Expanding the etiologic spectrum of spastic ataxia syndrome: chronic infection with human T lymphotropic virus type 1

Human T-lymphotropic virus type-1 (HTLV-1) is a neglected infection most often associated with an indolent process. However, a subset of HTLV-1 seropositive patients face the risk to develop life-threatening T-cell lymphoma/leukemia, or the highly disabling and incurable HTLV1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Over the years, other complications to HTLV-1 have been proposed and debated intensely. One of these, although rare, associations include cerebellar ataxia occurring most often in Japanese patients with manifest HAM/TSP. Here we present a HTLV-1 seropositive patient from the Middle East featuring a slowly progressive cerebellar syndrome with cerebellar atrophy but not evidence of spastic paraparesis. In addition, this patient suffered from autoimmune conditions such as Sjögren’s syndrome and vitiligo which are putatively associated with HTLV-1.


Case presentation
Written consent was obtained for this case report, approved by the Ethics Committee in Stockholm. A 68-year-old woman from Mashhad, Iran, was referred for a progressive movement disorder. Onset of neurological symptoms was at age 59, 6 years before HTLV-1 infection was diagnosed as a result of contact tracing. The patient reported insidious onset of gait difficulties, obstipation, and urinary urgency. During follow-up, falls started to occur motivating the use of a walker. Her comorbidities consisted of hypertension, fibromyalgia, right shoulder impingement, asthma, Sjögren's syndrome, vitiligo, tremor, and a history of surgery for ileus. Examination at age 62 revealed postural and action hand tremor, dysmetria, axial difficulties, and inability to perform tandem gait. The patient had brisk patellar reflexes (3+), normal Achilles reflexes, and absence of Babinski's sign. In addition, her muscle tone, strength, and sensation to touch and pin prick were normal. Vibration sense in her malleoli and proprioception were impaired with subsequent abnormal Romberg's test; the retropulsion test was normal. Her altering hand movements were irregular; bradykinesia was absent. The patient also displayed hypermetric saccades. Her Scale for the Assessment and Rating of Ataxia score rose from 7.5 to 9.5 and Instituto de Pesquisa Clinica Evandro Chagas HAM disability scale, from 8 to 10, over 5 years.
Neuroimaging demonstrated cerebellar atrophy ( Fig. 1) but not evidence of widespread white matter abnormalities (WMA); lumbar spondylosis was evident, but there were no abnormalities in the spinal cord. Electromyography, electroneurography, sensory (SEP), and motor-evoked potentials (MEP) were normal except for incidental carpal tunnel syndrome.
Computed tomography of her chest and abdomen showed an enlarged thyroid gland but the patient was euthyroid; a biopsy aspirate demonstrated colloid cells only. Mammography was initially normal but at age 68, she was diagnosed with a breast tumor treated with surgery and chemotherapy. Oral steroids were given with chemotherapy, but this did not alleviate the patient's motor symptoms.

Discussion
So far, 20 HTLV-1 seropositive patients displaying ataxia have been reported, mostly in Japan. All but two had manifest HAM/TSP, which suggests that pyramidal signs may overshadow subtle cerebellar signs and nystagmus (Kira et al. 1993). Only in three cases, cerebellar signs preceded pyramidal signs (e3, e4, e7). In our case, urgency, obstipation, hyperreflexia, and impaired vibration suggest an incipient myelopathy even though she does not have spastic paraparesis. Ataxia among HTLV-1-positive patients is associated with variable cerebellar atrophy (40% of cases) and rarely with WMA, pontocerebellar, or spinal cord atrophy (Kira et al. 1993 e-2-e-6). Insidious onset, slow course, and long latency between ataxia onset and diagnosis of breast cancer (9 years) argue strongly against paraneoplastic cerebellar degeneration (PCD). Furthermore, absence of onconeuronal antibodies and the pattern of CSF alterations add support to the exclusion of PCD.
β2M is elevated in some hematological malignancies and renal impairment but is also used as a surrogate marker for HAM/TSP (e-7). In this case, β2M and PVL increased during follow-up and PVL in the CSF was high. Of note, determining PVL in the CSF is challenging due to the low number of leukocytes in CSF.
Importantly, neurological complications are associated with high PVL (> 1 HTLV DNA copy per 100 PBMC, > 1%). β2M is a component of the major histocompatibility complex class 1 and a key element in immediate immune response. As a consequence of the inflammatory reaction, chronic inflammation of the nervous system may occur in predisposed individuals, leading to permanent neurological dysfunction. The pattern of interleukin elevation in the CSF has been reported in HAM/TSP patients with very slow progression (Sato et al. 2018). Clinical stratification with patterns of neopterin and CXCL10 predict response to treatment with steroids (Sato et al. 2018). Thus, very slow progression and mild elevations of neopterin and CXCL10 may explain the lack of benefit for treatment with oral steroid, albeit at a lower dosage than used in HAM/TSP, in our case. Raised serum β2M and HTLV-1 PVL > 1% in blood and higher in CSF, as well as elevated concentrations of neopterin and CXCL10 in CSF support the notion of a putative association between cerebellar ataxia and HTLV-1. Our findings have to be replicated in other ataxia and spastic ataxia cases associated with HTLV-1; in addition, more neuropathological studies are warranted in order to characterize the neuroanatomic correlations to motor dysfunction. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.