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C ASE O F TH E M O NTH A B S TR A C T: A 3-year-old girl w ith acute lym phocytic leukem ia (A LL) inrem ission developed low erextrem ity paraparesis and areflexia 15 days afterreceiving intrathecal m ethotrexate, cytarabine, and hydrocortisone. C ere-brospinalfluid protein w as 107 m g/dl. C om pound m uscle action potentialam plitudes w ere reduced, F w aves w ere absent, and sensory conductionstudies w ere norm al. N eedle electrom yography (E M G ) revealed reducedm otorunitpotentialrecruitm ent.M agnetic resonance im aging (M R I)show ed

lum bosacral ventral root enhancem ent. S he w as treated w ith intravenousim m unoglobulin and slow ly recovered.N erve conduction and E M G abnor-m alities correlated w ith M R Irootenhancem ent,facilitated early diagnosis,and distinguished this from a m yelopathy or distal polyneuropathy. Thesefindings could representselective ventralnerve rootvulnerability to intrathe-calchem otherapy.A selective autoim m une process cannot be excluded.

2002 John W iley & S ons,Inc.M uscle N erve 2 5 : 106110,2002

V E N T R A L P O L Y R A D IC U L O P A T H Y W IT H

P E D IA T R IC A C U T E L Y M P H O C Y T IC L E U K E M IA

S T E P H E N C . A N D E R S O N , M D ,1 ,2 G E O R G E D . B A Q U IS , M D ,1

A N T H O N Y J A C K S O N , M D ,2 P H IL IP M O N T E L E O N E , M D ,3 a n d

J . R O B E R T K IR K W O O D , M D 4

1 D epartm ent of M edicine,B aystate M edicalC en ter,Springfield,M assachusetts,U SA2 D ep artm en t of Pediatrics,B aystate M edicalC enter,Springfield,M assachusetts,U SA3 D ep artm ent of C hild H ealth,U n iversity of M issou riH ealth Sciences C enter,

C olum bia,M issou ri,U SA4 D epartm en t of R adiology,B aystate M edicalC en ter,Springfield,M assachusetts,U SA

A ccepted 26 July 2001

Intrathecal chem otherapy is com m only adm inis-tered for prophylaxis or treatm entof leukem ic m en-

ingitis.P araparesis is an uncom m on com plication ofintrathecal m ethotrexate and cytarabine (A ra-C ),and acute po lyradiculop athy has rarely been re-ported asa cause ofthissynd rom e.W e describe clini-cal ch aracteristics, m agn etic reson an ce im aging(M R I) abnorm alities,an d electrodiagn ostic findingsof a ch ild w ith acute lym phocytic leukem ia (A L L) inrem ission w ho develop ed an acute ventral polyra-diculopathy after treatm en t w ith intrathecal m etho-trexate,A ra-C ,and hydrocortison e.

C A S E R E P O R T

A 3-year-old girl w ith A L L in rem ission on m ainte-nance chem o therapy develop ed progressive low er

extrem ity flaccid w eakness, inability to w alk, an dm ild upp er extrem ity w eaknessovera 2-w eek period .

C hem otherapy 12 days prior to on set of sym p tom sincluded intrathecal m ethotrexate, A ra-C , and hy-drocortisone, along w ith intraven ous vincristin e.T his treatm ent w asp arto fC hildrens C ancer G rou pProtocol 1952, w hich also included L-asparaginase,cyclophosph am ide, oral m ethotrexate, and 6-m er-captop urine.She had received no radiation therapy.Sh e had a m ild fever and u pper respiratory infection1 m on th prior to the onseto fher sym ptom s.E xam i-nation revealed low er extrem ity flaccid paralysis,m ild upper extrem ity w eakness,absen t patellar andankle tendon reflexes,an d norm alsensation .Serumcreatine kinase, thyroid-stim ulating horm o ne, cal-cium , electrolytes, erythrocyte sed im en tation rate,com plete blood count,and blood culturesw ere n or-m al. C erebrospinal fluid (C SF) sh ow ed 0 w h iteblood cells/m m 3, absen ce of m align ant cells, el-evated totalprotein con centration (107 m g/ dl),nor-m al glucose level (55 m g/dl),and norm al electro-ph oresis. C am pylobacter jejuni, B orrelia burgdorferi,m ycop lasm a, hum an im m unod eficien cy viruses 1

A b b re v ia tio n s : A LL, acute lym p hocytic leukem ia; A ra-C, cytarabine;C SF , cerebrospinal fluid; EM G ,electrom yography; M R I, m ag netic reso-nan ce im agingK e y w o rd s : intrathecalchem otherap y;paraparesis;ped iatric acute lym -ph ocytic leukem ia; ventralp olyrad iculop athy;ventralrootenh anc em entC o rre s p o n d e n c e to : S.A nderson,B elchertow n W ellness C enter,95 Sar-ge nt Street,B elche rtow n, M A 01199;e -m ail:sand erso@ m assm ed .org

2002 John W iley & Sons, Inc.D O I 10.1002/m us.1219

1 0 6 VentralPolyradiculopathy M U SC LE & N ER VE January 2002

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and 2, cytom egalovirus, G M 1, asialo-G M 1, G D 1B ,and G Q 1B antibo dy titers w ere norm al.A bo ne scan

w asn orm al.SpinalM R I w ith gadolinium show ed ab-norm alen hancem ento fm ultiple ventralnerve roo ts

w ithin the con us m edullaris (Figs.1 and 2).E lectro-diagn ostic abnorm alities w ere presen t, consisten t

w ith an acute m ultilevel intraspinal disorder affect-

ing m otor nerves in allextrem ities.Low er extrem itynerve con duction velocities w ere norm al, F w aves

w ere absent, and com poun d m uscle action poten-tials w ere red uced in am plitude distally w ithoutm ul-tifocal con duction block (Table 1). N eedle E M G show ed absence of low er extrem ity m u scle activa-tion , a reduced m otor unit potential recruitm entpattern w ith norm alinsertionalactivity,absen tspon-taneousactivity,and m otor unitp otentialsof norm alcon figuration in the proxim al and distal righ t armm uscles.

Sh e w as em pirically treated w ith 1.7 g/kg of in-travenou s im m unoglob ulin, divided into tw o doses

given on 2 con secutive days,for a p ossible acu te im -m une dem yelinating polyradiculop athy,and w ithin3 days proxim al leg stren gth im proved. A fter 4m on ths she could w alk w ithou t assistance and herten don reflexes w ere norm al. Findings con sistent

w ith d en ervation and early reinervation w ere presen ton repeat electrom yograph ic (EM G ) study per-form ed 5 m on ths after on set of sym ptom s.A fter 12m onths, her exam ination w as norm al w ith the ex-

ception of a sligh tly w ide-based gait w hile run ning.Sh e con tinues to receive oral m ethotrexate, 6-m er-captop urine,and d exam ethason e.H erC SF hasbeenpersisten tly negative for m align ant cells and no fur-ther intrathecaltreatm ents have been given.

D I S C U S S I O N

O ur patientdeveloped a polyradiculop athy after sys-tem ic and intrathecal chem otherapy treatm ent of

A L L (in rem ission).M ultiple reports have describedpolyradiculopathy as a cause of flaccid bilateral legparalysis associated w ith intrathecal m ethotrexateand A ra-C .15,17,18,25,37 T hese cases d escribe m o torsyndrom es,occurring prim arily in children w ith el-evated C SF protein levels.EM G studies have show nm otor axon alpolyneurop athies w ith norm alsensoryconduction tests.Interpretation of the clinical find-ings issom etim escom plicated by con ditionsthatcanm ask the presence of a polyradiculop athy such asm yelop athic features and sim ultaneous treatm en t

w ith vincristine.In our case,initialelectrodiagnostic

testing w as consisten t w ith an acute diffuse intraspi-nal disorder affecting predom inantly low er extrem -ity nerve roots or anterior horn cells.A lthough theabsence ofF w aveshasbeen described w ith m yelop a-thies (anterior spinal artery synd rom e34 and trans-

verse m yelitis35), this abnorm ality in conjunctionw ith M R I gadolinium enh ancem en tof ventraln erverootsiscon sisten tw ith a polyradiculopathy.H er sub-sequen t electrodiagn ostic studies dem onstrated m o-

F IG U R E 1 . S elective ventral lum bar nerve root gadolinium en-

hancem ent(arrow s).

F IG U R E 2 . G adolinium enhancem ent ofthe cauda equina.

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tor axonal loss, rather than dem yelination, as thecause of her w eakness,w ith im p rovem entsecondaryto m uscle reinnervation.T here are severalreportsofparaparesis, som e w ith en cephalopathy, attributedto m yelop athy due to intrathecal m ethotrexate or

A ra-C .4,5,79,12,20,23,25,26,31,33,38,39 Som e have de-scribed abn orm alp eripheraln erve conduction stud-ies w ith m uscle d enervation.A utop sy pathology hasshow n inflam m atory changes in the spinalcord w ithnerve root involvem ent,including dem yelination ofthe spinal roots.22

T he pathogen esis of h er syndrom e is u nclear.Sh e had previously received intrathecal m ethotrex-ate and A ra-C uneventfully. A s her C SF levels w erenot m easured , the possibility of direct toxicity sec-on dary to redu ced clearance and prolon ged nerveroo t exp osure to elevated levels of m ethotrexate, a

previously described m echanism of toxicity,cannotbe exclud ed.3 B ecause the pathology of intrathecalm ethotrexate toxicity is sim ilar to that of subacu tecom bined degeneration of the spinalcord caused bycobalam ine deficien cy, localized folate deficien cyhas been postulated as a cause of this condition .22

M ethotrexate toxicity studies using cerebellar ex-plants from rats suggestthatm ethotrexate is prim ar-ily a neurotoxin and that dem yelination is a con se-

quence of axonalloss.10 H ow ever,electrod iagnosticstudies after a single intrathecal m ethotrexate ad-m inistration in 20 patien ts w ith non-H odgkins lym -ph om a revealed no alteration s of F w aves or periph-eral m otor nerve conduction values.13 A ra-C has alon g C SF elim in ation h alf-life com p ared w ithplasm a, w hich is related to low A ra-C deam inase ac-tivity in C SF and brain and cou ld con tribute to cen-tralnervous system toxicity.16 A lthou gh ou r patientreceived system ic chem otherapy w ith vincristine,theabsence of sensory sym ptom s or sensory nerve con -duction abn orm alities w ould be atypicalfor the gen -eralized axo nalsensorim o tor polyneuropathy associ-ated w ith vincristine toxicity.24 N erve root toxicitysecon dary to the chem otherapy diluent h as alsobeen d escribed,b ut ou r patientreceived a preserva-tive-free diluent.14

M R I has dem on strated nerve root dam age in avariety of diseases.36,37 H in gtgen and G arg andPisani et al. report tw o sim ilar cases o f paralysis inchildren w ith A L L receiving sim ilar intrathecal che-m o th erapy w ith ventral roo t en h ancem en t o nM RI.15,29 In addition, several series have reportedM R Ifindingsw ith ventralrooten hancem entin casesof G uillain-B arre syndrom e.6,11,40

O ur patients clinical presen tation, electrod iag-

T a b le 1 . N erve conduction stud y.

N erve and

stim ulation site

R esponse am p litud e

(m V, m otor;V, sensory)

C onduction velocity

(m /s)

Latency

(m s)

F-w ave latency

(m inim um ,m s)

Study 1 Study 2 Study 1 Study 2 Study 1 Study 2 Study 1 Study 2

M otor

R .peroneal (0.9) (42.2) (4.5)

A nkle 0.5* 1.5 4.5 3.6 N R N R Fibular head 0.4 1.3 39.5* 43.8

R .tibial (7.0) (42.3) (3.1)

A nkle 0.6* 4.8* 3.5* 3.6* N R 30

K nee 0.4 4.3 41.3* 52.7

R .m edian (3.2) (38.2) (3.5)

W rist 4.6 2.9 20

Elbow 3.7 45.6

R .ulnar (2.8) (44.8) (2.5)

W rist 5.5 7.3 1.9 2.0 18 18

B elow elbow 4.9 6.7 52.3 57

A bove elbow 4.8 6.6 54.6 55.3

Sensory

R .sural (7) (3.8)

C alf 22 26 1.6 1.6

R .m edian (13) (47.6) (3.0)W rist 19 1.7

Elbow 5 54.5

R .ulnar (8) (55.8) (2.2)

W rist 26 36 1.4 1.3

B elow elbow 9 10 63 63

N orm allim its in parentheses.*A bn orm alvalues.


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nostic studies, elevated C SF protein level, and M R Iim aging w ere also poten tially con sisten t w ith anacute im m un e-m ediated polyradiculop ath y. T h epossibility exists ofan im m une-m ed iated polyradicu-lop athy triggered by chem o th erapy. In addition ,acute leukem ia hasbeen associated w ith polyneu rop -athy an d G u illainB arre syndrom e in the absence of

chem otherapy.1,19,28,30,32

M cKhann et al. describedan acute m otor axo nal polyneuropathy in childrenand you ng adults w ith electrodiagn ostic featuressim ilar to our p atien t, w hich they term ed C hineseparalytic syndrom e.21 T his syndrom e hasbeen asso-ciated w ith prior Cam pylobacterjejuniinfection.2 Ithasbeen hypothesized that chem o therapy results in therelease of antigens w ith develop m en t of an auto-im m une reaction ,or that younger patients w ith im -m ature nervous system s m ay be at greater risk fordevelop m ent of m ethotrexate n eurotoxic com plica-tions.10 Im m unosup pression , secon dary to eitherleukem ia or system ic chem otherapy, could poten-

tially con tribu te to the develop m ent of an im m une-m ed iated polyradiculopathy.18,27

T he au thors thank D r. M au ra B renn an for translating the Japa-nese reference article. T his stud y w as presented at the ann ualm eeting o f the A m erican A ssociation of E lectrodiagn ostic M edi-cine, V ancou ver,B ritish C olum bia,C anada,O ctober 1999.

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