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Case Report

Progression of HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis after Pregnancy: A Case Series and Review of the Literature

by
Frederique A. Jacquerioz
1,2,
Mauricio La Rosa
3,
Elsa González-Lagos
2,
Carolina Alvarez
2,
Martin Tipismana
2,4,
Karen Luhmann
2 and
Eduardo Gotuzzo
2,*
1
Department of Tropical Medicine, Tulane School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA
2
Institute of Tropical Medicine Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima 15102, Peru
3
Department of Obstetrics and Gynecology, Pennsylvania Hospital, Philadelphia, PA 19107, USA
4
Department of Neurology, Hospital Cayetano Heredia, Lima 15102, Peru
*
Author to whom correspondence should be addressed.
Pathogens 2024, 13(9), 731; https://doi.org/10.3390/pathogens13090731
Submission received: 3 July 2024 / Revised: 22 August 2024 / Accepted: 23 August 2024 / Published: 28 August 2024
(This article belongs to the Special Issue Viral Infections of Humans: Epidemiology and Control)
Review Reports Versions Notes

Abstract

HTLV-1-associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is a progressive non-remitting and incapacitating disease more frequently seen in women and with a patchy worldwide distribution. HAM/TSP develops in a small percentage of HTLV-1-infected individuals during their lifetime and etiologic factors for disease progression are still unclear. This study aims to describe the first case series of the progression of HAM/TSP in relation to pregnancy. Between January and March of 2012, we reviewed medical charts of women with HAM/TSP currently enrolled in the HTLV-1 cohort at the institute of tropical medicine of Cayetano Heredia University. Inclusion criteria included having a diagnosis of HAM/TSP according to the WHO guidelines and self-reported initial symptoms of HAM/TSP during pregnancy or within six months of delivery. Fifteen women reported having had symptoms compatible with HAM/TSP within four months of delivery. Among them, ten women had no symptoms before pregnancy and reported gait impairment after delivery. Five women with mild gait impairment before pregnancy noticed a worsening of their symptoms after delivery. Symptoms worsened after successive pregnancies. Recent studies have shown that HTLV-1 infection induces a strong T cell-mediated response and that the quality of this response plays a role in HAM/TSP pathogenesis. The relative immunosuppression during pregnancy, including blunting of the T-cell response, might allowed in certain women enhanced replication of HTLV-1 and disease progression in the postpartum. This is the first study looking specifically at HAM/TSP and pregnancy and the number of cases is remarkable. Further prospective studies of HTLV-1-infected women assessing immune markers during pregnancy are warranted. Breastfeeding was the main route of transmission. Strategies to prevent vertical transmission need to be evaluated in HTLV-1 endemic countries of Latin America.

1. Introduction

Human T lymphotropic virus 1 (HTLV-1)associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is a slowly progressive inflammatory disease characterized by spastic paraparesis predominantly of the lower extremities, sphincter dysfunction, and mild sensory disorder [1]. Although an uncommon disease at a global level, it disproportionally affects families and communities in the endemic foci of Japan, the Caribbean, sub-Saharan Africa, Melanesia, and South America. People acquire HTLV-1 infection through breastfeeding (infancy), sexual intercourse, blood transfusion, or organ transplantation. Among HTLV-1-infected individuals, the lifetime risk of developing HAM/TSP is 0.25 to 4% [2]. The risk seems to be even greater in the Caribbean and South America [2,3] and is three times higher in women [4,5]. Socio-economic and psychological impacts of HAM/TSP are dramatic as the disease progresses irrevocably to severe disability in the span of years and to date, there is no effective treatment [6]. However, the actual prevalence and impact of HTLV-1 in pregnant women remain largely unknown, highlighting the importance of new studies and more research on this topic. The impact is not only on the affected individuals but also on their entire family and mothers with small children suffer most of the disease burden. Host immunity plays an important role in disease pathogenesis [1,2,7,8]. However, etiologic factors of disease progression are still unknown. Pregnancy induces significant immunological changes, which could potentially influence the progression of HAM/TSP in the immediate postpartum period [9]. Since 1989, an HTLV-1 cohort study has been carried out at the Instituto de Medicina Tropical Alexander von Humboldt (IMTAvH) in Lima, Peru. The observation of a few cases of onset of HAM/TSP in the immediate postpartum period raised the hypothesis of pregnancy as a trigger for disease progression. We report on the demographic and clinical characteristics of patients with HAM/TSP after pregnancy.

2. Patients and Methods

Ethics Statement: This study complied with the principles outlined by the Declaration of Helsinki and was approved by the Institutional Ethics Committee of Cayetano Heredia University and the Human Research Ethics Committee of Tulane University. Informed consents were signed by all participants.
Setting: The study was conducted at the IMTAvH at the National Hospital Cayetano Heredia in Lima, Peru. Since 1989, patients with HTLV-1 infections and associated diseases have been referred to IMTAvH from major public hospitals and private health facilities in Lima and its surrounding areas and enrolled in the HTLV-1 cohort study.
Procedures: Between January and March of 2012, we reviewed the medical charts of women with a diagnosis of HAM/TSP who were currently enrolled in the cohort study. Inclusion criteria were women 15 years of age or older with an HTLV-1 infection diagnosed by enzyme-linked immunosorbent assays and confirmed by Western blot and/or pro-viral load (PVL) measured by real-time PCR, and a diagnosis of HAM/TSP who self-reported initial symptoms of HAM/TSP during pregnancy or within 6 months of delivery. The diagnosis of HAM/TSP was based on the WHO guidelines and the revised definition by Castro-Costa [10,11]. Cases identified on medical charts were contacted and those alive and agreeing to participate were interviewed and examined by a neurologist to determine their current stage of HAM/TSP, and blood samples were drawn for PVL quantification. PVL was measured as reported previously [12] and expressed as the number of HTLV-1 copies per 104 peripheral blood mononuclear cells (PBMC). We collected information on demographics, risk factors for HTLV-1 infection, and clinical characteristics of HAM/TSP. Ethnic background was considered as Quechua if the participants defined themselves as such and/or they spoke the Quechua language. We considered breastfeeding as a likely route of transmission when the mother, father, and/or siblings were found HTLV-1 positive. Sexual transmission was considered when the husband but not the parents or siblings, was HTLV-1 positive. Transmission by blood transfusion was considered plausible when participants had received transfusions before 1998 when blood products started to be tested for HTLV-1 in Peru. Univariate analyses were performed using SPSS (PASW Statistics 18). When the time from delivery to onset or worsening of symptoms was less than a week, 0.5 weeks was used for calculations.

3. Results

Of the 1439 HTLV-1-positive women enrolled in the cohort study in March 2012, 333 had HAM/TSP (prevalent cases) and at least one pregnancy. From medical chart reviews, we identified fifteen women who had self-reported onset or worsening of symptoms of HAM/TSP in the months following pregnancy. We were able to contact twelve women and all agreed to be interviewed. Among the remaining three, two were lost to follow-up, and one died in 2008.
Demographic data and risk factors: Among the fifteen, nine women (60%) were Quechua. All women reported being breastfed, fourteen (93%) for at least six months, and eleven (73%) for more than one year. Six women (40%) were likely infected through breastfeeding. Three women received blood transfusions before 1998. One of them is a confirmed case of transmission by contaminated blood products. She received a transfusion while breastfeeding her one-year-old daughter and consequently infected her. For the other two women, transmission through this route is plausible but not confirmed. Sexual transmission was possible in three cases; for two, transmission through breastfeeding or transfusion was also possible. Eight women (53%) had one or more children with HTLV-1 infection. Eleven women (73%) had one or more family members with HTLV-1 infection. All women were negative for HTLV-2 and HIV. The median time between the onset of symptoms and diagnosis of HAM/TSP (serologic tests and clinical examination) was 6 years (range: 0–42) (Table A1 and Table A3).
Clinical and obstetric data: Of the fifteen women, ten were classified as having onset of HAM/TSP after delivery (cases #1 to #10). The mean age was 29.5 years (SD: 6.8) and the median time between delivery and onset of symptoms was 2 weeks (range: 0.5–16). Difficulty walking was the symptom most frequently reported on medical charts. In one woman, transitory cramps and weakness in the right leg during the first trimester were also reported. The remaining five women were classified as having worsening HAM/TSP after delivery (cases #11 to #15). They had a mean age of 26.2 years (SD: 7.6) when they first presented symptoms and 33.2 years (SD: 5.7) at delivery. The median time between delivery and worsening of symptoms was 1 week (range: 1–8). Difficulty walking was present before pregnancy in these women but a clear worsening of the symptoms was noted after delivery. Only two of the five had a confirmed diagnosis of HAM/TSP before pregnancy. One woman was not able to walk again after delivery and had to use a wheelchair (Table A1, Table A2 and Table A3).
During interviews, the main self-reported symptom after pregnancy was profound weakness (92%) that impeded their ability to walk normally. Stumbling (67%) (i.e., instability while walking, falls, and/or fear of falling) and numbness (42%) were also commonly reported. The symptomatology predominated in lower limbs but one patient also reported difficulties carrying her newborn in her arms. Three women (25%) also reported sphincter dysfunction. All twelve women reported that the symptoms affected their daily life activities and nine (75%) stopped working as a result of the disease. The findings of the 2012 neurologic examination are summarized in Table A3. The median duration of the disease was 16.5 years (range: 10–40). Five women were in a wheelchair after a median of 26 years (range: 9–36). A majority were receiving a muscle relaxant and three were treated with a combination of an antiretroviral, muscle relaxant, and prednisone. The score of the Kurtzke Expanded Disability Status Scale (EDSS) [13] used to assess disability in HAM/TSP patients, was 6 on a scale of 0 to 10 (range 4.5–8) [13]. Scores were not available for times of onset/worsening to assess the progression of the disease or to corroborate the above self-reported symptoms. Most women entered the cohort years after the onset/worsening of symptoms (Table A3).

4. Discussion

We describe fifteen HTLV-1-infected women with a progression of HAM/TSP following pregnancy. To date, the potential effect of pregnancy on HTLV-1 infection has been poorly investigated and published [14]. In 1994, Mizokami et al. [14] reported on a case of a Japanese woman with HTLV-1 infection who presented gait disturbance with progressive stiffness and weakness in her right leg four months after delivering her first child. The symptoms improved during her second pregnancy but were exacerbated five months after delivering her second child. She was then diagnosed with HAM/TSP and thyroiditis. The reason for very few reported cases might be explained by various epidemiological factors. Isolated cases might be difficult to recognize and interpret in clinical practice. Initial symptoms might be attributed to the pregnancy itself or to normal postpartum recovery. A puerperal woman in charge of a newborn might first minimize symptoms or deny them for fear of being sick [15]. The disease often affects people from low socio-economic backgrounds who, with a lack of financial resources to pay for healthcare, might delay seeking care [6,15]. More importantly, in many endemic countries, a majority of health professionals are unaware of HTLV-1 infection and its associated diseases [6,15,16]. By the time a diagnosis is confirmed, months or years have passed and by then the temporal connection between initial symptoms and pregnancy is likely to be overlooked. The recognition of our cases was made possible by an experienced HTLV-1 clinical and research team and the existence of an ongoing HTLV-1 cohort that allowed retrospective and specific evaluation of cases.
Gait impairment was the leading complaint and the main reason for seeking medical advice in our series of patients. We cannot be certain that symptoms such as weakness had not been present during pregnancy and either not recalled or thought to be due to the pregnancy itself. Similarly, less specific symptoms of HAM/TSP such as urinary incontinence or constipation could also have been present for some time but not attributed to the disease. However, after pregnancy gait impairment was clearly identified and reported by the women as unusual and an in-person interview confirmed this observation. This onset or worsening of HAM/TSP postpartum suggests that pregnancy could have elicited disease progression in these women, in particular the motor component.
The Japanese woman reported on by Mizokami [14] presented an onset of HAM/TSP after her first pregnancy and exacerbation following her second pregnancy. This was also true for the four of our patients who had another pregnancy and reinforces the hypothesis that pregnancy may play a role in HAM/TSP progression. A plausible hypothesis might be related to the role of cell-mediated immunity in both pregnancy and HAM/TSP [9,17]. Pregnancy induces immune tolerance to the fetus through a complex modulation of the immune system, which includes a shift of effector T-helper (TH) cells from TH 1 (cell-mediated) to TH 2 (antibody-mediated) dominance, expansion of FoxP3 regulatory T cells (Tregs), and down-regulation of TH17 cells [9,18]. All of these changes contribute to suppressing an excessive T cell-mediated immune response to fetal alloantigen and impaired function of these cells leads to inflammation and pregnancy-associated complications [9,19]. In contrast, it is now accepted that HTLV-1 induces strong cytotoxic T cell (CTL) immune response [20] and recent studies have shown that the quality of this response, partly defined by genetic factors, is important in determining disease progression [21,22,23,24,25]. In asymptomatic carriers, CTL response mounted against HTLV-1 seems to be efficient in killing virally infected T cells, mostly Tregs expressing FoxP3, and maintaining low proviral loads [23,24,25]. In HAM/TSP patients, an exaggerated inflammatory response characterized by higher PVLs, overproduction of pro-inflammatory cytokines such as interferon γ, and accumulation of anti-HTLV-1 CTLs in the cerebrospinal fluid is observed. In these patients, the underlying mechanism is thought to be due to deregulation in function and frequency of CTLs and subsets of Tregs expressing FoxP3 [17,21,24,26,27,28,29]. Thus, one can postulate that the relative but critical immunosuppression during normal pregnancy, including blunting of the CTL response, alters the Th1/Th2 immune response equilibrium of HTLV-1 infected women allowing enhanced replication of HTLV-1, increased inflammation, and disease progression postpartum.
A comparable pattern of disease progression or relapse in postpartum is observed in other inflammatory and T cell-mediated dominant diseases such as multiple sclerosis (MS), and rheumatic arthritis (RA) [30,31]. During pregnancy, MS relapses less frequently and is often managed without medication. In post-partum, MS flares are more severe and occur in almost 30% of women within 3 months of delivery [32,33,34]. Similarly, RA is five times more likely to develop after delivery than at any other time [32]. The exact mechanism of this phenomenon is not yet completely elucidated.
Studies have investigated the use of steroids in the management of HAM/TSP in HTLV-1 patients. It aims to alleviate symptoms and reduce inflammation in affected individuals. While some studies have reported short-term benefits, such as a reduction in inflammation and improvement in motor function, the long-term efficacy of steroid therapy remains uncertain. The prolonged use requires screening of other infectious diseases, otherwise it could carry the risk of adverse effects, such as infectious diseases or metabolic disturbances [35,36]. Given the hypothesis that immune suppression during pregnancy and its subsequent release postpartum may trigger or worsen HAM/TSP, further research is needed to explore the efficacy and safety of steroid administration during the postpartum period for patients with HAM/TSP. This research could help clarify whether steroids might be beneficial in managing postpartum exacerbations of HAM/TSP in the context of HTLV-1 infection.
In HTLV-1 infection, the effect of pregnancy on HTLV-1 infection and HAM/TSP might vary by geographic regions, host genetic determinants, mode of HTLV-1 acquisition, or virus subtypes and a combination of various factors may need to be present to elicit disease progression. There are no published observational studies of HTLV-1-infected pregnant women looking specifically at this issue. In 2003, Ando et al. [37]. described two cases of HAM/TSP diagnosed during pregnancy, one during the first trimester and the other at 22 weeks of gestation, suggesting opposing findings. However, it is unclear whether the symptoms were present before pregnancy but noticed during pregnancy, and their characteristics after delivery were not reported. In a case-control study conducted in Gabon in the early 1990s assessing the effect of HTLV-1 infections on maternal and fetal outcomes, the authors mentioned briefly that none of the 45 HTLV-1 positive cases presented HAM/TSP or other clinical manifestations of HTLV-1 infection during pregnancy, after delivery, or at one-year follow-up [38]. In 2021, Mori et al. [39] in Japan documented a case report of HTLV-1 infection concurrent with early-onset HAM/TSP during pregnancy. Their report indicated the absence of a complication pertaining to the gait impairment and/or neurological symptoms or worsening of symptoms. However, it is crucial to note that the case they described was characterized by severe HAM/TSP symptoms, including severe gait impairment (use of a wheelchair), prior to the onset of pregnancy. In Latin America, this phenomenon needs to be further tested through careful observational studies of asymptomatic HTLV-1 infected women during pregnancy and post-partum looking at genetic determinants, immune response, virus factors, and sexual hormones as potential factors in disease progression. Such studies will likely shed light on the role of pregnancy in HAM/TSP and bring opportunities for disease prevention and new targets for drug development. Additionally, it is necessary to study and identify that immunological changes during pregnancy and postpartum may have an effect on the development of complications associated with HTLV-1 [16,40].
In most Latin American countries including Peru, HTLV-1 screening of pregnant women is not done routinely and HTLV-1 awareness programs are nonexistent outside of a few specialized medical centers. In our series, six women (40%) were probably infected by their mothers during breastfeeding and at least eight (53%) transmitted HTLV-1 to their infants. These numbers might be higher as some relatives and children were not tested for HTLV-1 infection. The rate of transmission clearly increases with the length of breastfeeding from 4% when children are breastfed less than 6 months to almost 40% with prolonged breastfeeding (more than 1 year) [41,42,43,44,45]. In Peru, breastfeeding for up to 2 years is a common practice and is highly promoted as a strategy to reduce child morbidity and mortality, especially among women from lower socio-economic status. Therefore, interventions to screen pregnant women and prevent HTLV-1 vertical transmission should carefully balance the vital benefit of breastfeeding practices with the risk of transmission. In this perspective, counseling of HTLV-1 pregnant women and personalized interventions depending on socio-economic resources, familial support, and availability of national programs are crucial. In addition, if pregnancy does indeed play a role in disease progression, counseling of HTLV-1 infected women should be broadened to inform them about these risks.
Despite limitations related to the study design, the number of cases is high enough to be intriguing. We were only able to identify women who spontaneously reported symptoms in relation to pregnancy during previous medical visits; as a result, a comparison with other women in the cohort could not be performed. The lack of a control group limits our ability to directly assess the impact of pregnancy on the onset or worsening of HAM/TSP. Additionally, there is a lack of comprehensive literature specifically addressing the impact of pregnancy on HAM/TSP. The in-person interviews might have introduced recall bias in patients who presented the event of interest many years ago. For instance, they might have better recalled motor impairment than urinary or bowel disorder. We minimized this bias by comparing data from interviews to data from medical charts whenever possible.

5. Conclusions

There is an urgent need to better understand the disease pathogenesis of HAM/TSP and the triggers of disease progression to prevent irreversible neurologic damage. Also, the role of proviral load before, during, and after pregnancy should be studied to find correlations. This case series provides new insights into the possible role of gestational and postpartum immune changes on HAM/TSP progression that should be further evaluated. It has potential implications for counseling HTLV-1-infected women regarding pregnancy and in the development of novel therapeutic and preventive approaches. In addition, strategies to prevent vertical transmission and to counsel alternative feeding practices among HTLV-1-infected mothers should be developed and evaluated in endemic regions of Latin America, working towards stemming the tide of HTLV-1 transmission and reducing the burden of associated complications.

Author Contributions

Conceptualization, F.A.J. and M.L.R.; methodology, F.A.J., M.L.R., E.G.-L., C.A. and E.G.; software, M.L.R.; validation, F.A.J., M.L.R., E.G.-L., C.A., M.T., K.L. and E.G.; formal analysis, F.A.J., M.L.R. and M.T.; investigation, F.A.J. and M.L.R.; resources, F.A.J. and M.L.R.; data curation, F.A.J. and M.L.R.; writing—original draft preparation, F.A.J., M.L.R., E.G.-L., C.A., M.T. and E.G.; writing—review and editing, F.A.J., M.L.R., E.G.-L., K.L. and E.G.; visualization, K.L. and E.G.; supervision, E.G.; project administration, F.A.J., M.L.R., E.G.-L., C.A., K.L. and E.G.; funding acquisition, F.A.J., M.L.R., E.G.-L., and E.G. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of Universidad Peruana Cayetano Heredia (Protocol code 059195 6 March 2012).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

Data is not available publicly due to privacy and ethical restrictions.

Acknowledgments

We thank the nurses Suzeth Olivares, Viviana Quintana, Giovanna Campos, and Yessica Ramos for their help in conducting this research and Giovanni López from the laboratory for his help in performing PVL. The HTLV-1 cohort is funded by the Belgian Cooperation through a project of Institutional collaboration between the Institute of Tropical Medicine in Antwerp and the Instituto de Medicina Tropical Alexander von Humboldt in Lima.

Conflicts of Interest

The authors declare no conflict of interest.

Appendix A

Table A1. Individual demographic characteristics and risk factors for HTLV-1 acquisition.
Table A1. Individual demographic characteristics and risk factors for HTLV-1 acquisition.
Pt NoMarital StatusRace or Ethnicity aLength of Breastfeeding Received Blood Transfusion, YearFamily Members HTLV-1 Positive Family Members with Paralytic DiseaseProbable Way of Acquisition
1MarriedMestizo6 months to 1 year1981 bHusband, daughter-Sexual or transfusion?
2SingleAndean/Quechua>1 yearNoSister, 2 daughtersSister, daughterBreastfeeding?
3PartnerMestizo<6 months2000, 2005, 2006 cFather d, husband, sonHusband, sonSexual or breastfeeding?
4SingleMestizo6 months to 1 yearNo--UK
5MarriedAndean/Quechua>2 yearsNoHusband-Sexual?
6PartnerAndean/Quechua>1 yearNo--UK
7PartnerMestizo>2 yearsNoFather d, mother, 2 sistersMother, sisterBreastfeeding?
8WidowedAndean/Quechua>2 yearsNoSister, 3 childrenSisterBreastfeeding?
9PartnerAndean/Quechua6 months to 1 yearNoMother-Breastfeeding?
10SingleMestizo>2 yearsNoChild-UK
11MarriedAndean/Quechua1 to 2 yearsNo--UK
12MarriedAndean/Quechua1 to 2 years1981 bDaughter-Transfusion?
13MarriedAndean/Quechua1 to 2 yearsNoSister, niece, daughter-Breastfeeding?
14 eMarriedAndean/Quechua> 1 yearNo--UK
15PartnerMestizo> 1 year1995Daughter-Transfusion (confirmed)
UK: Unknown; pt: Patient; a Ethnic background was defined as Quechua if the patient defines herself as such and/or if she spoke the Quechua language; b These patients received a blood transfusion before their HTLV-1 diagnosis was confirmed; c This patient received a blood transfusion after her HTLV-1 diagnosis was confirmed; d Father died of adult T-cell leukemia/lymphoma (ATTL); e Patient died in 2008.

Appendix B

Table A2. Individual clinical and obstetrical characteristics.
Table A2. Individual clinical and obstetrical characteristics.
Pt NoYear of OnsetDx Delay (Years)DeliveryTime from Delivery to SymptomsSymptoms from Medical Chart In-Person InterviewType of Delivery and Postpartum ComplicationDelivery OrderWorsening after Successive DeliveriesPVL (Copies per 104 PBMC) (Year)
AgeYearSelf-Reported Symptoms aActivity Modifications
1 b199103819914 monthsDifficulty walking c, --UKLast (3)NA(Lost to follow up)
219951361995<1 weekDifficulty walking cWeakness, numbnessStop working, doing chores, and taking kids to schoolVaginal, postpartum depressionLast (3)NA7526 (2006); 5060 (2012)
3199513319952 monthsDifficulty walking c, Weakness R > L, constipation, mixed incontinenceStop working VaginalLast (5)NA5057 (2012)
420020392002<1 monthDifficulty walking c, Weakness L > R, electric currents, constipation, urge incontinenceStop going out alone, still workingVaginal First (1)NA1653 (2004), 4434 (2012)
5198212261982<1 weekDifficulty walking c, Weakness, stumbling, incontinence, constipationStop working, doing chores, still cookVaginalLast (3)NA9271 (2012)
6 b200702520071.5 monthDifficulty walking c,d--Hyperemesis gravidarumLast (2)NA2608 (2007)
7199913211999<1 weekDifficulty walking cWeakness, numbness, stumbling, knee painStop going out aloneC-section for fetal distressFirst (1)NA3176 (2012)
81962422019621 monthDifficulty walking cStumbling, numbnessStop working, doing choresVaginalFirst (7)Yes f2779 (2006), 4384 (2012)
9199962819992 monthsDifficulty walking cStumbling, lumbar painNormal activitiesC-section, cardiac malformation in NBFirst (2)Yes3035 (2006), 3849 (2012)
101996102919961 weekDifficulty walking cWeakness, cramps, spasmsStop working, doing choresVaginalFirst (2)Yes8150 (2012)
111978243519832 monthsDifficulty walking cWorsened weakness, spasms, stumbling d, paresthesiaStop working, doing choresVaginal, maternal malariaLast (2)NA8667 (2012)
12199053619931 weekDifficulty walking cWorsened weakness, numbness, stumbling dStop working, doing choresC-section, twinsLast (4)NA2267 (2012)
131999132420092 weeksDifficulty walking cWorsened weakness and stumbling dStop walking with heels, long distance, could not carry her NB in her armsC-section, preeclampsiaFirst (1)NA9981 (2012)
14 b198573919941 weekCould not walk anymore (wheelchair) e-Stop working, doing choresC-sectionLast (4)NA7473 (2007)
15199923420071 weekDifficulty walking cWorsened weakness, numbness, stumbling dStop workingVaginal, premature NBThird (4)Yes g3481 (2006), 8200 (2012)
Pt: Patient; Dx: Diagnostic; UK: Unknown; NA: Not applicable; NB: Newborn; R: right; L: left; a Symptoms are for lower extremities if not otherwise specified; b Lost to follow up: Pt #1 in 1997 when diagnosed with ATLL, Pt #6 in 2007 when diagnosed with HAM/TSP, and Pt # 14 in 2008, deceased; c Also includes difficulty climbing stairs, or getting up from chairs; d These four patients reported clear exacerbations of motor symptoms after delivery; e This patient had stumbling and mouth dryness before delivery and severe motor impairment after delivery (wheelchair); f This patient reported symptoms of HAM/TSP after first pregnancy and exacerbations after the 6th successive pregnancies; g This patient was infected by transfusion in 1995 while breastfeeding her second child, had first symptoms of HAM/TSP in2001 and exacerbations after third and fourth pregnancies in 2007 and 2010.

Appendix C

Table A3. Case series characteristics.
Table A3. Case series characteristics.
Characteristics (N = 15)Sub-Categoriesn (%)Mean (SD)Median (Range)
Quechua ethnicity 9 (60)
History of breastfeeding <6 months1 (7)
≥6 months–<1 year3 (20)
≥1 year11 (73)
History of blood transfusion before 1998 3 (20)
Women with HTLV-1 infected children 8 (53)
Women with HTLV-1 infected family members 11 (73)
Delay to diagnosis 6 (0–42
Age at delivery (years)Women with onset (n = 10) 29.5 (6.8)28.5 (20–39)
Women with worsening (n = 5) 33.2 (7.8)35 (24–39)
Time from delivery to symptoms (weeks)Women with onset (n = 10) 3 (0.5–16)
Women with worsening (n = 5) 1 (1–8)
Symptoms within 1 month of delivery 10 (67)
Symptoms within 4 months of delivery 15 (100)
In-person interviews (n = 12)
Self-reported symptoms at onsetWeakness11 (92)
Stumbling8 (67)
Numbness5 (42)
Sphincter dysfunction3 (25)
Other symptoms a5 (42)
Interference with daily activity 12 (100)
Stop working due to symptoms 9 (75)
Neurologic exam (2012)
Pyramidal symptoms b 12 (100)
Urinary complaints c 12 (100)
Bowel continence (constipation) 10 (83)
Duration of disease (years) 16.5 (10–50)
Time to wheelchair (years) 26 (13–36)
Permanent use of wheelchair use 5 (42)
Fast disease progression 1 (8)
Treatment with myorelaxant 10 (83)
Treatment with myorelaxant, antiretroviral, prednisone 3 (25)
Kurtzke EDSS d score 6 (4.5–8)
a Includes lumbar pain, cramps, spasms, paresthesia, electric current, knee pain; b Pyramidal signs: hyperreflexia, Babinski sign, clonus, and/or Hoffmann sign (stretching reflex in which the examiner snaps with his thumbnail on the nail of the patient’s middle finger: the sign is positive if the patient makes a grasping movement with the thumb and the index finger); c Includes urgency, incontinence or retention, or use of permanent catheter or regular use of relieve catheter; d The Kurtzke Expanded Disability Status Scale (EDSS), developed for multiple sclerosis, is used to measure disability in HAM/TSP. A score of 1 to 5.5 means ambulatory but with progressive limitation of the walking perimeter and impairment of daily activities, a score of 6 means permanent walking assistance, 7 means restriction to a wheelchair, 8.5 restriction to bed and 10 corresponds to death due to the disease [12].

References

  1. Verdonck, K.; Gonzalez, E.; Van Dooren, S.; Vandamme, A.M.; Vanham, G.; Gotuzzo, E. Human T-lymphotropic virus 1: Recent knowledge about an ancient infection. Lancet Infect. Dis. 2007, 7, 266–281. [Google Scholar] [CrossRef] [PubMed]
  2. Gessain, A.; Mahieux, R. Tropical spastic paraparesis and HTLV-1 associated myelopathy: Clinical, epidemiological, virological and therapeutic aspects. Rev. Neurol. 2012, 168, 257–269. [Google Scholar] [CrossRef]
  3. Araujo, A.Q.; Leite, A.C.; Lima, M.A.; Silva, M.T. HTLV-1 and neurological conditions: When to suspect and when to order a diagnostic test for HTLV-1 infection? Arq. Neuropsiquiatr. 2009, 67, 132–138. [Google Scholar] [CrossRef]
  4. Gotuzzo, E.; Cabrera, J.; Deza, L.; Verdonck, K.; Vandamme, A.M.; Cairampoma, R.; Vizcarra, D.; Cabada, M.; Narvarte, G.; Casas, C.D.L. Clinical characteristics of patients in Peru with human T cell lymphotropic virus type 1-associated tropical spastic paraparesis. Clin. Infect. Dis. 2004, 39, 939–944. [Google Scholar] [CrossRef] [PubMed]
  5. Olindo, S.; Cabre, P.; Lézin, A.; Merle, H.; Saint-Vil, M.; Signate, A.; Bonnan, M.; Chalon, A.; Magnani, L.; Cesaire, R.; et al. Natural history of human T-lymphotropic virus 1-associated myelopathy: A 14-year follow-up study. Arch. Neurol. 2006, 63, 1560–1566. [Google Scholar] [CrossRef] [PubMed]
  6. Casseb, J. Is human T cell lymphotropic type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) syndrome a neglected disease? PLoS Negl. Trop. Dis. 2009, 3, e487. [Google Scholar] [CrossRef]
  7. Bangham, C.R.; Osame, M. Cellular immune response to HTLV-1. Oncogene 2005, 24, 6035–6046. [Google Scholar] [CrossRef]
  8. Lepoutre, V.; Jain, P.; Quann, K.; Wigdahl, B.; Khan, Z.K. Role of resident CNS cell populations in HTLV-1-associated neuroinflammatory disease. Front. Biosci. 2009, 14, 1152–1168. [Google Scholar] [CrossRef]
  9. Saito, S.; Nakashima, A.; Shima, T.; Ito, M. Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy. Am. J. Reprod. Immunol. 2010, 63, 601–610. [Google Scholar] [CrossRef]
  10. WHO Diagnostic Guidelines for TSP/HAM. Report of WHO Scientific Group on HTLV-1 Infection and Associated Diseases (Kagoshima, Japan 10–15 December 1988). Weekly Epidemiological Record. March 1989. Available online: http://www.who.int/wer/en/ (accessed on 2 June 2013).
  11. De Castro-Costa, C.M.; Araújo, A.Q.C.; Barreto, M.M.; Takayanagui, O.M.; Sohler, M.P.; Da Silva, E.L.M.; De Paula, S.M.B.; Ishak, R.; Ribas, J.G.R.; Rovirosa, L.C.; et al. Proposal for diagnostic criteria of tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM). AIDS Res. Hum. Retroviruses 2006, 22, 931–935. [Google Scholar] [CrossRef]
  12. Adaui, V.; Verdonck, K.; Best, I.; González, E.; Tipismana, M.; Arévalo, J.; Vanham, G.; Campos, M.; Zimic, M.; Gotuzzo, E. SYBR green-based quantitation of human T-lymphotropic virus type 1 proviral load in Peruvian patients with neurological disease and asymptomatic carriers: Influence of clinical status, sex, and familial relatedness. J. Neurovirol. 2006, 12, 456–465. [Google Scholar] [CrossRef]
  13. Kurtzke, J.F. Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS). Neurology 1983, 33, 1444–1452. [Google Scholar] [CrossRef]
  14. Mizokami, T.; Okamura, K.; Sato, K.; Kuroda, T.; Itoyama, Y.; Fujishima, M. Postpartum exacerbation of HTLV-I associated myelopathy/tropical spastic paraparesis followed by an episode of painless thyroiditis. Intern. Med. 1994, 33, 703–705. [Google Scholar] [CrossRef]
  15. Zihlmann, K.F.; de Alvarenga, A.T.; Casseb, J. Living Invisible: HTLV-1-infected persons and the lack of care in public health. PLoS Negl. Trop. Dis. 2012, 6, e1705. [Google Scholar] [CrossRef] [PubMed]
  16. Bohiltea, R.E.; Turcan, N.; Berceanu, C.; Munteanu, O.; Georgescu, T.A.; Ducu, I.; Neacsu, A.; Furtunescu, F. Implications of human T-lymphotropic virus in pregnancy: A case report and a review of the diagnostic criteria and management proposal. Exp. Ther. Med. 2021, 21, 82. [Google Scholar] [CrossRef] [PubMed]
  17. Araujo, A.Q.; Silva, M.T. The HTLV-1 neurological complex. Lancet Neurol. 2006, 5, 1068–1076. [Google Scholar] [CrossRef] [PubMed]
  18. Toldi, G.; Saito, S.; Shima, T.; Halmos, A.; Veresh, Z.; Vásárhelyi, B.; Rigó, J.; Molvarec, A. The frequency of peripheral blood CD4+ CD25high FoxP3+ and CD4+ CD25- FoxP3+ regulatory T cells in normal pregnancy and pre-eclampsia. Am. J. Reprod. Immunol. 2012, 68, 175–180. [Google Scholar] [CrossRef] [PubMed]
  19. Steinborn, A.; Schmitt, E.; Kisielewicz, A.; Rechenberg, S.; Seissler, N.; Mahnke, K.; Schaier, M.; Zeier, M.; Sohn, C. Pregnancy-associated diseases are characterized by the composition of the systemic regulatory T cell (Treg) pool with distinct subsets of Tregs. Clin. Exp. Immunol. 2012, 167, 84–98. [Google Scholar] [CrossRef] [PubMed]
  20. Bangham, C.R. Human T-lymphotropic virus type 1 (HTLV-1): Persistence and immune control. Int. J. Hematol. 2003, 78, 297–303. [Google Scholar] [CrossRef]
  21. Tattermusch, S.; Bangham, C.R. HTLV-1 infection: What determines the risk of inflammatory disease? Trends Microbiol. 2012, 20, 494–500. [Google Scholar] [CrossRef]
  22. Asquith, B.; Mosley, A.J.; Barfield, A.; Marshall, S.E.; Heaps, A.; Goon, P.; Hanon, E.; Tanaka, Y.; Taylor, G.P.; Bangham, C.R.M. A functional CD8+ cell assay reveals individual variation in CD8+ cell antiviral efficacy and explains differences in human T-lymphotropic virus type 1 proviral load. J. Gen. Virol. 2005, 86 Pt 5, 1515–1523. [Google Scholar] [CrossRef] [PubMed]
  23. Bangham, C.R. CTL quality and the control of human retroviral infections. Eur. J. Immunol. 2009, 39, 1700–1712. [Google Scholar] [CrossRef] [PubMed]
  24. Saito, M. Immunogenetics and the Pathological Mechanisms of Human T-cell Leukemia Virus Type 1 (HTLV-1) Associated Myelopathy/tropical Spastic Paraparesis (HAM/TSP). Interdiscip. Perspect. Infect Dis. 2010, 2010, 478461. [Google Scholar] [CrossRef]
  25. Jeffery, K.J.M.; Usuku, K.; Hall, S.E.; Matsumoto, W.; Taylor, G.P.; Procter, J.; Bunce, M.; Ogg, G.S.; Welsh, K.I.; Weber, J.N.; et al. HLA alleles determine human T-lymphotropic virus-I (HTLV-I) proviral load and the risk of HTLV-I-associated myelopathy. Proc. Natl. Acad. Sci. USA 1999, 96, 3848–3853. [Google Scholar] [CrossRef] [PubMed]
  26. Vine, A.M.; Heaps, A.G.; Kaftantzi, L.; Mosley, A.; Asquith, B.; Witkover, A.; Thompson, G.; Saito, M.; Goon, P.K.C.; Carr, L.; et al. The role of CTLs in persistent viral infection: Cytolytic gene expression in CD8+ lymphocytes distinguishes between individuals with a high or low proviral load of human T cell lymphotropic virus type 1. J. Immunol. 2004, 173, 5121–5129. [Google Scholar] [CrossRef]
  27. Satou, Y.; Utsunomiya, A.; Tanabe, J.; Nakagawa, M.; Nosaka, K.; Matsuoka, M. HTLV-1 modulates the frequency and phenotype of FoxP3+CD4+ T cells in virus-infected individuals. Retrovirology 2012, 9, 46. [Google Scholar] [CrossRef]
  28. Ramirez, E.; Cartier, L.; Rodriguez, L.; Alberti, C.; Valenzuela, M.A. In vivo fluctuation of Tax, Foxp3, CTLA-4, and GITR mRNA expression in CD4(+)CD25(+) T cells of patients with human T-lymphotropic virus type 1-associated myelopathy. Braz. J. Med. Biol. Res. 2010, 43, 1109–1115. [Google Scholar] [CrossRef]
  29. Oh, U.; Grant, C.; Griffith, C.; Fugo, K.; Takenouchi, N.; Jacobson, S. Reduced Foxp3 protein expression is associated with inflammatory disease during human t lymphotropic virus type 1 infection. J. Infect. Dis. 2006, 193, 1557–1566. [Google Scholar] [CrossRef]
  30. Birk, K.; Rudick, R. Pregnancy and multiple sclerosis. Arch. Neurol. 1986, 43, 719–726. [Google Scholar] [CrossRef]
  31. De Man, Y.A.; Bakker-Jonges, L.E.; Dufour-Van Den Goorbergh, C.M.; Tillemans, S.P.R.; Hooijkaas, H.; Hazes, J.M.W.; Dolhain, R.J.E.M. Women with rheumatoid arthritis negative for anti-cyclic citrullinated peptide and rheumatoid factor are more likely to improve during pregnancy, whereas in autoantibody-positive women autoantibody levels are not influenced by pregnancy. Ann. Rheum. Dis. 2010, 69, 420–423. [Google Scholar] [CrossRef]
  32. Kaaja, R.J.; Greer, I.A. Manifestations of chronic disease during pregnancy. JAMA 2005, 294, 2751–2757. [Google Scholar] [CrossRef]
  33. Confavreux, C.; Hutchinson, M.; Hours, M.M.; Cortinovis-Tourniaire, P.; Moreau, T.; Pregnancy in Multiple Sclerosis Group. Rate of pregnancy-related relapse in multiple sclerosis. N. Engl. J. Med. 1998, 339, 285–291. [Google Scholar] [CrossRef] [PubMed]
  34. Hughes, M.D. Multiple sclerosis and pregnancy. Neurol. Clin. 2004, 22, 757–769. [Google Scholar] [CrossRef] [PubMed]
  35. Araujo, A.; Bangham, C.R.M.; Casseb, J.; Gotuzzo, E.; Jacobson, S.; Martin, F.; Penalva de Oliveira, A.; Puccioni-Sohler, M.; Taylor, G.P.; Yamano, Y. Management of HAM/TSP: Systematic Review and Consensus-based Recommendations. Neurol. Clin. Pract. 2021, 11, 49–56. [Google Scholar] [CrossRef] [PubMed]
  36. Yamauchi, J.; Tanabe, K.; Sato, T.; Nakagawa, M.; Matsuura, E.; Tsuboi, Y.; Tamaki, K.; Sakima, H.; Ishihara, S.; Ohta, Y.; et al. Efficacy of Corticosteroid Therapy for HTLV-1-Associated Myelopathy: A Randomized Controlled Trial (HAMLET-P). Viruses 2022, 14, 136. [Google Scholar] [CrossRef]
  37. Ando, Y.; Matsumoto, Y.; Kakimoto, K.; Tangigawa, T. Pregnancy complicated by HTLV-I associated myelopathy: Two cases. Arch. Gynecol. Obstet. 2003, 268, 61–64. [Google Scholar] [CrossRef]
  38. Ville, Y.; Delaporte, E.; Peeters, M.; Leruez, M.; Glowaczower, E.; Fernandez, H. Human T-cell lymphotropic virus type I infection and pregnancy: A case-control study and 12-month follow-up of 135 women and their infants. Am. J. Obstet. Gynecol. 1991, 65 Pt 1, 1438–1443. [Google Scholar] [CrossRef]
  39. Mori, H.; Shibata, E.; Kuwazuru, T.; Uchimura, T.; Kondo, E.; Iwanaka, Y.; Yoshino, K. Pregnancy complicated by HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP): A case report. Clin. Case Rep. 2021, 9, e04511. [Google Scholar] [CrossRef]
  40. Komatsu, N.; Iwanaga, M.; Hasegawa, Y.; Miura, S.; Fuchi, N.; Moriuchi, H.; Yanagihara, K.; Miura, K. Frequency of HTLV-1 seroconversion between pregnancies in Nagasaki, Japan, 2011–2018. Front. Microbiol. 2022, 13, 1036955. [Google Scholar] [CrossRef]
  41. Gotuzzo, E.; Moody, J.; Verdonck, K.; Cabada, M.M.; González, E.; Van Dooren, S.; Vandamme, A.-M.; Terashima, A.; Vermund, S.-H. Frequent HTLV-1 infection in the offspring of Peruvian women with HTLV-1 associated myelopahty/tropical spastic paraparesis or strongyloidiasis. Rev. Panam. Salud Publica 2007, 22, 223–230. [Google Scholar] [CrossRef]
  42. Hino, S. Establishment of the milk-borne transmission as a key factor for the peculiar endemicity of human T-lymphotropic virus type 1 (HTLV-1): The ATL Prevention Program Nagasaki. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 2011, 87, 152–166. [Google Scholar] [CrossRef] [PubMed]
  43. Wiktor, S.Z.; Pate, E.J.; Rosenberg, P.S.; Barnett, M.; Palmer, P.; Medeiros, D.; Maloney, E.M.; A Blattner, W. Mother-to-child transmission of human T-cell lymphotropic virus type I associated with prolonged breast-feeding. J. Hum. Virol. 1997, 1, 37–44. [Google Scholar] [PubMed]
  44. Catalan-Soares, B.C.; Almeida, R.T.; Carneiro-Proietti, A.B. Prevalence of HIV-1/2, HTLV-I/II, hepatitis B virus (HBV), hepatitis C virus (HCV), Treponema pallidum and Trypanosoma cruzi among prison inmates at Manhuaҁu, Minas Gerais State, Brazil. Rev. Soc. Bras. Med. Trop. 2000, 33, 27–30. [Google Scholar] [CrossRef]
  45. Li, H.; Biggar, R.J.; Miley, W.J.; Maloney, E.M.; Cranston, B.; Hanchard, B.; Hisada, M. Provirus load in breast milk and risk of mother-to-child transmission of human T lymphotropic virus type I. J. Infect. Dis. 2004, 190, 1275–1278. [Google Scholar] [CrossRef] [PubMed]
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MDPI and ACS Style

Jacquerioz, F.A.; La Rosa, M.; González-Lagos, E.; Alvarez, C.; Tipismana, M.; Luhmann, K.; Gotuzzo, E. Progression of HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis after Pregnancy: A Case Series and Review of the Literature. Pathogens 2024, 13, 731. https://doi.org/10.3390/pathogens13090731

AMA Style

Jacquerioz FA, La Rosa M, González-Lagos E, Alvarez C, Tipismana M, Luhmann K, Gotuzzo E. Progression of HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis after Pregnancy: A Case Series and Review of the Literature. Pathogens. 2024; 13(9):731. https://doi.org/10.3390/pathogens13090731

Chicago/Turabian Style

Jacquerioz, Frederique A., Mauricio La Rosa, Elsa González-Lagos, Carolina Alvarez, Martin Tipismana, Karen Luhmann, and Eduardo Gotuzzo. 2024. "Progression of HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis after Pregnancy: A Case Series and Review of the Literature" Pathogens 13, no. 9: 731. https://doi.org/10.3390/pathogens13090731

APA Style

Jacquerioz, F. A., La Rosa, M., González-Lagos, E., Alvarez, C., Tipismana, M., Luhmann, K., & Gotuzzo, E. (2024). Progression of HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis after Pregnancy: A Case Series and Review of the Literature. Pathogens, 13(9), 731. https://doi.org/10.3390/pathogens13090731

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