Journal of the Neurological Sciences 371 (2016) 112–116 Contents lists available at ScienceDirect Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP): A comparative study to identify factors that influence disease progression☆ Eiji Matsuura, MD, PhD a,⁎, Satoshi Nozuma, MD, PhD a, Yuichi Tashiro, MD a, Ryuji Kubota, MD, PhD b, Shuji Izumo, MD, PhD b, Hiroshi Takashima, MD, PhD a a b Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Japan Department of Molecular Pathology, Center for Chronic Viral Diseases, Kagoshima University, Japan 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 Keywords: HAM/TSP Disease course Rapid progression Gender a b s t r a c t 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 between 2002 and 2014 Laboratory data of cerebrospinal fluid 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 N grades within years Results: Of 150 HAM/TSP patients in our cohort, 114 cases (76%) were females Patients presenting with rapid disease progression are approximately 15 years older at the age of onset than those with a protracted disease 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 disease progression and gender Conclusions: 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 © 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/) Introduction Human T-lymphotropic virus type (HTLV-1) is the first human oncogenic 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 ☆ 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) 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 transmitted 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 pathological reflexes, urinary disturbance, mild sensory disturbance and sweating loss of the lower extremities are commonly observed in patients 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 http://dx.doi.org/10.1016/j.jns.2016.10.030 0022-510X/© 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/) E Matsuura et al / Journal of the Neurological Sciences 371 (2016) 112–116 progression of disease, meaning the time from onset of disease to inability to walk is b 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 several risk factors including HTLV-1 provirus load (PVL), HTLV-1 subtype, 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 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 [8,10–12] The reasons for these characteristics of this unique infectious disease also remain unknown A complex multi-step pathogenic 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 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 information 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 cerebrospinal fluid (CSF) tests Neurological disability was assessed using Osame's Motor Disability Score (OMDS) as reported previously 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 (N 10 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 by N grades within years This definition was applied to disease onset and any time point in the disease course A routine test for blood and cerebrospinal fluid of the patients were evaluated Anti-HTLV-1 antibodies in serum and CSF were detected using enzyme-linked immunosorbent assay and particle 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 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 averages 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 spinal fluid (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 parameters 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 phenotypes, 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, p b 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, p b 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×, p b 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, p b 0.001; 54.9 vs 36.1 mg/dl, p b 0.001, respectively) HTLV-1 PVL was significantly lower in patients with rapid progression than in those with slow progression (408 vs 1158 copies/104 PBMCs, p = 0.008) The PVL of the patients 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 of five common symptoms including gait disturbance, urinary and sensory disturbances, constipation and lumbago (Fig 2) Patients were separated into cohorts based on their respective divergent disease courses for further analysis (Fig 2a) Our result, albeit suggestive, demonstrates that urinary disorders were more often noticed in 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 and χ2 (Pearson χ2 test/Fisher exact test) for categorical variables Differences were considered significant when p b 0.05 113 Fig Distribution of ages at disease onset 114 E Matsuura et al / Journal of the Neurological Sciences 371 (2016) 112–116 Table HAM/TSP clinical and laboratory parameters between male and female Number of patients All (N = 150) Male (N = 36) Female (N = 114) p Age (mean ± s.d., range) Age of onset (mean ± s.d., range) Duration of illness (mean ± s.d., range) Anti-HTLV-1 titera Serum (mean ± s.d., range) 61.5 ± 12.2 (N = 151) 50.6 ± 15.7 (N = 151) 10.9 ± 10.1 (N = 151) 62.7 ± 11.8 (N = 36) 52.8 ± 14.1 (N = 36) 9.9 ± 10.9 (N = 36) 61.1 ± 12.3 (N = 114) 49.9 ± 16.1 (N = 114) 11.2 ± 9.8 (N = 114) NS NS NS 29,141 ± 34,518 (N = 137) 594.2 ± 1180.2 (N = 133) 28,067 ± 31,663 (N = 33) 544.5 ± 1013.6 (N = 32) 29,482 ± 35,368 (N = 104) 609.9 ± 1227.8 (N = 101) NS NS 16.3 ± 27.6 (N = 144) 41.0 ± 17.9 (N = 145) 33.5 ± 47.4 (N = 58) 942.1 ± 1628.2 (N = 118) 21.8 ± 48.3 (N = 36) 46.8 ± 19.9 (N = 36) 34.1 ± 17.6 (N = 12) 1040.0 ± 1165.5 (N = 29) 14.4 ± 15.0 (N = 108) 39.1 ± 16.8 (N = 109) 33.3 ± 52.4 (N = 46) 910.2 ± 1751.6 (N = 89) NS 0.010 NS NS CSF (mean ± s.d., range) CSF tests Cell count (/mm3) (mean ± s.d., range) Protein (mg/dl) (mean ± s.d., range) Neopterin (pmol/ml) (mean ± s.d., range) HTLV-1 proviral load (copies/104 PBMC; mean ± s.d., range) a Particle aggregation method Data is shown as mean value ± s.d (range), sample number patients 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 to find some association between the sexes and the disease courses There is no significant difference in OMDS and diseases course between the sexes (Table 3) We tabulated frequencies of five common symptoms including gait disturbance, urinary and sensory disturbances, constipation and lumbago to find 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 progression increased with the onset age both in male and female (Fig 3a–c) Discussion Our result showed that the male to female ratio was 1:3 in 150 sequential 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 extremities 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 expected 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 disease The rapid progression was defined with the past history of the patient 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 suggest inflammation, cellular and molecular events leading to spinal cord tissue damage in HAM/TSP are indeed virus mediated The high prevalence 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 difference 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 significantly 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 transfusion 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 Characteristics of the patients presenting with rapid and slow progression Type of diseases progression Rapid progression Slow progression Cases Female:Male Age (mean ± s.d.) Age of disease onset (mean ± s.d.) 39 (26%) 29:10 (74.4%:25.6%) 64.5 ± 8.4 61.5 ± 9.7 60.3 ± 10.2 (female) 65.1 ± 6.8 (male) 2.9 ± 4.4 1.4 ± 0.8 (N = 14) 111 (74%) 85:26 (76.6%:23.4%) 60.3 ± 13.3 46.8 ± 15.7 46.4 ± 16.3 (female) 48.1 ± 15.7 (male) 13.5 ± 10.0 15.7 ± 11.6 (N = 29) 29,965 ± 35,028 (N = 38) 1210 ± 1736 (N = 36) 28,952 ± 34,465 (N = 98) 366 ± 773 (N = 97) NS 11.1 ± 15.6 (N = 38) 54.9 ± 22.9 (N = 38) 66.3 ± 84.9 (N = 8) 408 ± 355 (N = 34) 3.3 ± 3.5 (N = 105) 36.1 ± 12.6 (N = 106) 24.0 ± 20.2 (N = 45) 1158 ± 1873 (N = 84) b0.001 b0.001 NS 0.008 Duration of illness (mean ± s.d.) Time between onset of disease to wheelchair use (mean ± s.d.) Anti-HTLV-1 titera Serum (mean ± s.d.) CSF (mean ± s.d.) CSF tests Cell count (/mm3) (mean ± s.d.) Protein (mg/dl) (mean ± s.d.) Neopterin (pmol/ml) (mean ± s.d.) HTLV-1 proviral load (copies/104 PBMC; mean ± s.d., range) a Particle aggregation method Data is shown as mean value ± s.d (range), sample number NS NS b0.001 b0.001 b0.001 b0.001 b0.001 b0.001 E Matsuura et al / Journal of the Neurological Sciences 371 (2016) 112–116 115 a) Initial symptom of patients with rapid and slow disease progression b) Initial symptom of male and female patients Fig a Initial symptom of patients with rapid and slow disease progression b Initial symptom of male and female patients some female patients infected by a sexual intercourse shows strong immune response to HTLV-1, resulting in presenting with a rapid progression in elderly female However, in the present study, we did not find out the difference in onset age, the ratio of rapid progression and the period 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 retrospective study are CSF cells, protein level, and HTLV-1 antibody titer Fig Proportion of patients with rapid and slow disease progression by age of onset 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 address the accepted hypothesis that disease progression and severity Table HAM/TSP clinical phenotypes and characteristics by gender Number of patients with rapid disease progression OMDS (mean, median, range) Number of patients with disease severity above OMDS grade Time between disease onset to wheelchair use (mean ± s.d., range) Number of patients with familial history of HAM Total (N = 150) Male (N = 36) Female (N = 114) p 39 (26%) 5.2, 5, 0–11 47 (31.3%) 9.8 ± 10.4 (N = 44) (5.3%) 10 (27.8%) 5.1, 5, 2–10 11 (30.6%) 13.8 ± 14 (N = 10) (2.8%) 26 (22.6%) 5.2, 5, 0–11 36 (31.6%) 8.7 ± 8.8 (N = 34) (6.1%) NS NS NS NS NS 116 E Matsuura et al / Journal of the Neurological Sciences 371 (2016) 112–116 are strictly driven by PVL in PBMC The reasons for these differing observations 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 Kagoshima 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 development, 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 References [1] A Gessain, F Barin, J.C Vernant, O Gout, L Maurs, A Calender, G de The, Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis, Lancet (8452) (1985) 407–410 [2] M Osame, K Usuku, S Izumo, N Ijichi, H Amitani, A Igata, M Matsumoto, M Tara, HTLV-I associated myelopathy, a new clinical entity, Lancet (8488) (1986) 1031–1032 [3] A Gessain, Epidemiology of HTLV-I and associated diseases, Human T-cell LymphotropicVirus Type I 1996, pp 33–64 [4] K Yamaguchi, Human T-lymphotropic virus type I in Japan, Lancet 343 (8891) (1994) 213–216 [5] G.P Taylor, The epidemiology of HTLV-I in Europe, J Acquir Immune Defic Syndr Hum 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M.R Hedayati-Moghaddam, A Amiri, P Hashemi, M Foroghipour, R.F Hoseini, A Bazarbachi, M.R Azarpazhooh, Clinical features of HTLV- 1- associated myelopathy/ tropical spastic paraparesis (HAM/ TSP) in... York 19 90, p 19 1 [14 ] M Nakagawa, S Izumo, S Ijichi, H Kubota, K Arimura, M Kawabata, M Osame, HTLV- I -associated myelopathy: analysis of 213 patients based on clinical features and laboratory... H Amitani, A Igata, M Matsumoto, M Tara, HTLV- I associated myelopathy, a new clinical entity, Lancet (8488) (19 86) 10 31? ? ?10 32 [3] A Gessain, Epidemiology of HTLV- I and associated diseases, Human