Pathophysiology

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Radiation therapy uses high-energy radiation to kill proliferating tumor cells with relative sparing of the surrounding normal cells, which are typically less active. Two main types of radiation are external beam radiation and internal radiation, also known as brachytherapy. A variety of new dose-sculpting techniques for delivering radiation have been developed.

From: Therapeutic Uses of Botulinum Toxin Edited by: G. Cooper © Humana Press Inc., Totowa, NJ

Fig. 1. Radiation fibrosis syndrome following radiation to the chest wall for a breast cancer recurrence. Note the dermal erythema and the contracture of the skin and underlying soft tissues.

These include intensity-modulated radiotherapy and image-guided radiotherapy, which allowed the radiation to be conformed to the size and shape of the tumor thereby delivering higher doses of radiation to the tumor while decreasing the radiation exposure to surrounding tissues with a high degree of accuracy (9). Radiation can be used either for intent to cure or palliatively with the intention of prolonging life or function or decreasing pain (10,11). Radiation is often used adjuvantly with surgery or chemotherapy to maximize its potential benefit (12,13).

The primary effect of radiation on tissues is the induction of apoptosis or mitotic cell death from free radical-mediated DNA damage. A variety of other secondary effects occur that are mediated by cytokines, chemokines, and growth factors. These secondary effects include activation of the coagulation system, inflammation, epithelial regeneration, and tissue remodeling that is mediated by a number of interacting molecular signals that include cytokines, chemokines, and growth factors. Radiation causes endothelial cell apoptosis, increased endothelial permeability, expression of chemokines, and expression of adhesion molecules with the subsequent loss of vascular thrombo-resistance. The loss of vascular thrombo-resistance is a result of decreased fibrinolysis, increased expression of tissue factor and von Willebrand factor, and decreased expression of prostacyclin and thrombomodulin. The increased expression of tissue factors and increased local thrombin formation occurs intravascularly and in the perivascular areas and extracellular matrix because of the increased vascular permeability. The accumulation of thrombin in the intravascular and extravascular compartments causes the progressive fibrotic sclerosis of the tissues that characterizes radiation fibrosis (14).

Radiation fibrosis can damage any tissue type, including skin, muscle, ligament, tendon, nerve, viscera, and even bone (refs. 15-17; Figs. 1 and 2). The effects of radiation can be acute

Fig. 2. Late effects of XRT on bone as seen on a T1-weighted magnetic resonance imaging scan. Note the increased signal in the C1 through C4 vertebral bodies. The signal change results from radiation damage to the normal marrow, which is replaced with fat, which in turn has a higher signal.

(occurring during or immediately after treatment), early-delayed (occurring up to 3 months after completion of treatment), or late-delayed (occurring more than 3 months following completion of treatment; ref. 18). Radiation fibrosis is an example of a late complication of radiation therapy, which may manifest years after treatment, progress rapidly or insidiously, and is not reversible (19,20).

The term radiation fibrosis syndrome (RFS) describes the clinical manifestations that result from the progressive fibrotic sclerosis that follows radiation treatment. RFS can result locally from treatment of any tumor or malignancy with radiation on any part of the body (21). Some radiation fields are quite extensive, as in the mantle field radiation used to treat Hodgkin's disease that involves all lymph nodes in the neck, chest, axilla, and at times the upper abdomen (Fig. 3). Such broad radiation fields can result in wide-spread sequelae of RFS (22). The radiation field can be focal, as when treating isolated vertebral metastases, an extremity sarcoma, a local breast cancer recurrence in the chest wall, or a head and neck neoplasm (23,24). Patients radiated for head and neck cancers are very likely to develop RFS because of the high doses of radiation often needed for tumor control and the close proximity of many vital tissues.

Patients with head and neck cancer typify the RFS and are often likely to benefit from treatment with BTX. Disorders attributable to the RFS in this population include radiation-induced trigeminal neuralgia, dermal sclerosis, cervical dystonia, trismus, and migraines. The spinal cord and peripheral nervous system can be affected (25). Radiculopathy, plexopathy, and neuropathy are very common and likely contribute to neck pain and spasms.

Fig. 3. Radiation fibrosis syndrome 20 years following mantle field radiation treatment for Hodgkin's disease. Note the marked atrophy in the cervical and thoracic paraspinal, bilateral supraspinatus, infraspinatus, and rhomboid muscles. The deltoids and triceps are preserved. Electromyography demonstrated cervical radiculoplexopathy and myopathic changes in the radiation field.

Fig. 3. Radiation fibrosis syndrome 20 years following mantle field radiation treatment for Hodgkin's disease. Note the marked atrophy in the cervical and thoracic paraspinal, bilateral supraspinatus, infraspinatus, and rhomboid muscles. The deltoids and triceps are preserved. Electromyography demonstrated cervical radiculoplexopathy and myopathic changes in the radiation field.

Such peripheral nervous system disfunction can result from ischemia resulting from fibrosis and stenosis of the vaso vasorum, from external compressive fibrosis of the skin and soft tissues, or both (26,27).

Muscle cramps are thought to arise from spontaneous discharges of the motor nerve sending volleys of activity to and across the neuromuscular junction (28). Ectopic activity in the spinal accessory nerve may be causally related to the spasms of the sternocleidomastoid muscle and trapezius that often characterize cervical dystonia. The spinal accessory nerve is involved in the radiation field of many head and neck cancers because it receives a large contribution of fibers from upper cervical nerve roots and the cervical plexus (29). Similarly, radiation damage to the cervical nerve roots can cause focal cervical paraspinal muscle spasms, pain, as well as weakness of the rotator cuff (C5 and C6) and other extremity muscles (30). Brachial plexus damage can be profound with resultant weakness and pain. The upper plexus may be more prone to damage because its superior location puts it within the field of many head and neck radiation ports and because the pyramidal shape of the chest provides less protective tissue around the upper plexus (31). As with C5 or C6 cervical radiculopathy, damage to the upper brachial plexus can weaken the rotator cuff muscles, biceps, and deltoid. Weakness of the rotator cuff with subsequent perturbation of normal shoulder motion is causally related to the development of rotator cuff tendonitis and adhesive capsulitis in this population (32). It is difficult to distinguish an upper trunk brachial plexopathy from an upper cervical radiculopathy both clinically and electrophysiologically in most instances because they are generally seen together in RFS.

Progressive fibrosis in muscle fibers within the radiation field can cause a focal myopathy that is associated with nemaline rods (16). Myopathic muscles are weak relative to normal muscle and prone to spasm and pain. Cervical myopathy, cervical radiculopathy, and brachial plexopathy are commonly seen together often with devastating effects. Progressive damage to the cervical paraspinal muscles and nerves can lead to severe head drop as a potentially devastating complication of the RFS (Fig. 4).

Our understanding of the mechanism of action of BTX in pain and spasm has continued to progress. Our understanding of BTX's role in the inhibition of muscle spasms and spasticity is well developed and discussed in Chapter 2. The mechanism by which BTX treats pain, particularly neuropathic pain, is less clear. Early studies demonstrated that BTX can inhibit the release of substance P from cultured rat dorsal root ganglion cells and regulate calcitonin gene-related peptide secretion from cultured rat trigeminal nerve cells (33,34). These findings initially led to speculation that BTX injected peripherally would somehow be transported centrally to inhibit the release of pain neurotransmitters in the central nervous system. This speculation has not been supported experimentally because intact BTX cannot be demonstrated centrally following peripheral injection. Other evidence suggests that the anti-nociceptive effects of BTX are in fact peripheral and related to a dose-dependent decrease in the release of glutamate and most likely other pain neurotransmitters (substance P and calcitonin gene-related peptide) at the site of peripheral inflammation (35). A BTX-induced block of peripheral pain neurotransmitter release would inhibit nociceptor sensitization and thus pain. Indirect central effects likely result from the secondary inhibition of central sensitization that occurs as a result of hyperexcitability in the peripheral nervous system (36). The mechanism of inhibition of release of the peripheral neurotransmitters is most likely, as at the neuromuscular junction, related to the cleavage of synaptosome-associated protein-25 and the resultant inhibition of vesicle release (37).

Fig. 4. Radiation fibrosis syndrome in a woman 5 years after radiation of a nasopharyngeal carcinoma. Note the dropped head from severe cervical paraspinal weakness as well as the marked atrophy of the rotator cuff muscles. Electromyography demonstrated cervical radiculoplexopathy involving predominately the upper cervical nerve roots and plexus as well as myopathic muscles in the radiation field.

Fig. 4. Radiation fibrosis syndrome in a woman 5 years after radiation of a nasopharyngeal carcinoma. Note the dropped head from severe cervical paraspinal weakness as well as the marked atrophy of the rotator cuff muscles. Electromyography demonstrated cervical radiculoplexopathy involving predominately the upper cervical nerve roots and plexus as well as myopathic muscles in the radiation field.

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