Handbook of Clinical Neurology, Vol. 115 (3rd series)Peripheral Nerve DisordersG. Said and C. Krarup, Editors© 2013 Elsevier B.V. All rights reserved

Chapter 43

Late radiation injury to peripheral nerves

PIERRE-FRANCOIS PRADAT1* AND SYLVIE DELANIAN2

1D�partement des Maladies du Syst�me Nerveux, Hopital Piti�-Salp�tri�re, Paris, France2Oncologie-Radioth�rapie-Radiopathologie, Hopital Saint-Louis, Paris, France

INTRODUCTION

Radiation-induced neuropathy is a rare complication oftherapeutic irradiation. Irradiated long-term cancer survi-vors have an unavoidable tissue trace of previous radia-tion therapy which, in most cases, is clinicallyasymptomatic (Delanian and Lefaix, 2004). However,some patients develop late clinical complications relatedto damage to normal tissues that may impair functionaland survival outcome. The symptoms are related to thevolume irradiated.Radiation-induced neuropathy is a rareand possibly orphan disease, classically considered as irre-versible (Pradat et al., 1994, Gilette et al., 1995). All irradi-ated patients, notably those with late effects, present acommon histological signature with radiation-inducedfibrosis of variable degrees. Symptom severity often cor-relates with the presence and intensity of this underlyingpathophysiological process, which usually is clinicallyinvisible. All these patients could concomitantly expressa specific pathological feature, depending on the damageto the organ concerned regarding loss or dysfunction ofspecific cells (Delanian and Lefaix, 2004).

Among radiation-induced injuries, neuropathies havea considerable impact on patients considered to be curedof their cancer, but whose quality of life is impaired.The most frequent form and the best understood periph-eral nerve damage is brachial plexopathy, whichmay fol-low irradiation for breast cancer.

Radiation-induced neuropathies are better under-stood today. Clinically, various presentations correspondto different anatomical localizations including nerveroots, plexuses, or nerve trunks.Modern imaging includ-ing magnetic resonance imaging (MRI) and positronemission tomography (PET-scan) permits the exclusionof tumor recurrence; more recently a posteriori

*Correspondence to: Pierre-Francois Pradat, M.D., Ph.D., DepaSalpetriere, APHP, 47, Bd de l’Hopital, 75013 Paris, France. Tel: 3

pradat@psl.aphp.fr

conformal radiotherapy with 3D-dosimetric reconstitu-tion (Delanian and Pradat, 2010) allows a precise anatom-ical site to be linked to unexpected excess irradiation.Electrophysiological tests can detect focal conductionblocks in some cases of radiation neuropathy. Morpho-logical studies have recently shownmultiple cavernomasassociated with nerve fibrosis (Ducray et al., 2008). Theimportance of promptly establishing the link between theclinical picture and its radiation-induced origin is under-scored by the emergence of newdisease-modifying treat-ments that could potentially slow disease progression oreven improve the neurological symptoms.

In this reviewwewill consider the pathophysiological,clinical, and therapeutic aspects of radiation-induceddamage to the peripheral nervous system.

PATHOPHYSIOLOGY

Microvascular lesions seem to be a key factor inradiation-induced neuropathy. Peripheral nerves, likeall irradiated tissues affected by advanced radiation-induced fibrosis and atrophy, may be subject to defectivehealing leading to radionecrosis within a fibrous andsenescent irradiated tissue, a process that may resemblepremature aging, and specific neurological damage.

Radiation-induced fibro-atrophic process

The radiation-induced fibrotic and atrophic process is arare, late, local, and unavoidable complication of high-dose radiation therapy. To develop therapeutic strategieswe need to understand the mechanisms that lead toradiation fibrosis, by deciphering the various levels ofperturbation of normal physiological balance or

rtement des Maladies du Systeme Nerveux, Hopital Pitie-3 1 42 16 24 71, Fax: 33 1 44 24 32 69, E-mail: pierre-francois.

ND

homeostasis (review in Denham and Hauer-Jensen,2002, Delanian and Lefaix, 2004).

Radiation fibrosis is a dynamic process whose inten-sity can vary from inflammation to sclerosis and whosequalitative expression varies with the structure of theaffected organ or tissue. Schematically, spontaneousradiation fibrosis is divided into three histopathologicalphases that involve predominantly cells or matrix orboth. They are characterized by stepwise worsening overa period of several years: (1) an initial prefibrotic phase,often asymptomatic, marked by signs of chronic localinflammation, where endothelial cells play an importantrole resulting from an imbalance between proangiogenicand antiangiogenic stimuli; (2) a phase of constitutiveorganized fibrosis, essentially composed of fibroblastsand extracellular matrix, characterized by a patchworkof areas of active fibrosis containing a high density ofmyofibroblasts in an unorganized matrix, surprisinglyadjacent to poorly cellularized fibrotic areas consistingof senescent fibrocytes in a dense sclerotic matrix; and(3) a late fibrotic-atrophic phase, with retractile fibrosisand gradual loss of parenchymal cells. The fibrotic tissueis gradually made denser by successive remodeling ofthe matrix deposits, and reduction of small vessels.

The cellular and molecular mechanisms involved inthis process are essentially based on the theory that avicious circle occurs after disturbance of several kindsof balance, including fibroblast proliferation and extra-cellular matrix deposition, amplified by the actionof cytokines and growth factors (TGFb1) (Martinet al., 2000). In particular, after irradiation, active myo-fibroblasts, which appear during the initial inflammatoryphase, are then present during fibrogenesis and persistduring the constitutive fibrotic phase. This correspondsto the histopathological description of hypercellularizedfibrotic areas, and is characterized by persistent cellularactivation, downregulation of which is overwhelmedbecause of permanent cytokine production. Surpris-ingly, at the same time, gradual fibroblast rarefactioncombined with incomplete cell replacement might corre-spond either to the paucicellular areas of fibrosisdescribed in histopathology, or to the clinical processesof atrophy and secondary radionecrosis. The usual fateof these irradiated fibrocytes is gradual aging by stress-induced premature senescence with reduction in matrixsecretion and slowed proliferation, or cell death. At thesame time, the homeostasis of collagen turnoverbetween its synthesis and degradation is unbalanced,depending on secreting degradation enzymes, andderegulation leading to excessive matrix deposition.

Cellular knowledge of chronic-active fibrosis hasidentified the “lowest common multiple” but chief par-ticipants in the radiation fibrosis process: free reactivespecies, i.e., reactive oxygen species (ROS) and reactive

744 P.-F. PRADAT A

nitrogen species (RNS). ROS/RNS are normallyinvolved in physiological functions such as cell differ-entiation, proliferation, and inflammation, but excessROS/RNS production may result in pathological stressto tissues. Excess production may be induced by phys-ical or chemical factors, infectious agents, or deficientantioxidant defences (glutathione peroxidase, superox-ide dismutase or SOD, vitamin E, vitamin C) (review inRobbins and Zhao, 2004). Tissue–radiation interactionsdirectly and transiently generate ROS from the initialseat of inflammation. But during secondary vascularexudation, polymorphonuclear cells and macrophagesstimulated by contact with collagen degradation prod-ucts release additional waves of free radicals that canbe self-maintained in chronic inflammation. In addi-tion, tissue hypoxia when present may disturb theROS/RNS balance and cause depletion of tissue NOlevel because of increased ROS. When the level of dam-age rises so much that the stress oxidative responsemechanisms are transiently overwhelmed, fibrogenesisbecomes possible. And, subsequent additional stress,chronic stress, or repeated short stress resulting inabnormal ROS concentrations, such as those producedby chronic inflammation after radiation therapy, mayenhance ROS production, thus helping to extend andintensify the fibrotic process.

Various theories concerning the pathogenesis of radi-ation fibrosis have been deduced from pathologicaldescriptions based on vascular or fibroblastic concepts.The vascular concept was initially based on a theory ofgradual ischemia-hypoxia, the debate being whetherthis results in or is a consequence of irradiation.Ischemic injury appears to be limited in human tissues,although the capillary network is particularly vulnerableto radiation therapy. The more recent ideas concerningradiation-induced vascular damage are: (1) reactions ofendothelial cells to irradiation (procoagulant, mitogenic,proinflammatory, profibrogenic effects of thrombin),which range from apoptosis to lasting phenotypechanges; and (2) changed microvascularization in rela-tion to intermittent hypoxia rather than chronic hypoxiathat is able to induce hypoxic inducible factor and thenvascular endothelial growth factor/neoangiogenesis pos-sibly leading to telangiectasia. However, although theseradiation-induced vascular dysfunctions play an impor-tant role in generating the initial prefibrotic phase, in theestablished fibrotic phase, this role seems more indirect.The fibroblastic stromal concept sheds a different butcomplementary light on the radiation fibrosis process,by postulating the existence of a “gravitational effect”that centers on the ROS–fibroblast interaction, whichis partly mediated by TGFb1, and sets up a vicious circle.This effect is attributed to the existence of continuousROS attack and deregulation of fibroblast proliferation

S. DELANIAN

TO P

and metabolism, as described in lung or liver fibrosisafter its induction by alcohol or virus.

Specificity of radiation-induced neuropathy

PATHOPHYSIOLOGY

Radiation-induced neuropathic lesions have been mostlydescribed from early experimental data using singlehigh-dose irradiation, the pattern of damage develop-ment depending on both total dose and its fractionation(Pradat et al., 1994). These reports indicate that theperipheral nerve of the rat is radiation resistant inshort-term follow-up, since rat sciatic nerve was normal8 weeks after exposure to 40–100Gy (Janzen andWarren, 1942). The latent period of rat paresis dependson the dose per fraction and the width of irradiated vol-ume (Bergstrom, 1962). Schwann cells appear to beinjured by significantly lower radiation dose than neededto injure neurons (Cavanagh, 1968). In fact, damage tonerve fibers affects the axon, the enveloping neuro-lemma (Schwann cells and myelin), and the endoneur-ium (connective tissue stroma) (Hassler, 1968). In theacute phase, the irradiated nerve shows transient electro-physiological and biochemical changes combinedwith analtered vascular permeability. Delayed radiation effectsenhance a disorganized patchwork structure in the irra-diated volume including (1) direct axonal injury anddemyelination; (2) indirect connective tissue damage:extensive fibrosis within and surrounding nerve trunks;and (3) ischemia by injury of capillaries supplying thenerves compensated by neovascularization.

Kinsella et al. (1985) reported radiation-induced lum-bosacral or sciatic neuropathies within 9 months of20–25 Gy single-dose intraoperative radiation therapy:only three out of five had delayed nerve function recovery(Kinsella et al., 1985). Experimental 20–75 Gy single-doseirradiation in dogs showed evident radiation-induced neu-ropathy with paresis developing after 1 to 19 months, withshorter latencies for larger doses; whereas histologicalevaluation found large myelinated fibers and perineurialfibrosis, without significant vascular injury.

FACTORS AFFECTING RADIATION-INDUCED

NERVE INJURY

The risk, severity, and nature of radiation-induced lateeffects in patients are not specific and depend on severalfactors (Delanian and Lefaix, 2004):

● Radiotherapy-related factors: 50 years ago low-

LATE RADIATION INJURY

energy machines with short source to skin distance(cobalt SSD 60 cm), alternating treated fields withsteep dose gradients within the body, and body posi-tion displacement (when the arm of the radiationtherapy RT machine was not able to turn around

patient) between each radiation therapy field favor-ing overlapping fields; large total dose (more than50Gy to plexus), large dose per fraction (fractionsize� 2.5Gy), radiation volume including a largeproportion of nerve fibers, a heterogeneous high-dose distribution, hot spot high dose especially inthe case of field junctions, in salvage radiotherapyof previously treated areas, in intracavitary radiumsource, or after intraoperative radiotherapy boost.

ERIPHERAL NERVES 745

● Combined treatment-related factors: combination of

radiation therapy with surgery particularly in the caseof extended lymph node dissection (axillary, retroper-itoneal or iliac nodes) or complication (hematoma,chronic infection); concomitant chemotherapy-radiotherapy or previous neurotoxic chemotherapysuch as cisplatin, vinca-alkaloids, and taxanes.

● Several patient-related factors have been incrimi-

nated: physiological status of the patient (advancedage, obesity), comorbidity factors (high blood pres-sure, diabetes mellitus) or pre-existing peripheralneuropathy (diabetic, alcoholic, genetic, etc.). Never-theless, the involvement in neuropathies of thesefactors of susceptibility, which are well known anddescribed in radiation-induced pathology, needs tobe confirmed by systematic studies. The same is truefor potential genetic susceptibility.

NEUROTOXICITYACCORDINGTOTHEAFFECTEDANATOMICAL SITE

By definition, only the nerve roots, nerve plexus, nervetrunk, and muscles within the irradiated volume areaffected by radiation-induced sequelae: the irradiationfield therefore conditions these anatomical structuresfor possible damage (Fig. 43.1 and Fig. 43.2A). The degreeof neurological involvement is subject to the above-mentioned risk factors (treatment-related and patient-related) and the radiosensitivity of the different structuresof the nerve tissue (cellular bodies of peripheral neurons,axons, myelin).

In a long-term cancer survivor, experience shows thatwhen complications arise years later, the link with previ-ous radiotherapy is often difficult to establish. The diag-nosis is therefore made at the end of a long series ofmedical consultations, tests, and examinations, some ofwhich are invasive (sampling of cerebrospinal fluid, nervebiopsy, etc.). The clinical picture is nonspecific. Cutane-ous atrophy with subcutaneous fibrosis and tattoo markscan be used to identify the field of irradiation (Fig. 43.2Aand Fig. 43.3). The diagnosis can also be guided by possi-ble radiation-induced extraneurological complications:sternoclavicular osteoradionecrosis, radiation-inducedcardiopathy, radiation-induced enteritis, and radiation-induced multiple basal cell skin carcinomas.

Fig. 43.1. Axial radiation-induced impairment clinical his-

tory: this woman treated by chemotherapy followed by mantle

then lumbar irradiation for Hodgkin disease, 27 years before,

developed a cervicoscapular and paraspinal muscle atrophy

(RT field black full line).

746 P.-F. PRADAT AND S. DELANIAN

The diagnosis is based on a series of arguments inwhich neurological expertise is central and on the analysisof symptoms and radiological studies such as PET-scan(Fig. 43.2B,C), MRI (Fig. 43.2D) and radiation therapydosimetric reconstitution (Fig. 43.4), and electrophysio-logical tests. Precise analysis of signs and collaborationwith the radiotherapist allow determination of whetherthe neurological symptoms and signs can be related todamage to nerves within the irradiation field. The workupeliminates tumor invasion (Table 43.1), a major differen-tial diagnosis, but the clinical picture may mimic manyneurological diseases, such as amyotrophic lateral sclero-sis among pure motor postradiation neuropathies of thelower limbs (Thomas et al., 1985, Harper et al., 1989,Delanian and Pradat, 2010).

Cranial nerve injury

Cranial nerve injury is a feared complication of high-dose irradiation of the base of the skull after brain orhead and neck tumors. Damage to cranial nerves afterirradiation of the head and neck is not exceptional. Ina series of 317 patients irradiated for nasopharyngealcarcinoma, 31% developed paralysis of one or more cra-nial nerves after a median period of 7.5 years (Konget al., 2010).

RADIATION-INDUCED OPTIC NEUROPATHY (II)

Radiation-induced optic neuropathy (RION) is observedafter irradiation of intra- and extracranial tumors involv-ing structures adjacent to the optic apparatus: orbittumors, head and neck cancers, such as paranasal sinus(nasal fossa, ethmoid, maxillar) or nasopharynx, andcentral nervous system tumors (pituitary adenoma,craniopharyngioma, chiasmal glioma, frontal meningi-oma and whole-brain irradiation for metastasis).

In a recent publication of 75 patients treated for headandneckor skull base tumorswith theopticnerve includedin the irradiated volume, RION incidence was 11% afterirradiation using proton or carbon ions (Demizu et al.,2009). This complication was described after irradiationof 215 patients for pituitary gland tumor (2% of cases),after stereotaxic radiosurgery (Stafford et al., 2003),and after cobalt 60 plaque therapy of choroidalmelanoma(Char et al., 1977). Five-year actuarial RION incidencewas13% above a dose of 60Gy (Parsons et al., 1994) and30–34% after a 60Gy median dose (51–70Gy) forcranio-pharyngioma (Jiang et al., 1994).

In addition to radiation therapy total dose>60 Gy(Parsons et al., 1994), the main factors are diabetes(Habrand et al., 1989), arterial hypertension or dyslipide-mia (Delattre et al., 1986), pre-existing compression ofthe optic nerve by the tumor (Danesh-Meyer, 2008),Cushing syndrome (Ballian et al., 2010), or concomitantchemotherapy with intrathecal methotrexate (Fishmanet al., 1976), 5-FU (Chan and Shukovsky, 1976), CCNU(Wilson et al., 1987, Croisile et al., 1990), or procarbazine(Wilson et al., 1987).

When RION affects the anterior part of the opticnerve, ophthalmological findings are those of acuteischemic anterior optic neuropathy (anterior RION):the decrease in visual acuity is sudden with papillaryedema, exudates, and hemorrhages, associated withareas of nonperfusion of the head of the optic nerveon fluorescence angiography. In a prospective study, 5out of 131 (4%) patients had this ischemic anterior RIONa median of 30 months after radiotherapy (range 2–4years) (Parsons et al., 1994).

However, chronic damage to the posterior portion ofthe optic nerve or the chiasma is the most frequent. Inretrobulbar (posterior RION) visual acuity is graduallyimpaired within a few weeks; MRI shows enlargementof the optic nerve, with hypointense lesions in T1- andT2-weighted sequences, with enhancement after gado-linium injection (Young et al., 1992). It may be difficultto rule out a tumor extension and a surgical explorationmay be necessary. In a prospective study, 12 out of 131(9%) patients had posterior RION amedian of 28monthsafter radiotherapy (range 1–14 years). Most RIONpatients deteriorate rapidly over several weeks and are

A

C

D

B

Fig. 43.2. Radiation-induced brachial plexopathy. (A) Clinical history: this woman treated by mastectomy followed by chest (RT

field black dotted line) and axillary-supraclavicular (RT field black full line) irradiation for left breast cancer 19 years ago devel-

oped arm lymphedema and supraclavicular fibrosis including brachial plexus (white dotted line) and showed progressive sensory

and motor (arrow) upper limb signs for 7 years. (B) PET-scan coronal view in RIBP with axillary compressive radiation-induced

fibrosis without breast cancer recurrence. (C) Corresponding frontal and sagittal views. (D) Axillary MRI of radiation-induced

neuropathy (arrow): frontal and sagittal views.

LATE RADIATION INJURY TO PERIPHERAL NERVES 747

200 mV

100 mS

Fig. 43.3. Electroneuromyography: myokymic discharges in

the biceps.

748 P.-F. PRADAT AND

left with irreversible severe vision loss and optic atrophy,whereas partial improvement, often after steroids,occurs in some patients.

OTHER RADIATION-INDUCED CRANIAL NEUROPATHIES

Other cranial neuropathies have mainly been describedafter irradiation of head and neck or skull base(Johnson et al., 1989; Kong et al., 2010). Just after RION,hypoglossal palsy (XII) is the most frequent cranial neu-ropathy. Based on results from an old radiotherapy tech-nique administered between 1958 and 1972, Berger andBataıni reported that 19 out of 35 (54%) patients withradiation-induced cranial neuropathies suffered fromhypoglossal palsy (Berger and Bataıni, 1977). Classically,patients develop tongue hemiatrophy, fasciculations,and deviation when protracting the tongue, 1 to 10 years

A

B

Fig. 43.4. Lower limb radiation-induced radiculoplexopathy (RIR

noma with a conformal 3D-dosimetry: indicative lumbo-iliac volu

this man treated by chemotherapy followed by mantle then lumba

sponding with lumbar muscle-subcutaneous atrophy (RT field blac

3D-dosimetry: indicative large pelvic volume in a sagittal view in

(mean 64months) after irradiation of head and neck can-cer, especially rhinopharynx lymphoepithelioma aftercombined chemotherapy including cisplatin (Johnsonet al., 1989; Liu et al., 2007).

Other cranial nerve injuries involve the glossopharyn-geal (IX) nerve, vagus nerve (X) after thoracic irradia-tion for breast cancer (Westbrook et al., 1974) or with9 out of 35 cranial nerve palsies in the head and neck irra-diated series (Berger and Bataıni, 1977), recurrent laryn-geal nerve with larynx palsy after irradiation for breastcancer (Westbrook et al., 1974) or for thyroid tumor(Craswell, 1972), and spinal accessory (XI) nerve withsternocleidomastoid and trapezius muscles palsy (“fall-ing shoulder”).

Facial paralysis (VII) can occur after radiotherapy orafter postoperative radiotherapy of a parotid tumor(Lefevre-Houller et al., 2004) and can be associated withcutaneous pretragial fibronecrotic lesions of the parotidgland.

Trigeminal neuropathy (V) may develop after cav-ernous sinus tumor irradiation, mainly meningiomaand chordoma (Tishler et al., 1993), and may manifestwith decrease in facial sensation, paresthesia, andpain. In a randomized clinical trial of treatment ofessential trigeminal neuralgia by radiosurgery, longernerve length irradiation did not improve pain relief butcould increase paresthesia (Flickinger et al., 2001).

S. DELANIAN

C

P). (A) Adjuvant irradiation after surgery for left testis semi-

me in coronal, sagittal, and frontal views. (B) Clinical history:r irradiation for Hodgkin disease 21 years ago has RIRP corre-

k full line). (C) Cervical carcinoma irradiation with conformal

cluding sacral plexus.

Table 43.1

Differential diagnosis between postradiation and

neoplastic plexopathies

Radiation-induced

plexopathy

Neoplastic

plexopathy

Clinical course Progressive

(months/years)

Rapid

(weeks/months)Early signs Paresthesia PainSensory signs Moderate IntenseMotor signs Delayed

progressive

Rapid often intense

Horner’s sign <10% Frequent 30�50%Myokymia Frequent 60% Absent

Neuroradiology(MRI, PET-scan)

Fibrosis Tumor mass

FromThomas andColby, 1972;Bagley et al., 1978;Harper et al., 1989.

LATE RADIATION INJURY T

Trigeminal neuropathy develops in approximately 10%of patients treated for essential trigeminal neuralgiaafter 40 Gy (50% isodose of the 80 Gy delivered).

Anosmia (I) and ageusia occurring immediately afterirradiation do not seem to be related to direct damage tothe olfactory cranial nerves, but to involvement of sen-sory receptors. Most of the time, smell is already lostafter surgery, just before postoperative irradiation.

Acute hearing loss during or just after cranial irradi-ation is common and transitory in relation to otitis. Hear-ing deterioration assessed with an audiogram maydevelop 3 to 5 years after radiosurgery (Bhandareet al., 2010). Delayed deafness is often correlated witha conductive loss or cochlear damage rather than theauditory nerve (VIII) injury itself.

CRANIAL NERVE NEUROMYOTONIA

Cranial nerve neuromyotonia is a rapid muscular contrac-ture, tonic, progressive and involuntary, with relaxation.It is characterized by complex repetitive electromyogramdischarges in multiple muscles innervated by cranialnerves. This delayed radiation-induced phenomenon ischaracterized by contraction lasting from a few secondsto minutes several times a day, sometimes with a triggerfactor (Lefevre-Houller et al., 2004). Pathophysiologi-cally, there is damage to the neuronal membrane, whichleads to cellular hyperexcitability and abnormal repeateddischarges (Tsang et al., 1999).

Neuromyotonia of the oculomotor nerves has oftenbeen reported in the literature (Lessell et al., 1986;Much et al., 2009). It causes involuntary and paroxysmalmovements of one eyeball leading to episodes of tran-sient diplopia lasting less than 1 minute.

Neuromyotonia of other cranial nerves has beenreported, including the motor branch of the trigeminalnerve, the facial nerve, and the hypoglossal nerve(Diaz et al., 1992; Liu et al., 2007). Symptoms can beimproved using drugs to stabilize the membrane, likecarbamazepine (Diaz et al., 1992).

Axial neurological injury

Dropped head syndrome, late-onset cervicoscapular mus-cle atrophy combined with cervical paraspinal and shoul-der girdlemuscle weakness, has been described amean of25 years (range 5–30) after upper diaphragmatic irradia-tion for lymphoma (Rowin et al., 2006; Furby et al., 2010).Apart from cervical pain, this clinical picture does notinclude sensory loss (Fig. 43.1). Electrophysiological stud-ies and muscle biopsies have been unable to clearly dis-criminate between a primarily myopathic or neuropathicdisorder, and it is assumed that there is a mixture of both.

Asymmetrical diaphragmatic weakness secondary tophrenic nerve paralysis is rare, initially described aftercervical high-dose radiotherapy for head and neck can-cer or more recently low-dose mantle radiotherapy forHodgkin disease (Avila et al., 2011).

Upper limb radiation-induced neuropathy

The main upper limb radiation-induced neuropathy ischronic progressive brachial plexopathy after breast can-cer treatment, which has been recognized as a possibleconsequence of irradiation since the 1950s, dependingstrongly on the parameters of radiation therapy.

DELAYED PROGRESSIVE RADIATION-INDUCED

BRACHIAL PLEXOPATHY

Epidemiology

Radiation-induced brachial plexopathy (RIBP) is a pro-gressive nerve injury in the axillary-supraclavicular ipsi-lateral node volume after irradiation for breast cancer.The time to onset ranges from several months to decadeswith amean incidence of 1.8–2.9% per year (Powell et al.,1990; Bajrovic et al., 2004). The incidence of RIBP todayis under 1–2% in patients receiving usual plexus totaldoses of less than 55Gy in 2Gy daily fraction.

Clinical findings

In its classic form, RIBP begins with paresthesiae or dys-esthesiae (Beglu et al., 1985). Subsequently, paresthesiaemay decrease with the development of hypoesthesia thenextensive anesthesia. The pressure of a zone of axillaryand/or supraclavicular induration can trigger or worsenparesthesiae (Tinel’s sign). Neuropathic pain is rare andusually moderate, unlike what is seen in malignant

O PERIPHERAL NERVES 749

ND S. DELANIAN

plexopathy. Motor weakness is often delayed by severalmonths and is progressive, accompanied by amyotrophyand sometimes fasciculations. Myokymia, with arrhyth-mic, involuntary flexion of the fingers, is rare.

The distribution of symptoms varies following theirradiation technique and the site damaged. The symp-toms frequently start in the median nerve territory, sim-ulating carpal tunnel syndrome, before spreadinggradually to proximal limb. The onset is often insidious,spreading over months or years. Exceptionally an acuteonset suggests an ischemic origin, and occlusion of thesupraclavicular artery (Gerard et al., 1989).

RIBP varies greatly in intensity, but graduallyworsens and after several years may result in paralysisof the upper limb with a mean time of 1.2 years (range0.2–5) from the first symptoms to hand paralysis(Match, 1975; Fathers and Trush, 2002). Rapid worsen-ing is possible after trauma that causes unusual tractionon the affected limb, notably carrying of heavy loads(Pradat et al., 1994).

Skin changes especially poikilodermia occurs, oftenin association with sclerosis and muscle atrophy(Fig. 43.2A), especially after orthovoltage and cobaltirradiation. These changes are associated with indurationof the axillary-subclavicular with subcutaneous fibrosis,advanced osteoporosis, and even sternoclavicular osteo-necrosis with, in older female patients, subcutaneouscalcifications. Lymphedema occurs in approximately20% of cases in old series (Fig. 43.2A), strongly linkedwith the extension of lymph node dissection and totalradiation therapy dose. However, these lesions are notpredictive of RIBP.

750 P.-F. PRADAT A

Diagnosis

Electroneuromyography is useful in this setting. The firstchanges are often characterized by alteration of the sen-sory action potentials of the median nerve in the fingers,which points to an involvement distal to the dorsal rootganglia. The decrease in amplitude of themotor potentialsgenerally starts in the thenar muscles (thumb). The nerveconduction velocity is preserved, in keeping with axonloss. A proximal conduction block of the motor fiberscan be detected (Soto, 2005). Myokymic discharges(Fig. 43.3) are found in approximately 60% of cases(Roth et al., 1988).

Exclusion of axillary tumor recurrence can be diffi-cult (Table 43.1). Clinical examination and electroneuro-myography can help, but formal diagnosis is essentiallybased on axillary MRI (Fig. 43.2D) and, when the lesionis very small, on PET-scan (Fig. 43.2B,C). The presenceof an intense hypermetabolic zone in the plexus suggestscarcinoma progression.

EARLY AND ACUTE RADIATION-INDUCED

BRACHIAL PLEXOPATHY

Acute RIBP is extremely rare andmust be differentiatedfrom cancer recurrence.

Early transient RIBP

Early brachial plexopathy within the year followingbreast cancer irradiation is of insufficient duration totrigger irreversible degenerative sequelae. It occurredin eight women with acute brachial plexopathy out of565 (1.4%) in 4.5 months (range 2–14) after an averagesupraclavicular-axillary dose of 50Gy in 5 weeks (RT1968–79) (Salner et al., 1981). In a series of 1117 patients,of the 16 women who developed an acute brachial plexo-pathy within 10 months, 80% recovered completely(Pierce et al., 1992). A case of transient brachial plexopa-thy has been reported after 43Gy mantle irradiation forHodgkin disease at 1 month (duration of symptoms6 months) and at 17 months (duration of symptoms6 months) with complete recovery (Churn et al., 2000).

Initial signs and symptoms include distal paresthesiaesometimes associated with proximal pain. Moderatemotor deficit occurs simultaneously or during the fol-lowing months. After 3 to 6 months of stability, the neu-rological deficit improves, often completely. The directand transient effect on Schwann cells, which causesreversible demyelination, may be causal, as suggestedby some experimental data (Davila et al., 1990). Anotherhypothesis concerns the role of compression caused byreversible postradiation edema.

Ischemic RIBP

Ischemic RIBP is uncommon, with an acute onset, but noprogression afterwards. Only two cases of ischemic bra-chial plexus neuropathy following radiation therapyrelated to acute ipsilateral occlusion of the subclavicularartery have been reported (Mumenthaler et al., 1984;Gerard et al., 1989). In addition one of us has followeda patient treated for 2 years for an oropharyngeal cancerwho manifested an acute, complete palsy due to brachialplexopathy without arterial occlusion, 6 years after60 Gy/30 fractions head-neck irradiation.

MONONEUROPATHIES

One case of isolated sudden-onset palsy of the long tho-racic nerve has been reported after supraclavicular irra-diation for breast cancer (Pugliese et al., 1987). Virtuallycomplete paralysis followed irradiation and almost fullrecovery occurred after 5 months.

Among 33 children irradiated for distal sarcomas,two developed radiation-induced neuropathy: one who

T

received a 25Gy boost in intraoperative radiation ther-apy (IORT) developed sensory dysfunction of the ulnarnerve 11 years after radiation therapy; the other devel-oped radial nerve palsy 3 years after postoperative radio-therapy (Paulino, 2004).

Lower limb injury

Lower limbs involvement is less common. It occurs intwo settings: (1) after extensive but low-dose radiother-apy for testicular cancer and lymphoma, in the form oflumbosacral radiculoplexopathy involving L2–S2 roots;(2) after local high-dose radiotherapy for sarcoma,mainly in the form of radiation-induced injury of nervetrunks.

Intraoperative radiotherapy (IORT) has yielded sub-stantial experimental and clinical data. The high riskof radiation-induced neuropathy of the lumbosacralplexus or sciatic and femoral nerves limits IORT becauseof the perioperative delivery of radiotherapy in a singlehigh-dose fraction (Kinsella et al., 1985; 1991).

DELAYED PROGRESSIVE LUMBOSACRAL

RADICULOPLEXOPATHY

Irradiation simultaneously affects in the same volumethe lumbosacral spinal cord, the nerve roots, the lumbo-sacral plexus, and the large nerve trunks. It seems best toprefer the term radiculoplexopathy to lumbosacralplexopathy, which is used by analogywith brachial plexo-pathy, but does not correspond to the reality of the exten-sion of the anatomical lesions.

Epidemiology

Some 75 cases of radiation-induced lumbosacral radicu-loplexopathy (RIRP) of the lower limbs have beenreported several decades after extensive irradiation vol-ume for testicular cancer (Fig. 43.4A,B) (Schi�dt andKristensen, 1978) or lymphoma (Delanian et al., 2008;Delanian and Pradat, 2010). The current “over-represen-tation” of Hodgkin disease seems to be related to theefficacy of older treatments, which enabled long-termsurvival. These survivors are then susceptible to late-onset neuropathy, delayed further because the total irra-diation dose was moderate (mean 40–45 Gy with 2 Gy/fraction) but sufficient to be toxic, given the large fieldvolume. This extensive irradiation covering the lumbo-aortic, iliac, and inguinal lymph node chains no doubtdamaged the nerves of the lumbosacral plexus over agreat length, emphasizing the importance of the volumeof nerve irradiated in generating radiation-induced neu-ropathy, as shown experimentally (Bergstrom, 1962).

RIRP occurs late (Chen and DeLaney, 2011) and isreported after high-dose radiotherapy (more than

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60 Gy) for pelvic cancers (Fig. 43.4C). Twenty-four casesof radiculopathy were reported after irradiation for cer-vical carcinoma including intracavitary radium(Pettigrew et al., 1984) or comorbidities or extensive nodedissection. RIRP was reported with weakness but nopain, unlike tumor plexopathy (Thomas et al., 1985). Ina long-term follow-up after high-dose (median 73 Gyequivalents) irradiation of the cauda equina forretroperitoneal-paraspinal sarcomas), 13 out of 53patients (25%) developed neurotoxicity (median 7 years)(Pieters et al., 2006).

Clinical findings

The interval between irradiation and symptom onsetranges between 1 and 30 years. RIRP occurs earlier afterhigh-dose radiotherapy delivered to a moderate volumeand later when moderate doses are delivered to a largevolume. Although irradiation is often delivered symmet-rically around the median, the neurological deficit,which is usually bilateral, is often asymmetrical, possiblywith initial unilateral damage (Lamy et al., 1991).

The onset of neurological signs is insidious, with dam-age that is purely or predominantly motor (Feistner et al.,1989). UnlikeRIBP, the sensory signs and paresthesiae areabsent or noted very late, in contrast to signs of peripheralneurogenic motor involvement, such as amyotrophy andfasciculations. Central signs are lacking, apart from pos-sible associated medullary damage. The handicap pro-gresses in severity, and use of a wheelchair is oftennecessary after a few years. Suddenworsening of the neu-rological deficit associated with lumbar painmay indicatevertebral compression with underlying radiation-inducedvertebral osteoporosis, notably following a fall because ofwalking difficulties. Intestinal and/or urinary disordersare associated after irradiation of pelvic cancer, eitherby peripheral neurogenic damage or by pelvic fibrosis.Disease progression generally proceeds stepwise, withperiods of stabilization.

Diagnosis

Diagnosis may be difficult and requires appropriate neu-roimaging examinations (scanner, MRI, even PET-scan)to exclude tumor invasion or another cause, such as alumbar spinal stenosis (Thomas et al., 1985). In puremotor forms, the main differential diagnosis is amyo-trophic lateral sclerosis: it is not rare for this initial diag-nosis to be questioned because there is no rapidprogression of the motor deficit to new territories orthe appearance of pyramidal syndrome.

Electroneuromyography shows denervation of sev-eral nerve roots, with preserved sensory action poten-tials. Decrease in sensory potentials may be caused byradiation-induced damage to dorsal root ganglia but

O PERIPHERAL NERVES 751

A

B

Fig. 43.5. Postradiation lumbosacral radiculopathy with spi-

nal root cavernomas mimicking carcinomatous meningitis.

(A) Clinical and electrophysiological examinations showed

ND S. DELANIAN

may also reflect sequelae of neurotoxic chemotherapyassociated with lesions of dorsal root ganglia causedby cisplatin or with axonopathy resulting from exposureto taxol. Myokymia is in favor of a radiation-inducedneuropathy.

Lumbar MRI usually shows radiation-induced degen-eration of the vertebral bodies, which confirms that theadjacent nerve roots were included in the field of irradia-tion. Lumbar and/or pelvic MRI does not play a determi-nant role in a positive diagnosis, but does eliminate adifferential diagnosis, such as tumor invasion or lumbarspinal stenosis. Gadolinium MRI enhancement of thenerve roots of the cauda equinamay be seen in postradia-tion radiculopathy (Hsia et al., 2003, Labauge et al., 2006,Ducrayet al., 2008),withanodular appearance suggestiveof leptomeningealmetastases, especially when associatedwith increased CSF protein content (Fig. 43.5A). In threecases reported in the literature, biopsy of the nerve rootof the cauda equina showed that there was no tumorinvasion: histopathological examination did not showfibrotic lesions, but revealedvasculardilationcorrespond-ing to cavernomas (Fig. 43.5B) (Ducray et al., 2008).

Recently, a new technique of a posteriori conformalradiotherapy with 3D-dosimetric reconstitution usingprevious field of irradiation data has been used to con-firm diagnosis of RIRP of the lower limbs. This recon-struction defines the anatomical regions that may havereceived high doses of radiation. In one case, the patienthad developed a pure, progressive motor deficit of thelower limbs, which was initially diagnosed as amyo-trophic lateral sclerosis. 3D-dosimetric reconstitutionshowed that the spinal cord and the lumbosacral nerveroots had in fact received an unplanned dose of 52Gyalong a length of 7cm (Delanian and Pradat, 2010).

752 P.-F. PRADAT A

lower motor neuron abnormalities in the lower limbs postga-

dolinium sagittal T1-weighted MRI demonstrating nodular

enhancement of cauda equina nerve roots. (B) Photomicro-

graph of a biopsy specimen of the spinal root cavernoma

blood-filled caverns, lined with a single layer of endothelial

cells (H&E, �40). Adjacent nerve fibers appear to be com-

pressed by the cavernous malformations (arrow).

ACUTE TRANSIENT LUMBOSACRAL PLEXOPATHY

Transient lumbosacral plexopathy was recently describedfollowing L-field (between T12 and L5) irradiation for tes-ticular cancer, with mild doses in 11 out of 346 patients(3.2%): seven patients presented with sensory symptoms(bilateral paresthesia), which lasted less than 3 months,within 6 months after a mean total dose of 25Gy radio-therapy; four patients had motor impairment lasting atleast 1 year, within 6.5 years (range 3–9) after a total doseof 36–40 Gy (Brydoy et al., 2007). As described for tran-sient RIBP, symptoms worsened over a few months, thenstabilized for a few more, before regressing, oftencompletely. The pathophysiology may be similar, withfocal demyelination.

A few single cases have been reported after pelvic orlumbar radiation: two patients had lower limb paralysis,4–5 months after pelvic irradiation (postoperative45 Gy/25 fractions chemoradiation for rectal cancer in

one case and 55 Gy chemoradiation for anal canalcancer in the other case). Symptoms decreased afterseveral months with mild residual weakness (Schi�dtand Kristensen, 1978; Thomas et al., 1985; De Caroliset al., 1986; Dahele et al., 2006).

NERVE TRUNK DAMAGE

The most common etiology of neuropathy after lowerlimb irradiation is tumor involvement (recurrence) andradiation-induced fibrotic compression: because of bet-ter soft tissue definition, MRI is the method of choice todiscriminate between these two processes.

Fig. 43.6. CoronalMRI view 23 years after postoperative irra-

diation for right biceps femoris muscle synovial sarcoma:

radiation-induced sciatic neuropathy closely linked to fibrosis

around the nerve trunk (arrow).

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Isolated cases of severe motor radiation-inducedinjury of the nerve trunk (sciatic, femoral) after externalirradiation of the thigh have been reported: identificationof risk factors such as irradiation over a long stretch of anerve, and large and deep surgical tumor resection of thethigh, exposing the sciatic nerve at the surface of the irra-diated volume. In one case (Fig. 43.6), a posteriori confor-mal radiotherapy with 3D-dosimetric reconstitutionshowed that the sciatic nerve had received a postoperativetotal dose of 66 Gy over a length of 25 cm during radio-therapy of sarcoma of the thigh (Pradat et al., 2009). In theother case, salvage radiotherapy (30 Gy) overlapped thevolume irradiated postoperatively (50 Gy) 1 year before.Femoral nerve paresis related to compression by scar tis-sue has been described in patients irradiated along theinguinal region and thigh nerve trajectory (Mendeset al., 1991). Some cases of radiation-induced neuropathywere reported in the follow-up of conservative treatmentof extremity sarcomas, including brachytherapy implantsin four cases (9%) at 6 to 20months (Zelefsky et al., 1990)and IORT in three cases (25%) at a mean 13 months(Azinovic et al., 2003). Moreover, radiation-induced neu-ropathy was observed after single-dose boost radiationusing high-energy electrons IORT in combination withstandard 45 Gy radiotherapy: in 9 out of 15 (2 mild,7 severe) patients at 10 years using 20 Gy IORT(Kinsella et al., 1988); in 24 out of 195 surviving patientsat 94 months after 15 Gy IORT (Azinovic et al., 2003).

Lastly, after prostate irradiation, in addition to sciaticpain, theremay be bladder incontinence of peripheral neu-rogenic origin caused by distal damage to nerve trunkssupplying the bladder or rectum (Russell et al., 1990).

TREATMENT

Treatment of radiation-induced neuropathy is symptom-atic and combined with attempts to limit aggravatingfactors. A curative strategy has yet to be defined andthe best approach is always prevention through respectof radiotherapy limits. Cancer patients are now surviving

for longer periods, and more studies are expected toaddress the problem of radiation-induced neuropathy.

Symptomatic treatment

Analgesics areused to treat neuropathicpain, notablynon-opioid analgesics, benzodiazepines, tricyclic antidepres-sants, and antiepileptics. Opioid treatments are seldomrequired. Benzodiazepines are used for paresthesia.Membrane-stabilizing drugs (carbamazepine)may reducenerve hyperexcitability, like myokymia. One study hasreported that dorsal root entry zone lesions are usefulfor the treatment of pain related to radiation-inducedplexopathy in seven of eight patients (Teixeira et al.,2007). However, this neurolysis is an additional surgicalmanipulation that can worsen nerve wall ischemia,whereasmechanical separation fromcompressive fibrosismay in theory release trapped nerves. Generally, surgicalmethods have never proven useful in the management ofradiation-induced neuropathy.

Physical therapy is valuable in maintaining functionand preventing joint complications, which cause painand hamper movement. It should be gentle and thepatient should be given advice on economy of neuromus-cular movements. It is important to prevent any stretch-ing of a plexus immobilized by fibrosis, notably byavoiding the carrying of heavy loads and extensivemovements, which may cause sudden neurological def-icit. In the case of RIBP, physical therapy can be used toprevent stiffening of the shoulders as a result of scapu-lohumeral periarthritis. Algoneurodystrophy may alsooccur and should be treated with general or local anti-inflammatory drugs, or by steroid injections.

Restriction of aggravating factors

Removal of inciting stimuli may be helpful in controllingthe progression of radiation-induced neuropathy.

REMOVING COMORBIDITY FACTORS

General measures include controlling any diabetes andhigh blood pressure, stopping alcohol abuse, avoidingfibrogenic drugs, and, as far as it is possible, avoid theuse of statins (muscular toxicity with creatine phospho-kinase elevation).

Local measures consist of avoiding any local traumain the irradiated volume, such as new surgery or biopsy(hematoma, infection).

Controlling acute inflammation

Corticosteroids have long been used as anti-inflammatoryagents in the treatment of radiation injury (Evans et al.,1987; Roden et al., 1990). In all cases, anti-inflammatorydrugs are of value in reducing the acute inflammation

O PERIPHERAL NERVES 753

ND

associated with fibrosis, and should first be used to cir-cumscribe fibrotic volume and density, despite lack ofany objective efficacy in reduction of fibrosis and nervelesions. Steroids have been used to attenuate late-onsetfibrotic effects since the 1950s. In vitro, steroids inhibitpolynuclear cell and macrophage recruitment, collagensynthesis, prostaglandins, and leukotrienes. In vivo, dexa-methasone has been used to treat radiation-induced pneu-monitis, nephropathy, and liver injury in rats, and appearstodelaydevelopmentof radiation-inducedorgandysfunc-tion. Histological evidence in rat lung indicates that thelong-term results of appropriately timed steroid treatmentmay include reduction of fibrosis.

Disease-modifying agents

VASCULAR APPROACH

The benefit of hyperbaric oxygen in radiation-inducedfibrosis is not proved (Guy and Schatz, 1986; Annaneet al., 2004; Bennett et al., 2005), and the literature is dom-inated by small trials with ill-defined recording of compli-cations. Hyperbaric oxygen reduces tissue edema andstimulates angiogenesis, fibroblast proliferation, and col-lagen formation in irradiated hypoxic tissue, which para-doxicallymay enhance fibrotic properties. In a study of 32women who underwent breast-conserving irradiation and12 controls, after 25 hyperbaric oxygen sessions andmedian follow-up of 9 months, significant reduction inpain, edema and erythema (inflammation) was observed,but fibrosis and telangiectasia were not affected (Carlet al., 2001). Therewas no clinical evidence that hyperbaricoxygen is beneficial in 34 patients with brachial plexopa-thy at 12 months of follow-up, although it may improvethe sensory threshold to warm (Pritchard et al., 2001).

Because of vascular changes associated with ischemia,heparin and warfarin have been used in an attempt to haltthe progression of radiation necrosis (Glantz et al., 1994).Less arm weakness and resolution of a radiation-inducedconduction block was reported after anticoagulation in apatient with brachial RIBP (Soto, 2005).

FIBROSIS/ATROPHY

Although pathogenesis of radiation-induced neuropathyinitially involves vascular mechanisms, fibrosis and atro-phy are the main targets for therapeutic intervention.It has been known for two decades that the combinationof pentoxifylline and tocopherol significantly reducesradiation-induced fibrosis (Delanian et al., 1999, 2003,2005b; Lefaix et al., 1999; Cosset, 2002). In a series ofpatients treated with pentoxifylline and tocopherol forsuperficial fibrosis, eight patients with brachial plexopa-thy showed neurological symptom stabilization, but noimprovement at 18 months (Delanian and Lefaix, 2007).

754 P.-F. PRADAT A

More recently, 10 out of 11 patients treated for cerebralradionecrosis after stereotaxic radiotherapy showed sig-nificant improvement after pentoxifylline treatment(Williamson et al., 2008).

Clodronate is a bisphosphonate that inhibits osteo-clastic bone destruction with anti-inflammatory effects.Clodronate also inhibits macrophagic myelin nervedestruction in rats (review in Delanian and Lefaix,2007). Recently, it has been shown that clodronate, whencombined with pentoxifylline-tocopherol, heals refrac-tory osteoradionecrosis in a median of 9 months(Delanian et al., 2005, 2011). Also, two patients with pro-gressive RIRP showed an improvement of neurologicalsymptoms after 3 years of treatment with this PENTO-CLO combination (Delanian et al., 2008). A phase IIIrandomized clinical trial in radiation-induced neuropa-thy is planned.

RADIATION-INDUCEDPERIPHERALNERVE TUMORS

Among 14000 childhood cancer survivors after brainirradiation, mainly for medulloblastoma, there was a7- to 10-fold increase in the risk of radiation-inducedtumors, within 5 years for gliomas and 15 years formeningiomas (Dropcho, 2010). A few cases ofradiation-induced peripheral nerve tumor such as aschwannoma (Zadeh et al., 2007) have been reported.This is a rare late complication that occurs from 4 to40 years after irradiation andmay be located in the nerveroots, nerve plexus, or nerve trunks (Donohue et al.,1967). This complication is revealed by the developmentof a painful mass in the irradiated volume associatedwith a rapidly increasing (few months) neurological def-icit. After biopsy, treatment involves large surgical exer-esis when possible, knowing that the prognosis is poorfor 2 years because of tumor growth and the high met-astatic potential. Type 1 neurofibromatosis (von Reck-linghausen disease) increases its incidence (Foley et al.,1980; Ducatman and Scheithauer, 1983).

CONCLUSION

Postradiation neuropathies vary clinically and electro-physiologically and may involve all the structures ofthe peripheral nervous system. Knowledge of these com-plications has improved and we can now distinguish sub-types and unravel the complex pathophysiology.However, more systematic descriptions of the epidemi-ology and history of these neuropathies are required. Forthis purpose longitudinal studies in large cohorts ofpatients are required.

Diagnostically, progress in structural and functionalimaging techniques enables better differentiation betweenradiculopathy and a recurrent tumor. The recently

S. DELANIAN

TO PERIPHERAL NERVES 755

developed technique of a posteriori conformal radiother-apy with 3D-dosimetric reconstitution is original andpromising. Improved understanding of these radiation-induced neuropathies and the use of new tools shouldenable earlier diagnosis of these complications, beforethe lesions become progressive and irreversible, and thisis particularly important given the recent emergence ofnew therapeutic agents. Overall improvement of the prog-nosis of numerous cancersmeans that patients are surviv-ing for many years, and so the management of latetreatment-related complications, which reduce the qualityof life of patients, has become a public health priority.

LATE RADIATION INJURY

ACKNOWLEDGMENTS

We thank the Association Pour la Recherche sur lesSequelles de la Radiotherapie (ARSeR) and particularlyits President Herve Lionel Marie for his commitment toour team’s research into the complications ofradiotherapy.

REFERENCES

Annane D, Depondt J, Aubert P et al. (2004). Hyperbaric oxy-

gen therapy for radionecrosis of the jaw: a randomized

placebo-controlled, double blind, trial from the ORN96

Study Group. J Clin Oncol 22: 4893–4900.Avila EK, Goenka A, Fontenla S (2011). Bilateral phrenic

nerve dysfunction: a late complication of mantle irradia-

tion. J Neurooncol 103: 393–395.Azinovic I, Martinez Monge R, Javier Aristu J et al. (2003).

Intraoperative radiotherapy electron boost followed by

moderate doses of external beam radiotherapy in resected

soft-tissue sarcoma of the extremities. Radiother Oncol

67: 331–337.

Bagley FH, Walsh JW, Cady B et al. (1978). Carcinomatous

versus radiation-induced brachial plexus neuropathy in

breast cancer. Cancer 41: 2154–2157.

Bajrovic A, Rades D, Fehlauer F et al. (2004). Is there a life-

long risk of brachial plexopathy after radiotherapy of

supraclavicular lymph nodes in breast cancer patients?

Radiother Oncol 71: 297–301.

Ballian N, Androulakis II, Chatzistefanou K et al. (2010).

Optic neuropathy following radiotherapy for Cushing’s

disease: case report and literature review. Hormones

(Athens) 9: 269–273.Beglu E, Kurland L, Mulder D et al. (1985). Brachial plexus

neuropathy in the population of Rochester, Minessota

1970–1981. Ann Neurol 18: 320–323.Bennett M, Feldmeier J, Hampson N et al. (2005). Hyperbaric

oxygen therapy for late radiation tissue injury. Cochrane

Database Syst Rev 3CD005005.Berger P, Bataıni JP (1977). Radiation-induced nerve palsy.

Cancer 48: 152–155.Bergstrom R (1962). Changes in peripheral nerve tissue after

irradiation with high energy protons. Acta Radiol 58:301–312.

Bhandare N, Jackson A, Eisbruch A et al. (2010). Radiation

therapy and hearing loss. Int J Radiat Oncol Biol Phys

76: S50–S57.BrydoyM, Storstein A, Dahl O (2007). Transient neurological

adverse effects following low dose radiation therapy for

early stage testicular seminoma. Radiother Oncol 82:137–144.

Carl U, Feldmeier J, Schmitt G et al. (2001). Hyperbaric oxy-

gen therapy for late sequelae in women receiving radiation

after breast-conserving surgery. Int J Radiat Oncol Biol

Phys 49: 1029–1031.Cavanagh JB (1968). Effects of x-irradiation on the prolifera-

tion of cells in peripheral nerve during Wallerian degener-

ation in the rat. Br J Radiol 41: 275–281.

Chan RC, Shukovsky LJ (1976). Effects of irradiation on the

eye. Radiology 120: 673–675.Char DH, Lonn LI, Margolis LW (1977). Complications of

cobalt plaque therapy of choroidal malanomas. Am J

Ophthalmol 84: 536–541.Chen Y-L, DeLaney T (2011). Peripheral nerves. In:

DC Shrieve, JS Loeffler (Eds.), Human Radiation Injury.

Lippincott Williams Wilkins, Philadelphia, pp. 236–245.

Churn M, Clough V, Slater A (2000). Early onset of bilateral

brachial plexopathy during mantle radiotherapy for

Hodgkin disease. Clin Oncol 12: 289–291.Cosset J-M (2002). Breur Gold Medal Award Lecture 2001:

irradiation accidents lessons for oncology. Radiother

Oncol 63: 1–10.Craswell PW (1972). Vocal cord paresis following radioactive

iodine therapy. Br J Clin Pract 26: 571–572.

Croisile B, Piperno D, Bascoulergue Y et al. (1990). Chiasmal

radionecrosis after irradiation of the sella turcica using a

conventional dosage. Contribution of magnetic resonance

imaging. Rev Neurol (Paris) 146: 57–60.Dahele M, Davey P, Reingold S et al. (2006). Radiation-

induced lumbosacral plexopathy: an important enigma.

Clin Oncol 18: 427–428.Danesh-Meyer HV (2008). Radiation-induced optic neuropa-

thy. J Clin Neurosci 15: 95–100.Davila L, Delattre JY, Said G et al. (1990). An experimental

model of radiation-induced neuropathy and plexopathy.

Neurology 40: 277.De Carolis P, Montagna P, Cipulli M et al. (1986). Isolated

lower motoneuron involvement following radiotherapy.

J Neurol Neurosurg Psychiatry 49: 718–719.Delanian S, Lefaix J-L (2004). The radiation-induced

fibroatrophic process: therapeutic perspective via the anti-

oxidant pathway. Radiother Oncol 73: 119–131.Delanian S, Lefaix J-L (2007). Current management for late

normal tissue injury: radiation-induced fibrosis and necro-

sis. Sem Radiat Oncol 17: 99–107.Delanian S, Pradat P-F (2010). A posteriori conformal radio-

therapy using 3D dosimetric reconstitution in a survivor

of adult-onset Hodgkin’s disease for definitive diagnosis

of a lower motor neuron disease. J Clin Oncol 28: 599–601.Delanian S, Balla-Mekias S, Lefaix J-L (1999). Striking

regression of chronic radiotherapy damage in a clinical trial

of combined pentoxifylline and tocopherol. J ClinOncol 17:3283–3290.

756 P.-F. PRADAT AND S. DELANIAN

Delanian S, Porcher R, Balla-Mekias S et al. (2003).

Randomized placebo-controlled trial of combined pentox-

ifylline and tocopherol for regression of superficial

radiation-induced fibrosis. J Clin Oncol 21: 2545–2550.

Delanian S, Porcher R, Rudant J et al. (2005a). Kinetics of

response to long term treatment combining pentoxifylline

and tocopherol in patients with superficial radiation-

induced fibrosis. J Clin Oncol 23: 8570–8579.Delanian S, Depondt J, Lefaix J-L (2005b). Major healing of

refractory mandible osteoradionecrosis after treatment

combining pentoxifylline and tocopherol: a phase II trial.

Head Neck 27: 114–123.Delanian S, Lefaix JL, Maisonobe T et al. (2008). Significant

clinical improvement in radiation-induced lumbosacral

polyradiculopathy by a treatment combining pentoxifyl-

line, tocopherol, and clodronate (PENTOCLO). J Neurol

Sci 275: 164–166.

Delanian S, Chatel C, Porcher R et al. (2011). Complete resto-

ration of refractory mandibular osteoradionecrosis by

prolonged treatment with a pentoxifylline-tocopherol-

clodronate combination (PENTOCLO): a phase II trial.

Int J Radiat Oncol Biol Phys 80: 832–839.Delattre JY, Poisson M, Pertuiset BF et al. (1986). Necrosis of

the optic tract, hypothalamus and brain stem after irradia-

tion of a pituitary adenoma with conventional doses. Rev

Neurol (Paris) 142: 232–237.Demizu Y, Murakami M, Miyawaki D et al. (2009). Analysis

of vision loss caused by radiation-induced optic neuropathy

after particle therapy for head-and-neck and skull-base

tumors adjacent to optic nerves. Int J Radiat Oncol Biol

Phys 75: 487–492.Denham J, Hauer-Jensen M (2002). The radiotherapeutic

injury: a complex wound. Radiother Oncol 63: 129–145.

Diaz JM, Urban ES, Schiffman JS et al. (1992). Post-irradiation

neuromyotonia affecting trigeminal nerve distribution: an

unusual presentation. Neurology 42: 1102–1104.

Donohue WL, Jaffe FA, Rewcastle NB (1967). Radiation

induced neurofibromata. Cancer 20: 589–595.Dropcho EJ (2010). Neurotoxicity of radiation therapy. Neurol

Clin 28: 217–234.

Ducatman B, Scheithauer B (1983). Postirradiation neurofi-

brosarcoma. Cancer 51: 1028–1033.Ducray F, Guillevin R, Psimaras D et al. (2008). Post-radiation

lumbosacral radiculopathy with spinal root cavernomas

mimicking carcinomatous meningitis. Neuro Oncol 10:1035–1039.

EvansM, GrahamM,Mahler P et al. (1987). Use of steroids to

suppress vascular response to radiation. Int J Radiat Oncol

Biol Phys 13: 563–567.Fathers E, Trush D (2002). Radiation-induced brachial plexo-

pathy in women treated for carcinoma of the breast. Clin

Rehabil 16: 160–165.Feistner H, Weissenborn K, Munte TF et al. (1989). Post-

irradiation lesions of the caudal roots. Acta Neurol Scand

80: 277–281.Fishman ML, Bean SC, Cogan DG (1976). Optic atrophy fol-

lowing prophylactic chemotherapy and cranial radiation

for acute lymphocytic leukemia. Am J Ophthalmol 82:571–576.

Flickinger JC, Pollock BE, Kondziolka D et al. (2001). Does

increased nerve length within the treatment volume

improve trigeminal neuralgia radiosurgery? A prospective

double-blind, randomized study. Int J Radiat Oncol Biol

Phys 51: 449–454.Foley KM, Woodruff JM, Ellis FT et al. (1980). Radiation-

induced malignant and atypical peripheral nerve sheath

tumors. Ann Neurol 7: 311–318.Furby A, Behin A, Lefaucheur JP et al. (2010). Late-onset cer-

vicoscapular muscle atrophy and weakness after radiother-

apy for Hodgkin disease: a case series. J Neurol Neurosurg

Psychiatry 81: 101–104.Gerard JM, Franck N, Moussa Z et al. (1989). Acute ischemic

brachial plexus neuropathy following radiation therapy.

Neurology 39: 450–451.Gilette EL, Mahler PA, Powers DVM et al. (1995). Late radi-

ation injury to muscle and peripheral nerves (Late Effects

Consensus Conference). Int J Radiat Oncol Biol Phys 31:1309–1318.

Glantz M, Burger P, Friedman A et al. (1994). Treatment of

radiation-induced nervous system injury with heparin

and warfarin. Neurology 44: 2020–2027.Guy J, Schatz NJ (1986). Hyperbaric oxygen in the treatment

of radiation-induced optic neuropathy. Ophthalmology 93:1083–1088.

Habrand JL, Austin-Seymour M, Birnbaum S et al. (1989).

Neurovisual outcome following proton radiation therapy.

Int J Radiat Oncol Biol Phys 16: 1601–1606.Harper CM, Thomas JE, Cascino TL et al. (1989). Distinction

between neoplastic and radiation-induced brachial plexo-

pathy, with emphasis on the role of EMG. Neurology 39:502–506.

Hassler O (1968). Cellular kinetics of the peripheral nerve and

striated muscle after single dose of x-rays. Zellforsch 85:62–66.

Hsia AW, Katz JS, Hancock SL et al. (2003). Post-irradiation

polyradiculopathy mimics leptomeningeal tumor on MRI.

Neurology 60: 1694–1696.Janzen A, Warren S (1942). Effect of roentgen rays on the

peripheral nerve of the rat. Radiology 38: 333–337.

JiangG,TuckerS,GuttenbergRet al. (1994).Radiation-induced

injury to the visual pathway. Radiother Oncol 30: 17–25.Johnson E, Hammond A, Cairncross J (1989). Bilateral hypo-

glossal palsies: a late complication of curative radiother-

apy. Can J Neurol Sci 16: 198–199.Kinsella TJ, SindelarWF, DeLuca AMet al. (1985). Tolerance

of peripheral nerve to intra-operative radiotherapy (IORT):

clinical and experimental studies. Int J Radiat Oncol Biol

Phys 11: 1579–1585.Kinsella TJ, Sindelar WF, Lack E et al. (1988). Preliminary

results of a randomized study of adjuvant radiation therapy

in resectable adult retroperitoneal soft tissue sarcomas.

J Clin Oncol 6: 18–25.

Kinsella TJ, DeLuca AM, Barnes M et al. (1991). Threshold

dose for peripheral neuropathy following intraoperative

radiotherapy (IORT) in a large animal model. Int J

Radiat Oncol Biol Phys 20: 697–701.Kong L, Lu JJ, Liss A et al. (2010). Radiation-induced cranial

nerve palsy: a cross-sectional study of nasopharyngeal

LATE RADIATION INJURY TO PERIPHERAL NERVES 757

cancer patients after definitive radiotherapy. Int J Radiat

Oncol Biol Phys 79: 1421–1427.Labauge P, Lefloch A, Chapon F et al. (2006). Postirradiation

spinal root cavernoma. Eur Neurol 56: 256–257.

Lamy C, Mas J, Varet B et al. (1991). Postradiation lower

motor neuron syndrome presenting asmonomelic amyotro-

phy. J Neurol Neurosurg Psychiatry 54: 648–649.

Lefaix J-L, Delanian S, Vozenin M-C et al. (1999). Striking

regression of subcutaneous fibrosis induced by high doses

of gamma rays using a combination of pentoxifylline and

alpha-tocopherol: an experimental study. Int J Radiat

Oncol Biol Phys 43: 839–847.Lefevre-Houller C, Willer JC, Delattre JY et al. (2004).

Neurotonie post-irradiation of the messeter. Rev Neurol

(Paris) 160: 1075–1077.Lessell S, Lessell IM, Rizzo JF (1986). Ocular neuromyotonia

after radiation therapy. Am J Ophthalmol 102: 766–770.

Liu LH, Chen CW, Chang MH (2007). Post-irradiation myo-

kymia and neuromyotonia in unilateral tongue andmentalis

muscles: report of a case. Acta Neurol Taiwan 16: 33–36.

Martin M, Lefaix J-L, Delanian S (2000). TGF-b1 and radia-

tion fibrosis: a master switch and a specific therapeutic tar-

get? Int J Radiat Oncol Biol Phys 47: 277–290.

Match RM (1975). Radiation-induced brachial plexus paraly-

sis. Arch Surg 110: 384–386.Mendes D, Nawalkar R, Eldar S (1991). Post irradiation fem-

oral neuropathy. J Bone Joint Surg 73A: 137–140.

Much JW,Weber ED, Newman SA (2009). Ocular neuromyo-

tonia after gamma knife stereotactic radiation therapy.

J Neuroophthalmol 29: 136–139.

Mumenthaler M, Narakas A, Gilliatt R (1984). Brachial plexus

disorders. In: PJ Dyck, PK Thomas, EH Lambert, R Bunge,

(Eds.), Peripheral Neuropathy. W.B. Saunders,

Philadelphia, pp. 1383–1424.

Parsons JT, Bova F, Fitzgerald C et al. (1994). Radiation optic

neuropathy after megavoltage external-beam irradiation:

analysis of time-dose factors. Int J Radiat Oncol Biol

Phys 30: 755–763.Paulino AC (2004). Late effects of radiotherapy for pediatric

extremity sarcomas. Int JRadiatOncolBiol Phys60: 265–274.

Pettigrew LC, Glass JP, Maor M et al. (1984). Diagnosis and

treatment of lumbosacral plexopathies in patients with can-

cer. Arch Neurol 41: 1282–1285.

Pierce SM, Recht A, Lingos TI et al. (1992). Long-term radi-

ation complications following conservative surgery (CS)

and radiation therapy (RT) in patients with early stage

breast cancer. Int J Radiat Oncol Biol Phys 23: 915–923.Pieters RS, Niemierko A, Fullerton BC et al. (2006). Cauda

equina tolerance to high-dose fractionated irradiation. Int

J Radiat Oncol Biol Phys 64: 251–257.

Powell S, Cooke J, Parsons C (1990). Radiation-induced bra-

chial plexus injury: follow-up of two different fractionation

schedules. Radiother Oncol 18: 213–220.

Pradat PF, Poisson M, Delattre JY (1994). Radiation-induced

neuropathies. Experimental and clinical data. Rev Neurol

(Paris) 150: 664–677.

Pradat PF, Bouche P, Delanian S (2009). Sciatic nerve mon-

europathy: an unusual late effect of radiotherapy. Muscle

Nerve 40: 872–874.

Pritchard J, Anand P, Broome J et al. (2001). Double-blind ran-

domized phase II study of hyperbaric oxygen in patients

with radiation-induced brachial plexopathy. Radiother

Oncol 58: 279–286.

Pugliese G, Green R, Antonacci A (1987). Radiation-induced

long thoracic nerve palsy. Cancer 60: 1247–1248.Robbins M, Zhao W (2004). Chronic oxidative stress and

radiation-induced normal tissue injury: a review. Int J

Radiat Biol 80: 251–259.Roden D, Bosley TM, Fowble B et al. (1990). Delayed

radiation injury to the retrobulbar optic nerves and chi-

asm. Clinical syndrome and treatment with hyperbaric

oxygen and corticosteroids. Ophthalmology 97:346–351.

Roth G, Magistris MR, Le Fort D et al. (1988). Post-radiation

branchial plexopathy. Persistent conduction block.

Myokymic discharges and cramps. Rev Neurol (Paris).

144: 173–180.Rowin J, Cheng G, Lewis SL et al. (2006). Late appearance of

dropped head syndrome after radiotherapy for Hodgkin’s

disease. Muscle Nerve 34: 666–669.Russell KJ, Laramore GE, Krieger JN et al. (1990). Transient

and chronic neurological complications of fast neutron

radiation for adenocarcinoma of the prostate. Radiother

Oncol 18: 257–265.Salner AL, Botnick LE, Herzog AG et al. (1981). Reversible

brachial plexopathy following primary radiation therapy

for breast cancer. Cancer Treat Rep 65: 797–802.Schi�dt AV, Kristensen O (1978). Neurologic complications

after irradiation of malignant tumors of the testis. Acta

Radiol Oncol Radiat Phys Biol 17: 369–378.Soto O (2005). Radiation-induced conduction block: resolution

following anticoagulant therapy. Muscle Nerve 31: 642–645.

Stafford SL, Pollock B, Leavitt J et al. (2003). A study of the

radiation tolerance of the optic nerves and chiasm after ste-

reotactic radiosurgery. Int J Radiat Oncol Biol Phys 55:

1177–1181.Teixeira MJ, Fonoff E, Montenegro M (2007). Dorsal root

entry zone lesions for treatment of pain-related to

radiation-induced plexopathy. Spine 32: E316–E319.

Thomas JE, Colby MY (1972). Radiation-induced or meta-

static brachial plexopathy? A diagnosis dilemma. JAMA

222: 1392–1395.

Thomas JE, Cascino TL, Earle JD (1985). Differential diagno-

sis between radiation and tumor plexopathy of the pelvis.

Neurology 35: 1–7.

Tishler RB, Loeffler JS, Lunsford LD et al. (1993). Tolerance

of cranial nerves of the cavernous sinus to radiosurgery. Int

J Radiat Oncol Biol Phys 27: 215–221.Tsang KL, Fong KY, Ho SL (1999). Localized neuromyotonia

of neck muscles after radiotherapy for nasopharyngeal car-

cinoma. Mov Disord 14: 1047–1049.Westbrook K, Ballantyne A, Eckles M et al. (1974). Breast

cancer and vocal cord paralysis. South Med J 67:805–807.

Williamson R, Kondziolka D, Kanaan H et al. (2008). Adverse

radiation effects after radiosurgery may benefit from oral

vitamin E and pentoxifylline therapy: a pilot study.

Stereotact Funct Neurosurg 86: 359–366.

758 P.-F. PRADAT AND S. DELANIAN

Wilson WB, Perez GM, Kleinschmidt-Demasters BK (1987).

Sudden onset of blindness in patients treated with oral

CCNUand low-dose cranial irradiation. Cancer 59: 901–907.Young WC, Thornton AF, Gebarski SS et al. (1992).

Radiation-induced optic neuropathy: correlation of

MR imaging and radiation dosimetry. Radiology 185:904–907.

ZadehG, Buckle C, Shannon P et al. (2007). Radiation induced

peripheral nerve tumors: case series and review of the lit-

erature. J Neurooncol 83: 205–212.ZelefskyMJ, Nori D, ShiuMet al. (1990). Limb salvage in soft

tissue sarcomas involving neurovascular structures using

combined surgical resection and brachytherapy. Int J

Radiat Oncol Biol Phys 19: 913–918.