cytomegalovirus ( cmv ) infection still remains a major cause of morbidity and mortality in allogeneic stem cell transplantation ( sct ) recipients .
while cmv infection of the central nervous system ( cns ) in acquired immune deficiency syndrome patients has been reported relatively frequently , it is an unusual presentation in allogeneic sct recipients , but fatal in all cases ( 1 - 4 ) .
recently , unrelated cord blood or t - cell depleted grafts have been increasingly used as an alternative source of hematopoietic stem cells .
however , the use of these grafts has been associated with an increased frequency of unusual cmv infections . here
, we report a case of cmv ventriculoencephalitis after unrelated double cord blood sct with an alemtuzumab - containing preparative regimen for philadelphia - positive acute lymphoblastic leukemia .
the patient had recurrent cmv dnaemia despite long - term treatment with antiviral agents ( foscarnet combined with ganciclovir ) and anti - cmv immunoglobulin .
a 20-yr - old man underwent unrelated cord blood sct using two cord blood units to treat philadelphia - positive acute lymphoblastic leukemia .
the patient was treated with total body irradiation ( 1,200 cgy ) , fludarabine ( 150 mg / m ) , cytarabine ( 9 g / m ) , and alemtuzumab ( 20 mg ) as a preparative regimen .
for prophylaxis of cmv reactivation , acyclovir ( 10 mg / kg intravenously every 8 hr ) and anti - cmv immunoglobulin ( 150 mg / kg intravenously biweekly ) were given from day -7 until engraftment .
the patients achieved successful neutrophil and platelet engraftment on day 27 and 51 , respectively . on day 33 ,
cmv dnaemia was detected by real - time quantitative polymerase chain reaction ( rq - pcr ) as 3,775 copies / ml and the viral load increased steadily thereafter .
the patient was treated preemptively for cmv dnaemia with foscarnet ( 60 mg / kg intravenously every 12 hr for 7 days , followed by 90 mg / kg intravenously daily ) from day 39 to day 93 . during this period ,
foscarnet had been chosen , instead of ganciclovir , since it had less potential bone marrow toxicity .
thirteen days after discontinuation of the foscarnet , cmv retinitis developed with an increase in cmv dna titer .
the foscarnet ( 90 mg / kg intravenously every 12 hr ) and anti - cmv immunoglobulin ( 150 mg / kg intravenously biweekly ) were re - administered .
however , 7 days later , the cmv rq - pcr titers increased despite the treatment . then we added ganciclovir ( 5 mg / kg intravenously daily ) on top of foscarnet ( 90 mg / kg intravenously daily ) .
clinically , the cmv retinitis improved and the cmv dnaemia resolved 40 days after the combination therapy . on day 171 , he was re - admitted complaining of progressive weakness of all four extremities .
the peripheral blood showed pancytopenia without leukemic cells ; a wbc count of 1,160/l , hemoglobin of 6.9 g / dl , and a platelet count of 6,000/l . despite administration of foscarnet and
1 ) showed multiple nodularity with high signal intensities in the bilateral fronto - parietal subcortical white matter , periventricular white matter , and the basal ganglia in the t2-weighted and flair images .
diffuse high signal changes in the t2-weighted and flair images were also noted along the wall of the lateral ventricles , which were enhanced with gadolinium on the t1-weighted images .
lumbar puncture was performed on day 186 ; the results showed a protein concentrate of 66.5 mg / dl , a glucose concentrate of 62 mg / dl ( serum glucose concentrate , 145 mg / dl ) , no white blood cells , and no red blood cells .
the microbiology of the cerebrospinal fluid ( csf ) was negative for bacteria , mycobacterium species , and fungi .
there was no skin lesion that suggested a varicella zoster virus infection , and the pcr analysis of the csf for herpes simplex virus ( type 1 & 2 ) and human herpes virus 6 were all negative .
2 ) . based on the typical radiologic findings , the positive pcr for cmv from the csf , and recurrent cmv dnaemia in the peripheral blood in spite of long - term antiviral therapy ,
recently , posttransplant immune reconstitution after sct varies because of availability of alternative donor and variety of preparative regimens and graft manipulations .
the unrelated cord blood sct and haploidentical transplantation themselves may be correlated with a high incidence of cmv reactivation , when compared to matched sibling or unrelated sct ( 5 , 6 ) , as well as the use of antithymocyte globulin , fludarabine , and alemtuzumab ( humanized monoclonal cd52 antibody ) as part of the preparative regimen ( 7 - 13 ) . in particular
, the combination of fludarabine and alemtuzumab might cause a higher risk of cmv infection and earlier cmv infection following allogeneic sct compared to other preparations ( 8) .
( 7 ) suggested that the patients receiving alemtuzumab , a total dose of 100 mg , had a higher incidence of cmv infection ; a lower dose of alemtuzumab might be related with a reduced risk of cmv infection .
our patient received a much lower dose of alemtuzumab , a total dose of 20 mg .
however , he had a recurrent cmv reactivation and finally developed cmv retinitis and ventriculoencephalitis .
a combination of intravenous foscarnet and ganciclovir has been advocated for treatment of single drug - resistant cmv disease ( 14 , 15 ) .
we tried the combination regimen of foscarnet and ganciclovir , expected to have synergistic effects , for the treatment of cmv retinitis because of two reasons ; 1 ) we used the combination of fludarabine and alemtuzumab for cbt preparation , which might have made the patient highly susceptible to cmv reactivation ; 2 ) cmv retinitis developed after treatment with cmv dnaemia despite the recent prolonged treatment with foscarnet . clinically , the treatment failure of cmv disease with antiviral drugs may be associated with antiviral resistance and/or inadequate penetration of the drug into the infected tissue ( 1 , 3 , 16 , 17 ) . the recurrent cmv dnaemia and progressive cmv disease unresponsive to antiviral agents and anti - cmv immunoglobulin for about 150 days , suggest antiviral resistant - mutant cmv in the case .
however , it is the limitation of the current study that we could not perform drug susceptibility analysis , cmv genotyping or phenotyping for drug resistance - associated mutations , or measurement of the drug levels in the plasma and csf . in summary ,
more aggressive prophylaxis as well as preemptive therapy for cmv infection and more diligent monitoring for progression to cmv diseases should be considered for a certain proportion of sct recipients with multiple risk factors of delayed immune reconstitution .
 despite the prophylaxis and preemptive strategies using potent antiviral agents , cytomegalovirus ( cmv ) remains a major infectious cause of morbidity and mortality in allogeneic stem cell transplantation ( sct ) recipients . delayed immune reconstitution after sct , such as cord blood and t - cell depleted sct with the use of alemtuzumab , has been associated with an increased frequency of cmv disease as well as cmv reactivation . 
 cmv disease involving central nervous system is an unusual presentation in the setting of sct . 
 we report a case of cmv ventriculoencephalitis after unrelated double cord blood sct with an alemtuzumab - containing preparative regimen for philadelphia - positive acute lymphoblastic leukemia . 
INTRODUCTION
CASE REPORT
DISCUSSION