Determinants of survival in progressive multifocal leukoencephalopathy.
ABSTRACT We sought to characterize the role of immunologic, virologic, and radiologic determinants of survival in patients with progressive multifocal leukoencephalopathy (PML).
We recorded the clinical outcome of 60 patients with PML (73% HIV+) who were prospectively evaluated between 2000 and 2007 for the presence of JC virus (JCV)-specific CD8+ cytotoxic T-lymphocytes (CTL) in blood.
Estimated probability of survival at 1 year was 52% for HIV+/PML and 58% for HIV- patients with PML. Patients with PML with detectable CTL within 3 months of diagnosis had a 1-year estimated survival of 73% compared to 46% for those without CTL (hazard ratio [HR] for death = 0.47, 95% confidence interval [CI] 0.13-1.75, p = 0.26). Patients with CTL response had an increased likelihood of having contrast enhancement of PML lesions and immune reconstitution inflammatory syndrome (odds ratio 3.7 and 7.8). Estimated 1-year survival was 48% in HIV+ patients with PML with CD4 count <200/microL at PML diagnosis compared to 67% in those with CD4 >200/microL (HR for death 1.41, 95% CI 0.27-7.38, p = 0.68). JCV DNA was detected in the urine of 48% and in the blood of 56% of patients with PML, but viruria and viremia were not associated with survival.
The presence of JC virus (JCV)-specific cytotoxic T-lymphocytes (CTL) was associated with a trend toward longer survival in patients with progressive multifocal leukoencephalopathy (PML), which was more pronounced than the impact of CD4 count in HIV+ patients with PML early after diagnosis. Despite the association of contrast enhancement and immune reconstitution inflammatory syndrome with JCV-specific CTL, these cannot be considered as surrogate markers for the prognostic value of the CTL. Strategies aiming at improving the cellular immune response may improve the course of PML.
- SourceAvailable from: Martyn Andrew French[Show abstract] [Hide abstract]
ABSTRACT: An immune reconstitution disorder occurs in up to 40 % of severely immunodeficient HIV patients who commence antiretroviral therapy (ART), with an immune reconstitution inflammatory syndrome (IRIS) being encountered most commonly. Differences in the immunopathogenesis of an IRIS associated with different types of pathogen have become apparent but common features have also been defined. These include severe immunodeficiency prior to commencing ART associated with a high pathogen load and 'compensatory' immune responses, particularly innate immune responses, which inadequately control the pathogen and increase the risk of immunopathology as the immune system recovers on ART. Prevention of an IRIS may be achieved by optimising therapy for opportunistic infections before ART is commenced, delaying ART or using immunomodulatory therapy to prevent or suppress the immune response that causes the immunopathology. However, further clinical studies are required to examine these options in a systematic manner for the various types of IRIS.Current HIV/AIDS Reports 06/2014; 11(3).
- [Show abstract] [Hide abstract]
ABSTRACT: With the widespread use of combination antiretroviral therapy (cART), the incidence of central nervous system (CNS) opportunistic infections and coinfections has significantly decreased. This review focuses on the clinical presentation, diagnostic laboratory and radiologic findings, as well as the treatment of neurosyphilis, progressive multifocal leukoencephalopathy, primary CNS lymphoma, and toxoplasmosis, which are CNS opportunistic infections and coinfections that are most relevant to clinicians in North America.Seminars in Neurology 02/2014; 34(1):61-9. · 1.51 Impact Factor
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ABSTRACT: No reliable treatment options are known for progressive multifocal leukoencephalopathy with underlying immunodeficiency. We describe successful compassionate use of recombinant human interleukin 7 in a patient with idiopathic CD4+ T-cell lymphocytopenia.JAMA Neurology 06/2014; 71(8). · 7.01 Impact Factor
Determinants of survival in progressive
A. Marzocchetti, PhD
T. Tompkins, BSc
D.B. Clifford, MD
R.T. Gandhi, MD
S. Kesari, MD, PhD
J.R. Berger, MD
D.M. Simpson, MD
M. Prosperi, PhD
A. De Luca, MD
I.J. Koralnik, MD
Background: We sought to characterize the role of immunologic, virologic, and radiologic determi-
nants of survival in patients with progressive multifocal leukoencephalopathy (PML).
Methods: We recorded the clinical outcome of 60 patients with PML (73% HIV?) who were pro-
spectively evaluated between 2000 and 2007 for the presence of JC virus (JCV)-specific CD8?
cytotoxic T-lymphocytes (CTL) in blood.
Results: Estimated probability of survival at 1 year was 52% for HIV?/PML and 58% for HIV?
patients with PML. Patients with PML with detectable CTL within 3 months of diagnosis had a
1-year estimated survival of 73% compared to 46% for those without CTL (hazard ratio [HR] for
death ? 0.47, 95% confidence interval [CI] 0.13–1.75, p ? 0.26). Patients with CTL response
had an increased likelihood of having contrast enhancement of PML lesions and immune reconsti-
tution inflammatory syndrome (odds ratio 3.7 and 7.8). Estimated 1-year survival was 48% in
HIV? patients with PML with CD4 count ?200/?L at PML diagnosis compared to 67% in those
with CD4 ?200/?L (HR for death 1.41, 95% CI 0.27–7.38, p ? 0.68). JCV DNA was detected in
the urine of 48% and in the blood of 56% of patients with PML, but viruria and viremia were not
associated with survival.
Conclusions: The presence of JC virus (JCV)–specific cytotoxic T-lymphocytes (CTL) was associ-
ated with a trend toward longer survival in patients with progressive multifocal leukoencephalop-
athy (PML), which was more pronounced than the impact of CD4 count in HIV? patients with PML
early after diagnosis. Despite the association of contrast enhancement and immune reconstitu-
tion inflammatory syndrome with JCV-specific CTL, these cannot be considered as surrogate
markers for the prognostic value of the CTL. Strategies aiming at improving the cellular immune
response may improve the course of PML. Neurology®2009;73:1551–1558
CE ? contrast enhancement; CI ? confidence interval; CTL ? cytotoxic T-lymphocytes; HR ? hazard ratio; IQR ? interquar-
tile range; IRIS ? immune reconstitution inflammatory syndrome; JCV ? JC virus; PBMC ? peripheral blood mononuclear
cells; PML ? progressive multifocal leukoencephalopathy.
Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the brain
which occurs in immunosuppressed individuals and is caused by JC virus (JCV). There is no
cure for PML and survival at 1 year has been reported to be between 38.6% and 56% in HIV?
patients on combination antiretroviral therapy (cART).1Our understanding of the factors
associated with PML survival remains incomplete. patients with PML who harbor in their
blood JCV-specific CD8?cytotoxic T-lymphocytes (CTL) have a better clinical outcome.2
Furthermore, contrast enhancement (CE) of PML lesions on CT or MRI had been associated
with a favorable prognosis.3Whether CE is triggered by components of the immune response is
From the Division of Viral Pathogenesis (A.M., T.T., I.J.K.) and Department of Neurology (I.J.K.), BIDMC, Harvard Medical School, Boston, MA;
Department of Neurology (D.B.C.), Washington University School of Medicine, St. Louis, MO; Department of Infectious Diseases (R.T.G.), MGH,
Harvard Medical School, Boston, MA; Department of Neurology (S.K.), Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard
Medical School, Boston, MA; Department of Neurology (J.R.B.), University of Kentucky College of Medicine, Lexington; Department of Neurology
(D.M.S.), Mount Sinai School of Medicine, New York, NY; Department of Virology (M.P.), National Institute of Infectious Diseases “L.
Spallanzani,” Rome; and Division of Infectious Diseases (A.D.L.), Catholic University, Rome, Italy.
Supported in part by NIH grant R01 NS041198 and 047029, and K24 NS 060950 to I.J.K., and the Harvard Medical School Center for AIDS
Research (CFAR), an NIH-funded program (P30 AI60354).
Disclosure: Author disclosures are provided at the end of the article.
Address correspondence and
reprint requests to Dr. Igor J.
Koralnik, Beth Israel Deaconess
Medical Center, E/CLS-1005,
330 Brookline Ave., Boston, MA
Copyright © 2009 by AAN Enterprises, Inc.
unknown. However, recovery of the immune
system can also lead to an immune reconstitu-
tion inflammatory syndrome (IRIS), which is
occasionally a lethal complication of PML in
cART-treated HIV? patients.4In addition,
although JCV uses 5HT2a receptors to enter
glial cells in vitro,5the effect of 5HT2A recep-
tor blockers on PML outcome is unclear. Fi-
nally, while JCV replication in the CNS is
always detected in PML, JCV can also be
found in the blood of some patients with
PML, but the impact of JC viremia on PML
survival has not been studied in detail. We
therefore sought to correlate immunologic,
radiologic, and virologic factors and the use of
5HT2A blockers with PML survival.
METHODS Study population. Sixty patients with viro-
logic, histologic, or clinical-radiologic diagnosis of PML, in-
cluding 44 HIV? (73%) and 16 HIV? (27%) patients, were
recruited between 2000 and 2007 from inpatient and outpa-
tient populations of the Beth Israel Deaconess Medical Cen-
ter, the Brigham and Women’s Hospital, and Massachusetts
General Hospital (MA), the University of Kentucky (KY),
Washington University (MO), and the Mount Sinai Medical
Center (NY). Twenty HIV? patients without PML (matched
for age and HIV RNA values with HIV? patients with PML)
and 15 healthy individuals served as controls. Blood and
urine samples were collected at baseline and, when possible,
every 3 months. A criterion of inclusion of patients with PML
in this analysis was to have an assay measuring their CTL
against JCV in their blood.
Standard protocol approvals, registrations, and patient
consents. Approval from an ethical standards committee on
human experimentation (institutional or regional) for any exper-
iments using human subjects was received. Written informed
consent was obtained from all patients (or guardians of patients)
participating in the study (consent for research).
Major histocompatibility complex class I typing. Major
histocompatibility complex class I alleles of the study subjects
were determined using standard serologic tissue-typing
Stimulation of peripheral blood mononuclear cells by
CTL epitope peptides of JCV. Peripheral blood mononu-
clear cells (PBMC) were cultured with A*0201-restricted
epitopes JCV VP1p36
jects or pools of peptides spanning the entire JCV VP1 protein
for HLA A0201? subjects. After 10–14 days of culture, cells
were tested for the presence of peptide-specific CTL by tetramer
staining or51Cr release assay as previously described.2
6and VP1p100peptides7for A*0201? sub-
Quantitative PCR detection of JCV DNA. Quantitative
PCR was used to measure JC virus load in the plasma, PBMC,
and urine as previously described.8
Statistical analysis. Categorical variables were compared us-
ing Fisher exact test. The Mann-Whitney U test was used to
calculate differences between the means of continuous variables.
Both tests were 2-tailed and an ? of 0.05 was employed. Survival
from the onset of neurologic symptoms of PML was analyzed by
time to death using the Kaplan-Meier method and differences
among groups were calculated with the log-rank test. Predictors
of death events were examined by univariate and multivariable
Cox regression models. The association between CTL response
and survival was analyzed using CTL as a baseline (first available
sample after diagnosis) or a time-updated variable. Multivariable
models included the CTL response and covariates showing a
significant association with the outcome of interest at univariable
analysis. All analyses were performed using the SPSS software
package (version 13, SPSS Inc., Chicago, IL).
RESULTS Study group characteristics. The median
age of HIV? patients with PML was 44 years (range
20–69), and it was 60 years (range 40–84) for
HIV? patients with PML, 46.5 years (range 32–56)
for HIV?, and 33 years (range 24–45) for healthy
control subjects. HIV? patients with PML were
older than other groups (p ? 0.0001). The median
baseline CD4? cell count was lower in HIV? pa-
tients with PML (223 cells/?L, range 8–957) than in
HIV? patients who did not have PML (347 cells/
?L, range 15–822, p ? 0.03). The median plasma
HIV RNA level was similar in these 2 groups (1.69
log10copies/mL, range 1.69–5.70, vs 2.3 log10cop-
ies/mL, range 1.69–5.70, p ? 0.28).
Characteristics of patients with PML. PML was diag-
nosed by experienced clinicians and defined by typi-
cal clinical and imaging findings and supported by
JCV DNA detection in CSF or biopsy. The charac-
teristics of HIV? and HIV? patients with PML are
summarized in the table. The first sample for the
JCV-specific CTL assay was obtained within 3
months of PML diagnosis in 29 cases, within 1 year
in 39 cases, while the remainder were collected at a
later time point.
Estimated survival according to the HIV serostatus of
patients with PML. Among 29 patients with PML
whose blood sample was collected within 3
months of PML diagnosis, the estimated propor-
tion of surviving at 1 year was 56%. Among these,
the 13 HIV? patients with PML had a 1-year
survival rate of 58% compared to 52% for the 16
patients in the HIV? PML group, a difference
which was not significant (HR for death [HR] ?
1.13, 95% confidence interval (CI) 0.36– 3.57,
p ? 0.83) (figure 1).
Estimated survival according to the presence of JCV-
specific CD8?CTL response detected in peripheral
blood cells. To determine the impact of the cellular
immune response on PML outcome, the 29 HIV?
and HIV? patients with PML who had an assay
measuring JCV-specific CTL in their blood within 3
months of diagnosis were divided according to the
presence (n ? 12) or absence (n ? 17) of these CTL.
There was a trend of better 1 year estimated survival
Neurology 73November 10, 2009
in those with detectable CTL (73%) compared to
those without (46%) a CTL response (HR for death
0.47, 95% CI 0.13–1.75, p ? 0.26) (figure 2A).
When this analysis was repeated in the 39 HIV?
and HIV? patients with PML (including the 29
mentioned above) who had an assay measuring JCV-
specific CTL in their blood within 1 year of diagno-
sis, this trend was accentuated with a 1-year
estimated survival in those 18 patients with detect-
able CTL of 77% compared to 43% in those 21 pa-
tients without a CTL response (HR ? 0.35, 95% CI
0.11–1.09, p ? 0.07) (figure 2B).
Since the CTL assay was performed at various
time intervals after diagnosis, this could have in-
troduced potential bias associated with better sur-
vival. In order to minimize the effect of this bias,
we also analyzed the CTL results as a time-
updated variable (i.e., each CTL test result con-
tributed to survival until the date of the result of
the subsequent assay). Within the whole PML pa-
tient group, those with CTL had a HR for death of
0.59 compared to those without CTL (95% CI
0.16–2.13, p ? 0.42). However, when considering the
HIV? patients with PML only, the detection of a
JCV-specific CTL response as a time-updated
variable showed a trend toward a decreased risk of
death (HR for death 0.32; 95% CI 0.06–1.66,
p ? 0.18). This difference was not present in the
HIV? PML group, where the patients with CTL
had a HR for death of 1.05 compared to the pa-
tients without CTL (95% CI 0.2–5.56, p ?
Association of contrast enhancement of PML lesions
on brain MRI with JCV-specific CTL response and
survival. Among 22 patients with PML who had
MRI and a CTL assay within 3 months of diagno-
sis, 7 (32%) had CE. All but 1 survived more than
1 year. JCV-specific CTL were detected in 5 of 7
(71%), and the presence of CTL response showed
a nonsignificant trend of detecting CE (CTL? vs
CTL?: odds ratio for CE 3.7, 95% CI 0.54–
26.04, p ? 0.18). Patients with PML with CE had
a trend toward a better survival at 1 year (83%)
compared with those without (39%) (CE ? vs
CE –: HR for death 0.24, 95% CI 0.03–1.93, p ?
Association of immune reconstitution inflammatory
syndrome with JCV-specific CTL response and sur-
vival. Among patients tested within 3 months of di-
agnosis, 8/26 (31%) patients with PML, including 7
HIV? and 1 HIV?, developed immune reconstitu-
tion inflammatory syndrome (IRIS) around the time
of evaluation of their cellular immune response. IRIS
was defined as an inflammatory reaction within PML
lesions occurring after initiation of cART in the set-
ting of a rise of CD4?T-cell count and a decrease of
HIV plasma RNA. IRIS was often associated with a
worsening of neurologic symptoms. Of all patients
with IRIS, 3 (37.5%) survived more than a year and
6 (75%) had detectable JCV-specific CTL. The pres-
ence of CTL response was associated with an in-
Table Clinical characteristics of HIV? and
HIV? patients with PML
(n ? 44)
(n ? 16)
Median age, y (range)
44 (20–69)60 (40–84)
Male gender, %
Virologic ? histologic
cART therapy at baseline, %
cART therapy after PML
Treatment for PML, %
Underlying diagnosis for
HIV? patients, n
RA treated with
Low-grade B-cell lymphoma
Chemotherapy for brain
cART ? combination antiretroviral therapy; AML ? acute
myeloid leukemia; CLL ? chronic lymphocytic leukemia;
HCL ? hairy cell leukemia; RA ? rheumatoid arthritis;
CVID ? common variable immunodeficiency.
Neurology 73November 10, 2009
creased likelihood of developing IRIS (CTL? vs
CTL?: odds ratio for IRIS 7.8, 95% CI 1.16–
52.35, p ? 0.03). Patients with PML who did or did
not develop IRIS had similar 1-year survival rate
(54% vs 49%; IRIS? vs IRIS–: HR for death 0.71,
95% CI 0.19–2.64, p ? 0.61) (figure 3A).
When this analysis was repeated in patients
tested within 1 year from diagnosis, patients with
PML who developed IRIS had a 1-year survival
rate of 53% compared to 65% for those who did
not develop IRIS (IRIS? vs IRIS–: HR for death
1.18, 95% CI 0.38–3.63, p ? 0.77) (figure 3B).
Association of CD4 T-cell counts at the time of PML diag-
nosis and survival in HIV? patients with PML. The 16
HIV? patients with PML with available CD4 counts
at the time of PML diagnosis, who were enrolled in the
study within 3 months of diagnosis, were divided ac-
cording to their CD4 count below (n ? 6) or above
(n ? 10) 200 cells/?L. As expected, those with CD4
cell counts below 200 had a trend toward a lower sur-
vival rate at 1 year (48%) compared with those with
CI 0.27–7.38, p ? 0.68) (figure 4A).
patients with PML with available CD4 counts at the
time of PML diagnosis divided according to their CD4
count below (n ? 26) or above (n ? 17) 200 cells/?L,
the difference between the 2 groups became significant.
Those with CD4 cell count below 200 had a lower sur-
vival rate at 1 year (58%) compared with those with
higher CD4 cell count (88.5%; crude HR for death
4.46, 95% CI 1.29–5.33, p ? 0.02) (figure 4B). In a
multivariable model, after adjusting for the presence of
JCV-specific CTL response, the CD4 cell count was
still as strong a predictor of survival (adjusted HR for
death 4.16, 95% CI 1.16–14.85, p ? 0.03).
Estimated survival of patients with PML according to treat-
ment with a 5HT2a receptor blocker after PML diagnosis.
Fourteen patients with PML (7 HIV? and 7 HIV?)
were treated with 5HT2A receptor blockers mirtazap-
Figure 1 EstimatedsurvivalaccordingtotheHIVserostatusofpatientswith
Continuous lines denote HIV? serostatus; dashed lines HIV? serostatus. Differences
among groups were calculated with the log-rank test.
Figure 2Estimated survival according to the detection of JCV-specific CD8?cytotoxic T-lymphocytes (CTL) response in blood
(A) Continuous lines denote the presence and dashed lines the absence of JCV-specific CTL response measured by tetrameric HLA-A*0201/JCV VP1p36
or VP1p100complexes for A*0201?patients6,7or51Cr release assay for HLA A*0201?subjects.2(B) Continuous lines denote the presence and
dashed lines the absence of JCV-specific CTL response. Differences among groups were calculated with the log-rank test. PML ? progressive
Neurology 73 November 10, 2009
ine (Remeron) 15–45 mg at bed time within 1 year
after PML diagnosis and did not discontinue the medi-
cation until they died or until the end of the observation
period. This group was compared with 11 patients with
other treatment except cART, matched for CD4 count
and HIV viral load. The 1-year survival rate was 62% in
patients treated with 5HT2A receptor blockers vs 45% in
untreated patients, a difference which was not significant
(5HT2A? vs 5HT2A?: HR for death 0.63, 95% CI
Comparison of JCV viruria and viremia in patients
with PML and control subjects. There was no associa-
tion between the presence or absence of JCV DNA
in the blood or urine of patients with PML and sur-
vival. JCV DNA was detected in the urine of 12/25
(48%) patients with PML, 11/18 (61%) HIV? pa-
tients, and 4/15 (27%) healthy individuals. There
was no difference between JC viruria in patients with
PML and the 2 control groups, but JC viruria was
more frequent in HIV? patients (61%) compared to
healthy individuals (27%; p ? 0.008). JCV DNA
Figure 3Estimated survival of progressive multifocal leukoencephalopathy (PML) according to the occurrence of immune reconstitution
inflammatory syndrome (IRIS)
(A) Continuous lines denote the occurrence of IRIS and dashed lines indicate the absence of IRIS in patients with PML. (B) Continuous lines denote the
occurrence of IRIS and dashed lines the absence of IRIS in patients with PML. Differences among groups were calculated with the log-rank test. CTL ?
Figure 4Estimated survival according to the presence of CD4 T-cell count <200/?L or >200/?L at the time of progressive multifocal
leukoencephalopathy (PML) diagnosis in HIV? patients with PML
(A) Continuous lines denote CD4 count ?200/?L and dashed lines CD4 count ?200/?L at baseline. (B) Continuous lines denote CD4 count ?200/?L while
dashed lines CD4 count ?200/?L at baseline. Differences among groups were calculated with the log-rank test. CTL ? cytotoxic T-lymphocytes.
Neurology 73November 10, 2009
was not detectable in the blood (plasma or PBMC) of
healthy subjects but was detected in 33 of 59 (56%)
PML and 6 of 20 (30%) HIV? control subjects.
JCV DNA was more frequent in the plasma of pa-
tients with PML (23/59, 39%) than HIV? control
subjects (2/20, 10%; p ? 0.024). There was a trend
for a higher frequency of JCV DNA detection in
PBMC as compared with plasma in both groups, in-
cluding 20/37 (54%) patients with PML and 6/20
(30%) HIV? controls. There was no difference be-
tween median JC viral load in blood from patients
with PML (PBMC 1.60 log10copies/?g of DNA,
interquartile range [IQR] 1.13–2.00; plasma 2.98
log10copies/mL, IQR 2.80–3.20) and HIV? con-
trols (PBMC 1.26 log10copies/?g of DNA, IQR
1.08–1.71; plasma 3.20 log10copies/mL, IQR
2.80–3.60). The median JC viral load in urine was
similar among patients with PML (3.68 log10copies/
mL, IQR 3.42–6.02), HIV? (4.97 log10copies/mL,
IQR 4.30–7.40), and healthy control subjects (4.53
log10copies/mL, IQR 3.05–5.93).
DISCUSSION The 52% 1-year survival in our
HIV? PML patient population is comparable with
that reported in previous studies.9-11However, the
58% 1-year survival in our HIV? PML group is
higher than previously reported. In one review,12
80% of patients died within 9 months. In patients
with PML with underlying lymphoproliferative dis-
orders,13median survival was 3 months and only 5
(12%) of 42 patients were reported to have a survival
exceeding 10 months. The better survival in our pop-
ulation may result from selection bias. In part, the
requirement of our patients to give consent for this
study may have excluded the most neurologically ad-
vanced cases. Also, HIV? patients with PML are a
very heterogeneous population and the clinical out-
come may vary greatly based on the severity of their
Our results are consistent with and expand
those from previous studies on the role of the cel-
lular immune response in PML outcome,2,6since
the detection of JCV-specific CTL in blood within
3 months from diagnosis was associated with a
trend toward increased survival. However, when
the CTL was analyzed as a time-dependent vari-
able, this trend was present in HIV? individuals
only. These results suggest that the beneficial ef-
fect of the CTL is predominant in individuals
whose immunosuppression may be reversible such
as in cART-treated HIV? patients.
In a small study, CE of PML lesions on MRI was
associated with a better outcome.3Our results sug-
gest that the presence of JCV-specific CTL in PML
lesions may trigger local inflammation leading to the
breakdown of the blood–brain barrier and CE.
Therefore, the previously detected beneficial effect of
CE on PML survival may be due in part to the pres-
ence of the CTL. Whether CE may be used as a
surrogate marker for the presence of CTL responses
deserves further study.
IRIS was also associated with JCV-specific CTL
but not with survival. This is consistent with the
pathologic descriptions of PML IRIS which feature
abundant CD8? cells in the inflammatory response
in the brain.14The fact that IRIS can be a lethal
complication of PML had also been reported by oth-
ers.14Therefore, other components of the immune
response may be implicated in the pathogenesis of
IRIS in patients with PML. Of note, although IRIS
is commonly thought to be associated with CE of
PML lesions on MRI, a recent retrospective analysis
indicated that such features occur only in 56.7% of
PML/IRIS cases.15However, whether all of these
cases truly had IRIS has been questioned.16It is pos-
sible that enhancement is transient in IRIS and may
not be present at the time of the MRI. Conversely,
CE is often subtle and may also occur independently
from the full-blown phenomenon of IRIS.
Consistent with earlier reports, higher baseline
CD4 cell count was associated with better survival
when considering the entire group of HIV? patients
with PML.10,17,18However, CD4 cell count showed
only a weak trend among patients tested within 3
months of PML diagnosis. It is therefore possible
that immediately after the development of PML, the
presence of memory CTL that can be activated
against JCV, and not the absolute number of CD4?
T cells, is the most important predictor of survival of
HIV? patients with PML.
Since JCV uses 5HT2A receptors to enter glial
cells, 5HT2A receptor blockers have been given em-
pirically to patients with PML with variable suc-
cess.19,20Such medications may prevent entry of JCV
in uninfected glial cells in the brain, but they are not
expected to impede viral replication. Likewise, our
results do not suggest that 5HT2A receptor blockers
confer an advantage in PML survival. However, the
number of subjects in the current study is small, and
a randomized controlled trial is necessary to defini-
tively assess the role of these drugs in the manage-
ment of PML.
The presence of JC viremia or viruria at diagnosis
did not have a significant impact on PML survival, as
has been previously reported.21JCV excretion in the
urine was not correlated with the immunologic status
of the subjects. JCV was not detected in the blood of
healthy subjects and was higher in plasma of patients
with PML vs HIV? controls.
Neurology 73November 10, 2009
There are several limitations to this study. Since
patients were required to give consent, some of the
more advanced cases could not be enrolled and there-
fore, our population is not entirely representative of
the general PML population. In addition, PML is a
rare disease and is often mistaken for a stroke or brain
tumor, especially in HIV? patients, which delays
the diagnosis. Therefore, only half of our patients
with PML were tested within 3 months from diagno-
sis. Nevertheless, the trend toward improved survival
associated with JCV-specific CTL was present in
those study subjects enrolled within 3 months of di-
agnosis, which was accentuated in the larger group of
patients tested within 1 year. We had previously
shown in a prospective study that the CTL response
to JCV is stable in PML survivors for more than a
year from disease onset.2
Autologous dendritic cells can efficiently expand
JCV-specific T-cell responses in vitro.22Such meth-
ods may constitute a promising approach for PML
Statistical analysis was conducted by Dr. Andrea De Luca and Dr. Mattia
Dr. Marzocchetti reports no disclosures. T. Tompkins holds stock options
in BioMarin Pharmaceutical, Inc. Dr. Clifford serves/has served on scien-
tific advisory boards for Biogen Idec, Elan Corporation, Roche, Forest
Laboratories, Inc., Genentech, Inc., GlaxoSmithKline, Millennium Phar-
maceuticals, Inc., Schering-Plough Corp., Bristol-Meyers Squibb, and
Genzyme Corporation; received speaker honorarium and funding for
travel from GlaxoSmithKline; has received research support from Pfizer
Inc., Schering-Plough Corp., Bavarian Nordic, NeurogesX, GlaxoSmith-
Kline, Tibotec Therapeutics, Boehringer Ingelheim, and Gilead Sciences,
Inc.; and receives research support from the NIH [UO1 NS32228 (PI),
UO1 AI69495 (PI), NIMH 22005 CHARTER Project (Site PI), NIDA
RO3 DA022137 (Co-I), NIMH MH058076 (Site PI), and R21 3857-
53187 (PI)]. Dr. Gandhi serves on the editorial board of Journal Watch
Infectious Diseases, received speaker honorarium from GlaxoSmithKline,
received educational support from Gilead Sciences, Inc. and Abbott, and
receives research support from Tibotec Therapeutics. Dr. Kesari serves on
scientific advisory boards for Bristol-Meyers Squibb and Genentech, Inc.;
serves on editorial boards for the Journal of Neuro-Oncology and the Inter-
national Journal of Biomedical Nanoscience and Nanotechnology; receives
royalties from publishing Cancer Neurology in Clinical Practice (Humana,
2008); served on a speakers’ bureau for Enzon Pharmaceuticals, Inc.; and
receives research support from GE Healthcare, the NIH [K08CA124804
(PI)], and the Sontag Foundation. Dr. Berger serves/has served on scien-
tific advisory boards for Millennium Pharmaceuticals, Inc., Bayer Scher-
ing Pharma, Merck Serono, Genentech, Inc., Astellas Pharma Inc., and
Asphelia Pharmaceuticals; has received speaker honoraria from EMD Se-
rono, Inc., Teva Pharmaceutical Industries Ltd., and Bayer Schering
Pharma; and receives research support from Bayer Schering Pharma,
EMD Serono, Inc., Biogen Idec, Sanofi-Aventis, Genentech Inc., and
UCB. Dr. Simpson has served on scientific advisory boards for Boehringer
Ingelheim, Cephalon, Inc., Pfizer Inc., Endo Pharmaceuticals, Glaxo-
SmithKline, Merz Pharmaceuticals, LLC, MEDA Pharmaceuticals Inc.,
Alpharma Pharmaceuticals LLC, and Biogen Idec; serves on the editorial
boards of the Clinical Journal of Pain and AIDS Patient Care; has served as
a consultant to NeurogesX, Eli Lilly and Company, Regeneron Pharma-
ceuticals Inc., GlaxoSmithKline, Allergan, Inc., Merz Pharmaceuticals,
LLC, and Torrey Pines Institute for Molecular Studies; served on speak-
ers’ bureaus for Eli Lilly and Company and GlaxoSmithKline; receives
research support from NeurogesX, Pfizer Inc., and Allergan, Inc.; and
receives research support from the NIH [NINDS R24 MH59724, UO1
NS32228 (Co-I) and NIMH 00-AI-0005 (Co-I)]. Dr. Prosperi reports no
disclosures. Dr. De Luca has served on scientific advisory boards for
Monogram Biosciences, Janssen-Cilag, Tibotec Therapeutics, Gilead Sci-
ences, Inc., and Siemens Healthcare Diagnostics; serves on the editorial
board of Reviews in Antiviral Therapy; and has received speaker honoraria
from GlaxoSmithKline, Abbott, and Boehringer Ingelheim. Dr. Koralnik
serves/has served on scientific advisory boards for Roche, GlaxoSmith
Kline, and Merck Serono; serves on the editorial board of the Journal of
NeuroVirology; receives royalties from publishing “Topics on the manage-
ment of HIV and CNS mass lesions and on PML” (UpToDate, 2002); has
served as a consultant to Bristol-Myers Squibb, Ono Pharmaceutical Co.
Ltd., Merck Serono, Roche, GlaxoSmithKline, Alnylam Pharmaceuticals,
and Antisense Pharma GmbH; and receives research support from Biogen
Idec and the NIH [R01 NS 041198 (PI), R01 NS 047029 (PI), and K24
NS 060950 (PI)].
Received March 31, 2009. Accepted in final form July 30, 2009.
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Earn Practice Management CME with AAN Audio
The Academy is helping members take some of the confusion out of coding with a four-part series.
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Neurology 73 November 10, 2009