CASE OF THE MONTH ABSTRACT: Neurophysiologic studies documented proximal conductionblocks in a patient harboring a delayed radiation-induced brachial plexopa-thy. Since anticoagulants have been reported to be beneficial in radiation-induced neuropathies, the patient was started on acenocumarol. After 3months of treatment there was significant improvement of clinical deficits,which correlated with resolution of conduction blocks. This observationsuggests that ischemic nerve injury leading to disruption of the conductionproperties of motor axons contributes to the pathogenesis of delayed radi-ation-induced peripheral nerve injuries.

Muscle Nerve 31: 642–645, 2005

RADIATION-INDUCED CONDUCTION BLOCK: RESOLUTIONFOLLOWING ANTICOAGULANT THERAPY

OSCAR SOTO, MD, PhD

Neurology Department, Clı́nica Universitaria de Navarra, Pamplona, Navarra, Spain

Accepted 12 November 2004

Neurophysiological abnormalities indicative of pe-ripheral nerve demyelination, such as conductionblock and myokymia, are commonly observed indelayed radiation-induced peripheral nerve dam-age.1,8,18 Indeed, the presence of myokymic dis-charges is considered supportive of such radiation-induced damage as opposed to alternativeetiologies,8 and such activity has been shown to arisefrom blocked axons.18 Currently available therapiesdo not significantly alter the natural history of thiscondition and relentless deterioration often leads tosevere loss of function.2 Pathologically, delayed radi-ation-induced peripheral nerve damage is character-ized by fibrosis, vascular lesions, and parenchymaldamage, both axonal and demyelinating.5,17 How-ever, the relative pathogenic importance of theselesions remains incompletely understood. Some de-gree of recovery following the use of anticoagulantagents has been reported in radiation injuries ofboth the central and peripheral nervous systems,7

raising questions concerning the exact mechanismsby which these agents exert their beneficial effect. Inparticular, it remains uncertain whether ischemicdemyelinating nerve injury has a pathogenic role in

this condition. The case described in this reportsuggests that it does.

CASE REPORT

A 53-year-old man complained of a 4-year history ofpins and needles in the fingertips of both hands.Approximately 2 years later, he developed insidiousbilateral hand weakness, which progressed graduallywith more severe involvement on the right. He com-plained of frequent flexor cramps affecting fingerand wrist joints. He sought neurological assessmentwhen he was no longer able to write or fasten but-tons. He received a short course of high-dose oralcorticosteroids elsewhere, for uncertain reasons,without significant benefit.

His past medical history was relevant for radia-tion therapy prescribed for lymphocyte-predomi-nant Hodgkin’s lymphoma, stage IIIA, at 27 years ofage. Radiated fields included the mediastinum (36Gy), axillary fields (39 Gy), cervical fields (43 Gy),and lumboaortic and pelvic fields. Simultaneously hereceived chemotherapy with vinblastine, cyclophos-phamide, procarbazine, and methylprednisolone. Atage 45 he had a relapse in the nasopharyngeal ca-vum for which he received chemotherapy alone (cy-clophosphamide, doxorrubicin, vincristine, andmethylprednisolone). Other medical conditions in-cluded cardiac branch block and carbohydrate intol-erance.

Physical examination disclosed atrophic and hy-perpigmented skin over the right cervical region.Weakness affected distal muscles in both upperlimbs. Manual muscle testing of weak right-sided

Abbreviations: ADM, abductor digiti minimi; APB, abductor pollicis brevis;CB, conduction block; CMAP, compound muscle action potential; GM1,GM1 gangliosideKey words: anticoagulation; conduction block; demyelination; nerve isch-emia; radiation neuropathyCorrespondence to: O. Soto, EMG Unit, Teknon Medical Center, Marquesade Vilallonga 16, Barcelona 08017, Spain; e-mail: 39191ost@comb.es

© 2005 Wiley Periodicals, Inc.Published online 5 January 2005 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mus.20273

642 Radiation-Induced Conduction Block MUSCLE & NERVE May 2005

muscles disclosed a score of 3 on the Medical Re-search Council scale for finger adduction and abduc-tion, thumb abduction, proximal and distal inter-phalangeal flexion, and wrist flexion; wrist extensionwas grade 4. There was no muscle atrophy. Therewere profuse fasciculations affecting the intrinsichand muscles and forearm flexors on both sides.There was generalized areflexia. Mild stocking-and-glove sensory loss was noted for light touch, vibra-tion, temperature, and pain modalities, with markedaccentuation over the right C-8 dermatome.

Neurophysiological Data. Motor conduction studiesshowed normal amplitude of the compound muscleaction potential (CMAP) and conduction velocityalong distal and intermediate nerve segments forright and left tibial, peroneal, radial, median, ulnar,axillary, musculocutaneous, and spinal accessorynerves. Minimal F-response latencies were withinnormal limits for all tested nerves except for absenceof the right ulnar response. H-reflexes were absentbilaterally. Sensory conduction studies showed nor-

mal sensory nerve action potential amplitude andconduction velocity for both sural nerves, but re-duced amplitude of sensory nerve action potentialsof the radial, median, and ulnar nerves, with normalconduction velocities. Cervical roots were stimulatedon the right side using a monopolar needle tech-nique (inserted at the C-6 level).19 A single stimulusof submaximal intensity (80 mA; 1-ms duration) wasgiven, followed by two stimuli of maximal intensity(100 mA; 1-ms), without a change in size of theresponse. There was a greater than 50% decline inCMAP amplitude/area compared to distal stimula-tion sites, without increased temporal dispersion,consistent with proximal partial conduction block(CB) of motor fibers to both abductor pollicis brevis(APB) and abductor digiti minimi (ADM) muscles(Fig. 1). Needle examination showed neither fibril-lation potentials nor positive waves, but abundantfasciculation potentials and myokymic dischargeswere present in the right first dorsal interosseous,APB, flexor carpi radialis, and extensor digitorum

FIGURE 1. APB (top) and ADM (bottom) CMAPs obtained after stimulation of the median and ulnar nerves at different sites. Axillary androot stimulation to APB was performed using a collision technique of ulnar fibers.19 Each of the CMAP waveforms are shown adjacentto data that quantify their percent change in amplitude/duration/area relative to distal stimulation. Left panels: before treatment; rightpanels: after treatment. Abbreviations: WR, wrist; BE, below elbow; E, elbow; AE, above elbow; AX, axilla; C-root, cervical root. Horizontalcalibration: 5 ms; vertical calibration: 5 mV.

Radiation-Induced Conduction Block MUSCLE & NERVE May 2005 643

communis muscles. Additionally, changes of chronicdenervation and reinnervation, as well as reducedmotor unit recruitment, were documented in thosemuscles and also in the deltoid and contralateral firstdorsal interosseous. At the patient’s request, no fur-ther muscles were examined.

Magnetic resonance imaging of the brain, cervi-cal spine, and brachial plexus (gadolinium-enhanced) on both sides was noncontributory. Com-plete blood count and sedimentation rate, serumbiochemistry (including HbA1c and creatine kinase,lipid screen, and liver function tests), serum andurine immunofixation, and Lyme serology were ei-ther normal or negative. Antinuclear antibodies,anti-DNA, anti-extractable nuclear antigens, and an-ti-GM1 antibodies were negative.

Based on these findings, the patient received adiagnosis of mild residual polyneuropathy with su-perimposed bilateral radiation-induced brachialplexopathies. The patient was started on an oralanticoagulation schedule with acenocumarol target-ing for an international normalized ratio between 2and 3, in the hope of inducing an arrest or reversalof disease progression.7

On clinical and neurophysiological assessmentfollowing 3 months of continued anticoagulant ther-apy, the patient reported improvement in muscleforce; he was now able to write and fasten buttons.His cramps had reduced in frequency and he no-ticed less fasciculations. Manual muscle testing ofpreviously weak muscles disclosed improvement inmuscle strength for the following: finger adductionand abduction (4); thumb abduction (4); proximaland distal interphalangeal flexion (4); and wrist flex-ion and extension (5). On average, there was a re-covery of strength of greater than 1 point in thosemuscles. On neurophysiological testing after reversalof anticoagulation, motor conduction studiesshowed resolution of the proximal CBs (Fig. 1). Atthat time, acenocumarol was discontinued, but thiswas followed by a symptomatic relapse. Symptomsagain reversed upon reinstitution of anticoagulants,remaining stabilized over the next 9 months of con-tinued treatment.

DISCUSSION

In this patient the observed improvement in musclestrength occurred most likely as a consequence ofthe resolution of motor CB associated with the use oforal anticoagulants. The possibility of pseudo-CB re-lated to submaximal stimulation with the use of cer-vical root stimulation has been raised.15 Several rea-sons argue against this possibility. First, distal CMAPs

were well within the normal range for amplitude/area, indicating that axonal loss did not contributesignificantly to weakness. Second, the amplitude/area of CMAPs obtained from stimulation at sitesproximal to the block plateaued before maximalstimulation was applied. Third, clinical weakness waspresent in muscles innervated by the blocked fasci-cles. Finally, the CB was maximal in a target muscle(ADM) preferentially supplied by the C-8 ratherthan the T-1 root, which lies closer to the stimulatingcathode.9

A different issue is whether the clinical fluctua-tions could have related to the natural history ofdelayed radiation-induced peripheral nerve damage,as occasionally this disorder may improve spontane-ously.4 However, in agreement with previous re-ports,7 in our case there was a clear temporal rela-tionship between treatment with anticoagulants andimprovement in muscle strength, suggesting a ther-apeutic effect. This raises the possibility that nerveischemia had a pathogenic role in the clinical andneurophysiological abnormalities in this patient.Pathologically, delayed radiation injuries are associ-ated with a reduction in the vascular tree, dilation ofcapillaries and sinusoids, endothelial hypertrophy,and, importantly, intravascular thrombi and occlu-sion of small vessels.5 Accelerated arteriosclerosisoccurs in larger vessels, and fresh thrombi are com-monly observed overlying vascular-wall lesions.5 Thevascular endothelium is particularly radiosensi-tive,5,17 making small-vessel injury a central compo-nent of late radiation injuries. Indeed, the use ofvascular radioprotective agents is associated with aprotective action for parenchymal injury in an ani-mal model of cerebral radionecrosis.10 Thus, paren-chymal ischemia is likely to have a central patho-genic role in delayed radiation-induced peripheralnerve damage.10,17

Although severe and extensive nerve ischemiaresults in prominent axonal loss, milder ischemiamay be dominated pathologically by demyelinatinglesions or endoneural edema alone.13 Physiologi-cally, acute ischemia may produce CB as a conse-quence of a pathologically demonstrable lesion(ischemic demyelination)6,12 or secondary to meta-bolic disruption of axonal electrical properties.16

The extent to which prolonged ischemia results inlong-lasting metabolic CB remains uncertain, butdemyelination is observed in pathological specimensfrom patients with peripheral neuropathy related tovascular disease14 or chronic hypoxia.11 Therefore,the beneficial effect of oral anticoagulants observedin this as well as other reported cases might relate toimproved nerve perfusion. Either remyelination or

644 Radiation-Induced Conduction Block MUSCLE & NERVE May 2005

restoration of axonal electrical properties may un-derlie the observed resolution of CBs. However, ex-perimental data indicate that the proliferative capa-bility of Schwann cells is disrupted in irradiatednerve tissue, suggesting that remyelination was not acentral mechanism underlying the physiological re-covery documented in our patient.3

In conclusion, although our observation does notprovide a definitive explanation for the mechanismunderlying nerve conduction failure, it suggests apathogenic role of nerve ischemia in conductionblock in delayed radiation-induced peripheral nerveinjuries and supports the use of strategies to improvenerve perfusion in this condition.

The author thanks Dr. Didier Cros for his kind advice during thepreparation of this manuscript.

REFERENCES

1. Albers JW, Allen AA, Bastron JA, Daube JR. Limb myokymia.Muscle Nerve 1981;4:494–504.

2. Basso-Ricci S, della Costa C, Viganotti G, Ventafridda V,Zanolla R. Report on 42 cases of postirradiation lesions of thebrachial plexus and their treatment. Tumori 1980;66:117–122.

3. Cavanagh JB. Effects of previous x-irradiation on the cellularresponse of nervous tissue to injury. Nature 1968;219:626–627.

4. Enevoldson TP, Scadding JW, Rustin GJ, Senanayake LF.Spontaneous resolution of a postirradiation lumbosacral plex-opathy. Neurology 1992;42:2224–2225.

5. Fajardo LF, Berthrong M. Vascular lesions following radia-tion. Pathol Annu 1988;23:297–330.

6. Fowler CJ, Gilliatt RW. Conduction velocity and conductionblock after experimental ischaemic nerve injury. J Neurol Sci1981;52:221–238.

7. Glantz MJ, Burger PC, Friedman AH, Radtke RA, Massey EW,Schold SC Jr. Treatment of radiation-induced nervous systeminjury with heparin and warfarin. Neurology 1994;44:2020–2027.

8. Harper CM Jr, Thomas JE, Cascino TL, Litchy WJ. Distinctionbetween neoplastic and radiation-induced brachial plexopa-thy, with emphasis on the role of EMG. Neurology 1989;39:502–506.

9. Levin KH, Maggiano HJ, Wilbourn AJ. Cervical radiculopa-thies: comparison of surgical and EMG localization of single-root lesions. Neurology 1996;46:1022–1025.

10. Lyubimova N, Hopewell JW. Experimental evidence to sup-port the hypothesis that damage to vascular endotheliumplays the primary role in the development of late radiation-induced CNS injury. Br J Radiol 2004;77:488–492.

11. Malik RA, Masson EA, Sharma AK, Lye RH, Ah-See AK,Compton AM, et al. Hypoxic neuropathy: relevance to humandiabetic neuropathy. Diabetologia 1990;33:311–318.

12. Nukada H, Powell HC, Myers RR. Perineurial window: demy-elination in nonherniated endoneurium with reduced nerveblood flow. J Neuropathol Exp Neurol 1992;51:523–530.

13. Nukada H, Powell HC, Myers RR. Spatial distribution of nerveinjury after occlusion of individual major vessels in rat sciaticnerves. J Neuropathol Exp Neurol 1993;52:452–459.

14. Nukada H, van Rij AM, Packer SG, McMorran PD. Pathologyof acute and chronic ischaemic neuropathy in atheroscleroticperipheral vascular disease. Brain 1996;119:1449–1460.

15. Olney RK. Consensus criteria for the diagnosis of partialconduction block. Muscle Nerve 1999;22(suppl 8):S225–229.

16. Parry GJ, Linn DJ. Conduction block without demyelinationfollowing acute nerve infarction. J Neurol Sci 1988;84:265–273.

17. Rezvani M, Hopewell JW, Robbins ME. Initiation of non-neoplastic late effects: the role of endothelium and connec-tive tissue. Stem Cells 1995;13(suppl 1):248–256.

18. Roth G, Magistris MR, Le Fort D, Desjacques P, Della Santa D.Post-radiation branchial plexopathy. Persistent conductionblock. Myokymic discharges and cramps [in French]. RevNeurol (Paris) 1988;144:173–180.

19. Sander HW, Menkes DL, Triggs WJ, Chokroverty S. Cervicalroot stimulation at C5/6 excites C8/T1 roots and minimizespneumothorax risk. Muscle Nerve 1999;22:766–768.

Radiation-Induced Conduction Block MUSCLE & NERVE May 2005 645