varicella zoster virus ( vzv ) disease is one of the most frequent infectious complications after allogeneic hematopoietic stem cell transplantation ( allo - hsct ) ; during the first year , its incidence ranges from 13 to 55% ( 1 ) .
although cutaneous herpes zoster is the most common clinical form of reactivation , allo - hsct recipients may present with fatal systemic dissemination ( 1,2 ) . among the various types of vzv infection , infections of the central nervous system ( cns ) , especially meningitis and encephalitis ,
are only rarely reported ; however , they represent severely life threatening conditions and may compromise the patient 's quality of life ( 3 ) .
we herein report a case of post - transplant vzv meningitis and myelitis that developed after the cessation of immunosuppressant therapy , which was successfully treated with the intravenous administration of foscarnet .
a 42-year - old chinese man with myelodysplastic syndrome ( mds , raeb-2 ) underwent cord blood transplantation ( cbt ) from a japanese donor in october 2011 .
the conditioning regimen consisted of total - body irradiation ( tbi ) ( 12 gy ) , cyclophosphamide ( total dose , 120 mg / kg ) , and cytarabine ( total dose , 12 g / m ) .
prophylaxis against graft - versus - host disease ( gvhd ) consisted of cyclosporine ( csa ) and a short course of methotrexate .
acyclovir ( acv ) ( 1,000 mg / day , orally ) was administered from day -7 to 35 as prophylaxis against herpes virus .
this was maintained at a reduced dose of 200 mg / day until day 213 .
the patient 's serum immunoglobulin g ( igg ) levels remained within the normal limits , and his peripheral post - transplant leukocyte counts remained within the normal range . on day 241 after cbt ,
the patient presented with blisters on his face and on day 245 , a herpes zoster rash developed on his face , body , and extremities .
the patient was clinically diagnosed with a systemic vzv infection and intravenous acv ( 5 mg / kg three times a day ) was promptly administered .
the cutaneous lesions were reduced on the 8th day after the initiation of acv treatment , and the treatment was then switched to oral valaciclovir .
however , the patient developed a high fever , paralysis of the lower extremities , ischuria , neck stiffness , and spinal automatism on the second day of valaciclovir treatment .
the patient 's cerebrospinal fluid ( csf ) showed an increased number of mononuclear cells ( 77/l ) , an elevated protein level , and a normal glucose level .
the enzyme immunoassay ( eia ) values in the patient 's csf and serum were 2.56 and 13.5 , respectively , for vzv - igg , and 5.32 and 3.90 for vzv - igm .
vzv - dna was not detected in a polymerase chain reaction ( pcr ) . at 5.3 ,
the presentation of spinal automatism , paralysis of the lower extremities and ischuria led to a diagnosis of vzv meningitis , myelitis , and radiculitis .
intravenous acv was resumed at an increased dose ( 10 mg / kg , three times a day ) , on the 12th day after the initial diagnosis of the vzv infection .
magnetic resonance imaging ( mri ) of the thoracic vertebrae and the lumbosacral spinal cord on days 6 and 7 after the resumption of acv , respectively , revealed no evident abnormalities .
seventeen days after the resumption of acv , a high mononuclear cell count ( 69/l ) was still present in the patient 's csf , and the patient 's paralysis and ischuria showed no improvement .
acv was then switched to foscarnet ( 90 mg / kg , twice a day ) on day 20 after the initial diagnosis .
after 12 days of foscarnet treatment , the patient showed a complete recovery from ischuria and was able to walk by himself .
the patient 's csf showed a significantly decreased cell count , and foscarnet was discontinued after 51 days of treatment . on day 25 after the discontinuation of foscarnet therapy , the vzv - igm level in the patient 's csf dropped to negative value of 0.78 , whereas the vzv - igg level in the patient 's csf rose to 7.53 ; in contrast , the value at time of the patient 's diagnosis was 2.56 .
the patient has been in complete remission without recurrent neurological symptoms for 3.5 years since transplantation .
the long - term administration of acv after transplantation has been recommended to reduce the risk of vzv reactivation ( 1 ) .
a large retrospective study showed that the prophylactic administration of acv for 1 year reduced the incidence of vzv disease , and that the incidence was further decreased by the continuation of prophylaxis in patients who remained on immunosuppressive drugs ( 4 - 7 ) .
however , the cumulative incidence of vzv disease after the cessation of long - term acv is reported to be approximately 28.4% at 1 year ( 8) , suggesting that further studies are required to evaluate the optimal duration of low - dose acv prophylaxis .
our patient had a normal peripheral blood lymphocyte count and serum immunoglobulin levels ; thus , we discontinued prophylaxis with low - dose acv after the cessation of csa , which may have been associated with the reactivation of vzv .
furthermore , one report described the case of a patient without any known risk factors who developed vzv meningoencephalitis at 22 months after hsct following the cessation of immunosuppressants and prophylactic treatment with low - dose acv ( 9 ) .
these rare experiences suggest that vzv meningitis is a complication that may occur in any allo - hsct recipient at any time after transplantation .
the initial symptoms of vzv meningitis and myelitis in post - transplantation patients vary and may include dermatomal zoster before the onset .
leveque et al . ( 10 ) reported two recipients who developed meningitis without skin manifestations .
in contrast , fukuno et al . ( 11 ) described a bone marrow transplantation recipient in whom vzv meningoencephalitis occurred suddenly at 21 days after the completion of acv therapy for a localized cutaneous vzv infection .
our patient 's disseminated skin lesions developed first , and his neurological symptoms became obvious as the skin rash disappeared after acv therapy .
thus , cns infections should always be considered when cns symptoms emerge without skin lesions or develop after a cutaneous vzv infection .
although we could not detect vzv dna in this patient 's csf , the patient 's csf was positive for anti - vzv igm and igg , which was helpful in establishing the diagnoses of vzv meningitis and myelitis .
the detection of anti - vzv antibodies in the csf appears to have greater sensitivity in the diagnosis of vzv infections of the nervous system , than the detection of viral dna .
reported that vzv - dna positivity and the detection of antibodies in the csf can dramatically change during the clinical course of a viral infection ( 12 ) . in this report , 0% and 61% of the csf samples that were collected within the first 7 days after the onset of rash were positive for anti - vzv antibodies and vzv dna , respectively
however , after 7 days the rate of anti - vzv antibody - positive samples increased to 83% , while the rate of vzv dna - positive samples decreased to 25% . in our present case ,
csf sampling was performed on day 15 after the onset of rash , which was a relatively late time point .
we hypothesize that the vzv dna in the csf decreased to an undetectable level while the csf became antibody - positive .
thus , both assays are recommended in the assessment of csf samples in order to accurately diagnose vzv infections ( 13 ) .
vaccination may help decrease the risk of reactivation . although the data on the safety and efficacy of live - attenuated varicella vaccines in allo - hsct recipients are limited ( 14,15 )
, no serious adverse events were reported in a previous study involving 110 adult allo - hsct patients ( 16 ) .
thus , the guidelines recommend varicella vaccination at 2 or more years after transplantation in allo - hsct patients without active chronic gvhd or ongoing immunosuppressive therapy ( evidenced - based rating : ciii ) ( 17,18 ) .
however , even at 2 years after hsct , 30 - 40% of the patients are considered to be ineligible for vaccination ( 19,20 ) . for these recipients ,
the continuation of acv treatment for an extended period of time may be necessary to decrease the incidence of serious vzv reactivation .
intravenous acv ( 10 mg / kg , every 8 hours ) , is the recommended treatment for vzv infections of the cns ( 21 ) .
however , acv activation is dependent on intracellular virus - encoded thymidine kinase ( tk ) , which implies that tk - deficient vzv strains are resistant to acv .
described a case in which a patient with vzv encephalitis was successfully treated with the addition of foscarnet to acv ( 22 ) .
the pharmacological action of foscarnet is tk - independent , which enables the elimination of acv - resistant vzv ( 23 ) . in our case
, acv appeared to be insufficient for improving the patient 's neurological symptoms , and the patient was then successfully treated when acv was switched to foscarnet , suggesting that an acv - resistant vzv strain was involved in the patient 's meningitis .
it is possible that the strain of vzv that caused the meningitis was the same strain as that which caused the cutaneous infection , and the present patient might have been a late responder to acv .
however , several reports have shown that the interval between the initiation of acv treatment and clinical improvement ranged from 3 to 9 days in patients with zoster- or varicella - induced myelitis ( 24 - 27 ) .
the paralysis and ischuria of the present patient showed no improvement during the 17 days in which he received a sufficient dose of intravenous acv , and the number of mononuclear cells in the patient 's csf showed a minimal decrease .
we therefore hypothesized that the strain of vzv that was responsible for the patient 's meningitis was acv - resistant and that it was unlikely that the patient was a late responder to acv , and decided to switch the therapy to foscarnet . in conclusion
, we described the case of a patient with vzv meningitis , radiculitis and myelitis after the cessation of immunosuppressant therapy and long - term acv prophylaxis .
vzv cns infections may be severe life threatening events and have the potential to compromise a patient 's quality of life .
thus , when initial acv therapy is found to be insufficient for the treatment of vzv infections in transplant recipients under long - term acv prophylaxis , physicians should immediately consider changing to second line therapies , such as foscarnet .
further investigation is necessary to develop optimal prophylactic strategies and effective vaccination schedules may be needed to eradicate post - transplant vzv disease .
 infections of the central nervous system ( cns ) with varicella zoster virus ( vzv ) is a rare occurrence after allogeneic hematopoietic stem cell transplantation . 
 we herein report a case of vzv meningitis , radiculitis and myelitis that developed 8 months after cord blood transplantation , shortly after the cessation of cyclosporine and low - dose acyclovir . 
 although treatment with acyclovir did not achieve a satisfactory response , the patient was successfully treated with foscarnet . 
 our report indicates that vzv infection should be considered in allo - hematopoietic stem cell transplantation ( hsct ) patients with cns symptoms and that foscarnet may be effective for the treatment of acyclovir - resistant vzv infections of the cns . 
 the development of optimal prophylactic strategies and vaccination schedules may eradicate post - transplant vzv disease . 