The spinal cord is considered to be an extension of the central nervous system house and protected by the vertebral bodies (Fig. 2a). The spinal nerves constitute the peripheral nervous system (PNS) and will be presented sequentially after the spinal cord to provide continuity in discussing the nervous topical headings in this chapter outline.

The spinal cord consists of bundles of motor and sensory tracts, surrounded by the thecal sac, which is, in turn, encased by the spinal canal (Goetz 2003). The spine canal consists of 7 cervical, 12 thoracic, 5 lumbar, and 5 sacro-coccygeal bony vertebrae. Together the spinal canal and cord comprise the spine. While the spinal cord proper extends from the base of skull through the top of the lumbar spine—typically, the level of the first or second lumbar vertebrae in adults versus the second or third lumbar vertebrae in neonates—individual nerves continue down the spinal canal to the level of the pelvis. The conus medullaris is the cone-shaped termination of the caudal cord located in the upper lumber spinal canal. The cord is tethered to the coccyx caudally by the filum terminale, a continuation of the pia mater. The cauda equina (L. horse tail) consists of lumbar and sacral spinal nerve roots traveling inferiorly from the cord prior to emerging from the spine through the intervertebral foramina.

The major neurolinks between the brain and the body is via the spinal cord through the peripheral nervous system via spinal nerves that branch out to somatic peripheral nerves or the autonomic neurons to vital viscera.

A large number of small-animal studies have been conducted to explore spinal cord tolerance to de novo radiation and re-irradiation, including time-dependent repair of such damage. A number of reports suggest regional differences in radiosensitivity across the spinal cord (Corderre et al. 2006; Phillipens et al. 2007). The clinical endpoint in most of these studies is paralysis, with the spinal cord exhibiting non-specific white matter necrosis pathologically. The principal pathogenesis of injury is generally believed to be due to vascular endothelial damage, glial cell injury, or both (Schultheiss et al. 1995; Corderre et al. 2006). Utilizing precisely focused proton irradiation of the rat spinal cord, Bijl et al. (2002, 2005) demonstrated large regional differences in cord radiosensitivity. There was a rightward shift in the dose response curve from 20.6 Gy (ED50) with full thickness irradiation, compared to 28.9 and 33.4 Gy for lateral cord treatment (wide and narrow geometry, respectively), and 71.9 Gy when only the central portion of the cord was treated. White matter necrosis was observed in all paralyzed rats, with none seen in non-responders. No damage was observed in central gray matter for doses up to 80 Gy. The differences in central versus peripheral response were attributed to vascular density differences in these regions, with a potential role for differential oligodendrocyte progenitor cell distribution. However, an alternative explanation may be the functional differences in the cord white matter regions irradiated (Nelson et al. 2009), especially given the clinical endpoint of paralysis, which would not be expected if sensory tracts were preferentially irradiated. No similar reports are available in higher order species, making application of these findings to SBRT difficult.

Various small-animal studies support a time-dependent model of repair for radiation damage to the spinal cord (Ang et al. 1983, 1993, 2001; Knowles et al. 1983; Ruifrok et al. 1994; Wong and Hao 1997). For example, Ang et al. (1993) treated the thoracic and cervical spines of 56 Rhesus monkeys to 44 Gy, and then re-irradiated these animals with an additional 57.2 Gy at 1 or 2 years (n = 36), or 66 Gy at 2 or 3 years (n = 18), yielding total final doses of 101.2 and 110 Gy, respectively. The primary endpoints of this study were lower extremity weakness or balance disturbances at 2.5 years after re-irradiation. Of 45 animals evaluated at the completion of the observation period, four developed endpoint symptoms. A re-irradiation tolerance model developed by combining this data with that of a prior study of single dose tolerance in the same animal model resulted in an estimated recovery of 33.6 Gy (76 %), 37.6 Gy (85 %), and 44.6 Gy (101 %) at 1, 2 and 3 years, respectively (Ang et al. 2001). Using conservative assumptions, an overall recovery estimate of 26.8 Gy (61 %) was obtained. In other words, after an initial course of ≈44 Gy, the cord “forgot” roughly 60 % of this dose ≈2 years later.

In the initial evaluation, a detailed history and physical exam, with special attention to neurologic signs and symptoms, should be obtained. These data are essential for establishing a baseline status against which changes in neurologic function can be measured, correlating functional deficits with anatomic lesions identified on imaging (below), and identifying patient factors, such as diabetes, peripheral vascular disease, pre-existing cognitive deficits, social support resources and recent/concurrent medications, that will influence the choice of and response to therapy.

The most widely observed clinical dose limits are 45 Gy in 22–25 fractions of 1.8–2.0 Gy, and a TD₅ of 50 Gy has been suggested. However, this TD₅ value is overly conservative. While a 5 % risk might be considered clinically acceptable for other organs, a 5 % risk is clearly unacceptable for the spinal cord given the severe clinical consequences of myelopathy. Thus, the historical TD₅ value was more accurately describing the dose that would yield a clinically acceptable complication rate (closer to ≈1 per 1,000; i.e., the TD_0.1).

Published reports of radiation myelopathy rates for 335 and 1,946 patients receiving radiotherapy to the cervical and thoracic spine, respectively, are summarized in Tables 3 and 4. While a few of these patients received relatively high doses/fraction, none were treated using stereotactic techniques to exclude a portion of the circumference of the cord. Note that the dose to the cord is the prescribed dose reported in those studies; typically, dosimetric data were not available to calculate the true cord dose. The probability of myelopathy was derived from the raw percentage of patients developing myelopathy by correcting for the estimated overall survival as described by Schultheiss (2008).

Using the above data, Schultheiss (1986, 2008) estimated the risk of myelopathy as a function of dose. The 2-Gy equivalent dose using the LQ model with the α/β ratio of 0.87, is calculated for each study (Schultheiss 2008) in Tables 3 and 4. A good fit to the combined cervical and thoracic cord data reportedly was not possible and separate analyses were performed. For the cervical cord data, values of D₅₀ = 69.4 Gy and α/β = 0.87 Gy were obtained with a Pearson χ² statistic of 2.1 for 5 degrees of freedom, providing a reasonable fit of the model as shown in Fig. 6a. The 95 % confidence intervals were 66.4–72.6 Gy for D₅₀ and 0.54–1.19 Gy for α/β. At 2-Gy per fraction, the probability of myelopathy is 0.03 % for a total dose of 45 Gy and 0.2 % at 50 Gy. However, the further one gets into the tail of the dose–response function, the more dependent the estimates become on the statistical distribution used to model this function.

Because of the dispersion in the thoracic cord data, a good fit of these data reputedly could not be obtained. As shown in Fig. 6b, most of the thoracic cord data points lie to the right of the dose–response curve for the cervical cord. This suggests that the thoracic cord is less radiation sensitive than the cervical cord. For external beam radiotherapy (EBRT) to the spinal cord in 2 Gy daily fractions, the risk of myelopathy appears low (<0.2 %) at 50 Gy and modest (<10 %) at 60 Gy, with an approximately 50 % risk of myelopathy at 70 Gy, based on the above analysis. Note that earlier “consensus opinions” (Withers et al. 1988; Emami et al. 1991) suggested more conservative guidelines for spinal cord tolerance, likely as a result of the concern for the severe disability resulting from spinal cord damage (Fowler et al. 2000).

There is an increased risk of myelitis following use of a continuous hyperfractionated accelerated radiation treatment (165), suggesting that a 6-h interval between treatments is insufficient to allow for significant repair. Shortening the interval between treatments from 24 h to 6–8 h reduces spinal cord tolerance by 10–15 %. In animal models, the dose rate also influences risk (van der Kogel 166, 167).

A suggested association between dose, volume, and risk of myelopathy is shown in Fig. 6c. The right y-axis indicates the tolerance dose ranges for the TD_5–50 for whole organ irradiation. The left axis relates dose to risk for variable volumes irradiated. (Modified from Rubin et al. 1997). The volume effect has been assessed in animal studies.

In recent series of experiments, four different lengths of the rat spinal cord (2, 4, 8, and 20 mm) were irradiated with single doses of protons (150–190 MeV) using paralysis as functional endpoint. A minor increase in tolerance was observed when the irradiated rat cord length was decreased from 20 mm (ED₅₀ = 20.4 Gy) to 8 mm (ED₅₀ = 24.9 Gy), whereas a large increase in tolerance was observed when the length was further reduced to 4 mm (ED₅₀ = 53.7 Gy) and 2 mm (ED₅₀ = 87.8 Gy). These results suggest that for small field lengths there may be a volume effect and that tiny overlaps of RT fields in the clinic might be tolerable, but that anything more than a few mm would not be tolerated.

These investigators also addressed the significance of partial volume irradiation and inhomogeneous dose distributions to the cord using a “bath and shower” approach. “Bath” irradiation represents doses to a larger volume that are on both sides of a “shower” irradiation focused on a smaller volume (i.e., a low dose bath with a focal hot spot shower in the middle). For different bath doses, the ED₅₀ for spinal cord damage was determined, and compared to the situation with a bath dose of zero (i.e., homogeneous irradiation of the spinal cord to the shower dose). With a bath dose of zero, the ED₅₀ is relatively high (e.g., >80 Gy for a 2 mm length of cord irradiated). The ED₅₀ values drop dramatically even at modest bath doses (Fig. 6d). The effect of the bath dose was greatest at smaller size shower doses, and was relatively modest when the shower field lengths increased to 8 mm (Bijl et al. 2002, 2003).

In concert, one interpretation of these data is that there are neighborhood effects that ‘protect/mitigate’ the cord injury, but that these protective effects can extend only a few mm in length. For example, one might hypothesize that a 2 mm focus of high dose radiation (i.e., shower in the above vernacular) leads to local damage that is “mitigated by the neighborhood” only a mm or two away. As the focus of high dose is enlarged, there is less capability for such mitigation since the distance between the irradiated and non-irradiated tissues is, on average, greater. The bath dose, that is low enough not to cause any evident functional consequences by itself, appears to reduce the ability of the neighboring tissues to provide mitigation. The clinical implications of these data are interesting. Inadvertent overdoses of the cord may occur in the setting of abutting RT fields (e.g., via mis-calculated gaps, or set-up errors). At first blush, the data on the far left-hand side of Fig. 6d might suggest that tiny regions of overlap (e.g., 1–2 mm) might be tolerable, but that anything more than a few mm would not be tolerated. However, even with very small overlaps of 1–2 mm, the dose to the adjacent spinal cord would largely eliminate this ‘neighborhood mitigation effect.’ Thus, any overlap of abutting fields is likely not tolerable in the clinic.

The most recognized example of adverse combined radiation and drug effects involves methotrexate (Fig. 7) (Bleyer 1981; Bernaldez-Rios et al. 1998; Evans et al. 1981). Large doses of methotrexate alone can lead to leukoencephalopathy; however, this complication is seen most often when the drug is given intrathecally and/or in high doses intravenously combined with whole brain irradiation.

It had been assumed that most drugs would not cause CNS late effects because of their inability to cross the blood–brain barrier. However, because radiation alters and increases capillary permeability, (Rubin et al. 1994) a combined-modality regimen may lead to systemically administered drugs entering the brain (Williams et al. 1993; Qin et al. 1997). In addition, damage to the vascular choroid plexus can affect methotrexate clearance, decreasing turnover, thereby leading to higher drug concentrations. Therefore, combination therapy sequencing for brain neoplasms should be approached with caution (Remsen et al. 1997). For example, a 1998 study employing a combination of high-dose systemic methotrexate with intrathecal methotrexate followed by whole brain irradiation for primary CNS lymphoma has observed a high rate of severe leukoencephalopathy in patients older than 60 years of age (Abrey et al. 1998).