TSP/HAM during HIV/HTLV-1 Coinfection • CID 2005:41 (15 September) • e57
M A J O R A R T I C L E
Tropical Spastic Paraparesis/Human T Leukemia
Virus Type 1–Associated Myelopathy in HIV
Type 1–Coinfected Patients
Mark A. Beilke,1,2Shanker Japa,1,2Christiane Moeller-Hadi,1and Sheryl Martin-Schild1
1Tulane University Health Sciences Center and
New Orleans, Louisiana
2Charity/Tulane/Louisiana State University General Clinical Research Center,
(TSP/HAM) is rarely reported in the United States. The causative agents of TSP/HAM are HTLV-1 and, possibly,
its cosmopolitan variant, human T leukemia virus type 2 (HTLV-2). Among HTLV-1– or HTLV-2–monoinfected
individuals, the estimated lifetime risk for development of TSP/HAM is !2%. However, it has been suggested that
HIV/HTLV coinfection may increase the risk for development of TSP/HAM.
A total of 2239 human immunodeficiency virus (HIV)–infected patients were tested for HTLV-1
and HTLV-2 infection at the New Orleans Outpatient Clinic (Louisiana) during the period 1991–1998. HTLV-1–
infected patients with suspected myelopathy were referred for additional evaluation.
Four cases of TSP/HAM (9.7%) were identified among 41 individuals with Western blot–confirmed
HTLV-1 infection. The diagnosis was confirmed with use of molecular diagnostic assays and viral isolation. No
TSP/HAM cases were identified among 65 patients with HIV–HTLV-2 coinfection. An additional patient with
HIV–HTLV-1 coinfection also received a diagnosis of TSP/HAM at the New Orleans Veteran’s Affairs HIV Out-
patient Clinic (Louisiana). All patients had normal CD4+T cell counts at the time of diagnosis.
Given the high rates of HIV-HTLV coinfection in the United States, a heightened suspicion for
TSP/HAM should be considered in HIV-infected patients who present with normal CD4+T cell counts and
myelopathy in the absence of other acquired immunodeficiency syndrome–defining conditions.
Tropical spastic paraparesis/human T leukemia virus type 1 (HTLV-1)–associated myelopathy
In 1985, it was proposed that human T leukemia virus
(HTLV) type 1 (HTLV-1) was the etiologic agent of
tropical spastic paraparesis/HTLV-1–associated myelo-
pathy (TSP/HAM) on the basis of evidence accumu-
lated in HTLV-1 seroprevalence studies from Marti-
nique, Trinidad, Jamaica, Japan, and Colombia [1–4].
The causative role of HTLV-1 has been validated
through several lines of evidence: (1) the isolation of
HTLV-1 from CSF specimens obtained from patients
with TSP/HAM , (2) intrathecal synthesis of HTLV-
1 antibodies , (3) detection of viral genome in in-
volved tissues [7, 8], (4) oligoclonal expansion of
Received 26 April 2005; accepted 30 May 2005; electronically published 29
Reprints or correspondence: Dr. Mark A. Beilke, Tulane University Health
Sciences Center, Section of Infectious Diseases, SL-87, 1430 Tulane Ave., New
Orleans, LA 70112 (email@example.com).
Clinical Infectious Diseases2005;41:e57–63
? 2005 by the Infectious Diseases Society of America. All rights reserved.
HTLV-1–specific cytotoxic T lymphocytes in the CSF
, and (5) development of TSP/HAM after transfu-
sion of blood from an HTLV-1–infected donor to an
HTLV-1–seronegative recipient . It has also been
suggested that the antigenically related virusHTLVtype
2 (HTLV-2) also causes TSP/HAM, although less de-
finitive evidence of a causal role exists [11, 12].
TSP/HAM is rarely diagnosed in the United States,
given the low prevalence of HTLV-1 among low-risk
individuals . Among American Red Cross blood
donors, the seroprevalence of HTLV-1/HTLV-2 anti-
bodies is only 0.03%, and TSP/HAM is estimated to
develop in only 1%–2% of HTLV-1–infected individ-
uals over their lifetimes [13, 14]. Moreover, testing for
HTLV-1 infection outside of blood donation situations
is rarely conducted in the United States, except in high-
risk populations. However, among HIV-infected indi-
viduals in large metropolitan areas, the prevalence of
coinfection with either HTLV-1 or HTLV-2 may ap-
proach 5%–10% [15–17].
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e58 • CID 2005:41 (15 September) • Beilke et al.
In this article, we describe 5 HIV–HTLV-1–coinfected Af-
rican American men who presentedwithTSP/HAM,4ofwhom
presented with myelopathy in the absence of any other AIDS-
defining conditions. Molecular diagnostic assays and viral iso-
lation studies confirmed HTLV-1 infection in blood and CSF
samples. Remarkably, all 5 patients had normal or elevated
CD4+T cell counts at the time of TSP/HAM diagnosis.
All procedures were conducted in accordance with the ethics
standards of the Tulane University Health Sciences Center In-
stitutional Review Committee on the Use of Human Subjects
(New Orleans, LA) and with the Helsinki Declaration of 1975,
as revised in 1983.
A previously noted high seropreva-
lence of HTLV-1/HTLV-2 infection in New Orleans, Louisiana
[16, 18], prompted routine testing for HTLV-1/HTLV-2 infec-
tion in HIV-infected patients attending the Medical Center of
Louisiana HIV OutpatientClinic beginninginlate1991.Testing
for HTLV-1/HTLV-2 infection at the New Orleans Veteran’s
Affairs HIV Outpatient Clinic was subsequently initiated in
2001. Screening for HTLV-1/HTLV-2 antibodies wasconducted
in the hospital laboratories with use of an EIA (Abbott Lab-
oratories). Western blot confirmatory tests (Zeptometrix) were
performed to confirm and differentiate HTLV-1 infection and
Case finding and neurologic evaluations.
clinic’s database, we identified all HTLV-1/HTLV-2–coinfected
patients with an International Classification of Diseases, Ninth
Revision, code for neuropathy, myelopathy, or peripheral neu-
ropathy. Their medical records were then reviewed.Forpatients
identified with a diagnosis of myelopathy, detailed neurologic
examinations were performed in the infectious diseases and
neurology subspeciality clinics. These included examination of
cranial nerves; motor strength; reflexes; sensory, vibratory, and
position sense; and mini-mental status examinations. Radiol-
ogic evaluations included either CT and/or MRI of the brain
and spinal cord with contrast.
Routine laboratory evaluations
included the following: HIV-1 tests with Western blot confir-
matory analysis, measurement of T cell subsets (including ab-
solute CD4+and CD8+T cell counts and CD4+and CD8+T
cell percentages), determination of plasma HIV-1 loads, com-
plete blood cell counts, complete metabolic panels (including
determination of creatine phosphokinase [CPK] level), sero-
logic tests for syphilis, determination of vitamin B12 and folate
levels, viral hepatitis panels, Toxoplasma serologic tests, and
tuberculin skin tests. Specific laboratory evaluations for HTLV-
1 included separation of PBMCs from whole-blood samples
for HTLV-1 isolation and/or nucleic acid isolation and HTLV-
1 PCR analysis, as well as analysis of CSF specimens for HTLV-
With use of the
1 antibody determination and/or HTLV-1 PCR. Detection of
HTLV-1 in PBMC cultures was conducted as described else-
where . For detection of HTLV-1 proviral DNA in CSF
specimens, 1 mL of CSF was centrifuged, and the cell pellet
was suspended in 50 mL of DNA lysis buffer and was tested by
PCR, as described elsewhere . Detection of HTLV-1/HTLV-
2 tax/rex mRNA gene products was used as anadditionalmeans
to measure active viral transcription in uncultured PBMC sam-
During the period of 1991–1998, a total of 2339 HIV-infected
patients at the New Orleans HIV Outpatient Clinic were tested
for HTLV-1/HTLV-2 coinfection. Among those tested, 172
tested positive for HTLV-1/HTLV-2 infection, representing a
seroprevalence of 7.4%. One hundred fifteen serum samples
were available for confirmatory Western blot testing, of which
41 (35.7%) were HTLV-1 reactive, 65 (56.5%) were HTLV-2
reactive, 2 (1.7%) had combined HTLV-1 and HTLV-2 reac-
tivity, and 7 (6.1%) had indeterminate results.
Chart Reviews and Case Reports
Using the clinic’s database, 44 of the dually infected patients
had documented diagnoses of peripheral neuropathy (32 pa-
tients) or myelopathy (4 patients). A fifth patient was identified
by the authors at the Veteran’s Affairs HIV Outpatient Clinic.
All 5 patients were HIV–HTLV-1 seropositive. No patientswith
HIV-HTLV-2 coinfection and myelopathy were found. A sum-
mary of the clinical and laboratory features of each patient is
shown in table 1, with a narrative summary below.
the hospital in 1991 with a 1-year history of bilateral lower
extremity weakness and spasticity with urinary frequency and
urgency. Bilateral lower extremity clonus and Babinski reflexes
were demonstrated. Grade 3/5 proximal motor weakness was
also noted; 5 years earlier, the patient had received a diagnosis
of biopsy-proven polymyositis (previously reported by Wiley
et al. ), for which he was given corticosteroid therapy.
Steroid therapy was associated with the development of extra-
pulmonary tuberculosis in 1986, at which time the patient’s
CD4+T cell count transiently decreased to !200 cells/mm3.
initiated at that time, and the patient’s CD4+T cell count then
By the time of the patient’s presentation in 1991, his CD4+
and CD8+T cell counts were 1163 and 1677 cells/mm3, re-
spectively, and his serum CPK level was 253 U/L. MRI of the
head and thoracic and lumbar spinal cord revealed scattered,
A 27-year-old African American man presented to
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Characteristics of patients who are coinfected with HIV and human T leukemia virus type 1 (HTLV-1) and who have tropical spastic paraparesis/HTLV-
associated myelopathy, New Orleans, Louisiana.
Year of diagnosis
Leg weakness, urinary urgency
Leg weakness, lumbar
pain, urinary urgency
Leg weakness, urinary urgency,
Leg weakness, urinary
Loss of balance, erectile dysfunc-
tion, urinary urgency
Findings of neurologic
Hyperreflexia, Babinski, clonus,
gait ataxia, proximal muscle
Hyperreflexia, Babinski, gait
ataxia, proximal muscle
clonus, proximal mus-cle weakness
Hyperreflexia, gait ataxia
Uveitis, myositis, pneumonitis
White matter lesions in spinal
Mild thoracic cord atrophy
Brain and spinal cord were within
Mild thoracic cord atrophy
Diffuse white matter lesions in
brain, thoracic cord atrophy
CD4+T cell count, cells/mm3
CD8+T cell count, cells/mm3
HIV load, copies/mL
Results of CSF tests
HTLV-1 detected by Western
blot and PCR; lymphocytic pleocytosis detected
Test was refused
HTLV-1 detected by PCR; lym-
HTLV-1 detected by PCR;
HTLV-1 detected by Western blot
and PCR; lymphocytic pleocy-
tosis and oligcoclonal bands
detected; IgG synthesis rate,142 mg/day (nl ! 10 mg)
Results of PBMC cultures
Results of HTLV-1 tax/rex
mRNA detection in
PBMCs by RT-PCR
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e60 • CID 2005:41 (15 September) • Beilke et al.
focal white-matter lesions. CSF examination revealed a modest
elevation in the protein level and lymphocytic pleocytosis. The
results of HTLV-1 isolation from PBMC cultures were positive,
and HTLV-1 tax/rex mRNA was detected by RT-PCR. The CSF
specimen was found to be strongly reactive for antibodies to
HTLV-1 by Western blot analysis (dilution, 1:500). CSF spec-
imens were processed to obtain DNA for HTLV-1 PCR, the
results of which were also positive. The patient subsequently
died in 1993 of a massive pulmonary embolism, at which time
his CD4+T cell count was 1089 cells/mm3. A full autopsy was
In addition to complete occlusion of the right pulmonary
artery with hemorrhagic infarction, extensive perivascularlym-
phocytic infiltration was noted in the heart,lungs,liver,trachea,
kidney, colon, skeletal muscle, pancreas, and leptomeninges.In
addition, extensive perivascular lymphocytic infiltration was
present in both the brain and spinal cord, and there was evi-
dence of lateral cortical spinal tract degenerationatthethoracic
level. The brain also demonstrated multifocal cerebral white-
matter degeneration and reactive microgliosis.
A 42-year-old African American man presented
to the hospital in 1992 with a 6-month history of progressive
lower extremity weakness and urinary frequency. Neurologic
evaluation revealed bilateral lower extremity clonus and Ba-
binski signs. Motor strength was diminished in both lower
extremities, and sensory examination findings were withinnor-
mal limits. Findings of CT of the spinal cord were normal
except for mild atrophy. The patient refused to undergolumbar
puncture. CD4+and CD8+T cell counts were 1184 and 1908
cells/mm3, respectively. The CPK level was 914 U/L.Thepatient
was given zidovudine, as well as ditropan for his urinary com-
plaints. HTLV-1 was isolated from PBMC cultures, and HTLV-
1 tax/rex mRNA was detected in PBMCs by RT-PCR.
Neurologic examinations revealed that the patient’s condi-
tion remained stable, until approximately 2002, when his lower
extremity weakness began to progress and he began to fallwhen
walking. As of March 2005, the patient has required the use of
a wheelchair, except short distances, which he can ambulate
with a cane. As of March 2005, his CD4+T cell count was 2307
cells/mm3while he was not receiving any antiretroviraltherapy.
A 42-year-old African American man presented
to the hospital in 1997 with a ∼1- year history of progressive
lower extremity weakness and numbness. Bilateral Babinski
signs were noted, and mild cognitive impairment was also
noted. The findings of CT and MRI of the brain with contrast
were interpreted to be normal. His CD4+and CD8+T cell
counts were 890 and 1743 cells/mm3, respectively. Six months
after presentation, the patient began complaining of urinary
urgency and frequency. Examinationof CSFspecimensrevealed
an increased protein level and modest lymphocytic pleocytosis.
HTLV-1 proviral DNA was detected in CSF specimens, PBMC
cultures were positive for HTLV-1, and HTLV-1 tax/rex mRNA
was detected in PBMC specimens by RT-PCR. PCR of CSF was
negative for herpes simplex virus and JC polyoma virus. By
November, 1998, the patient became fully wheelchair bound.
MRI with contrast of thoracic and cervical spinal cord revealed
increased white matter disease and atrophy. The patient died
in 1999 of unrelated causes, and an autopsy was notperformed.
A 38-year-old male African American prisoner
presented to the clinic in 1998 complaining of a ∼6-month
history of mild lower extremity weakness and urinary fre-
quency. Physical examination revealed bilaterallowerextremity
hyperreflexia and 4-beat clonus of the right ankle. Bilateral
Babinski reflexes were present. CD4+and CD8+T cell counts
were 1141 and 1005 cells/mm3, respectively. MRI revealed mild
thoracic cord atrophy. PBMC cultures were positive for HTLV-
1, and PCR of blood and CSF specimens was also positive for
HTLV-1. The patient was also notedto havemediastinallymph-
adenopathy and interstitial pulmonary infiltrates, which were
originally thought to be sarcoid. No further diagnostic evalu-
ation was performed.
A 51-year-old male military veteran withknown
HIV infection presented to the clinic in 2002 requesting neu-
rologic evaluation for unsteady gait. He also requested evalu-
ations for urinary urgency, urinary frequency, and erectile dys-
function. He was noted by his primary care physician to have
a clumsy tandem gait. Initial evaluation in a neurology clinic
revealed gait ataxia and a positive Romberg sign. There was
reduced vibratory sense in the feet. In 2003, his problems with
walking had stabilized, but he believed that his legs weregetting
weaker, and his vibratory sensory loss was more prominent on
examination. By 2004, he complained of worsening urinary
urgency and progression of erectile dysfunction. He had brisk
suprapatellar reflexes, and a unilateralBabinskireflexwasnoted
in 2005. The findings of neuroimaging studies of the brain and
spinal cord were within normal limits. The CD4+and CD8+T
cell counts were 1317 and 2280 cells/mm3, respectively. CSF
studies revealed a CSF ratio of IgG to albuminof140%(normal
value, !25%) with an IgG index of 2.65 (normal, !0.65). Oli-
goclonal bands were present, and a CSF western blot was
strongly reactive (dilution, 1:100).
TSP/HAM is characterized as a slow-onset disorder, with pre-
dominant findings including lower lumbar pain, spastic par-
aparesis of the lower extremities with ankle clonus and positive
Babinski reflex, variable impairment of superficial and deep
sensation, and interference of bladder and bowel function [23–
25]. Some hyperreflexia of the upper extremities may occur,
and ataxia occurs less frequently. In areas where HTLV-1 is
endemic, there is a preponderance of female patients, and the
most frequent age at onset is 35–50 years. There appears to be
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TSP/HAM during HIV/HTLV-1 Coinfection • CID 2005:41 (15 September) • e61
HAM) among HIV-HTLV–coinfected US residents.
Summary of reports of tropical spastic paraparesis/human T leukemia virus (HTLV)–associated myelopathy (TSP/
T cell count,
TSP/HAM, T cell leukemia
TSP/HAM, T cell leukemia,
TSP/HAM, lymphoid pneumonitis
1 27 African AmericanM LouisianaType 1 TSP/HAM, uveitis, polymyositis,
TSP/HAM, uveitis, lymphoid
5 51 African AmericanM Louisiana Type 11317
aDetermined by serologic testing.
some geographic variability in terms of other clinical signs,
which may include visual disturbances, cranial nerve deficits,
function . Virally mediated autoimmune injury involving
other systems may be frequently observed in conjunction with
TSP/HAM, including polymyositis,Sjo ¨grensyndrome,arthrop-
athy, uveitis, interstitial pneumonitis, and thyroiditis [27–32].
Adult T cell leukemia caused by HTLV-1 has been infrequently
diagnosed concomitantly with TSP/HAM [33, 34]. These re-
lated conditions were seen in some of our patients, including
3 patients with myositis or myopathy, 3 with uveitis, and 2
with pulmonary involvement.
TSP/HAM is rarely diagnosed outside of regions where
HTLV-1 is endemic. The largest published study from the
United States included a total of 63 patients with TSP/HAM
in Florida ; however, the majority of the patients were
originally residents of Haiti,Jamaica,orotherCaribbeanislands
or were sex partners of individuals from these regions. Two of
these patients were coinfected with HIV-1. In a second, smaller
study, 25 patients were described, 19 of whom were black, and
12 of whom were born in the United States . All patients
but 2 became symptomatic while living in the United States.
Additional case reports include 3 Texas-born patients , a
resident of California , and a blood transfusion recipient
in New York (the infected donor was originally from the Ca-
ribbean) . Murphy et al.  reported 4 cases of TSP/HAM
among 166 HTLV-1–infected blood donors (2.4%) and 1 case
among 404 HTLV-2–infected donors (0.2%). The authors are
personally aware of at least 5 Louisiana residents (who are
uninfected with HIV-1) with TSP/HAM who have presented
in neurology clinics in Tulane during the past 8 years (data not
It has previously been suggested that HIV-1–HTLV-1 coin-
fection may increase the risk for development of TSP/HAM,
but this has not been studied in any systematic way . The
published lifetime risk for the development of TSP/HAM
among HTLV-1 monoinfected individuals is 2%; our rate
(9.7%) for 41 HIV–HTLV-1–coinfected patients was signifi-
cantly higher ( ). We did not diagnose TSP/HAM in anyP ! .04
patients with HIV–HTLV-2 coinfection, although high rates of
peripheral neuropathy were noted among both HTLV-1– and
HTLV-2–coinfected patients. However, whether HTLV-1 or
HTLV-2 contributed to the development of peripheral neurop-
athy among these patients is uncertain.
A search of the Ovid database for publications from the
period of 1985–2005 yielded only 8 case reports of TSP/HAM
among HIV-HTLV–coinfected individuals in the United States
[35, 40–42]. The present report brings the total to 13. The
reports are summarized in table 2. Several possible reasons for
underreporting exist. First, HTLV-1/HTLV-2 serologic testing
is not routinely performed in most HIV clinical settings, and
HIV care providers may not be familiar with the clinical sig-
nificance of HTLV-1/HTLV-2 infections. Moreover, inadequate
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e62 • CID 2005:41 (15 September) • Beilke et al.
may result in underrecognition of early myelopathy. Finally, in
the era preceding HAART, patients may not have lived for a
sufficient period for the disorder to develop, and these patients
were often affected with other, more serious and life-threat-
ening opportunistic conditions.
The 4 patients identified in this clinic, as well as the addi-
tional fifth patient from the Veteran’s Affairs HIV Outpatient
Clinic, all presented with fairly typical upper motor neuron
signs and symptoms of TSP/HAM. Although coexisting poly-
myositis could complicate the neurologicexaminationfindings,
this would not explain the prominent upper motor neuron
findings seen in these patients. Additional features included
normal or elevated CD4+T cell counts in the absence of receipt
of antiretroviral therapy, and (with the exception of patient 1,
who was also being treated with steroids) the absence of other
opportunistic infections or malignancies. The indolent neu-
rologic progression seen in patient 2, who has been observed
at the clinic for 13 years, in the absence of other HIV-related
clinical complications, is consistent with TSP/HAM among
HTLV-1–monoinfected individuals. Patient 3, however, had an
unexpectedly more rapid progression of his condition associ-
ated with some cognitive impairment.
In contrast to the presentations observed in our small series,
the vacuolar myelopathy associated with HIV infection of the
spinal cord typically presents in individuals with advanced im-
munodeficiency and often in conjunction with low CD4+T cell
counts, dementia, and opportunistic infections .
An increased risk for TSP/HAM during HIV–HTLV-1 coin-
fection may be the result of up-regulated HTLV-1 expression
during HIV-HTLV coinfection. We have previously reported
that both HIV–HTLV-1 coinfection and HIV–HTLV-2 coin-
fection are associated with higher levels of HTLV-1/HTLV-2
tax/rex mRNA expression in PBMCs, compared with samples
obtained from HTLV-1–HTLV-2–monoinfected individuals
. HIV–HTLV coinfection did not appear to result in a
change in the HIV load, compared with the HIV load incontrol
subjects. Also, it was observed that higher levels of HTLV-1/
HTLV-2 proviral burden in PBMCs are associated with higher
CD4+T cell counts .
Little information is available concerning the benefit of
HAART for treatment of TSP/HAM. Efforts to treat of TSP/
HAM and HTLV-1–associated autoimmune diseases,usingvar-
ious antiretroviral compounds has been disappointing [45, 46].
Corticosteroids and immunosuppressive agents, such as aza-
thioprine, may ameliorate disease progression but are unsuit-
able for long-term use because of adverse effects. Immuno-
therapy with IFN-a has produced minimal to moderateresults,
in the involved tissue . Given these data, we cannot rec-
ommend early treatment of patients with HIV–HTLV-1 coin-
fection who present with TSP/HAM.
In conclusion, our findings suggest that HIV–HTLV-1 coin-
fection results in an increased risk of TSP/HAM. Clinicians
should consider testing for HTLV-1/HTLV-2 infection in pa-
tients who present with myelopathy in the absence of AIDS or
of other causes for neurologic complications. The role of
HAART in treatment of TSP/HAM remains controversial.
(R01-AI-79744; to M.A.B.) and the National Center for ResearchResources
(5 M01-RR-04096-10, Charity/Tulane/LSU General Clinical Research Cen-
ter; to M.B. and S.J.)
Potential conflicts of interest.
All authors: no conflicts.
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