N Engl J Med 2020;383:1838-1847.
8. Lou N. Colchicine's rebirth as a cardiovascular drug approved by FDA. MedPage Today. Published June 20, 2023. https://www.medpagetoday.com/cardiology/prevention/105096