2. Gale EA. The Rise of Childhood Type 1 Diabetes in the 20th Century.Diabetes 2002 51: 3353-3361.

3. NSF Diabetes. Standards.Clinical care of children and young peoplewith diabetes. Health Services Circular (HSC 2001/026). Dept ofHealth, December 2001. www.doh.gov.uk/nsf/diabetes.

4. McNally PG,Raymond NT,Swift PG et al. Does the prepubertalduration of diabetes influence the onset of microvascular

complications? Diabet Med 1993;10:906-8.5. Diabetes control and complications trial Research Group. Effect of

intensive diabeles trealment on the development and progression oflong-term complications in adolescents with insulin dependentdiabetes mellitus: Diabetes Control and complications Trial.J Pediatr1994;125:177-88.

6. CG 15. Diagnosis and management of Type 1 Diabetes in children andyoung people. National Institute for Clinical Excellence,July 2004.www.nice.org,uk.

7. Roche et al.Nalionallncidence of Type 1 diabetes in childhood andadolescence. Ir Med J Apr 2002:95;4.

8. Eilish 0 Regan,Health Correspondent, Irish Independent. March 4,2005.

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Services 1O.

10. Anon. The principles of good practice for the care of young peoplewith diabeles. A British Diabetic Association Report. london, 1995.

11. Fleming Eo Carter B, Gillibrand W (2002). "The lransition ofadolescents wilh diabetes from children's heallh care service into theadult health care service: a review of the literature.' Journal of Clinical

Nursing 11: 560-7.12. Holmes-Walker et al Bridging the gap from child to adult: a transitional

care programme. 18th International Diabetes Federation Congress,Paris.Aug 2003.

13. Anon. The role and qualifications of the nurse specialising inpaediatric diabetes. london: Royal College of Nursing of the UnitedKingdom, Paediatric Diabetes Special Interest Group, 1993.

14. Tamborlane'tN,Bonfig W, Boland E. Recent advancesin treatment ofyouth with type 1diabetes: beller care through technology. DiabeticMed 2001 ;18:864 -70.

15. The St. Vincent Declaration, Diabetes Action Programme,St Vincent,Italy.Oct 1989,

Cytomegalovirus Infection in Paediatric Haemopoietic Stem Cell Transplantation

A Lee Chong!, F Clinton!, F Breatnachl, A O'Marcaighl, K Butler2, A O'MearalDepartments of 1Haematology & Oncology and 21nfectious Diseases, Our Lady's Children's Hospital, Crumlin, Dublin 12

AbstractA retrospective audit of CMV infection was undertaken to determine prevalence and outcome in the national paediatric HaemopoieticStem Cell Transplant (HSCT) unit, with particular reference to surveillance and treatment All patients undergoing HSCT (125allogeneic, 50 autologous) from January 1994 to December 2004 were included. Nine underwent a second transplant for graftfailure or disease recurrence. Of 134 allogeneic transplants performed, 52 were unrelated. Shell vial cultures of throat swabs andurine, and blood samples for pp55 antigenemia +/- PCR were tested weekly for a mean of 147 days post transplant CMV negativeblood products and filters were used in all. 11rec+/donor-, 12rec-/donor+ and 10rec+/donor+ transplants were performed. Allreceived prophylactic acyclovir, IVIG was prescribed for all but CMV -/- transplants. Initial detection of CMV was urine in 5 cases, fourof whom developed antigenemia. Of ten patients who developed antigenemia, nine were treated with ganciclovir ± foscamet and twoof these patients developed CMV pneumonitis and died. The current policy of strict surveillance, matching donor and recipient CMVstatus, use of CMV negative blood products and filters and pre-emptive therapy appears to be effective in controlling CMVdisease/infection in the peri transplant period.

IntroductionCytomegalovirus infection (CMV) remains among the most seriousinfectious complications after allogeneic haemopoietic stem celltransplantation (HSCT); despite prophylactic and pre-cmptivestrategies, it still remains a major cause of morbidity and mortalitypost transplant especially in those who are CMV antibodypositive.l,2.3.4 The most common targets of CMV infection includelung, gastrointestinal tract and the eye with CMV pneumonia amajor manifestation of late disease.4,5.6

The aims of this audit were a) to de.termine the prevalence ofCMV infection in a paediatric haemopoietic stem cell transplant(HSCT) population, b) to review the effectiveness of prophylacticand therapeutic strategies and c) to assess the surveillancepolicies with particular reference to clinical outcome.

MethodsPatients

All patients who underwent HSCT at Our Lady's Children'sHospital, Dublin between January 1994 and December 2004were eligible for inclusion. The cohort was subdivided into threecatagories dependent on the expectcd'risk of CMV infection andalso type of transplant performed. A retrospective chart reviewwas undertaken as well as collation of laboratory results. Donorsand recipients had molecular typing of HLA Class II antigens andserotyping of Class I antigens. the latter being replaced bymolecular typing in 2000. Donors were selected on the basis of

HLA compatibility; from 1999, whenever possible, CMV positivedonors were chosen for CMV positive recipients.

Conditioning regimensIncluded a) cyclophosphamide and total body irradiation, b)busulphan and cyclophosphamide, c) BEAM and d) high dosemelphalan. The pan T-cell antibody Campath was incorporatedinto conditioning regimens for patients undergoing unrelatedtransplants. Three patients had ex vivo T-cell depletion ofunrelated grafts while a further two patients had T-cell addback.All patients received CMV negative, irradiated and filtered bloodproducts.

GVHD prophylaxisAll patients were commenced on cyclosporin; short coursemethotrexate was added for patients over five years receivinggrafts from HLA identical relatives and all unrelated donortransplants.

Antimicrobial prophylaxisPatients received cotrimoxazole for Pneumocystis prophylaxis anditraconazole as antifungal prophylaxis from start of conditioning.All recipients of unrelated grafts were prescribed intravenousimmunoglobulin (lVIG) weekly to D+35, then three weekly forthree months.

Risk adapted CMV preventive strategiesPatients were stratified into three groups based on CMV status of

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donor and recipient: 1) Minimal risk (recipient and donor CMVnegative), 2) Intermediate risk (recipient negative and donor CMVpositive) or 3) High risk (CMV positive recipient and donornegative or both donor and recipient CMV positive). Intermediateand high-risk patients were prescribed Acyclovir (500mg/m2 tdsIV weekly for 3-4 weeks and then 400-800mg qds PO for3 months) in conjunction with IVIG (weekly till D+35 and thenq3 weekly for 3 months). Minimal risk patients received acyclovir(10mg/kg tds IV for 3 weeks and then 200-400mg qds PO up to3 months).

CMV screeningScreening was performed at least once weekly post transplant forup to 6 months. Shell vial cultures were performed on urine andthroat swabs in all patients; following engraftment, peripheralblood leucocytes were screened for pp65 antigenemia From1999, CMV-DNA screening by PCR (Roche Diagnostics, UK) wasundertaken, in addition to pp65 antigenemia. Bronchoalveolarlavage (BAL) was undertaken only in those patients whodeveloped severe respiratory symptoms.

Pre-emptive treatmentCriteria for pre-emptive therapy included CMV pp65 antigenemiaon peripheral blood sample or 2 consecutive positive CMV-ONAPCR tests. These patients were commenced on IV Ganciclovir at adose of 5mg/kg bd for 2-3 weeks, then 5mg/kg/day for5 days/week for 6 weeks. The course was continued if screeningremained positive or if patient redeveloped antigenemia

CMV treatment

Ganciclovir was given as per the pre-emptive protocol, with theaddition of Foscarnet (60mg/kg tds) IV and IVIG IV alternate daysfor 10 doses.

Results

A total of 175 patients (95M:80F), age range 3 weeks to 18.5 yrs(mean 7yrs, median 6.6) who underwent HSCT between January1994 and December 2004 were included in the study. Allogeneic

transplants were performed on 125 patients while 50 patientsunderwent autologous transplantation. Nine CMV negativepatients underwent a second transplant from CMV negativerecipients for recurrent disease or graft failure. Indications forHSCT included ALL, AML & CML (n=79), Aplastic anaemia andFanconi anaemia (n=23), solid tumours (n=45) and Inborn errors/Immunodeticiencies (n=37). 133 patients had stem cells frombone marrow, 36 from peripheral blood (auto 33, allo 5) and sixpatients received cord blood transplants,

Of the 136 patients, in which both the recipient and donor wereCMV negative there were no cases of post transplant acquiredCMV disease. Thirty-nine of 175 (22%) patients were deemed atrisk of CMV reactivation (on the basis of recipient and/or donorCMV positivity), 33 allogeneic and 6 autologous. The at risk group,will be the focus of this review and information pertaining to BMTtype, screening results, treatment and outcome is summarised inTable 1.

Recipient positive/donor negativeOf eleven patients in this high-risk category, four patients hadpositive screening tests, three of whom were treated. One patientwas treated pre-emptively, based on antigenemia One patientdeveloped early respiratory signs, coinciding with a positive BAL,was treated with ganciclovir and made a complete recovery. Onepatient received an unrelated, unmanipulated graft and developedgrade 4 GVHD on 0+ 12. On 0+33, he had severe haematuria

and BK virus was isolated from urine. Having had 7 negative urinetests, he developed CMV interstitial pneumonitis on D+45,coinciding with CMV antigenemia, which failed to respond toganciclovir and foscarnet and died on 0+56.

Recipient negative/donor positiveOne out of twelve patients in this intermediate-risk categorydeveloped CMV antigenemia and CMV pneumonitis. She hadengrafted within 15 days and was discharged home on D+29.Early screening was negative. While on prophylactic acyclovir, shedeveloped antigenemia on D+75 coinciding with respiratory signs,

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Reel

TypeBMTIn vivo Teel!UrinePp65/P ThroatBALTreatment OutcomeDonor

DepletionCRSwab

R+ / D-

ALLUDYes D+103D+117NoNDGan (D+ 127) A+WI..

ALL

UONo No0+49NoNOGan (D+48), Fos (0+50)Died D+56

AML

SibNo 0+0NoD+29NDDid not progress furtherA+W

AML

SibNo NoNoNoD+27Gan (D+54) A+W

R- / D+

AMLUDYes D+67D+57NoNeg x 2Gan (D+77), Fos (0+97)Died D+119

R+/ D+

ALLUDYes-add backNo0+32D+17NDGan x 2· (D+43/+82) A+W

HS

SibNo' 0+54D+49D+167NOGan (0+54) A+W

ALL

UOYes-add backD+38D+47NoNDGan x 2· (D+46/ + 109)DOD

FA

UDYes D+156D+44NoNDGan (D+45) A+W

FA

SibNo D+33D+51D+40NDDid not treat A+W

ALL

SibNo D+43D+43NoNOGan (D+47) A+W

FA

SibNo NoD+36NoNDGan (D+37) A+W

R+/D- Recipient CMV positive/Donor CMV negative, R-/D+ Recipient CMV negative/Donor CMV positive, R+/D+ Recipient CMVpositive/Donor CMV negativeAll Acute lymphoblastic leukaemia, AMl Acute myeloid leukaemia, FA Fanconia anaemia, HS Hurlers SyndromeUD Unrelated donor, Sib Sibling donorND Not doneGan GanciclovirA+W Alive and well, ODD Died of primary disease

.*2 courses Ganciclovir

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deteriorated despite ganciclovir and foscarnet and died on 0+ 118of CMV pneumonitis, Screening of all other patients was negative.

Recipient and donor positiveSeven of ten patients in this high-risk group, developedantigenemia, six of whom met the criteria (>5x 1Ot2 neutrophils ortwo positive PCR) for pre-emptive treatment Three receivedgrafts from unrelated donors and two patients had T-cell addback.Two patients required repeated courses of ganciclovir. No patientin this category developed CMV disease.

PCR testing only became available in recent years, initiallyexclusively for high-risk patients. While there was insufficient data

to make meaningful comparison, positivity coincided with pp65antigenemia. The initial site of detection of CMV was mostcommonly in urine, which was noted in five patients, four of whomdeveloped antigenemia.

Discussion

While management of CMV infection in the peritransplant periodhas improved in recent years, this herpes virus remains asignificant cause of morbidity and mortality in both children andadults. Current strategies aimed at reducing CMV disease intransplanted patients are focused on a) identifying the mostappropriate donor b) universal antiviral prophylaxis c) improvedsurveillance accompanied by pre-emptive therapy and d) therapywhich encompasses both pharmacological and immunemodulated therapy.

Controversy is ongoing in relation to choice of donor. In 2000, theCenter for Disease Control and Prevention issued guidelines forpreventing opportunistic infections in patients undergoing HSCT,using an evidence based system to guide practice.? While thechoice of a CMV negative donor is strongly recommended for aCMV negative recipient (AI), no such recommendation however ismade in relation to the choice of CMV positive donor for CMVpositive recipient Ljungman et al for European Bone MarrowTransplant Group reported improved survival in CMV positivepatients undergoing unrelated non T-depleted transplant fromCMV positive d0:1ors2, although this was not supported in anNational Marrow Donor Program Study.S Two recent paediatricreports have noted reduced incidence of CMV reactivation and

disease in double positive transplanted patients4,9. The onlyvariable which appears to significantly influence incidence of CMVdisease and mortality in CMV positive recipients is donor statuslO.Worth noting, Ljungman et al2 demonstrated improved diseasefree survival in CMV negative recipients who received grafts fromunrelated CMV positive donors, commenting that the developmentof HLA-restricted cytotoxic T-Lymphocyte (CTL) function was themost important immune response for protection of the host fromsevere disease and mortality after BMT. In that study, CMV statuswas not relevant in HLA identical related transplants.

From a survey by the Irish Blood Transfusion Service12 24% of thegeneral population have had previous exposure, representing oneof the lowest reported CMV sero-pr,evalence rates. This might atleast partially explain the lower incidence of CMV (9%) noted inthis study, in comparison with other paediatric groups (30-38%)4,9,though this figure is likely to change with the increasing ethnicdiversity.13 Twelve of 125 patients in one series developed CMVdisease, nine of whom died.4 In this study, only two patientsdeveloped CMV disease, both of whom, died. While GVHD maywell have been a precipitating factor in one patient, thedevelopment of CMV pneumonitis in a CMV negative, donorpositive patient was unexpected. CMV pneumonitis, onceestablished, carries a grave prognosis; in spite of the considerableimprovement in intensive care, mortality rates are high.4.10Onset isapproximately 7 to 10 weeks after BMT and most episodes occurin the first 100 days. Late onset CMV pneumonitis has also beenincreasingly reported, at least partially attributable to prophylacticand pre-emptive therapy delaying recovery of CMV-specific T cellimmunity and chronic GVHD.5,11 Mortality in this situation was

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46% in one study6 and, with concurrent infections, is usuallyassociated with 100% mortality.14

Four of the seven CMV+ve/+ve patients who developedantigenemia had sibling transplants and had neither in vivo or invitro T cell depletion. None of these patients developed CMVdisease. All but one patient in the entire group reactivated within100 days of transplant Boech & Ljungman have reported thatalmost 80% of CMV positive patients reactivated within 100 daysof transplant, while only 28% of seronegative patientstransplanted using a seropositive donor did SO.15 Donor sourcewas also relevant in that study; the risk of CMV reactivation was2.4% in recipients of a related donor and 4.4% using matchedunrelated donor, compared with autologous transplants. None ofthe six CMV positive patients receiving autologous transplants inthis study reactivated; none of these patients had ahaematological malignancy although all were heavily pretreated.Stem cells were un manipulated in all. Numbers in this study aretoo small to make meaningful comparisons.

All intermediate and high risk patients in this group receivedintravenous immunoglobulin. This is no longer recommended aseffective prophylaxis (011)7,16although, a modest beneficial effecthas been demonstrated by others.17 The same can be stated formore specific passive immunity in the form of CMV specificmonoclonal antibody.IS

The incorporation of pre-emptive therapy has now becomeestablished practice in HSCT; it is recommended that any level ofantigenemia or two positive quantitative PCR CMV assays withinone week, occurring within 3 months of transplant should warrantantiviral therapy.19 Ganciclovir and foscarnet are the drugs ofchoice. Foscarnet is associated with nephrotoxicity and closeelectrolyte monitoring is strongly recommended. Ganciclovir, onthe other hand is not without side effects, most notable of which isthe association with myelosuppression, occurring at a time whenengraftment is at a precarious stage. An induction period of 1-2weeks is recommended or until CMV load begins to decrease.Maintenance period varies between centres, ranging from 2weeks to treatment until CMV load is negative.20 Aftermaintenance therapy, 30-50% of patients are likely to relapse,particularly after short-term treatment.19 While the standard pre-emptive strategies have generally proved successful in matchedsibling and matched unrelated transplants, some authorsrecommend that patients whose grafts are T cell depleted and arein vivo T cell depleted prior to transplant as well as patients at highrisk for development of GVHD should be considered forprophylactic, rather than pre-emptive treatment.2t,:;!2 Kroger et allreported that in an unrelated donor transplant population whowere T cell depleted pre transplan~ mortality in CMV seropositivepatients was three times higher than seronegative patients; thiswas despite monitoring for CMV antigenemia and pre-emptivetherapy with ganciclovir. They noted that transplant relatedmortality was identical in seropositive patients with or withoutreactivation. Late reactivation of CMV has been well-

documented5.6,14 and is attributable to factors including chronicGVHD and delayed immune reconstitution raising questions inrelation to duration of prophylaxis.

Given that the risk of CMV reactivation is greatest afterengraftment, when pp65 antigenemia and CMV PCR can beemployed, the role of shell vial rapid culture assay of urine, whichcomprised a major component of surveillance in this study, wouldappear to be in doubt. An advantage of the latter however mightbe an awareness of imminent antigenemia and an indication forgreater vigilance with surveillance. Throat swabs, on the other

hand, were unreliable and negative in both patients with CMVpneumonitis.

The role of acyclovir in reducing reactivation of CMV is notcompletely understood. It is postulated that its pan herpes effectimproves the overall survival in patients with CMV disease, rather

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than a specific CMV effectn This has not been observed howeverin patients undergoing autologous transplanf24 nor in allogeneic

transplant recipients who developed antigenemia or were treated

with ganciclovir at engraftment.25,26 Valcyclovir, an improved oral

formulation of acyclovir, has been demonstrated to be superior for

maintaining CMV suppression and may have a role in CMVprevention.25 Recent discussion has focused on universal

prophylaxis with valganciclovir, an oral prodrug , which is rapidly

converted to gancliclovir by intestinal and hepatic esterases. Data

has indicated comparable activity with IV ganciclovir when given

pre-emptively in HSCT patients.27 While the efficacy of this agentdoes not appear to be in doub~ current debate is focused on the

most appropriate scheduling, whether as prophylaxis in high-risk

patients or as an alternative to IV ganciclovir as pre-emptive

therapy.28.29 While there are advantages and disadvantages toboth approaches, it would appear that this agent might wellreplace conventional treatment in the foreseeable future. To date,

however, there has been no guideline re appropriate schedulingfor paediatric patients.

other drugs include Cidofovir, which has been used as an

alternative agent when first line therapy fails; while recommendedfor treatment of CMV retinitis,19 it has not been recommended for

prophylaxis. Limited success has been reported in treatment of

CMV disease.3D Newer agents e.g. Leflunomide, animmunosuppressant used in autoimmune disorders and treatment

of solid organ rejection has been noted to have anti CMV

properties but has yet to be investigated in clinical studies.31

Other approaches including the concept of donor-derived,

adoptive cellular immunotherapy are being currently investigated

with the ex vivo expansion of CMV-specific CTLs.32 This approach

would appear to offer realistic options, particularly in CMV

resistant disease. Research is also ongoing in the area of vaccine

development, applicability for which would extend far beyond theconfines of organ transplantation.33,34

In conclusion, the incidence of CMV antigenemia, reactivation and

disease in this paediatric population has been lower than

published series and may well be partially attributable to the low

prevalance of CMV in the normal population. CMV surveillance

with pp65 antigenemia +/-PCR was effective in monitoring

patients at risk of reactivation, while routine use of CMV negative,

filtered blood products may have contributed to the relatively low

incidence of CMV disease. Pre-emptive therapy with ganciclovirwas effective while the incorporation of shell vial cultures of urineand throat swabs were of little value. Whether intravenous

immunoglobulin contributed to a reduction of infection related

morbidity remains an unanswered question ..

Correspondence: A O'Meara

Haematology & Oncology Dept, Our Lady's Children's HospitalCrumlin, Dublin 12

Email: anne.omeara@olhsc.ie

Referenc:es ,

1. Kroger N, Zabelina T, Kruger W et a!. Patient cytomegalovirus

seropositivity with or without reactivation is the most important

prognostic factor for survival and treatment-related mortality in stem

cell transplantation from unrelated donors using pretransplant in vivo Tcell depletion with ATG. Br J Haematol2001 ;113:1060-1071.

2. Ljungman P, Brand R, Einsele H et al. Donor CMV serological status

and outcome of CMV seropositive recipients after unrelated donor

stem cell transplantation: an EBMT megafile analysis. Blood2003:102:4255-4260.

3. Boeckh M, Nichols WG. The impact of cytomegalovirus serostatus of

donor and recipient before hematopoietic stem cell transplantation in

the era of antiviral prophylaxis and preemptive therapy. Blood2004; 103:2003-2008.

4. Matthes-Martin S, Lion T, Aberle SW et a!. Pre-emptive Treatment of

CMV DNAemia in Paediatric Stem Cell Transplantation: the Impact ofRecipient and Donor CMV Serostatus on the Incidence of CMV

Disease and CMV-related Mortality. Bone Marrow Transplant2003:31 :803-808.

5. Griffiths PD. Chapter 10: Clinical Approach to Infection in the

Compromised Hoslln: Rubin RH & Young LS eds. NY KluwerAcademic/Plenum Publishers.

6. Boeckh M, Leisenring W, Riddell SR et al. Late Cytomegalovirus

disease and Mortality in Recipients of Allogeneic Haematopoietic

Stem Cell Transplants: Importance of Viral Load in T-cell Immunity.Blood 2003;101 :407-14.h.

7. CDC Guidelines for preventing opportunistic infections among

hematopoietic stem cell transplants recipients. Morb Mort Wkly RepOct 2000: 49: 1-128. www.cdc.gov/mmwr/preview/mmwrhtml/

rr4910al.htm (accessed 23rd April 2006).8. Kollman C, Howe CW, Anasetti C et a!. Donor characteristics as risk

factors in recipients after transplantation of bone marrow from

unrelated donors: the effect of donor age. Blood 2001;98:2043-2051.

9. Patel SR, Ridwan RU, Ortin M,CMV Reactivation in Pediatric

Hemopoietic Progenitors Transplanl A Retrospective Study on theRisk Factors and the Efficacy of Treatmenl J Pediatr Hematol Oncol.2005:27:411-415.

1o, Castagnola E. Capelli B, Erba D et at Cytomegalovirus infection after

bone marrow transplantation in children. Hum Immunol 2004;65:416-422.

11. Einsele H, Hebart H, Kauffmann-Schneider C et al. Risk factors for

treatment failures in patients receiving PCR-based preemptive therapyfor CMV infection. Bone Marrow Transplant 2002;25:757-63.

12. Horgan S, Pitt G, O'Riordan J, Dunne C, Ni Conghaile M, O'Brien M,

O'Meara A, Browne P, Lawlor E. Experience with CMV matching indonor recipient pairs. Irish Haemotology Association 2007.

13, Knowles SJ, Grundy K, Cahill I et a!. Low cytomegalovirus sero-

prevalence in Irish pregnant women.lr Med J 2005:98:210-2.

14. Nguyen 0, Champlin R, Giralt S et a!. Late cytomegalovirus pneumoniain adult allogeneic blood and marrow transplant recipients. Clin InfectDis 1999:28:618'23.

15. Boeckh MJ, Ljungman P. Cytomegalovirus infection after

haemopoietic stem cell transplantation. In: RA Bowden, P Ljungman &VP Paya, eds, Transplant Infections. Philadelphia: Lippincott -Williams& Wilkins, 2002.

16. Ljungman P, Reusser P, de la Camara R et a!. Management of CMV

Infections: recommendations from the infectious diseases workingparty of the EBMT. Bone Marrow Transplant 2004;33:1075-1081.

17. Sass E, Powe N, Goodman S et a!. Efficacy of immune globulin in

preventing complications of bone marrow transplantation: a meta

analysis, Bone Marrow Transplant 1993 Sept; 12:273-82.

18. Boeckh M, Bowden RA, Storer B et al Randomised, placebo

controlled, double blind study of a CMV glycoprotein H-specificmonoclonal antibody (MSt: 109) for prevention of CMV infection after

allogeneic haemopoietic stem cell transplanl Bioi Blood MarrowTransplant 2001 ;7: 343-354.

19. Zaia JA Prevention of Cytomegalovirus Disease in HematopoieticStem Cell Transplantation. Clin Infect Dis 2002;35:999-1 004.

20. Reusser P, Einsele JL, Lee T et al. Randomised multicenter trial of

foscarnet versus ganciclovir for pre-emptive therapy of

cytomegalovirus infection after allogeneic stem cell transplantation.Siood 2002:99: 1159-64.

21. Ljungman P, Aschan J, Lewensohn-Fuchs I et al. Results of different

strategies for reducing cytomegalovirus-associated mortality in

allogeneic stem cell transplant recipients. Transplantation1998:66:1330-1334.

22. Soeckh M. Current antiviral strategies for controlling cytomegalovirusin hematopoietic stem cell transplant recipients: prevention andtherapy. Transpllnfect Dis 1999; I :165-78.

23. Prentice HG. Gluckman E, Powles RL et al.lmpact of longterm

acyclovir on cytomegalovirus infection and survival after allogeneicbone marrow transplantation. Lancet 1994:343:749-753.

24. Boeckh M, Gooley TA, Bowden RA. Failure of high dose acyclovir for

prevention of CMV disease after autologous marrow transplant JInfect Dis 1995; 172: 939-943.

25. Ljungman P, de la Camara R, Milpied N et al. A randomised study of

-. _.- - --- __ Supplied by The British Library - "The world's knowledge" -

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valaclovir as prophylaxis against CMV reactivation in allogeneic bonemarrow transplant recipients. Blood 2002;73;930-936.

26. Boeckh M, Gooley TA, Bowden RA. Effect of high dose acyclovir onsurvival in allogeneic marrow transplant recipients who receivedganciclovir at engraftment or for cytomegalovirus pp65 antigenaemia.J Infect Dis 1998; 178: 1153-1157.

'27. van der Heiden Pl, Kalpoe JS, Barge RM et al.Oral valganciclovir aspre-emptive therapy has similar efficacy on cytomegalovirus DNA loadreduction as intravenous ganciclovir in allogeneic stem celltransplantation recipients. Blood Marrow Transplant 2006:37:693-8.

28. Nichols G, Price TH, Gooley T.Transfusion transmitted CMV infectionafter receipt of leukoreduced blood products. Blood 2003; 10 I :4195-4200.

29. Hart GO, Paya CV.Prophylaxis for CMV should now replacepreemptive therapy in solid organ transplantation. Rev Med Virol2001;11:73-81.

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30. ljungman P,Deliliers Gl, Platzbecker U et at Cidofovir forCytomegalovirus infection and disease in allogeneic stem celltransplant recipients: the Infectious Diseases Working Party of theEuropean Group for Blood and Marrow Transplantation.Blood2001;97:388-92.

31. Avery RK, Bolwell BJ, Yen-Lieberman B et at Use of leflunomide in anallogeneic bone marrow transplant recipient with refractorycytomegalovirus infection. Bone Marrow Transplant 2004;34:1 071-5.

32. Einsele H & Hebart H. CMV-specific immunotherapy.Hum Immunol2004;65:558-564.

33. Paston SJ, Dodi lA, Madrigal JA. Progress made towards thedevelopment of a CMV peptide vaccine. Hum Immunol2004;65:544 9.

34. Arvin AM, Fast P,Myers M et al. National Vaccine Advisory Committee.Vaccine development to prevent CMV disease: report from theNational Vaccine Advisory Committee. Clin Infect Dis 2004;39:233-9.

.l

A Role for Myelography in Assessing Paraparesis

A Merwick1, SS O'Suilivan2, KN O'Regan3, CJ Marks4, DO Ryder3, BJ Sweeney!Departments of IClinical Neurology, 3Radiology and 4Neurosurgery, Cork University Hospital, Wilton, Cork21nstitute of Neurology, University College London, 1 Wakefield Street, London WC 1N 1PJ

Abstract

Imaging of the spine is a fundamental part of assessment of paraparesis. Since the advent of MRI the indications for myelogramshave diminished. However, a myelogram, although an invasive test, should still be considered a useful investigation for localisinglesions in the spinal cord and for identifying rare causes of myelopathy. This case illustrates how a CT myelogram identified anarachnoid cyst, which is a potentially treatable cause of paraparesis.

Introduction

Spinal arachnoid cysts are a rare, but potentially treatable cause ofparaparesis. Radiological investigations are essential fordiagnosing and localising the lesion. We illustrate a case where amyelogram was the key diagnostic tool.

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Case ReportA 58-year-old Caucasian woman was referred for assessment ofspastic paraparesis. She had a 4-year history of bilateral lowerlimb paraesthesia and decreased pain perception. She developedincreasing difficulty walking upstairs and described a gradualdeterioration in lower limb power. She also experiencedconstipation and urinary urgency. She is a non-smoker, with nohistory of travel or residence in tropical areas. She has no familyhistory of neurological disease

Clinical examination showed proximal weakness (4/5) bilaterallyin the hip flexors, a scissoring gait and difficulty with tandem gait.There was mildly decreased pain sensation to Tl O. Hyperreflexiabilaterally at knees and ankle in conjunction with upgoing planterswas noted.

InvestigationsNerve conduction studies were normal.

CSF analysis was normal, without oligoclonal bands.Serology for poliovirus, syphilis and Iyme disease was negative.

MRI of spine demonstrated thinning of the spinal cord in thethoracic region. CSF signal intensity was seen surrounding thecord and there was no evidence of an extra-axial mass causingextrinsic cord compression (Figure 1).

~.CT myelogram was performed following fluoroscopically-guidedInjection of 8ml of nonionic contrast medium into the

subarachnoid space. This demonstrated a well-circumscribed,ex~ra-medullary, CSF-density collection posterior to the thoracicSPinal cord, which did not fill with contrast. This collection

Figure 1 Sagittal T2-weighted MRI of dorsal spine showingfocal thinning of the thoracic spinal cord, surroundedby CSF signal intensity

extended from T 4 to T8 levels, measuring 1.1em in maximumanteroposterior diameter and 9.6cm from its superior to its inferiormargin (Figure 2). The findings were consistent with a largearachnoid cyst.

An elective T6 laminectomy was performed. Following a midlinedural opening a bulging arachnoid cyst was seen, which waspunctured after introduction of a microscope. Histology showedsclerosed fibrovascular connective tissue partially lined bymeningothelial cells.

At 2 months follow-up after surgery, our patient wasindependently mobile. Her power was grade 5 throughout thelower limbs, with normal reflexes and sensory examination.