Radiation Fibrosis Syndrome: Neuromuscular and Musculoskeletal Complications in Cancer Survivors

Radiation Fibrosis Syndrome: Neuromuscular and Musculoskeletal Complications in Cancer Survivors

Clinical Review: Current Concepts Radiation Fibrosis Syndrome: Neuromuscular and Musculoskeletal Complications in Cancer Survivors Michael D. Stubble...

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Clinical Review: Current Concepts

Radiation Fibrosis Syndrome: Neuromuscular and Musculoskeletal Complications in Cancer Survivors Michael D. Stubblefield, MD Radiation-induced toxicity is a major cause of long-term disability after cancer treatment. Radiation fibrosis describes the insidious pathologic fibrotic tissue sclerosis that can occur in response to radiation exposure. Radiation fibrosis syndrome describes the myriad clinical manifestations of progressive fibrotic tissue sclerosis resulting from radiation treatment. Radiation-induced damage can include “myelo-radiculo-plexo-neuro-myopathy,” causing muscle weakness and dysfunction and contributing to neuromuscular injury. Similarly, radiation damage to neuromuscular structures contributes to radiation-induced trismus and cervical dystonia in head and neck cancer survivors. This narrative review discusses the pathophysiology, anatomy, evaluation, and treatment of neuromuscular, musculoskeletal, and functional disorders that can result as late effects of radiation treatment. Rehabilitation medicine physicians with extensive training in neuromuscular and musculoskeletal medicine as well as in the principles of functional restoration are uniquely positioned to help lead efforts to improve the quality of life for cancer survivors with radiation fibrosis syndrome. PM R 2011;3:1041-1054

INTRODUCTION Radiation-induced toxicity is a major cause of long-term disability after cancer treatment. Radiation can be used with the intention to cure or palliatively with the intention of prolonging life, improving or maintaining function, or alleviating pain [1,2]. Radiation is often used as an adjuvant with surgery or chemotherapy to maximize potential benefit for the patient [3,4]. Radiation fibrosis (RF) describes the insidious pathologic fibrotic tissue sclerosis that often occurs in response to radiation exposure. The term radiation fibrosis syndrome (RFS) describes the myriad clinical manifestations of progressive fibrotic tissue sclerosis that result from radiation treatment. Radiotherapy is often combined with surgery and/or chemotherapy; therefore, the toxicities of these modalities may be cumulative and difficult to separate clinically. There are approximately 14 million cancer survivors in the United States [5]. Approximately one-half of these patients will receive radiation treatment at some point during the course of their disease [6]. Although not all patients treated with radiation therapy will experience significant long-term sequelae, many will. There are no good estimates as to how many patients will experience complications from radiation. The specialized neuromuscular, musculoskeletal, pain, functional, and other needs of this population of survivors are ideally suited for the unique knowledge and skills of rehabilitation medicine specialists. This review will discuss specific long-term neuromuscular and musculoskeletal complications of radiation therapy likely to be encountered in cancer survivors.

PATHOPHYSIOLOGY Radiation is composed of packets of energy that include photons and particles such as protons, neutrons, and electrons. These packets penetrate human tissue and ionize to cause direct and indirect tissue damage via the production of hydroxyl radicals. The therapeutic goal of radiation therapy is to kill rapidly dividing cancer cells with relative sparing of the more slowly dividing somatic cells. PM&R 1934-1482/11/$36.00 Printed in U.S.A.

M.D.S. Department of Neurology, Rehabilitation Medicine Service, Memorial Sloan-Kettering Cancer Center, MSKCC Outpatient Rehabilitation Center, 515 Madison Avenue, 5th Floor, New York, NY 10022; and Department of Physical Medicine and Rehabilitation, Weill Medical College of Cornell University, New York City, NY. Address correspondence to M.D.S.; e-mail: [email protected] Disclosure: nothing to disclose Submitted for publication January 4, 2011; accepted August 18, 2011.

© 2011 by the American Academy of Physical Medicine and Rehabilitation Vol. 3, 1041-1054, November 2011 DOI: 10.1016/j.pmrj.2011.08.535

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Two basic strategies of radiation delivery are used. These include external beam radiation, in which radiation is delivered from outside the body, and brachytherapy, in which radiation is delivered from within the body. Dosesculpting techniques include intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy [7]. In IMRT the intensity of the radiation is controlled (or modulated) across the treatment field by the use of a multileaf collimator to subdivide the radiation beams in to beamlets and aim them at the tumor from multiple directions. This technique allows nonuniform coverage of the radiation field to minimize exposure to normal tissues while maximizing the dose to the tumor by shaping the beam to closely approximate its shape in 3 dimensions. Imaging is used for initial planning in IMRT. In image-guided radiotherapy, a more accurate and sophisticated technique, imaging such as computed tomography is used to compensate for tumor movement between treatment sessions, with organ filling, or with breathing. The radiation can be controlled to such a degree that radiosensitive structures such as the spinal cord can be spared, even if they are only a few millimeters away from the tumor [8]. This technique provides for very high doses of radiation to be administered to the tumor volume in fewer fractions, often a single fraction, and has dramatically changed our treatment strategies for many tumors. Tumors such as melanoma and renal cell carcinoma, which are generally unresponsive to standard radiotherapy techniques, may be more sensitive to hypofractionated dose-sculpting techniques [8]. The mechanisms linking radiation to chronic vascular dysfunction and subsequent tissue sclerosis, fibrosis, and atrophy are complex and not completely understood. In one theory, Hauer-Jensen et al [6] postulates that the predominant mechanism by which radiation causes tissue injury in tumors and normal tissues is the induction of apoptosis or clonogenic cell death via free radical-mediated DNA damage. In normal tissues, radiation toxicity occurs in response to a sequence of overlapping events that are attributable to direct radiation-induced changes in cell function as well as indirect responses to tissue injury, causing activation of the coagulation system, inflammation, epithelial regeneration, and tissue remodeling, which is precipitated by molecular signals including cytokines, chemokines, and growth factors. Hauer-Jensen hypothesizes that injury to the vascular endothelium likely plays a key role in the response of most normal tissues to ionizing radiation. Vascular endothelial damage is particularly important in chronic radiation toxicity, where microvascular injury seems pivotal to the unique self-perpetuating nature of the disorder. A radiation-induced thrombomodulin deficiency develops in radiation-damaged endothelial cells, resulting in their subsequent inability to scavenge locally formed thrombin and causing a procoagu-

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lant, proinflammatory, mitogenic, and profibrogenic effect on smooth muscle cells, fibroblast, myofibroblasts, and other cell types in the irradiated tissues. “Feedback” by cytokines and other inflammatory mediators sustains the endothelial thrombomodulin deficiency and thus contributes to the chronicity of radiation injury, leading to proliferative fibrin production and subsequent sclerosis. The abnormal accumulation of fibrin in the intravascular, perivascular, and extravascular compartments as a result of this fibrinogenic positive feedback loop may be responsible for the progressive tissue fibrosis and sclerosis that characterizes RF and underlies RFS. Three histopathological phases of RF are described, including: (1) a prefibrotic phase characterized by chronic inflammation in which endothelial cells are thought to play an important role; (2) an organized fibrosis phase with patchy areas of active fibrosis containing a high density of myofibroblasts in an unorganized matrix adjacent to poorly cellularized fibrotic areas of senescent fibrocytes in a dense sclerotic matrix; and (3) a late fibroatrophic phase, characterized by retractile fibrosis and gradual loss of parenchymal cells [9]. RF can affect any tissue type, including skin, muscle, ligament, tendon, nerve, heart, lung, gastrointestinal or genitourinary tract, and bone [10-13]. The effects of radiation can be acute (occurring during or immediately after treatment), early delayed (up to 3 months after completion of treatment), or late delayed (occurring more than 3 months after completion of treatment) [14]. RF is generally a late complication of radiation therapy that may not manifest clinically for several months or years after treatment. When it does manifest, it may progress rapidly but more often takes a slow and insidious course and is not reversible [15,16]. Although invariably progressive, the clinical course of RFS is a moving target that can change with time and the age and health status of the patient. Although fibrosis seems a key component of radiation damage in most, if not all affected tissues, it is ultimately tissue atrophy, likely attributable to the loss of neurovascular innervation, that characterizes the clinical features seen in many of these patients [17].

RISK FACTORS FOR RF No group of cancer survivors better exemplify the long-term complications of radiation therapy than those treated for Hodgkin lymphoma (HL). Understanding the complications that affect HL survivors allows us to translate the basic rehabilitation principles applicable to this group so that they may be generalizable to other groups of cancer survivors afflicted by similar complications. In addition to the neuromuscular and musculoskeletal complications, long-term survivors of HL are at increased risk for a number of late

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complications that can significantly impact their rehabilitation. Although many are a direct result of the radiation, others are caused by the toxic effects of chemotherapy, such as anthracycline-induced cardiomyopathy [13]. Mortality is increased as the result of secondary malignancies (leukemias, non-HLs, solid tumors) and cardiovascular disease (pericardial disease, valvular disease, conduction abnormalities, ventricular dysfunction, coronary disease) [18]. Noncoronary vascular complications such as subclavian and carotic artery stenosis may also complicate radiation treatment in certain HL survivors [18]. There are several possible factors that may determine a patient’s risk for developing clinical manifestations of RFS, including age; overall health; medical and degenerative disorders, particularly degenerative spine disease; cancer status; exposure to neurotoxic, cardiotoxic, and other chemotherapy types; location of radiation; size of radiation field; type of radiation; and time since radiation was administered [19]. Although some associations seem obvious, others cannot be easily explained. It is common to see patients with very similar treatment histories develop divergent complications. This phenomenon may reflect differences in individual biology, genetics, occupation, environment, and other factors not yet realized.

RADIATION FIELDS One of the major determinants of the potential severity of RFS is the size of the radiation field and the tissues encompassed by it. The fields used for HL are illustrated in Figure 1. The mantle field (MF) was, and in select instances still is, used to treat supradiaphragmatic disease (HL and other types of lymphoma) and includes all lymph nodes in the neck, chest, and axilla. The inverted-Y field for infradiaphragmatic HL (and other lymphomas) involves the periaortic and ilioinguinal lymph nodes. The combination of MF and inverted-Y radiation is known as total nodal radiation. The impact of these fields will be discussed in detail below. Patients radiated for head and neck cancer (HNC) are also likely to develop RFS because of the high doses of radiation given, as well as the proximity of many vital tissues to the radiation field (Figure 2) [20]. Patients treated with standard external-beam protocols for breast cancer are less likely to develop significant sequela of RFS because critical structures outside of the breast are unlikely to be affected by radiation [21]. Understanding the radiation fields are instrumental to recognizing which signs, symptoms, or functional deficits can be attributed to RFS. In general, for a structure to be considered affected by RFS, it must either be within the radiation field or have tendons, neurovascular innervation, or lymphatic flow that traverses the field.

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COMPLICATIONS OF RADIATION Neuromuscular Nerve. The neuromuscular complications of radiation stem from both direct and indirect effects of progressive fibrotic sclerosis on neural structures, including the brain, spinal cord, nerve root, plexus, all components of the peripheral nerve (motor, sensory, autonomic), and muscle [12,14]. Understanding the effect of RF on nerve is one of the most important aspects of understanding both the neuromuscular and musculoskeletal complications of RFS. Any nervous system structure can be affected by RFS. The clinical neurologic manifestation observed will depend on which nerve structures are involved, how severely they are involved, and the context of their involvement with respect to surrounding structures. Peripheral nervous system dysfunction results from external compressive fibrosis of soft tissues, ischemia caused by fibrosis and subsequent compromise of the vas vasorum, or both [22,23]. Pain, sensory loss, and weakness are the most commonly observed clinical features of peripheral nervous system dysfunction. Autonomic dysfunction with resultant orthostatic hypotension, bowel and bladder change, sexual dysfunction, and other abnormalities can also be seen. Neuropathic pain is an extremely common component of RFS. The mechanisms contributing to the generation of neuropathic pain are complex and generally involve processes in both the central and peripheral nervous system [24]. One factor likely common to the pathogenesis of neuropathic pain in RFS is the generation of ectopic activity in a radiationdamaged component of the sensory nervous system. Damage to descending modulatory pathways may also play a role in the pathogenesis of neuropathic pain [25]. Because ectopic signals are not physiologically generated, the experience of pain can be severe and out of proportion to the perceived pathology. Radiation-induced ectopic activity can develop in any affected neural structure, including the thalamus, ascending spinothalamic tracts of the spinal cord, nerve roots, plexus, and peripheral nerves. The etiology of the ectopic signal can be compressive and/or ischemic with subsequent demyelination and or axonal loss. When the ascending spinothalamic tracts of the spinal cord are the primary generator of ectopic activity, the resulting pain can be both excruciating and nebulous. This is known as funicular pain [26]. Although very uncommon, funicular pain should be considered in patients treated with radiation fields that involve the spinal cord. Funicular pain can be very difficult to diagnose because it does not follow a fixed (eg, dermatomal) referral pattern familiar to most clinicians. Radiation damage to the funiculi of the cervical spinal cord, for instance, can cause pain perceived in any body part caudal to the lesion. This may result in pain in the thorax, abdomen, or lower extremities and mimic radiculopathy, plexopathy, polyneuropathy, mononeuropathy multiplex, or

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Figure 1. Radiation fields used to treat HL. Reprinted with permission from Stubblefield MD, O’Dell MW. Cancer Rehabilitation Principles and Practice. New York: Demos Medical Publishing; 2009.

mononeuropathy, with more than one body area, unilaterally or bilaterally, being affected. The culprit lesion cannot be localized on the basis of the symptoms of patients with funicular pain. The neuropathic pain associated with RFS results from damage to neural structures, such as the nerve roots, plexus, and/or peripheral nerves involved within the radiation field [27,28]. Pre-existing medical or degenerative disorders such as diabetes or spinal degeneration (eg, cervical radiculopathy) may also affect these structures, leaving them more susceptible to neuropathic pain in RFS [29]. Multiple neural structures are involved, depending on the size of the radiation field and the proximity of the neural structures.

Neuropathic pain is often accompanied by loss or perturbation of sensation. Sensory loss can exist without pain. The primary faculties affected include light touch, pain, temperature, vibration, and position sensation. A deficit in any of these can potentially render the patient susceptible to other injuries. Similarly, sensory loss can profoundly affect gait and performance of activities of daily living. As with neuropathic pain and sensory loss, weakness can be caused by damage to any level of the neuromuscular axis, including the brain, spinal cord, peripheral nerve, and muscle. Radiation-induced myelopathy can be “early-delayed,” which is almost always reversible, and “late-delayed,” which is almost always progressive and permanent [30]. Damage to

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Figure 2. Vital structures included in the radiation field in patients with HNC. Reprinted with permission from Stubblefield MD, O’Dell MW. Cancer Rehabilitation Principles and Practice. New York: Demos Medical Publishing; 2009.

the nerve roots cause weakness in a myotomal pattern. Multiple nerve roots are often involved depending on the radiation field, which has important clinical implications for many groups of patients, particularly HNC patients, who often receive very high radiation doses to multiple upper cervical nerve roots, and HL survivors, who have received either mantle or total nodal radiation. Radiation-induced plexopathy can affect the cervical, brachial, and lumbosacral plexus depending on the radiation field. It results in significant pain and functional disability. Differentiating radiation-induced plexopathy from neoplastic plexopathy represents a diagnostic challenge [31]. The

upper brachial plexus may be more susceptible to radiation injury. This phenomenon may be attributable to its apical location in the neck and the long course traversed by its fibers relative to the middle and lower trunk. These anatomical differences would place more of the upper trunk of the plexus within the radiation field of many HNC ports. The pyramidal shape of the thorax and the clavicle may also provide some protection for the middle and lower plexus relative to the upper plexus, but the clinical validity of this phenomenon is unclear [31]. Mononeuropathies caused by radiation should be obvious when a major structure such as the sciatic nerve is involved in

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the radiation field [32]. Radiation-induced mononeuropathies may be less obvious when the dorsal scapular nerve to the rhomboids or the suprascapular nerve to the supraspinatus and infraspinatus muscles are involved. Dysfunction of these nerves is important to the pathogenesis of shoulder dysfunction in many cancer survivors. Similarly, bilateral phrenic nerve dysfunction may be a late complication of MF radiation and contribute to pulmonary insufficiency in many HL survivors [33].

Figure 3. A, Gadolinium-enhanced T1-weighted MRI demonstrating mild nodular cauda equina enhancement (polyradiculopathy) as a late complication of total-nodal radiation for a patient with HL 29 years previously. The patient experienced progressive gait dysfunction and lower extremity weakness as well as upper extremity weakness, neck extensor weakness, atrophy, and pain in addition to several other sequelae of RFS. He had seen multiple specialists and had been misdiagnosed as having chronic idiopathic demyelinating polyradiculoneuropathy. All of his signs, symptoms, and functional deficits as well as his imaging and electrophysiologic findings are fully attributable RFS and various components of myelo-radiculo-plexo-neuro-myopathy. B, Coronal T1-weighted MRI depicting the bilateral brachial plexus in an HL survivor 37 years after mantle field and inverted-Y field radiation each with 4000 cGy. She suffers from severe and

Muscle. Radiation damage to muscle can cause focal myopathy associated with the nemaline rods [11]. Myopathic muscles are prone to painful spasms mediated by several pathologic mechanisms, including the myopathy itself, relative weakness and fatigability of affected muscles, and ectopic activity in the innervating motor nerve. Spontaneous discharges in the motor nerve sends volleys of neural activity to and across the neuromuscular junction, resulting in a muscle spasm [34]. The spasm is not always obvious and may be perceived by the patient as vague stiffness or tightness. This process may contribute significantly to disorders such as radiation-induced cervical dystonia in HNC patients, in whom the sternocleidomastoid and scalene muscles as well as the spinal accessory nerve are affected by radiation resulting in severe spasms and ultimately contracture of the neck [35]. The pain associated with muscle spasm is very similar to that associated with myofascial trigger points and tends to occur in similar anatomic regions such as the cervical paraspinal, midtrapezius, and rhomboid muscles. Ectopic activity in the motor nerve results in elevated activity at the motor endplate zone, excessive local acetylcholine production, and sarcomere shortening. Sustained focal muscle contraction requires high levels of energy and oxygen to be maintained, resulting in local acidity. This continuous muscle contraction coupled with a low pH further constricts local blood flow, causing local tissue hypoxia. Focal hypoxia and acidification result in the release of inflammatory mediators, neuropeptides, catecholamines, and cytokines with subsequent sensitization of nociceptive nerve fibers and perpetuation of the contraction, hypoxia, acidification, and pain cycle. The sensitization of these local pain neurons results in the generation of localized muscle pain [36]. This phenomenon is common in patients with RFS and is often misdiagnosed as a fibromyalgia or a rheumatic disorder.

asymmetric damage of the right brachial plexus. Note the thickening of plexus structures at the white arrow. This is just one example of the clinical heterogeneity likely to be encountered inexplicibly in patients undergoing radiation. Clinically she has right pan-brachial plexopathy that is most severe in the muscles innervated by the lower trunk and medial cord of the brachial plexus.

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Myelo-radiculo-plexo-neuro-myopathy. Patients treated with large radiation fields will often develop dysfunction in multiple underlying neuromuscular structures. In the case of patients with HL treated with MF radiation, it is not uncommon to see clinical evidence of myelopathy (eg, spasticity, paraplegia, quadriplegia, detrusor-sphincter dyssynergia) [14], radiculopathy (eg, radicular pain, myotomal weakness, appropriate EMG findings, appropriate magnetic resonance imaging [MRI] findings) [37], plexopathy (eg, upper or lower trunk, flail atrophic arm, appropriate electromyographic findings, appropriate MRI findings) [31], mononeuropathy (eg, spinal accessory, dorsal scapular, phrenic nerves) [33], and myopathy (eg, appropriate electromyographic findings in the radiation field) [11]. The term myelo-radiculo-plexo-neuro-myopathy accurately describes, in anatomical sequence, the structures responsible for the development of neuromuscular dysfunction in many patients with RFS. Not all structures need to be clinically affected, and there is tremendous variability in clinical presentation. (Figure 3). Most patients with HL treated with MF radiation present with neck extensor weakness or “head drop” and associated cervicothoracic pain as their predominant manifestation (Figure 4). Other similarly treated patients, however, may present with various degrees of paraplegia, spasticity, plexopathy, bowel or bladder dysfunction, pulmonary insufficiency, cardiac dysfunction, or any number of other disorders. It is important to remember that only neuromuscular structures within the field or structures whose innervation traverses the field are subject to RF. Contemporary conformal radiation techniques used to treat patients with HNC, for instance, are unlikely to produce myelopathy because they dose-sculpt around the spinal cord (Figure 5). The nerve roots, plexus, peripheral nerves, and local muscles, however, receive high doses of radiation, making the development of varying degrees of radiculo-plexo-neuro-myopathy likely to be seen clinically.

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Figure 4. Typical physical examination findings in a HL survivor treated with MF radiation years previously. Moderate neck extensor weakness, or “dropped-head syndrome,” is present. (A) Note the atrophy in the cervicothoracic, RTC muscles, and rhomboid muscles with relative preservation of the upper trapezius muscles. (B) The pectoral muscles are also relatively preserved likely because of the shielding used to protect the lungs. The strength imbalance between the strong pectoral muscles weakened back and RTC muscles contributes to the forwardly positioned neck and shoulders that characterize the “C-shaped” posture often assumed by unrehabilitated HL survivors.

Tendons and Ligaments. Experimental data concerning the effect of radiation on tendons and ligaments are lacking. Clinically, the effect of radiation on these structures is progressive fibrosis and sclerosis with loss of elasticity, shortening, and contracture, which can result in loss of function and range of motion. It is commonly seen in the neck, shoulder, elbow, wrist, hip, knee, ankle, or digits. The effects of radiation do not always have to be direct. For instance, radiation to an upper leg can result in marked ankle contracture via effects on the muscles, tendons, and neurovascular innervation of the distal leg. Bone. Radiation renders bone brittle and prone to injury, including osteoradionecrosis of the mandible, pelvic insufficiency fracture, hip fracture, long bone fracture, rib fracture,

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Figure 5. The 100% isodose curves used to plan radiation treatment of a nasopharyngeal cancer is depicted overlying a computed tomogram. Only one level is shown, and the actual treatment area would extend caudal and rostral to encompass the left cervical nerve roots, brachial plexus, dorsal scapular nerve, and suprascapular nerve and RTC muscles as well as the trachea, esophagus, and other important structures. Note how the radiation is sculpted around the spinal cord so as to minimize toxicity to this critical structure. Reprinted with permission from Stubblefield MD, O’Dell MW. Cancer Rehabilitation Principles and Practice. New York: Demos Medical Publishing; 2009.

and pediatric growth abnormalities [38]. Children who undergo radiation for sarcoma or other malignancies of the long bones or spine may not mature normally if the growth plate is affected [39]. Growth may be further affected if radiation, particularly to the cranium, causes endocrine abnormalities during development [40]. Radiation-induced neoplasms can also be seen [41]. Osteopenia and osteoporosis are clinically silent diseases that are common and potential late-term complications of radiation, leaving patients more susceptible to osteoporotic fractures in later life. Vigilance and monitoring for osteopenia and osteoporosis are recommended in cancer survivors because they may be more likely, as a group, to demonstrate accelerated bone loss when compared with their aged-matched peers without a cancer diagnosis [42].

COMMON CLINICAL SYNDROMES Neck Extensor Weakness In the author’s experience, neck extensor weakness with or without associated cervicothoracic pain is the most common

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neuromuscular disorder encountered in HL survivors (Figure 4). There have been several reports on the so-called “dropped-head syndrome” in the literature, which is characterized clinically by severe atrophy and weakness of the cervicothoracic paraspinal and shoulder girdle musculature [43-46]. The most recent series by Furby et al [46] demonstrates the heterogeneous nature of the syndrome’s electrophysiological and pathological findings that may be neuropathic, myopathic, or mixed. Similar heterogeneity was found by Rowin et al [44]. The heterogeneous clinical findings are consistent with what is routinely encountered in our electrodiagnostic laboratory and what would be expected with variable expression of the myelo-radiculo-plexo-neuro-myopathy (described previously). The severe atrophy likely results from a combination of damage to the motor nerve (at the anterior horn cell, root, plexus, and/or peripheral nerve level) and/or the muscle itself that varies from patient to patient. The size and location of the radiation field relative to the anatomic course of the nerve may dictate how afflicted the nerve is and the potential degree of muscle dysfunction and atrophy. For instance, the upper trapezius is often considerably less atrophic relative to the lower trapezius in HD survivors treated with MF radiation (Figure 4) because the fibers innervating the upper trapezius are at the apex of the field and relatively spared from radiation compared with the lower fibers. Similarly, the pectoral muscles are usually considerably less atrophic compared with the paraspinal and rotator cuff (RTC) muscles (Figure 4). This finding likely has to do with a combination of factors, including the shielding used to protect the lung fields during radiation also directly protecting the pectoral muscles. The upper cervical nerve roots, upper plexus, and RTC muscles are usually affected out of proportion to the other upper extremity neuromuscular structures. As a result, these muscles, particularly the biceps, deltoids, and rotator cuff muscles, are considerably weaker than other muscle groups in the upper extremity. Neck extensor weakness is found in HNC survivors but in the author’s experience it is generally less common and severe. This reduction is severity is likely because of preservation of the thoracic paraspinal muscles, which are important in neck extension. The thoracic paraspinal muscles are excluded from the radiation field of head and neck cancer treatments, which usually terminate in the low neck with the cervical lymph nodes. The pain associated with neck extensor weakness is likely multifactorial. Fatigue and painful spasm of the cervicothoracic muscles associated with myofascial trigger points (as described previously) usually are associated with functional overload and usually peak later in the day or after activities that exceed the work capacity of affected muscles. The muscle imbalance caused by weak cervicothoracic paraspinal and rotator cuff muscles opposed by relatively strong pectoral muscles contributes to characteristically poor posture,

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wherein the shoulders and head are flexed foreword relative to the chest and assume a “C”-shape (Figure 4). This stance puts the cervicothoracic and rotator cuff muscles at a biomechanical disadvantage, further contributing to pain and dysfunction. Degenerative cervical spine disorders are also common, particularly in older patients, and can cause significant pain. Referred radicular pain either as a late effect of radiation or from degenerative disease can cause local axial neck pain or referred pain to the shoulders or arms. The mainstay of neck extensor weakness treatment in HL survivors is physical therapy (PT), which should emphasize postural retraining through core strengthening, flexibility (especially the pectoral girdle), and conditioning of the cervicothoracic and rotator cuff muscles. Although these muscles are impaired, they often respond well to rehabilitative efforts, and even small gains in muscle stamina coupled with improved posture can translate into large functional improvement for the patient. Correction of anatomic malalignment and posture alone will help decrease energy expenditure and pain in most patients. Because the fibrotic process that underlies RFS is cannot be directly affected, insidious progression of weakness and dysfunction is ultimately unavoidable. The adherence to a life-long exercise program emphasizing home maintenance exercises is of paramount importance to help maximize and maintain function and quality of life. When rehabilitative efforts are inadequate to maintain adequate posture and pain relief, a cervical orthotic should be considered. Many patients prefer the Headmaster Cervical Collar (Symmetric Designs in Salt Spring Island, British Columbia) because it is smaller, lighter, and more adjustable than other collars (Figure 6). Some patients prefer alternative cervical collar designs, and their preferences should be accommodated when appropriate. A cervical collar is not intended for continuous use; rather, it should be used as an energy conservation device. Patients with difficulty maintaining their head in an upright position or who experience pain as the day progresses because of muscular overload should wear the collar whenever possible and convenient. Activities amenable to use of the collar include housework, eating, working at a computer, watching television, and reading, to name a few. Resting the cervicothoracic muscles in the collar during the work day should make it possible to enjoy leisure activities out of the collar later in the evening with less pain and fatigue. It should be expressly stated that a collar is not a substitute for a lifelong home-exercise program. Residual cervicothoracic pain that does not respond to therapy or a collar may respond to nerve-stabilizing agents including pregabalin, gabapentin, or duloxetine. Newer agents, particularly pregabalin, are generally preferred over older agents such as the tricyclic antidepressants because they have excellent efficacy, little potential for drug-drug interactions, and favorable pharmacokinetics [47]. Opioids relieve pain but are not effective for muscle spasm and other

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Figure 6. The Headmaster Cervical Collar is smaller, lighter, and less cumbersome than many other cervical collars and provides anterior support for patients with neck extensor weakness such as those with HL or HNC who are treated with radiation.

neuropathic symptoms. They should generally be reserved for second-line use or added to nerve-stabilizing agents when treating pain in RFS. Injection of local anesthetic into myofascial tender points may offer pain relief lasting up to a month in many HL survivors with cervicothoracic pain, but because of the significant atrophy and the potential to worsen neck extensor weakness, they should only be performed by experienced practitioners.

Shoulder Pain and Dysfunction Shoulder pain and dysfunction are common in HL and HNC survivors. Such issues may be directly related to radiation if the shoulder muscles, nerves innervating the shoulder girdle, or other shoulder structures are affected by radiation. Myopathic changes in the deltoid muscles found on biopsy, by as reported by Furby et al [46], suggest that even the lateral shoulder has been included in the MF radiation port in some

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HL survivors. Directly radiated structures in HL survivors may include the cervicothoracic paraspinal muscles, cervical nerve roots, brachial plexus, the RTC muscles, rhomboids, and the peripheral nerves that innervate the RTC. Damage to the C5 or C6 cervical nerve roots and/or upper brachial plexus further weakens the RTC (myotome of C5 and C6) and would refer pain to the lateral shoulder and arm (dermatome of C5 and C6). Such damage is common in HNC patients. Weakened RTC musculature would perturb shoulder motion, allow for anterior translation of the humerus within the glenoid, impinge the RTC tendons with motion, and cause a secondary RTC tendonitis and potentially a tertiary adhesive capsulitis because of the local inflammation within the shoulder capsule [48,49]. Ultimately a “vicious cycle” may develop wherein weakness and pain from radiation-induced neuromuscular shoulder dysfunction contributes to and causes painful shoulder disorders such as RTC tendonitis and adhesive capsulitis. The diagnosis of RTC tendonitis in radiation survivors is generally made on clinical grounds and is not different from the general population. Marked atrophy of the RTC muscles is often present. Imaging of the RTC is only indicated if the clinical assessment, including history and physical examination, is not consistent with what is expected or if the patient does not respond to initial treatment measures and surgical intervention is contemplated. Although rare, HL survivors are at risk for radiation-induced malignancies such as malignant peripheral nerve sheath tumors, and these should be included in the differential diagnosis of shoulder pain and dysfunction (Figure 7) [50,51]. Although no data are available on the treatment of shoulder disorders in radiation survivors, the author’s clinical experience strongly favors conservative measures as the mainstay of treatment because damage to neuromuscular structures may limit the long-term success of surgical interventions. PT is the primary therapeutic intervention and has the potential to confer long-term benefit if the patient diligently follows a home-exercise program. Therapy should address core strength and posture, neck extensor weakness, pectoral girdle tightness, and RTC weakness with the goal of restoring the normal anatomic alignment of the shoulder and thus the RTC tendons within the coracoacromial arch. Antiinflammatory and/or nerve-stabilizing medications (eg, pregabalin, gabapentin, duloxetine) are often indicated. Subacromial injection with steroid and anesthetic, although not curative, may facilitate PT efforts. As a general rule, shoulder surgery should be avoided in patients with RFS because severe dysfunction and atrophy of the underlying neuromuscular structures confer poor surgical outcomes.

Cervical Dystonia HNC patients treated with radiation often demonstrate painful spasm and contracture of the anterior neck, termed radi-

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Figure 7. Gadolinium-enhanced T1-weighted MRI depicting a malignant peripheral nerve sheath in the right brachial plexus of an HL survivor treated with mantle field radiation (arrows). Secondary malignancies are common cause of morbidity and mortality in HL survivors and should be considered when one evaluates new signs and symptoms. Reprinted with permission from Stubblefield MD, O’Dell MW. Cancer Rehabilitation Principles and Practice. New York: Demos Medical Publishing; 2009.

ation-induced cervical dystonia [35]. The sternocleidomastoid (when not surgically resected as in a radical neck dissection), scalenus, trapezius muscles, and other cervical muscles are usually involved clinically (Figure 8). Ectopic activity is often present in the spinal accessory nerve, cervical nerve roots, and cervical plexus, with subsequent involuntary and often subclinical contracture and spasm of the trapezius, sternocleidomastoid, scalene, and other neck muscles (Figure 9). Affected muscles are generally painful and indurated to palpation. Needle electromyography of affected muscles may demonstrate decreased or “woody” insertional activity, mixed neuropathic and myopathic motor units, and various types of spontaneous activity, including fibrillation potentials, positive sharp waves, myokymia, and complex repetitive discharges. Many patients also undergo resection of the primary tumor and neck dissection combined with neurotoxic (usually platinum-based) chemotherapy, which can significantly and adversely affect local structures and increase toxicity [52]. As RF progresses, fixed contractures of the tendons, ligaments, muscles, skin, and other soft tissues develop, aided by the dynamic pathologic sustained contractions of the anterior cervical musculature. Inability to position the head as the result of progressive fibrosis can affect

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swallowing, phonation, and activities of daily living, such as driving and work-related tasks. Prompt identification of progressive loss of neck range of motion is encouraged so that treatment can be initiated as early as possible. The primary treatment modality is PT that emphasizes restoration and maintenance of neck range of motion. A life-long home exercise program is generally necessary to maintain function because of the insidious and progressive nature of RFS. Many patients have significant pain. Nerve-stabilizing agents may relieve the pain and spasm and are generally used as first-line treatments. Opioids may be added or used as second-line treatments in select cases. The injection of botulinum toxin into painful muscles has demonstrated potential in relieving pain and muscle spasm in RFS [35]. It should be noted that botulinum toxin injections will not improve neck range of motion when used in isolation as only muscle spasm and peripheral pain sensitization are affected and not the static structures such as tendons and ligaments. Botulinum toxin injections should be combined with therapy to obtain the maximal effect on range of motion. Patients with HNC are a high-risk group in terms of dysphagia, dysarthria, neck extension weakness, and risk of infection, in addition to demonstrating altered neck anatomy from radiation and surgery. Injection with botulinum toxin in this population should only be performed by experienced practitioners.

Figure 8. T1-weighted MRI depicting changes after a left radical neck dissection. Note the absence of the left sternocleidomastoid muscle and the left internal and external jugular veins. Postsurgical and radiation changes have obscured the usual clear demarcation between structures, particularly in the left neck.

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Figure 9. Radiation-induced cervical dystonia in a young woman who was treated twice with radiation for recurrent nasopharyngeal carcinoma. She has marked painful spasm bilateral sternocleidomastoid, scalene, and other neck muscles with contracture of the soft tissues of the anterior neck prohibiting extension of the neck.

Trismus Impaired mouth opening, or trismus, is a common complication of HNC and its treatment with a prevalence reported to range from 5% to 38% (Figure 10) [53]. The normal mouth opening in adults ranges between 23 and 71 mm when it is measured between the incisors [54]. This variation in reported incidence reflects the lack of uniform criteria for the definition of trismus [55]. Impairment in mouth opening may have adverse effects on chewing, swallowing, maintenance of oral hygiene, surveillance for cancer recurrence, pulmonary function, and other components of quality of life [56,57]. Trismus in HNC can result from local invasion of the tumor into the masseter or pterygoid muscles, their neural

Figure 10. Trismus in a head and neck cancer patient treated with surgery and radiation therapy. The patient is trying to actively open his mouth.

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innervation, the temporal mandibular joint, and/or other supportive tissues [58]. Surgery and radiation are major causes of trismus in HNC patients. Radiation results in trismus in up to 45% of patients who received curative doses of RT [59]. Trismus usually evolves most rapidly for the first 1-9 months after completion of RT [60]. Mandibular opening worsens as the dose of radiation delivered to the pterygoid muscles increases with the probability of developing trismus increasing 24% for every 10 Gy of additional radiation delivered to the pterygoid muscles [61,62]. Ectopic activity in the trigeminal nerve with involuntary spasm in the masseter and pterygoid muscle with ultimate contracture of the tendons, ligaments, and other soft tissues of the jaw likely underlie the development of trismus in HNC patients with RFS. As opposed to the other complications of radiation, there is a small body of literature concerning the treatment of radiation-induced trismus. PT is generally considered firstline treatment for trismus in HNC patients. The very limited literature on the use of PT in this population has not demonstrated significant efficacy [63-65]. Hyperbaric oxygen and pentoxifylline have shown no and modest efficacy, respectively [66,67]. Forced mouth opening under general anesthesia can improve trismus, but the effect is often short-lived, and caution is advised because of the risk of alveolus fracture and adjacent soft-tissue rupture. Surgical coronoidectomy has demonstrated significant efficacy in a single noncontrolled trial of HNC patients who had did not respond to PT [68]. Botulinum toxin injection may benefit selected complications of the RFS in HNC patients [35]. A report on the use of botulin toxin injection into the masseters of HNC patients with radiation-induced pain and trismus did not demonstrate improved trismus but did demonstrate reduced local pain [69]. A variety of jaw-opening devices are available treat trismus (Figure 11) [70]. Devices currently in use include stacked tongue depressors, corkscrew devices, the TheraBite Jaw Motion Rehabilitation System (TB; Atos Medical AB, Hörby, Sweden and the Dynasplint Trismus System (DTS; Dynasplint Systems Inc., Severna Park, MD). The TB, which works on the principle of high-torque short duration passive stretch, was efficacious in a small trial of 7 patients when used within 6 weeks of surgery for oropharyngeal carcinoma [71,72]. The TB was efficacious when combined with unassisted exercise in a group of patients who had undergone radiation therapy within the preceding 5 years (most within the preceding year) compared with unassisted exercise alone and when compared with mechanically assisted mandibular mobilization with the use of stacked tongue depressors combined with unassisted exercise [65]. Figure 11. Jaw-stretching devices use to treat trismus include (A) stacked tongue depressors, (B) a corkscrew device, (C) the TB, and (D) the DTS. Reprinted with permission from Stubblefield MD, O’Dell MW. Cancer Rehabilitation Principles and Practice. New York: Demos Medical Publishing; 2009.

PM&R

The fabrication and/or use of dynamic jaw-opening devices to treat both benign and oncologic causes of trismus have been detailed in reports as far back as 1968 [73-78]. The DTS is a commercially available dynamic jaw-opening device that operates on the principle of low-torque, prolonged duration stretch, which may be more effective at improving range of motion in an experimental model [79]. The DTS demonstrated efficacy in achieving improved jaw opening in a retrospective evaluation of 48 patients with trismus from 4 cohort groups, including radiation therapy for HNC, dental treatment, oral surgery, and stroke [80]. A recent study of the DTS system as part of multimodal treatment of trismus in HNC patients demonstrated significant improvement in maximal interincisal distance, particularly in patients who were able to be compliant with the program from 16 to 27 mm [72].

CONCLUSION Neuromuscular and musculoskeletal complications of radiation are major components of RFS. Rehabilitation medicine physicians, with their fundamental training in neuromuscular and musculoskeletal medicine as well as their extensive training in functional restoration, are uniquely qualified to help restore and maintain quality of life in cancer survivors with RFS.

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