HTLV-1 associated myelopathy/tropical spastic paraparesis HAM/TSP:Eiji Matsuura, MD, PhDa,⁎ , Satoshi Nozuma, MD, PhDa, Yuichi Tashiro, MDa, Ryuji Kubota, MD, PhDb, a Department of Neuro
Trang 1HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP):
Eiji Matsuura, MD, PhDa,⁎ , Satoshi Nozuma, MD, PhDa, Yuichi Tashiro, MDa, Ryuji Kubota, MD, PhDb,
a Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Japan
b Department of Molecular Pathology, Center for Chronic Viral Diseases, Kagoshima University, Japan
a b s t r a c t
a r t i c l e i n f o
Article history:
Received 20 March 2016
Received in revised form 18 October 2016
Accepted 19 October 2016
Available online 21 October 2016
Objective: HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) can progress slowly or rapidly even though a set of symptoms such as spastic paraparesis with pathological reflexes and sweating loss of the lower extremities are commonly observed in patients Although most of the patients are thought to be infected
to HTLV-1 from their mothers by breast feeding, symptoms of HAM/TSP typically manifest in patients later in life (50–60 years old in age) and also with a higher prevalence of women to men at a ratio of approximately 3:1 Probability of developing HAM/TSP and how fast an individual's disease may progress from the time of diagnosis could be multifactorial
Methods: We reviewed the records of 150 patients with HAM/TSP admitted to Kagoshima University Hospital be-tween 2002 and 2014 Laboratory data of cerebrospinalfluid and serum and the clinical measurements including age, age of disease onset, progression rate, duration of illness, initial symptoms, Osame's Motor Disability Score were evaluated Rapid disease progression of the disease was defined by deterioration of motor disability by N3 grades within 2 years
Results: Of 150 HAM/TSP patients in our cohort, 114 cases (76%) were females Patients presenting with rapid dis-ease progression are approximately 15 years older at the age of onset than those with a protracted disdis-ease course, and have increased number of cell, and elevated levels of protein as well as anti-HTLV-1 antibody titer in the CSF, suggesting a more active inflammatory process There is no significant difference in the average values of clinical and laboratory parameters between the sexes Furthermore, there is no apparent correlation between rate of dis-ease progression and gender
Conclusions: Our results suggest that age and virus mediated inflammation are correlated with disease pheno-types while additional factors such as host or HTLV-1 genetics and gender may influence disease susceptibility
© 2016 The Authors Published by Elsevier B.V This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/)
Keywords:
HAM/TSP
Disease course
Rapid progression
Gender
1 Introduction
Human T-lymphotropic virus type 1 (HTLV-1) is thefirst human
on-cogenic retrovirus to be identified and is thought to infect at least 50
million people worldwide[1,2] Several endemic areas for HTLV-1 are
known in the world such as southern Japan, the Caribbean, Central
and South America, Middle East, Central and West Africa, Melanesia, and there are smaller foci in the aboriginal populations of Australia, Papua New Guinea, and northern Japan[3–5] HTLV-1 can be transmit-ted through breastfeeding from mother to child, blood transfusion, and sexual intercourse The majority of infected individuals remain lifelong asymptomatic carriers, and approximately 2–5% develop adult T-cell leukemia/lymphoma (ATLL) [6,7] and another 0.25–3.8% develop HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) Disease phenotypes of HAM/TSP can be heterogeneous even though a set of symptoms such as spastic paraparesis with patholog-ical reflexes, urinary disturbance, mild sensory disturbance and sweating loss of the lower extremities are commonly observed in pa-tients Based on longitudinal clinical observations and follow-ups, HAM/TSP can be characterized as rapidly or slowly progressive types Approximately 30% of HAM/TSP patients exhibit rapid
☆ The authors have no conflicting financial interests to declare Authors' contribution:
Eiji Matsuura designed the experiments, analyzed the data and wrote the manuscript;
Satoshi Nozuma analyzed the data; and Ryuji Kubota provided the information of the
patients and supervised the project; Shuji Izumo and Hiroshi Takashima developed the
concept and supervised the project All authors approved the final version of this paper.
⁎ Corresponding author at: Department of Neurology and Geriatrics, Kagoshima
University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka,
Kagoshima 890-8520, Japan.
E-mail address: pine@m.kufm.kagoshima-u.ac.jp (E Matsuura).
http://dx.doi.org/10.1016/j.jns.2016.10.030
Contents lists available atScienceDirect
Journal of the Neurological Sciences
j o u r n a l h o m e p a g e :w w w e l s e v i e r c o m / l o c a t e / j n s
Trang 2progression of disease, meaning the time from onset of disease to
in-ability to walk isb2 years Contrasting the rapid disease phenotype is
the slow, protracted form of disease which can take as long as
15 years to progress[8] Factors that may influence how fast an
individual's disease may progress are yet to be identified, while
sev-eral risk factors including HTLV-1 provirus load (PVL), HTLV-1
sub-type, human leukocyte antigen (HLA) and non-HLA gene
polymorphisms are closely associated with the development of
HAM/TSP[9] The major route of HTLV-1 infection is from mothers
by a breastfeeding Symptoms of HAM/TSP, however, typically
man-ifest in patients later in life (50–60 years old in age) and also with a
higher prevalence of women to men at a ratio of approximately 3:1
[8,10–12] The reasons for these characteristics of this unique
infec-tious disease also remain unknown A complex multi-step
pathogen-ic process leading to disease manifestation may in part explain the
long latency in disease development Nevertheless, few studies
have to-date attempted to address the elevated female prevalence
in HAM/TSP
We designed a retrospective comparative study of 150 sequential
patients admitted to our hospital in the last 12 years and tried to
identify disease determinants or biomarkers that may be of value
to clinicians when assessing HTLV-1 related disease subtypes
2 Subjects and methods
We reviewed the medical records of 150 consecutive patients
with HAM/TSP who were admitted to Kagoshima University Hospital
from January 2002 to June 2014 HAM/TSP was diagnosed according
to the World Health Organization diagnostic criteria[13] Clinical
in-formation was obtained from medical records of patient attendance
at our hospital Clinical variables included sex, age, age at onset, an
initial symptom, a score of a neurological disability and blood and
ce-rebrospinalfluid (CSF) tests Neurological disability was assessed
using Osame's Motor Disability Score (OMDS) as reported
previous-ly The score were defined as follows: 0, no disability; 1, walking
slow; 2, a little trouble when walking; 3, unable to run; 4, needs
guardrail while going up the stairs; 5, needs one hand support
while walking; 6, needs two hands support while walking (N10 m);
and 7, needs two hands support while walking (b10 m); 8, needs
two hands support while walking (b5 m); 9, unable to walk but
can crawl; 10, unable to crawl but can move; 11, unable to move
but can roll over on the bed; 12 unable to roll over; 13, unable to
flex toes[14]
The subgroup of the patients with rapid progression was defined
by deterioration of motor disability byN3 grades within 2 years This
definition was applied to disease onset and any time point in the
dis-ease course A routine test for blood and cerebrospinalfluid of the
patients were evaluated Anti-HTLV-1 antibodies in serum and CSF
were detected using enzyme-linked immunosorbent assay and
par-ticle agglutination methods (Fijirebio Inc., Tokyo, Japan) HTLV-1
PVL in peripheral blood mononuclear cells (PBMCs) was assayed by
quantitative PCR using the ABI PRISM 7700TM sequence detection
system as reported previously[15] We analyzed these laboratory
data and the clinical parameters including the sex, age of disease
onset, initial symptom and disease course
HTLV-1 PVL of asymptomatic carriers was measured with the blood
samples from 89 individuals after obtaining informed consent
2.1 Statistical analysis
Data were analyzed using SPSS-20 (SPSS, Chicago, Illinois)
Statistical analyses were performed using parametric (t-test) and
non-parametric tests (Mann–Whitney test) for continuous variables
andχ2(Pearsonχ2test/Fisher exact test) for categorical variables
Differences were considered significant when p b 0.05
3 Results 3.1 Clinical and laboratory data of the patients with HAM/TSP
We made a bar chart representing a frequency distribution of age of disease onset with 150 consequent patients who had been diagnosed with HAM/TSP from 2002 and 2014 The probability of developing symptoms at any given age was in accordance with a skewed normal distribution pattern (Fig 1) Between the 5th and 7th decades, was when the chances of developing HAM/TSP disease increase The aver-ages of age, age of onset, and duration of illness of all the patients were 61.5 years old, 50.6 years old and 10.9 years, respectively (Table
1) On the laboratory data, the average of anti-HTLV-1 antibody titer (PA) in serum and cerebral spinalfluid (CSF) of all the patients were 29,141 × and 594.2 ×, respectively Average of HTLV-1 proviral load (PVL) was 9.42% in PBMCs There is no significant difference in these pa-rameters other than the level of protein in the CSF between the sexes The level of protein in the CSF of the female patients was significantly less than that of the male patients, while there is no difference in a cell count and a level of neopterin between them (Table 1)
3.2 Characteristics of the patients presenting with rapid and slow disease progression
We segregated patients into two groups based on disease pheno-types, and compared the groups (Table 2) The patients presenting with rapid progression were significantly older at onset than those with slow progression (61.5 vs 46.8 years old, pb 0.001) The time elapse between onset and wheelchair use in daily life was markedly shorter among patients with rapidly progressing disease (1.4 vs 15.7 years, pb 0.001) Anti-HTLV-1 antibody titer was also significantly higher in the CSF of the patients with rapid progression than in that with slow progression (1210× vs 366×, pb 0.001), but the difference in the titer was not found in the serum Cell counts and the protein level were significantly higher in the CSF of the patients with rapid progression than in that with slow progression (11.1 vs 3.3 cells, pb 0.001; 54.9
vs 36.1 mg/dl, pb 0.001, respectively) HTLV-1 PVL was significantly lower in patients with rapid progression than in those with slow pro-gression (408 vs 1158 copies/104PBMCs, p = 0.008) The PVL of the pa-tients with rapid progression was slightly higher than that with asymptomatic carriers in our hospital is 366 ± 657 copies
We wondered if initial presentations were prognostic, and tabulated frequencies offive common symptoms including gait disturbance, uri-nary and sensory disturbances, constipation and lumbago (Fig 2) Pa-tients were separated into cohorts based on their respective divergent disease courses for further analysis (Fig 2a) Our result, albeit sugges-tive, demonstrates that urinary disorders were more often noticed in
Fig 1 Distribution of ages at disease onset.
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Trang 3patients affected with the protracted form of disease, while sensory
symptoms were markedly increased in patients with rapid progression
3.3 Difference in clinical course between the sexes
We compared the clinical features of the female patients with those
of male patients tofind some association between the sexes and the
dis-ease courses There is no significant difference in OMDS and diseases
course between the sexes (Table 3) We tabulated frequencies offive
common symptoms including gait disturbance, urinary and sensory
dis-turbances, constipation and lumbago tofind a difference between the
sexes There is no significant difference in the initial symptom between
the sexes (Fig 2b) Lastly, we calculated the ratio of rapid progression in
each decade of onset age The proportion of patients with rapid
progres-sion increased with the onset age both in male and female (Fig 3a–c)
4 Discussion
Our result showed that the male to female ratio was 1:3 in 150
se-quential patients with HAM/TSP The prevalence in sex is almost as
same as that of previous studies Approximately 25% of the patients in
our cohort manifested rapid disease progression and it is consistent
with previous studies showing 10–30% of all HAM/TSP patients follow
a disease course that progresses rapidly Advanced age is shown to be
associated with rapid progression of the disease[14,16–18] One may
think this phenomenon is attributed to the weakness of the lower
ex-tremities by aging or sex However, the measured values of CSF cell
count, and protein levels were specifically elevated in patients with
rapid disease in the present study Additionally, HTLV-1 antibody titer
in both serum and CSF were evaluated Only in the CSF was a difference detected between rapid and slow progression Although we also
expect-ed the significant elevation of neopterin, the difference did not reach statistical significance It may be because of a small number of rapidly progressing cases In addition to small number of samples, we have to take it into consideration the time point of the sample collection The blood samples were not always collected during progression of the dis-ease The rapid progression was defined with the past history of the pa-tient in this study When the level of neopterin was elevated just during the period of disease progression, the difference must be smaller than
we expected in our retrospective study Together, these biomarkers sug-gest inflammation, cellular and molecular events leading to spinal cord tissue damage in HAM/TSP are indeed virus mediated The high preva-lence of rapid progression in older age is attributed to not only the weakness of the legs by aging but also to some other factors
A previous study on donated blood samples shows that there was no difference in prevalence of HTLV-1 carrier between the sexes until 5th decades and that the prevalence in female become to be higher than that in male after 5th decades in Japan.[19] The exact reason for the dif-ference in prevalence is not elucidated A sexual transmission may be partially contributed to the difference Concerned to blood transfusion, the frequency of blood transfusion before the onset of the disease is
sig-nificantly high compared with that in the general population[20] HAM/ TSP sometimes occurs in the short period after blood transfusion The immune response of the host in an infection to HTLV-1 by blood trans-fusion may be different from that in a mother-to-child infection by breast feeding Similarly, the immune response of the host to HTLV-1
in an infection by sexual intercourse in older age may be different from that in a mother-to-child infection So we hypothesized that
Table 1
HAM/TSP clinical and laboratory parameters between male and female.
Age (mean ± s.d., range) 61.5 ± 12.2 (N = 151) 62.7 ± 11.8 (N = 36) 61.1 ± 12.3 (N = 114) NS Age of onset (mean ± s.d., range) 50.6 ± 15.7 (N = 151) 52.8 ± 14.1 (N = 36) 49.9 ± 16.1 (N = 114) NS Duration of illness (mean ± s.d., range) 10.9 ± 10.1 (N = 151) 9.9 ± 10.9 (N = 36) 11.2 ± 9.8 (N = 114) NS Anti-HTLV-1 titer a
Serum (mean ± s.d., range) 29,141 ± 34,518
(N = 137)
28,067 ± 31,663 (N = 33)
29,482 ± 35,368 (N = 104)
NS
CSF (mean ± s.d., range) 594.2 ± 1180.2 (N = 133) 544.5 ± 1013.6 (N = 32) 609.9 ± 1227.8 (N = 101) NS CSF tests
Cell count (/mm 3
) (mean ± s.d., range) 16.3 ± 27.6 (N = 144) 21.8 ± 48.3 (N = 36) 14.4 ± 15.0 (N = 108) NS Protein (mg/dl) (mean ± s.d., range) 41.0 ± 17.9 (N = 145) 46.8 ± 19.9 (N = 36) 39.1 ± 16.8 (N = 109) 0.010 Neopterin (pmol/ml) (mean ± s.d., range) 33.5 ± 47.4 (N = 58) 34.1 ± 17.6 (N = 12) 33.3 ± 52.4 (N = 46) NS HTLV-1 proviral load (copies/10 4
PBMC; mean ± s.d., range) 942.1 ± 1628.2 (N = 118) 1040.0 ± 1165.5
(N = 29)
910.2 ± 1751.6 (N = 89) NS
a
Particle aggregation method Data is shown as mean value ± s.d (range), sample number.
Table 2
Characteristics of the patients presenting with rapid and slow progression.
60.3 ± 10.2 (female) 46.4 ± 16.3 (female) b0.001 65.1 ± 6.8 (male) 48.1 ± 15.7 (male) b0.001
Time between onset of disease to wheelchair use (mean ± s.d.) 1.4 ± 0.8 (N = 14) 15.7 ± 11.6 (N = 29) b0.001 Anti-HTLV-1 titer a
(N = 38)
28,952 ± 34,465 (N = 98)
NS
CSF tests
Cell count (/mm 3
Protein (mg/dl) (mean ± s.d.) 54.9 ± 22.9 (N = 38) 36.1 ± 12.6 (N = 106) b0.001 Neopterin (pmol/ml) (mean ± s.d.) 66.3 ± 84.9 (N = 8) 24.0 ± 20.2 (N = 45) NS HTLV-1 proviral load (copies/10 4 PBMC; mean ± s.d., range) 408 ± 355 (N = 34) 1158 ± 1873 (N = 84) 0.008 a
Trang 4some female patients infected by a sexual intercourse shows strong
im-mune response to HTLV-1, resulting in presenting with a rapid
progres-sion in elderly female However, in the present study, we did notfind
out the difference in onset age, the ratio of rapid progression and the
pe-riod from onset to wheelchair-use between the sexes Although we
think HTLV-1 can be transmitted by a sexual intercourse, one's gender
is not strongly associated with age of onset or diseases course of HAM/
TSP in the present study
Biomarkers that are highly differential and may be of value in
supporting disease diagnosis which we identified in this
retrospec-tive study are CSF cells, protein level, and HTLV-1 antibody titer
HTLV-1 PVL in PBMC has been demonstrated to strongly correlate with disease severity in a number of previous studies And its utility
as a biomarker to aid in disease prognosis was also suggested by Olindo et al.[16,18,21] Unexpectedly, in our study, the patients with rapid disease progression had lower PVL Because the PVLs were evaluated with the samples at their admission to our hospital, the PBMCs are collected both from the patients before and during rapid progression We should warrant further investigations to ad-dress the accepted hypothesis that disease progression and severity
a) Initial symptom of patients with rapid and slow
disease progression.
b) Initial symptom of male and female patients
Fig 2 a Initial symptom of patients with rapid and slow disease progression b Initial
symptom of male and female patients.
Table 3
HAM/TSP clinical phenotypes and characteristics by gender.
Total (N = 150) Male (N = 36) Female (N = 114) p Number of patients with rapid disease progression 39 (26%) 10 (27.8%) 26 (22.6%) NS
Number of patients with disease severity above OMDS grade 5 47 (31.3%) 11 (30.6%) 36 (31.6%) NS Time between disease onset to wheelchair use (mean ± s.d., range) 9.8 ± 10.4
(N = 44)
13.8 ± 14 (N = 10)
8.7 ± 8.8 (N = 34)
NS
Fig 3 Proportion of patients with rapid and slow disease progression by age of onset.
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Trang 5are strictly driven by PVL in PBMC The reasons for these differing
ob-servations are unclear at this point
Our results suggest that age and virus mediated inflammation are
correlated with disease phenotypes while additional factors such as host
or HTLV-1 genetics and gender may influence disease susceptibility
Ethics statement
This study was approved by the Institute Review Boards of
Kagoshi-ma University All participants provided their written informed consent
Acknowledgement
This study was supported by the Research program for conquering
intractable disease from Japan Agency for Medical Research and
devel-opment, AMED Grant Number 26310301 and JSPS KAKENHI Grant
Numbers 25293205 We would like to express the deepest appreciation
to Yao Karen on English proofreading of our manuscript
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