Complications of spinal cord irradiation

INTRODUCTION — Radiation therapy can cause toxicity to either the central or peripheral nervous system when these structures are exposed to radiation doses beyond their tolerance. Nervous system toxicity is usually subdivided into acute (during the course of radiation), early delayed (weeks to three months after radiation), and delayed reaction (more than three months after radiation).

Several syndromes of radiation injury to the spinal cord have been described, the most prominent of which are a self-limited transient myelopathy and the more serious chronic progressive myelopathy. Other more disabling manifestations of radiation injury, including acute paralysis secondary to ischemia, hemorrhage within the spinal cord, and a lower motor neuron syndrome, are much less common, with only a few case reports in the literature [1,2].

The complications that can occur following irradiation of the spinal cord will be reviewed here. Other relevant topics include:

●Complications of cranial irradiation (see "Acute complications of cranial irradiation" and "Delayed complications of cranial irradiation")

●Complications of irradiation of peripheral nerves (see "Brachial plexus syndromes", section on 'Neoplastic and radiation-induced brachial plexopathy' and "Lumbosacral plexus syndromes", section on 'Radiation plexopathy')

EARLY RADIATION-INDUCED MYELOPATHY — Although acute central nervous system damage has been reported following brain irradiation, there is no clinical or experimental evidence that radiation induces acute spinal cord toxicity. In historical studies, single doses of up to 100 Gy did not result in immediate acute toxic effects [3].

A transient radiation-induced myelopathy may develop two to six months following spinal cord irradiation. This condition is believed to represent reversible demyelination of ascending sensory neurons due to inhibition of oligodendrocyte proliferation, which makes the axons more sensitive to irritation from neck flexion. The typical duration of this acute myelopathy is approximately six months, and it is not generally a precursor of chronic progressive myelitis.

The characteristic manifestation of transient radiation myelopathy is the development of Lhermitte sign, a nonpainful but unpleasant electric shock-like sensation that shoots down the spine during neck flexion. Increased spinal cord metabolic activity and positive positron emission tomography (PET) imaging have been described in association with Lhermitte sign [4].

The incidence of Lhermitte sign is difficult to estimate [5-7]. In two large observational series in patients with Hodgkin lymphoma and nasopharyngeal cancer, Lhermitte sign developed in 4 and 10 percent, respectively, at a mean of three months after radiation [5,7]. Some dose dependence of radiation to the cervical spinal cord was noted: a mean spinal cord dose of 30 Gy and spinal cord volumes exposed to doses higher than 40 Gy were described as risk factors for development of Lhermitte sign [5,8].

The differential diagnosis of Lhermitte sign in cancer patients includes tumor progression causing spinal cord compression, as well as other treatment complications, such as cisplatin or docetaxel neurotoxicity. Other causes of spinal cord disease that can result in Lhermitte sign include demyelinating diseases (eg, multiple sclerosis), vitamin B12 deficiency, and structural abnormalities of the spinal canal (eg, cervical spondylosis). (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression" and "Overview of neurologic complications of conventional non-platinum cancer chemotherapy" and "Overview of neurologic complications of platinum-based chemotherapy" and "Manifestations of multiple sclerosis in adults" and "Treatment of vitamin B12 and folate deficiencies".)

No active intervention is required other than explanation and reassurance; the syndrome usually resolves spontaneously over a period of months to a year. If the discomfort is severe, carbamazepine or gabapentin may be beneficial. (See "Cancer pain management: Role of adjuvant analgesics (coanalgesics)".)

LATE RADIATION-INDUCED MYELOPATHY — Delayed injury to the spinal cord typically presents as a chronic, progressive myelopathy. Although rare, chronic progressive myelopathy is an ominous late complication of radiation. Unlike transient myelopathy, it is usually irreversible, and there is no treatment with established benefit [9].

Pathology and pathogenesis — Two types of pathologic change can occur in patients with radiation myelopathy [10,11]. The first is damage to white matter that ranges from demyelination, through Wallerian degeneration of axons, to frank necrosis. The second change is in blood vessels that can extend from morphologically intact vessels to fibrinoid necrosis and hemorrhage [11,12]. The degree of morphologic derangement does not always correlate with clinical severity of the myelopathy. Symptoms usually reflect the size and location of the lesions [10].

The pathogenesis of radiation myelopathy is incompletely understood [13]. The adult spinal cord contains multipotential stem cells that can differentiate into oligodendroglial cells as well as astrocytes. Both oligodendroglial cells and their precursor cells can be damaged by radiation, leading to loss of myelin function. Radiation also stimulates astrocytes and microglial cells to produce cytokines. One of these cytokines, vascular endothelial growth factor (VEGF), increases the permeability of spinal cord blood vessels leading to edema [14]. The role that this and other cytokines play in the damage to blood vessels and cellular structures of the spinal cord is unknown.

Radiation dose-volume effects and risk — The influence of dose and fractionation on the risk of chronic radiation myelopathy can be understood in three contexts: fractionated radiation, hypofractionated radiation, and reirradiation. Whereas conventional or three-dimensional (3D) conformal radiation techniques resulted in rather homogeneous dose exposure of the spinal cord, modern intensity-modulated radiotherapy techniques are frequently characterized by inhomogeneous doses within the spinal cord, both on an axial as well as on a craniocaudal level. In this context, maximum doses are considered to be most closely correlated with the risk of myelopathy. However, exposure of a large low-dose bath around a high-dose peak (shower) has been proposed to increase the risk of myelopathy [15].

Historically, analyses of the impact of dose and fractionation on radiation myelopathy have been inconsistently reported, in part because older treatment planning systems are less reliable in reporting maximum point dose and other parameters along the dose-volume histogram of the spinal cord. Additionally, survival has improved in many cancer types, especially in the palliative setting, which needs to be considered when interpreting historical data with only short follow-up.

Fractionated radiation — A Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) study, sponsored by the American Society for Radiation Oncology (ASTRO) and the American Association of Physicists in Medicine (AAPM), analyzed the literature on the risk of chronic radiation myelopathy as a function of the total dose of radiation, the extent of the spinal cord included in the treatment field, and the size of individual treatment fractions [16]. In this review, using a conventional fractionation schedule (2 Gy per day) and including the entire cross-section of the spinal cord, total doses of 50, 60, and 69 Gy were associated with risks of chronic myelopathy of 0.2, 6, and 50 percent, respectively.

Hypofractionated radiation — Hypofractionated radiation employs dose and fractionation schedules with a daily dose of ≥4 Gy per day. It is typically used in either low-dose palliative radiotherapy or in high-dose stereotactic body radiation therapy (SBRT).

The QUANTEC study determined that with SBRT to a partial section of the spinal cord, the risk of radiation myelopathy with a single fraction of 13 or 20 Gy divided into three fractions was less than 1 percent [16,17]. Subsequent data reported that for de novo SBRT delivered in one to five fractions, the following spinal cord point maximum doses (Dmax) are estimated to be associated with a 1 to 5 percent risk of radiation myelopathy: 12.4 to 14 Gy in one fraction, 17 Gy in two fractions, 20.3 Gy in three fractions, 23 Gy in four fractions, and 25.3 Gy in five fractions [18,19].

Practice patterns from an international research consortium reported spinal cord limits that varied from 10 to 11 Gy in one fraction, 15 to 18 Gy in three fractions, and 20 to 23.75 Gy in five fractions [20]. In most centers, these doses were applied to a 1 to 1.5 mm expansion around the spinal cord.

Reirradiation — The use of spinal reirradiation is growing as patients with spinal metastases are living longer and experiencing failures after conventional radiation therapy. In all cases of reirradiation, caution and conservatism must be used in patient selection, target delineation, and choice of cord tolerance. Preclinical data suggest that there is substantial recovery in primate spinal cord tolerance over time, to 76, 85, and 101 percent of the initial dose at one, two, and three years, respectively [21,22].

A retrospective study analyzed predictive factors for development of myelopathy in 40 patients treated with spine reirradiation, 11 of whom developed myelopathy after a median of 11 months [23]. A risk score was proposed with three key parameters resulting in low risk of myelopathy: cumulative radiotherapy doses of ≤135.5 Gy (biologically effective dose [BED] with alpha/beta = 2 Gy [cervical and thoracic spine] and alpha/beta = 4 Gy [lumbar spine]), ≥6 month interval between the two radiotherapy courses, and dose of each course ≤98 Gy.

The QUANTEC study reviewed 13 single-center series, all of which reported a median interval of ≥6 months between radiation courses [16]. No cases of myelopathy were observed for cumulative doses of ≤60 Gy in 2 Gy equivalent doses.

In the context of spine SBRT for reirradiation, a systematic review of the literature reported a low risk of radiation-induced myelopathy of 1.2 percent [24]. A multicenter study concluded that reirradiation appeared to be safe when five or more months elapsed after conventional radiation and specific dosing parameters were met [25], which was confirmed by another large multicenter analysis reporting no cases of myelopathy after SBRT reirradiation in 215 patients [26]. A Canadian series reviewed outcomes of reirradiation after prior spine SBRT [27]. Fifty-six spinal segments in 40 patients were previously treated with a first course of a median of 24 Gy in two fractions. At the time of progression, a salvage course of SBRT was provided with a median dose of 30 Gy in four fractions. The one-year local control was 81 percent, and no cases of myelopathy were reported.

Clinical presentation — The clinical manifestations of radiation myelopathy range from minor sensory or motor deficits to complete paraplegia. Symptom onset is most often insidious. The latency period prior to onset of symptoms is often greater than six months. In one series, the mean latency period was 18.5 months after a first course of radiation and 11.4 months in previously irradiated patients [28].

The initial signs can be subtle, such as decreased temperature sensation or decreased proprioception. These signs may stabilize or slowly but inexorably progress to lower extremity weakness, foot drop, the Brown-Sequard syndrome, incontinence, hyperreflexia, loss of bowel and bladder function, or complete paresis below the irradiated section of the spinal cord. Rarely, neurologic symptoms remit [29,30]. Unlike with spinal metastases, back pain is absent.

Risk factors — In addition to dose and field of radiation, there is evidence that radiosensitizing systemic agents may increase the risk of late radiation myelopathy. Case reports describe late myelopathy after radiation in combination with doxorubicin, cisplatin/fluorouracil, and high-dose busulfan/melphalan [31-33].

In preclinical studies, agents such as intrathecal cytarabine and intraperitoneal fludarabine enhance radiation injury to the spinal cord [34,35]. Preclinical data also suggest that an immature spinal cord may be at higher risk for radiation myelopathy, and therefore additional caution should be used in very young patients [36].

Diagnosis — Other etiologies should be excluded prior to diagnosing chronic radiation myelopathy. The most common cause of myelopathy in cancer patients is disease progression or development of new metastases [10]. The differential diagnosis also includes neurotoxicity caused by chemotherapy, trauma, B12 deficiency, paraneoplastic syndromes, and demyelinating diseases such as multiple sclerosis [37]. (See "Disorders affecting the spinal cord".)

The diagnosis of radiation myelopathy is usually made clinically and supported by spinal magnetic resonance imaging (MRI). Factors that can help clarify the role of radiation-induced damage include the dose of radiation to the spinal cord and the latency period between radiation and the onset of symptoms [10].

On MRI, radiation-induced myelopathy is typically characterized by intramedullary T2 hyperintensity and T1 hypointensity spanning the affected segments. Focal contrast enhancement after gadolinium may be present. Limited data suggest that apparent diffusion coefficients (ADCs) may add additional sensitivity [38]. Much later there may be only atrophy without evident signal abnormality [39]. When radiotherapy records are unavailable, the radiation port can often be discerned by the hyperintense appearance of the irradiated vertebral bodies on T1-weighted images.

Spinal fluid examination is usually not helpful with only an increase in the protein concentration. Evoked potentials may show a spinal conduction velocity block.

Treatment — Because of the severity of chronic progressive radiation myelopathy, a variety of treatment approaches have been suggested. However, none are supported by robust clinical data [40].

Glucocorticoids are the most common first treatment for radiation myelopathy. Symptomatically, some patients will respond at least partially to a trial of glucocorticoids (eg, dexamethasone 4 to 8 mg per day). Care should be taken to use the lowest effective dose and to taper steroids in patients who do not respond clinically. Steroid myopathy related to chronic steroid use is of particular concern, as it may worsen preexisting deficits related to the myelopathy itself.

Other strategies have been extensively studied in preclinical settings but have few clinical data to support their use [41]. The strongest supporting evidence is for antiangiogenic agents such as bevacizumab, a monoclonal antibody against VEGF-A. In a small placebo-controlled randomized trial for central nervous system radiation necrosis (not specifically limited to spinal cord), bevacizumab led to both radiographic and neurologic improvements in the majority of patients [42]. Case reports describe successful use in several patients with late radiation-induced myelopathy; however, despite improvements in imaging follow-up, only limited clinical benefit was observed [43]. (See "Delayed complications of cranial irradiation", section on 'Treatment'.)

Some anecdotal evidence suggests that therapy with hyperbaric oxygen might be useful [44,45], but in animal models prophylactic hyperbaric oxygen did not prevent radiation myelopathy [46]. A study of 11 patients suggested that anticoagulation with heparin and warfarin could play a role in recovery of function [47].

There is no clinically proven strategy to prevent the onset of radiation myelopathy. Growth factors (eg, platelet-derived growth factor, insulin-like growth factor 1, VEGF, and basic fibroblast growth factor) appear to prevent or delay radiation myelopathy in preclinical studies [48]. In animal models, both magnesium and vitamin E ameliorate lipid peroxidation [49], a biochemical abnormality believed to be related to radiation damage.

OTHER LATE COMPLICATIONS — Delayed injury to the spinal cord typically is manifested by a chronic, progressive myelopathy. Less commonly, such injury can be manifested as a lower motor neuron syndrome or as a hemorrhagic injury from a radiation-induced telangiectasia or cavernous angioma.

Lower motor neuron syndrome — The lower motor neuron syndrome was originally described after radiation therapy for testicular cancer, but this syndrome can follow any radiation therapy involving the lower spinal cord and cauda equina [50-52]. Although this was originally thought to reflect damage to anterior horn cells, it is in fact a radiculopathy rather than a neuronopathy [53]. The disorder follows radiation therapy by 3 to 25 years, after which patients develop slowly progressive weakness of lower extremities with little or no sensory loss and normal, or almost normal, bladder and bowel function. The magnetic resonance imaging (MRI) shows gadolinium enhancement of the roots of the cauda equina. Pathologic changes suggest a vasculopathy of proximal spinal roots with preservation of lower motor neurons within the spinal cord. Many patients remain ambulatory for many years, although weakness continues to progress.

Spinal cord hemorrhage — Damage to spinal cord blood vessels can, in rare instances, lead to telangiectasia and even cavernous malformations [6]. As many as 30 years after radiation therapy to the spinal cord, patients can develop acute hemorrhage [2,54]. There is usually sudden onset of weakness and sensory change, sometimes associated with pain. The MRI shows evidence of acute hemorrhage. Patients usually recover.

SUMMARY

●Early myelopathy – A transient radiation-induced myelopathy may develop in up to 10 percent of patients two to six months following spinal irradiation. This condition, which is manifested by Lhermitte symptom, is self-limited and does not predict for the subsequent development of chronic progressive myelopathy. (See 'Early radiation-induced myelopathy' above.)

●Late myelopathy – Chronic progressive myelopathy is an ominous late complication of radiation. Unlike transient myelopathy, it is usually irreversible. (See 'Pathology and pathogenesis' above.)

Radiation myelopathy is typically manifested by paresis, numbness, and sphincter dysfunction developing 6 to 12 months after irradiation. Symptoms are progressive and there is no established treatment. (See 'Clinical presentation' above and 'Diagnosis' above and 'Treatment' above.)

The risk of chronic myelopathy after radiation is proportional to the total radiation dose, anatomic extent of spinal cord irradiation, and radiation fraction size. These risks must be understood in the contexts of fractionated radiation, hypofractionated radiation, and reirradiation. (See 'Radiation dose-volume effects and risk' above.)

●Lower motor neuron syndrome – The lower motor neuron syndrome is a disorder that follows radiation therapy by 3 to 25 years. Patients slowly develop progressive weakness of lower extremities with little or no sensory loss and normal, or almost normal, bladder and bowel function. (See 'Lower motor neuron syndrome' above.)

●Spinal cord hemorrhage – Damage to spinal cord blood vessels can lead to telangiectasia and even cavernous malformations, which can result in an acute hemorrhage. (See 'Spinal cord hemorrhage' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Brian Kavanagh, MD, MPH, and Kevin Oh, MD, who contributed to an earlier version of this topic review.