LETTERS TO THE EDITOR

HTLV-1–ASSOCIATED MYELOPATHY/ TROPICAL SPASTIC PARAPARESIS AND PERIPHERAL NEUROPATHY FOLLOWING LIVE-DONOR RENAL TRANSPLANTATION A 59-year-old Jamaican woman with renal failure due to diabetic nephropathy developed weakness, sensory loss, and gait difficulty 8 years after live-donor organ renal transplantation from a healthy Jamaican woman. She had stable allograft function on tacrolimus 5 mg/day, prednisone 5 mg/day, and mycophenolate mofetil 1000 mg/ day. She denied exposure to illicit drugs, blood transfusions, contaminated needles, or sexual exposure to human T-lymphotropic virus type 1 (HTLV-I). Examination showed 31/5 strength in proximal and distal leg muscles, with stocking vibratory, proprioceptive, and cold temperature sensory loss. Tendon reflexes were hypoactive in the ankles, but were otherwise brisk throughout with Hoffman and Babinski signs and sustained ankle clonus. Arm function, cranial nerves, and cognition were normal. Laboratory evaluation showed positive HTLV-I/II serum antibodies according to enzyme-linked immunosorbent assay (ELISA), with strongly reactive GD21, p19, p24, p26, p36, and rgp46-I bands on Western blot analysis. Cerebrospinal fluid (CSF) also showed positive HTLV-I/II antibodies by ELISA and strong reactivity to GD21, p19, p24, and rgp46-I bands on Western blot analysis. Non-contrast brain and spinal magnetic resonance imaging (MRI) showed abnormal periventricular and subcortical white-matter changes with diffusely decreased caliber of the mid-thoracic spinal cord. Electrodiagnostic (EDX) studies of the legs were consistent with chronic axonal and demyelinating neuropathy. Epidermal nerve fiber (ENF) analysis of the distal leg showed 0.13 fibers/mm skin (range 0–0.35 fibers/mm, 5th percentile reference value 5.0/mm) with excessively thin, shortened, and focally swollen axons (Fig. 1a). Head-up tilt showed symptomatic orthostatic intolerance evidenced by a drop of 37 mm Hg in systolic blood pressure at 4.5 minutes and a 14-beat/minute increase in heart rate. Sural nerve biopsy showed a significant reduction in axonal density with foci of axonal sprouting and

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Letters to the Editor

clusters consistent with regeneration (Fig. 1b). Thinly myelinated fibers were surrounded by layers of Schwann cell processes forming onion bulbs (Fig. 1c). Unmyelinated fibers were moderately reduced in density. A demyelinating component was evidenced by segmental demyelination, tomacula formation, and remyelination in a significant percentage of teased fibers. Cellular inflammation was absent. The patient was treated with raltegravin 400 mg twice daily upon diagnosis of HTLV-I– associated myelopathy/tropical spastic paraparesis (HAM/TSP) and has since remained on that medication. She was unchanged when last examined in July 2014. The patient met formal clinical, laboratory diagnostic and histopathologic criteria of the World Health Organization (WHO) for HAM.1 These criteria established equivalency of the 2 disorders and proposed the acronym HAM/TSP for future case ascertainment. With an overall estimated HTLV-I seroprevalence of 6.1%, the age-standardized incidence rate of 1.8 per 100,000 person-years in Jamaica,2 and absent information as to the serologic status of the patient and the organ donor, it was uncertain whether HAM/TSP resulted from an infected organ transplant or reactivation of prior retroviral exposure. Recognizing the reported lifetime risk of progression from HTLV-I to HAM/TSP of only 1.8% in Jamaica,3 it seems likely that HTLV-I exposure occurred at the time of transplantation from the donor. A terminally ill child received a live-donor kidney from her infected mother and developed neurological disease after 4 years.4 Two other patients who received renal transplants from a single asymptomatic seropositive living donor infected with a large inoculum of the highly virulent Cosmopolitan A strain rapidly developed subacute myelopathy.5 The EDX and histopathologic findings in this patient were consistent with previously described peripheral nervous system involvement in HAM/TSP.6,7 ENF results correlated with autonomic studies and the reduced density of unmyelinated fibers in sural nerve sections. The lesions identified on MRI corresponded to those reported in the central nervous system of patients with chronic HTLV-I infection.8,9 Such lesions were distributed concomitantly in the brain and spinal cord and corresponded to areas of reduced blood flow that included deep subcortical white matter and lateral columns of the middle thoracic cord in patients with either acute or MUSCLE & NERVE

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appears to protect against the associated central nervous system inflammatory disease by reducing the proviral load; however, when the latter exceeds a threshold level, cytotoxic T cells can contribute to infection.12 Although the effect of immunosuppression on the development of HAM/TSP in the patient described here is not well understood, posttransplant immunosuppression could theoretically slow progression of HAM/TSP by suppressing proliferation of infected T cells.13 The Organ Procurement Transplantation Network/United Network of Organ Sharing recommends confirmatory immunoblot testing for positive HTLV-I results by ELISA14 to assure that non-diseased organs are not discarded unnecessarily. David S. Younger, MD Department of Neurology, New York University School of Medicine, New York, New York

FIGURE 1. (a) Epidermal nerve fibers exhibit focal swelling along the dermoepidermal junction (arrows). Rare axons entering into the epidermis are thin and markedly short (PGP 9.5; original magnification: 4003). (b) A section of sural nerve shows a significant reduction in axonal density with foci of axonal sprouting and clusters (arrows) (semithin epoxy resin; original magnification: 6003). (c) A section of sural nerve shows thinly myelinated fibers surrounded by thin multilayered Schwann cell processes (arrows) (semithin epoxy resin; original magnification: 6003).

chronic infection. Immunohistochemical staining of chronic lesions of the brain and spinal cord lesions typically shows predominance of perivascular University College Hospital lymphocyte-1 (UCHL-11) with cluster-ofdifferentiation (CD)1 B cells, CD41, and CD81 cytotoxic T cells. There may be variable expression of interleukin1b (IL-1b), tumor necrosis factor-a (TNF-a), interferon-c (INF-c), migration inhibitory factor–related protein 8 (MRP8), MRP14, and endothelial versican-1 (VCAN-1) in the spinal cord of affected patients.9,10 The etiopathogenesis of HAM/TSP is attributed to inflammatory and immune responses induced by penetration of HTLV-I into the nervous system with spread between lymphocytes.11 The virus appears to spread directly between lymphocytes through specialized viral cell–cell synapses and, instead of making extracellular virions, HTLV-I uses the mobility of the host cell to spread within and between hosts.11 However, once acquired, predictive risk factors for progression of HTLV-I infection to HAM/TSP have included increased proviral load, HTLV-I tax subgroup 1, host human leukocyte antigen (HLA) determinants, and cytokine transcription. A strong cytotoxic T-cell response to HTLV-I

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1. WHO. Virus diseases: human T lymphotropic virus type I, HTLV-I. Wkly Epidemiol Rec 1989;64:382–383. 2. Murphy EL, Figueroa JP, Gibbs WN, Holding-Cobham M, Cranston B, Malley K, et al. Human T-lymphotropic virus type 1 (HTLV-1) seroprevalence in Jamaica I. Demographic determinants. Am J Epidemiol 1991;133:1144–1124. 3. Glynn SA, Kleinman SH, Schreiber GB, Murphy EL, Wright DJ, Tu Y, et al. Trends in incidence and prevalence of major transfusiontransmissible viral infections in US blood donors, 1991 to 1996. Retrovirus Epidemiology Donor Study (REDS). JAMA 2000;284:229–235. 4. Remesar MC, del Pozo AE, Pittis MG, Mangano AM, Sen L, Briones L. Transmission of HTLV-1 by kidney transplant. Transfusion 2000; 40:1421. 5. Toro C, Rod es B, Poveda E, Soriano V. Rapid development of subacute myelopathy in three organ transplant recipients after transmission of human T-cell lymphotropic virus type 1 from a single donor. Transplantation 2003;75:102–104. 6. Bhigjee A, Bill PLA, Wiley CA, Windsor IM, Matthias DA, Amenomori T, et al. Peripheral nerve lesions in HTLV-1 associated myelopathy (HAM/TSP). Muscle Nerve 1993;16:21–26. 7. Kiwaki T, Umehara F, Arimura Y, Izumo S, Arimura K, Itoh K, et al. The clinical and pathological features of peripheral neuropathy accompanied with HTLV-1 associated myelopathy. J Neurol Sci 2003;206:17–21. 8. Iwasaki Y. Pathology of chronic myelopathy associated with HTLV-1 infection (HAM/TSP). J Neurol Sci 1990;96:103–123. 9. Aye MM, Matsuoka E, Moritoyo T, Umehara F, Suehara M, Hokezu Y, et al. Histopathological analysis of four autopsy cases of HTLV-1associated myelopathy/tropical spastic paraparesis: inflammatory changes occur simultaneously in the entire central nervous system. Acta Neuropathol 2000;100:245–252. 10. Abe M, Umehara F, Kubota R, Moritoyo T, Izumo S, Asami M. Activation of macrophages/microglia with the calcium-binding proteins MRP14 and MRP8 is related to lesional activities in the spinal cord of HTLV-1 associated myelopathy. J Neurol 1999;246:358–364. 11. Bangham CRM. The immune control and cell-to-cell spread of human T-lymphotropic virus type 1. J Gen Virol 2003;84:3177–3189. 12. Bangham CRM. The immune response to HTLV-1. Curr Opin Immunol 2000;12:397–402. 13. Nakamura N, Tamaru S, Ohshima K, Tanaka M, Arakaki Y, Miyauchi T. Prognosis of HTLV-1-positive renal transplant recipients. Transplant Proc 2005;37:1779–1782. 14. Kaul DR, Taranto S, Alexander C, Covington S, Marvin M, Nowicki M, et al. Donor screening for human T-cell lymphotropic virus 1/2: changing paradigms for changing testing capacity. Am J Transplant 2010;10:207–213.

Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.24450

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tropical spastic paraparesis and peripheral neuropathy following live-donor renal transplantation.

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