Hypergammaglobulinemia and corneal opacities in patients with human T-cell lymphotrophic virus type-1

PURPOSE: To investigate the relationship between serum immunoglobulin levels and corneal opacities in a cohort of patients with human T-cell lymphotrophic virus type-1 (HTLV-1). DESIGN: Retrospective case series. METHODS: Complete ophthalmologic examination was performed on 44 patients with HTLV-1 infection (25 patients with adult T-cell leukemia/lymphoma [ATL], 18 patients with HTLV-1 that was associated myelopathy/tropical spastic paraparesis [HAM/TSP], and one patient who was asymptomatic). Corneal opacities were described by shape, size, color, and location. Serum immunoglobulin (Ig) levels (IgG, IgM, and IgA) were measured by nephelometry. RESULTS: Corneal opacities were identified in 15 of 25 patients (60%) with ATL and five of 18 patients (28%) with HAM/TSP. The prevalence of corneal opacities was associated statistically with elevated IgG level (P = .023) in patients with ATL, but not in patients with HAM/TSP (P > .99). CONCLUSION: Although the mechanism remains unclear, hypergammaglobulinemia is associated with the development of the corneal opacities in patients of African descent with ATL.     

HTLV-1感染者的眼部临床表现

人类T淋巴细胞白血病病毒Ⅰ型(HTLV-1)感染比较少见,主要流行于日本、加勒比海地区、中非和南美洲。已知感染者主要眼部表现包括成人T细胞白血病(ATL)患者的眼部恶性浸润、视网膜变性、眼部神经病变,HTLV-1相关性脊髓病/热带痉挛性瘫痪(HAM/TSP)患者的干燥性角结膜炎及HTLV-1葡萄膜炎(HU)等。HTLV-1相关性眼部病变的范围正在扩大,病程中可能出现免疫调节失常引起的眼部病变或眼部肿瘤,遗传和环境因素可能在不同人群中HTLV-1患者的眼部表现起一定作用。本文就HTLV-1相关眼部表现及最新进展作一综述。     

Ocular manifestations of human T-cell lymphotropic virus type 1 infection

PURPOSE OF REVIEW: Human T-cell lymphotropic virus type 1 (HTLV-1) infection is endemic in Japan, the Caribbean islands, and parts of Central Africa and South America. Known ophthalmic manifestations of HTLV-1 include malignant infiltrates in patients with adult T-cell leukemia/lymphoma, retinal degeneration, neuroophthalmic disorders, and keratoconjunctivitis sicca in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis, and HTLV-1-associated uveitis. This report reviews the recent developments and ocular findings reported in patients with HTLV-1-related diseases. RECENT FINDINGS: Most of the knowledge of the ocular manifestations of HTLV-1 comes from southwestern Japan, which has the highest incidence of infection worldwide. During the past few years, however, ocular disease associated with HTLV-1 has been described in patients from other endemic areas genetically distinct and geographically distant from Japan. The most interesting of these was the recognition of corneal pathology in Brazilian and Caribbean patients with HTLV-1 that have not been described in Japanese patients. Other developments include the use of molecular techniques in the diagnostic evaluation of ocular tissues from HTLV-1 patients, and clinical studies demonstrating choroidal involvement by indocyanine green angiography in patients with HTLV-1-associated uveitis, and suggesting that retinal vasculitis unresponsive to corticosteroid therapy maybe a poor prognostic sign. SUMMARY: The spectrum of ocular disease related to HTLV-1 continues to expand. Routine evaluation of HTLV-1-infected patients is important because immune-mediated or neoplastic ocular involvement may occur during the disease course. Genetic and environmental factors may play a role in the ocular manifestations of HTLV-1 in different populations.     

Conjunctival T-cell lymphoma caused by human T-cell lymphotrophic virus infection

PURPOSE: To examine the cause of adult T-cell leukemia/lymphoma. METHODS: We examined a conjunctival biopsy from a 29-year-old Jamaican man who developed bilateral conjunctival masses. Adult T-cell leukemia/lymphoma was diagnosed using routine histology, immunohistochemistry, electron microscopy, microdissection, and the polymerase chain reaction. RESULTS:Histopathologic examination revealed a conjunctival lymphoma. Clonality of the T-cell receptor gamma gene and human T-cell lymphotrophic virus gag gene were detected in the malignant cells. The demonstration of the human T-cell lymphotrophic virus gene and the rearrangement of the T-cell receptor gene in this neoplasm provide proof that human T-cell lymphotrophic virus is the cause of this conjunctival T-cell lymphoma. CONCLUSION: Human T-cell lymphotrophic virus is the cause of adult T-cell leukemia/lymphoma, an aggressive malignancy of CD4+ lymphocytes.     

A description of human T-lymphotropic virus type I-related chronic interstitial keratitis in 20 patients

OBJECTIVE: This study aimed to describe a syndrome that the authors call human T-lymphotropic virus type I-related chronic interstitial keratitis. METHODS: A consecutive series of 194 human T-lymphotropic virus type I-infected patients (divided into 119 patients with human T-lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis and 75 asymptomatic human T-lymphotropic virus type I carriers) was systematically examined. RESULTS: Twenty patients (10.3%) had bilateral anterior stromal lesions made up of approximately 10 elevated, rounded or cloudy whitish opacities that were more or less confluent. The opacities were characteristically situated at the periphery of the anterior stroma, and the visual axis remained unaffected. The interstitial keratitis was chronic and unresponsive to topical administration of corticosteroids. It was mainly observed in patients affected by human T-lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis among whom there were 18 cases (15.1%), as opposed to two cases (2.7%) in asymptomatic carriers. CONCLUSION: A new cause of interstitial keratitis is reported. Human T-lymphotropic virus type I infection may have a much broader spectrum of ocular manifestations than previously described. As with the other manifestations of human T-lymphotropic virus type I infection, corneal lesions could be linked to a lymphoplasmocytic infiltration of the stroma leading to corneal opacities.     

Retinal Vasculitis Caused by Adult T-cell Leukemia/Lymphoma

Background To report a case of lymphomatous infiltration and bilateral retinal vasculitis observed among 83 cases of adult T-cell leukemia (ATL) treated in the University Hospital Center in Fort-de-France (Martinique, French West Indies) between 1984 and 2003.Case A complete clinical ophthalmologic examination was performed in this patient along with fluorescein angiography.Observations After being checked for diffuse adenopathies, myodesopsias, and phosphenes, the 35-year-old patient was diagnosed with ATL. The ocular impairment, present since the onset of ATL as peripheral subretinal infiltrates, spread progressively and afferently to the rest of the retina in the form of an essentially venous vasculitis. Impairment of the vitreous was noted only in the end stages of disease progression. As ocular lesions progressed, the general state of the patient degraded at the same time despite chemotherapeutic measures.Conclusion Among the more than 300 seropositive for human T-cell lymphotropic virus type 1 (HTLV-1) or patients with HTLV-1-associated myelopathy/tropical spastic paraparesis treated at our hospital in the last 20 years, and among the 83 cases of ATL, only this single case of retinal vasculitis associated with HTLV-1 was observed (1/83, 1.2%) in Martinique, confirming the geographic variability of the clinical phenotype of HTLV-1 infection. The incidence of retinal vasculitis in ATL patients may signify an even worse prognosis than initially indicated. Jpn J Ophthalmol 2005;49:41–45 © Japanese Ophthalmological Society 2005     

Ocular lesions in 200 patients infected by the human T-cell lymphotropic virus type 1 in martinique (French West Indies)

PURPOSE: To describe the ophthalmologic features observed in patients infected by the human T-cell lymphotropic virus, type 1 (HTLV-1) in Martinique (French West Indies). DESIGN: Prospective consecutive observational case series. METHODS: A complete ophthalmic examination was performed. PATIENTS: Of 200 patients infected by HTLV-1, 77 (38.5%) were seropositive and 123 (61.5%) had HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). RESULTS: Uveitis was found in 29 cases (14.5%). Symptoms were mild and the uveitis had little effect on visual function. Ten cases of uveitis were discovered through a systematic examination and had no ocular symptoms. Most of the uveitis was anterior or intermediate. The lesions responded to corticosteroid therapy, but tended to recur. Keratoconjunctivitis sicca existed in 74 patients (37%), accompanied by lymphoplasmocytoid infiltration of the secondary salivary glands rated 3 or 4 on the Chisholm scale in nearly 50% of cases. Corneal alterations were observed in 20 cases (10%), and alterations in the retinal pigment epithelium in 3 cases. CONCLUSION: The three types of ocular affections seen most frequently were uveitis, keratoconjunctivitis sicca, and interstitial keratitis. In patients with HAM/TSP, uveitis was more frequent among younger patients, patients with earlier onset of HAM/TSP, and patients with severe motor disability. Because uveitis is related to a high intrathecal production of immunoglobulin, it could represent a marker for severity of HTLV-1 infection with respect to the course of HAM/TSP. The sicca syndrome related to HTLV-1 virus differs from primary or secondary Sj?gren syndrome, because it does not reveal any of the immunologic anomalies generally seen in this disease. Interstitial keratitis was more frequent among patients with HAM/TSP who had high proviral DNA levels.     

Ocular manifestations in patients infected with human T-lymphotropic virus type I

Ocular manifestations in patients infected with human T-lymphotropic retrovirus type I (HTLV-I) consisted of a wide range of neoplastic, infectious and noninfectious vascular or inflammatory lesions. These disorders were associated with two distinct HTLV-I-induced systemic diseases, ie, adult T-cell leukemia/lymphoma and HTLV-I-associated myelopathy. Five of the 10 cases of adult T-cell leukemia/lymphoma had inflammatory or opportunistic infectious ocular lesions, including cytomegalovirus retinitis or eyelid tumor as part of generalized lymphomas. Four of the 17 cases of HTLV-I-associated myelopathy showed noninfectious lesions such as isolated, transient cotton-wool spots and granulomatous iridocylitis. Twenty-four (26.9%) of 89 cases with various ocular diseases but no HTLV-I-induced systemic disease had antibodies to HTLV-I in the serum. The aqueous humor antibodies to HTLV-I in the seropositive carriers were negative, except one carrier case who showed isolated cotton-wool spots in one eye and massive vitreous opacities in the other eye.     

Sicca syndrome and HTLV-I-associated myelopathy/tropical spastic paraparesis

PURPOSE: The objective of this study is to describe the clinical and immunological aspects observed in patients with both human T-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis and ocular dryness. METHODS: In 15 such patients, clinical and biological examinations completed with a biopsy of secondary salivary glands were performed to assess the etiology of the ocular dryness. RESULTS: Histological study of the biopsy specimens indicated that 80% of the patients had grade 3 or grade 4 lesions, according to the Chisholm scale. Polyclonal hypergammaglobulinemia was found in 60% of patients and lymphocytic alveolitis in 80%. Three patients had past medical history of chronic uveitis. CONCLUSIONS: All findings in these patients were compatible with Sj?gren's syndrome; however, no immunological disorders characteristic of the syndrome were found. Tests for antinuclear antibodies and rheumatoid factor proved negative in all cases.     

Interleukin-2 Receptor Targeted Therapy of Ocular Disease of HTLV-1-associated Adult T-cell Leukemia

Purpose: To report two cases of patients with ocular manifestations of human T-cell lymphotropic virus type-1 (HTLV-1) associated adult T-cell leukemia/lymphoma (ATL) who were successfully treated with interleukin-2 receptor targeted therapies.

Method: Case series.

Results: Two patients with HTLV-1-associated ATL developed symptomatic scleritis. In the first case, conjunctival biopsy showed leukemic infiltration that was confirmed by T-cell receptor polymerase chain reaction (PCR) demonstrating a clonal rearrangement. As treatment for ATL, both cases received interleukin-2 receptor targeted therapy. In one patient, daclizumab, a monoclonal antibody directed against the alpha chain of the interleukin-2 (IL-2) receptor, was used. The second patient was treated with denileukin diftitox, an immunotoxin fusion protein that targets the IL-2 receptor. Improvement in scleritis was noted in both patients.

Conclusion: Scleritis in patients with underlying HTLV-1-associated ATL is responsive to IL-2 receptor targeted therapies.     

Human T-cell lymphotropic virus type-1 associated t-cell leukemia/lymphoma masquerading as necrotizing retinal vasculitis

OBJECTIVE: To report a case of adult T-cell leukemia/lymphoma (ATL) presenting as a bilateral retinal vasculitis and diagnosed by molecular detection of a rearrangement in the T-cell receptor (TCR) and the presence of the human T-cell lymphotropic virus type 1 (HTLV-1) pol gene in the malignant lymphoid cells. DESIGN: Case report. METHODS: Routine histologic and immunohistochemical analyses were performed on the retinal biopsy specimen before referral to the National Eye Institute. Lymphoid cells associated with granulomatous inflammation infiltrating the retina and surrounding retinal blood vessels were microdissected from the paraffin sections of the retinal biopsy specimen. The polymerase chain reaction (PCR) was performed using primers for the TCR gene and HTLV-1 pol and gag genes. RESULTS: Microscopic examination showed a necrotizing granulomatous retinal vasculitis with a predominant T-cell infiltrate detected by immunohistochemistry. Molecular analysis demonstrated a clonal rearrangement of the TCR and the presence of the HTLV-1 pol gene in the microdissected lymphoid cells diagnostic of ATL. CONCLUSIONS: Necrotizing retinitis and retinal vasculitis are rare manifestations of ATL. Human T-cell lymphotropic virus type 1 infection should be considered in the differential diagnosis of patients from endemic areas who have retinal vasculitis at presentation. This case further demonstrates the usefulness of microdissection and PCR for the diagnosis of ocular disease, including HTLV-1 infection.     

Clinical course of HTLV-I-associated uveitis

PURPOSE: To define the long-term clinical course and visual outcome of human T-cell lymphotrophic virus type I (HTLV-I)-associated uveitis (HAU). METHODS: We reviewed the clinical data on 96 eyes of 70 patients, 26 men and 44 women, with HAU, with specific reference to recurrence of the disease and long-term visual outcome. The mean follow-up period was 83 months (range, 12-276 months). RESULTS: The mean age of onset was 42.8 years (range, 7-78 years of age), with men presenting at a significantly younger age. Forty-seven patients had isolated HAU; in 10 patients, HTLV-I-associated myelopathy occurred before or after the onset of HAU; in 14 patients, hyperthyroidism had preceded HAU. A single episode of mild to moderate acute uveal inflammation with resolution in a few weeks or more occurred in 44 (62.9%) patients, and multiple episodes in 26 (37.1%), with a mean interval of 16 months (range, 1-250 months), which affected the same eye, fellow eye, or both. The majority of patients had favorable visual outcome at the last examination, whereas only a few patients suffered poor vision resulting from steroid cataract and retinochoroidal degeneration. CONCLUSIONS: The clinical course of HAU is virtually benign and its visual outcome is favorable, although its recurrence is common. The uveitis is usually isolated and affects a portion of otherwise unremarkable HTLV-I carriers, but it may sometimes be manifest as a symptom of syndromic diseases such as HTLV-I-associated myelopathy or hyperthyroidism. This study describes for the first time cases of HAU that occurred many years before manifestation of HTLV-I-associated myelopathy.     

Intermediate uveitis due to human T-cell lymphotropic virus type 1

CASE REPORT: The case of a 66-year-old woman with intermediate uveitis in both eyes and progressive weakness of lower limbs is reported. A human T-lymphotropic virus type 1 (HTLV-1) infection was detected in the serological study, with the patient being diagnosed with tropical spastic paraparesis and HTLV-1 intermediate uveitis. The patient made good progress with oral steroid treatment. DISCUSSION: The clinical and epidemiological aspects of HTLV-1 infection are discussed. We recommend a serological determination of the virus in intermediate uveitis of unknown origin in people from endemic areas or with neurological symptoms.     

Herpes simplex virus-specific T cells infiltrate the cornea of patients with herpetic stromal keratitis: no evidence for autoreactive T cells

PURPOSE: Herpetic stromal keratitis (HSK) is a T-cell-mediated inflammatory disease initiated by a herpes simplex virus (HSV) infection of the cornea. Recently, studies in the HSK mouse model have shown that the immunopathogenic T cells are directed against the HSV protein UL6 cross-reacting with an unknown corneal autoantigen. Whether this type of autoimmunity plays a role in human HSK was analyzed. METHODS: T-cell lines (TCLs) were generated from corneal buttons of 12 patients with different clinical stages of HSV-induced necrotizing stromal keratitis (n = 9) or immune stromal keratitis (n = 3). The initiating virus was identified by polymerase chain reaction and immunohistology performed on the corneal buttons. Peripheral blood mononuclear cells (PBMCs) were isolated, and B cell lines (BLCLs) were generated by transformation with Epstein-Barr virus. Proliferative responses of these intracorneal TCLs were determined by culturing T cells with autologous BLCLs infected with HSV-1, HSV-2, wild-type vaccinia virus (VV-WT), or VV expressing HSV-1 UL6 (rVV-UL6). Alternatively, T cells were incubated with PBMCs pulsed with human cornea protein extract. RESULTS: Irrespective of clinical diagnosis or treatment, T cells were recovered from the corneal buttons of all the 12 HSK patients. The intracorneal TCLs of 9 of the 12 HSK patients showed HSV-specific T-cell reactivity. In none of the TCLs, T-cell reactivity against HSV-1 UL6 or human corneal antigens was detected. CONCLUSIONS: These data suggest that the potentially immunopathogenic intracorneal T-cell response in HSK patients is directed to the initiating virus and not to a human corneal autoantigen or HSV-1 UL6.     

Orbital T-cell Lymphoma Human T-cell Leukemia Virus-I Infection

This is the first report of orbital involvement in systemic adult T-cell leukemia/lymphoma (ATLL). The etiologic agent of ATLL is the human T-cell leukemia virus-I (HTLV-I), the first retrovirus demonstrated to induce cancer in humans. The diagnosis of ATLL is based on characteristic clinicopathologic features in combination with serologic or virologic evidence of HTLV-I infection. Serum antibodies to HTLV-I were identified by immunofluorescent microscopy. Viral particles characteristic of HTLV-I were found in a culture of the patient's peripheral blood lymphocytes. The patient was a native of the Caribbean, one of the known endemic foci of HTLV-I infection. Adult T-cell leukemia/lymphoma should be considered in the differential diagnosis of orbital T-cell lymphomas.     

Human T-cell lymphotropic virus type 1-associated retinal vasculitis in children.

PURPOSE: To describe predominant retinal vasculitis in children carrying human T-cell lymphotropic virus type 1 (HTLV-1). METHODS: The authors examined clinical records of patients with HTLV-1-associated uveitis between 1987 and 2001 in Kagoshima University Hospital and reviewed cases of extensive, smoldering retinal vasculitis. RESULTS: Three previously healthy teenagers noted mild visual symptoms and presented with extensive sheathing of retinal vessels, complicated by mild anterior segment inflammation. The retinal vascular disease responded poorly to systemic corticosteroids, had a smoldering course with persistent sheathing of retinal vessels, and eventually resulted in diffuse chorioretinal degeneration. Results of laboratory studies were unremarkable except for the presence of serum antibodies to HTLV-1. One patient developed HTLV-1-associated myelopathy 11 years after the onset of ocular disease. CONCLUSIONS: The retinal vasculitis differed from the retinal vascular changes commonly seen in HTLV-1-associated uveitis. The authors suggest a clinical disease HTLV-1-associated retinal vasculitis that affects young HTLV-1 carriers, characterized by smoldering retinal vasculitis with ultimate retinal degeneration.     

Ophthalmic abnormalities in patients with cutaneous T-cell lymphoma.

OBJECTIVE: To determine the frequency of ophthalmic abnormalities in patients with cutaneous T-cell lymphoma (mycosis fungoides and Sézary syndrome) and T-cell lymphoma involving the skin and to describe the clinical course of the disease with selected examples. DESIGN: Retrospective, clinic-based, cross-sectional study. PARTICIPANTS: A computerized diagnostic retrieval system was used to identify all patients with T-cell lymphoma involving the skin who were examined at the Mayo Clinic (Rochester, Minnesota) between January 1, 1976 and December 31, 1990. The medical records of affected patients were reviewed. MAIN OUTCOME MEASURES: Identification of ophthalmic abnormalities. RESULTS: During the 15-year interval from 1976 through 1990, cutaneous T-cell lymphoma was diagnosed in 2155 patients. Of these, 42 (1.95%; 26 male and 16 female) had at least one ophthalmic abnormality attributable to the disease. The diagnoses in these 42 patients were mycosis fungoides in 19, clinical variants of T-cell lymphoma of the skin (most commonly peripheral T-cell lymphoma) in 11, and Sézary syndrome in 12. Cicatricial eyelid ectropion was the most common finding, affecting 17 (40.4%) of the 42 patients. Thirty-seven patients had findings that, although probably not a direct consequence of cutaneous T-cell lymphoma, have been cataloged in previous studies. CONCLUSION: Although ophthalmic abnormalities in patients with cutaneous T-cell lymphoma are relatively uncommon, the manifestations of the disease are diverse and frequently difficult to treat.     

Duane's retraction syndrome and spastic paraparesis

Duane's retraction syndrome (DRS) is a neurogenic eye movement abnormality frequently associated with other congenital defects involving ocular, skeletal and neural structures. The authors report on a patient who had DRS associated with a severe spastic paraparesis, which progressed from childhood until young adulthood with subsequent stabilization. The patient had severe limitation of abduction of the left eye, narrowing of the palpebral fissure, and globe retraction in adduction. Neurological examination revealed a severe spastic paraparesis. Extensive clinical neurophysio-logical evaluation, including electromyography, nerve conduction studies, somatosensory evoked responses and transcranial magnetic stimulation, was consistent with a severe myelopathy. Magnetic resonance imaging of the spinal cord demonstrated significant thinning of the cervical and thoracic spinal cord. This previously unreported association is unlikely coincidental, given the rarity of both findings, and may be explained by the abnormal development of neural structures during a critical period of gestation.     

HTLV-III in the tears of AIDS patients

The human T-cell leukemia/lymphotropic virus type III (HTLV-III), the causative agent of the acquired immunodeficiency syndrome (AIDS), has been isolated from the tears of five AIDS patients. When combined with data from our previous study, 5 of 16 samples from patients with AIDS or AIDS-related complex (ARC) showed positive isolates for HTLV-III from the tears. Normal control tears were negative for HTLV-III. Based upon these findings, the Centers for Disease Control (CDC) has issued precautions to prevent any possible spread of the virus by this route. Although there is no evidence to suggest transmission of HTLV-III by contact with the tears, until more is known about the possible transmissibility and infectious dose of this virus, such precautions should be taken during ophthalmic examination.