Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders.

BACKGROUND: Mikulicz's disease (MD) has been considered as one manifestation of Sjögren's syndrome (SS). Recently, it has also been considered as an IgG(4)-related disorder. OBJECTIVE: To determine the differences between IgG(4)-related disorders including MD and SS. METHODS: A study was undertaken to investigate patients with MD and IgG(4)-related disorders registered in Japan and to set up provisional criteria for the new clinical entity IgG(4)-positive multiorgan lymphoproliferative syndrome (IgG(4)+MOLPS). The preliminary diagnostic criteria include raised serum levels of IgG(4) (>135 mg/dl) and infiltration of IgG(4)(+) plasma cells in the tissue (IgG(4)+/IgG+ plasma cells >50%) with fibrosis or sclerosis. The clinical features, laboratory data and pathologies of 64 patients with IgG(4)+MOLPS and 31 patients with typical SS were compared. RESULTS: The incidence of xerostomia, xerophthalmia and arthralgia, rheumatoid factor and antinuclear, antiSS-A/Ro and antiSS-B/La antibodies was significantly lower in patients with IgG(4)+MOLPS than in those with typical SS. Allergic rhinitis and autoimmune pancreatitis were significantly more frequent and total IgG, IgG(2), IgG(4) and IgE levels were significantly increased in IgG(4)+MOLPS. Histological specimens from patients with IgG(4)+MOLPS revealed marked IgG(4)+ plasma cell infiltration. Many patients with IgG(4)+MOLPS had lymphocytic follicle formation, but lymphoepithelial lesions were rare. Few IgG(4)+ cells were seen in the tissue of patients with typical SS. Thirty-eight patients with IgG(4)+MOLPS treated with glucocorticoids showed marked clinical improvement. CONCLUSION: Despite similarities in the involved organs, there are considerable clinical and pathological differences between IgG(4)+MOLPS and SS. Based on the clinical features and good response to glucocorticoids, we propose a new clinical entity: IgG(4)+MOLPS.

[Three ocular sarcoidosis patients examined by indocyanine green angiography].

PURPOSE: To assess the findings of indocyanine green angiography(IA) in patients with ocular sarcoidosis. SUBJECTS AND METHODS: Three active ocular sarcoidosis patients with various retinochoroidal findings diagnosed by biopsy or systemic examination. Two patients were diagnosed pathologically and one patient was diagnosed clinically. IA & fluorescein angiography(FA) were performed before and after treatment with systemic steroid administration. RESULTS: IA revealed hyperfluorescence surrounding the presumed granulomatous lesions. This hyperfluorescence disappeared immediately after the treatment. FA showed hyperfluorescence continuing even after therapy. CONCLUSIONS: It is purposed that the ring-form hyperfluorescence in IA is due to accelerated vascular permeability in the active sarcoid granuloma. IA, which vividly reflects activity of sarcoid lesions, is an important tool for clinical evaluation of ocular sarcoidosis.

Zoster sine herpete with bilateral ocular involvement.

PURPOSE: To report a case of zoster sine herpete with bilateral ocular involvement. METHOD: Case report. RESULTS: A 65-year-old man showed bilateral iridocyclitis with sectoral iris atrophy and elevated intraocular pressure unresponsive to steroid treatment. No cutaneous eruption was manifest on the forehead. A target region of varicella-zoster virus DNA sequence was amplified from the aqueous sample from the left eye by polymerase chain reaction. Bilateral iridocyclitis resolved promptly after initiation of systemic and topical acyclovir treatment. Secondary glaucoma was well controlled by bilateral trabeculectomy. CONCLUSIONS: Zoster sine herpete should be considered and polymerase chain reaction performed on an aqueous sample to detect varicella-zoster virus DNA for rapid diagnosis whenever anterior uveitis accompanies the characteristic iris atrophy, even in the case of bilateral involvement.

A case of orbital lymphoproliferative lesion diagnosed as malignant lymphoma after recurring 11 years later

Background: Most primary lymphoproliferative lesions in the ocular adnexa, including the eyelid, conjunctiva, and orbit, are diagnosed as low-grade malignant lymphomas. Recurrence and dissemination of these tumors are rare in Japan. The long-term prognosis for this disorder still remains to be clarified.Case and Method: A 53-year-old woman was first referred to us for right orbital tumor in 1986. After subtotal resection of the tumor, the patient received no additional treatment. She visited us in 1997 with the complaint of bilateral orbital tumor. Biopsied specimens were examined histologically using hematoxylin-eosin and immunohistological staining. Southern blot hybridization was used to detect immunoglobulin gene rearrangement. The paraffin-embedded specimen obtained in 1986 was also examined for immunoglobulin gene rearrangement using nested polymerase chain reaction technique. Findings: The specimens from 1997 and 1986 were both diagnosed as lymphoid type of inflammatory pseudotumor, based on polyclonal B cell immunohistological staining. Immunoglobulin gene rearrangement was present in both specimens.Conclusions: The orbital tumor resected in 1986 was a low-grade malignant lymphoma which disseminated systematically 11 years later. This case shows a long-term course of orbital lymphoproliferative lesion with positive immunoglobulin gene rearrangement. It also shows the importance of follow-up over 10 years in the case of low-grade malignant lymphoma of the ocular adnexa.

Ophthalmic artery blood flow velocity changes in diabetic patients as a manifestation of macroangiopathy.

PURPOSE: The hemodynamic characteristics of ophthalmic artery (OA) blood flow velocity in diabetic patients with ocular involvement were evaluated. METHODS: Changes in OA blood flow of eyes with background diabetic retinopathy (BDR), proliferative retinopathy (PDR) and ocular ischemic syndrome (OIS) were analyzed by Color Doppler imaging. RESULTS: Patients with BDR and PDR had significantly lower diastolic and mean blood flow velocities and higher pulsatility indices compared to controls. Diabetic patients with OIS had significantly lower systolic, diastolic and mean anterograde OA blood flow velocities than the controls. Pulsatility indices were higher in anterograde OA blood flow measurements compared to controls. Systolic blood flow velocities in rubeotic eyes with OIS were significantly lower than in rubeotic eyes with PDR. CONCLUSION: OA blood flow measurements by color doppler imaging may detect macroangiopathies in diabetic patients as manifested by carotid atheromas and arterio- and atherosclerosis of the OA and its branches.

Activation of the TCL1 protein in B cell lymphomas.

The TCL1 gene, localized near the break point of chromosome 14q32.1 often involved in T cell leukemias, is also expressed in normal precursor T and B cells, and B cell lymphoma cell lines. We investigated the expression of the TCL1 protein in various types of B cell lymphomas according to the Revised European-American Classification of Lymphoid neoplasms. Paraffin-embedded tissue sections of lymphoma specimens were subjected to TCL1 immunohistochemistry, and positivity was scored on a three-tiered scale: - (< 25% cells), + (25-50% cells), and ++ (> 50% cells). The TCL1 protein was expressed in low-grade B cell lymphomas including mucosa-associated lymphoid tissue type in ocular adnexa (18/20, 90%). It was also expressed in follicular, lymphoplasmacytic, and mantle cell lymphoma, but not in high-grade diffuse large B cell lymphoma (2/11, 18%). These data suggest that the expression of the TCL1 gene characterizes low-grade B cell lymphomas, and may be involved in certain processes of lymphomatogenesis.

[A case of orbital lymphoproliferative lesion diagnosed as malignant lymphoma after recurring 11 years later].

BACKGROUND: Most primary lymphoproliferative lesions in the ocular adnexa, including the eyelid, conjunctiva, and orbit, are diagnosed as low-grade malignant lymphomas. Recurrence and dissemination of these tumors are rare in Japan. The long-term prognosis for this disorder still remains to be clarified. CASE AND METHOD: A 53-year-old woman was first referred to us for right orbital tumor in 1986. After subtotal resection of the tumor, the patient received no additional treatment. She visited us in 1997 with the complaint of bilateral orbital tumor. Biopsied specimens were examined histologically using hematoxylin-eosine and immunohistological staining. Southern blot hybridization was used to detect immunoglobulin gene rearrangement. The paraffin-embedded specimen obtained in 1986 was also examined for immunoglobulin gene rearrangement using nested polymerase chain reaction technique. FINDINGS: The specimens from 1997 and 1986 were both diagnosed as lymphoid type of inflammatory pseudotumor, based on polyclonal B cell immunohistological staining. Immunoglobulin gene rearrangement was present in both specimens. CONCLUSION: The orbital tumor resected in 1986 was a low-grade malignant lymphoma which disseminated systemically 11 years later. This case shows a long-term course of orbital lymphoproliferative lesion with positive immunoglobulin gene rearrangement. It also shows the importance of follow-up over 10 years in the case of low-grade malignant lymphoma of the ocular adnexa.

Ocular ischemic syndrome in diabetic patients.

PURPOSE: Diabetes mellitus aggravates carotid occlusive disease, that can manifest as ocular ischemic syndrome (OIS). Ocular manifestations and visual prognosis of OIS in diabetic patients were retrospectively analyzed. METHODS: Twenty-three consecutive diabetic patients with OIS were divided into two groups according to the presence of iris neovascularization, and the clinical features were reviewed. RESULTS: In the first group, 14 eyes of 12 diabetic patients (11 men and 1 woman) had no iris neovascularization. Two patients had bilateral OIS. The ages in this group ranged from 50-75 years. Four eyes with optic atrophy or ischemic optic neuropathy had severe visual loss. Six eyes with hypoperfusion retinopathy or retinal vein obstruction and 2 eyes with cataract had mild visual loss. Each eye with amaurosis fugax or retinal neovascularization had no visual deterioration. Asymmetrical retinopathy was observed in 2 patients. Carotid surgery stabilized and resolved amaurosis fugax and hypoperfusion retinopathy. In the second group, 11 eyes of 11 patients had iris neovascularization. The patients were all male and their ages ranged from 53-77 years. All eyes with iris neovascularization had severe visual deterioration. In 5 patients, asymmetrical ocular manifestation was observed. Carotid reconstruction surgery and ophthalmological treatment were not successful for recovering a satisfactory visual outcome in OIS. CONCLUSION: The features of OIS in diabetic patients mimic diabetic retinopathy and manifest with asymmetrical ocular findings. Iris neovascularization is an indicator of poor visual prognosis. It is essential to recognize the early stages of OIS associated with diabetes mellitus.

[A case of syringomatous carcinoma derived from the lid].

A 73-year-old male presented with a slowly growing tumor in the right lower eyelid of one year's duration. The condition had been diagnosed elsewhere as poorly differentiated squamous cell carcinoma by biopsy. The residual tumor progressed rapidly and metastatized to the ipsilateral preauricular lymph nodes. We performed orbital evisceration and radical neck resection. Microscopically, the tumor showed small epithelial nests, cords, and ductal structure buried in abundant collagenous stroma. Besides focal squamous differentiation with keratinization in the surface area, the tumor showed, as cardinal features, ductal differentiation possessing comma-like extensions identical to syringoma. Cellular atypia, invasive growth pattern, and remarkable perineural invasion were suggestive of malignancy. These features led to the diagnosis of syringomatous carcinoma. Immunohistologically, the tumor showed positive staining for cytokeratine and epithelial membrane antigen (EMA). It was mostly negative for S-100 and carcinoembryonic antigen (CEA).

T cells in the uninjected eye after anterior chamber inoculation of herpes simplex virus type 1.

PURPOSE: To investigate T cell infiltration in the posterior segment of the uninjected eye after uniocular anterior chamber inoculation of HSV-1. METHODS: The anterior chamber of one eye of euthymic BALB/c mice was injected with 1 x 10(4) plaque-forming units (PFU) to 2 x 10(4) PFU of herpes simplex virus type 1 (HSV-1; KOS strain). All mice were examined for retinitis on day 8 postinoculation (p.i.). Only mice with retinitis were retained and used in these experiments. Animals were killed on days 9, 11, 14, 21, 35, and 63 p.i. The uninjected eyes were removed. Some of the uninjected eyes were sectioned and stained for CD4+ and CD8+ cells using the avidin-biotinylated enzyme complex method. Infiltrating cells were collected from the remaining uninoculated eyes and stained using rat anti-mouse monoclonal antibodies specific for CD4+ or CD8+ T cells, and the percentage of CD4+ and CD8+ T cells was determined by flow cytometry. RESULTS: At day 9 p.i. (acute retinitis), T cells were observed in the uvea but not in the retina of the contralateral eye. CD4+ and CD8+ cells were observed in the sensory retina coincident with the onset of retinal necrosis (day 11 p.i.), and CD4+ and CD8+ T cells continued to be detected in the remnants of the retina up to and including day 63 p.i. The maximum percentage of both CD4+ and CD8+ T cells was observed at day 21 p.i. CONCLUSIONS: These results demonstrate that T cells enter the retina of the uninoculated eye during HSV-1 infection. The observation that T cells arrive in the sensory retina at the onset of retinal necrosis and not during acute retinitis and the peak of virus replication provides further evidence that T cells play a role in development of retinal necrosis. The result that T cells are observed in the uninjected eye as late as day 63 p.i. suggests that T cells might also have a role in the resolution phase of the disease.

Iridopathy in eyes with proliferative diabetic retinopathy: detection of early stage of rubeosis iridis.

Forty-two eyes of 31 proliferative diabetic retinopathy patients with laser flare intensity > or = 20 photon counts/ms underwent fluorescein iris angiography to evaluate any changes in the blood-iris barrier and iris biomicroscopy to detect rubeosis iridis. Fluorescein iris angiography revealed abnormal dye leakage in all eyes. Laser flare intensity significantly correlated with the degree of dye leakage. Eyes with dye leakage from only the pupillary border had no rubeosis. In 11 out of 18 (61%) eyes with moderate dye leakage, proliferative diabetic iridopathy with early rubeosis was present in 8 and advanced iridopathy in 3 eyes. In all eyes with excessive leakage, rubeosis iridis was detected under slitlamp examination. High laser flare intensity has a close relationship with advanced blood-ocular barrier disruption. High flare intensity may be a helpful indicator in detecting incipient rubeosis or advanced diabetic iridopathy.

The Kobe earthquake and recurrent endogenous uveitis.

The mechanism of recurrent endogenous uveitis remains uncertain but it is generally believed to be affected by both heredity and environment. On January 17, 1995, the Hanshin-Awaji (Kobe) area of Japan experienced a major earthquake which killed more than 6300 people and forced 310,000 to take refuge in emergency shelters. All inhabitants of this area suffered severe stress due to the sudden changes in their living environment. We investigated the recurrence rate of endogenous uveitis before and after the earthquake in 116 patients who had been followed for more than 2 years (since July 17, 1993) at Kobe University Hospital. The postquake rate was significantly higher than the prequake rate (10% vs 3%); women were more often affected than men. Our data suggests that psychological stress due to the sudden changes in living conditions following the earthquake may have triggered the recurrences. It might be important to provide psychological as well as physical care for these patients after a disaster.

[The Hanshin-Awaji earthquake and the recurrence of endogenous uveitis].

The recurrence mechanism of endogenous uveitis remains to be explained, but it is popularly believed that hereditary background and environmental changes affect this mechanism. On Jan 17, 1995, the Hanshin-Awaji distinct in Japan was struck by a major earthquake. Over 6,300 people were killed and more than 310,000 were made homeless. The inhabitants of this area suffered emotional stress from the sudden changes in their living environment. In 116 endogenous uveitis patients who were being followed up for more than 2 years after Jul 17, 1993, at Kobe University Hospital in the stricken area, we investigated the recurrence rate of endogenous uveitis before and after the earthquake. The recurrence rate after the earthquake was significantly higher than before the earthquake (10% vs 3%), and women were more often affected than men after the earthquake. Our data suggests that psychological stress from sudden changes in the living environment after the earthquake can trigger the recurrence of endogenous uveitis. It might be important to provide psychological as well as physical care of endogenous uveitis patients after a disaster.

T lymphocyte infiltration in the brain following anterior chamber inoculation of HSV-1.

Following inoculation of the KOS strain of herpes simplex virus type 1 (HSV-1) into one anterior chamber of euthymic BALB/c mice, virus spreads from the injected eye to the central nervous system and from the central nervous system to the optic nerve and retina of only the uninoculated eye. In contrast, in athymic BALB/c mice or mice depleted of both CD4+ and CD8+ T cells, virus spreads to the optic nerve and retina of both the injected eye and the uninjected eye. To determine the location in the central nervous system where spread of virus to the optic nerve and retina of the injected eye is prevented, euthymic BALB/c mice were injected with a mixture of KOS and RH116, a mutant of KOS that contains the Escherichia coli beta-galactosidase (beta-gal) gene. Several animals were sacrificed each day; serial frozen sections of the brain were prepared and sequential sections were stained for beta-gal or for T cells. At all sites except the suprachiasmatic nuclei, virus and T cells arrived at approximately the same time. However, at day 5 post inoculation (PI), T cells were present in both the ipsilateral and the contralateral suprachiasmatic nuclei, but only the ipsilateral suprachiasmatic nucleus was virus-positive. Since virus spreads from the ipsilateral suprachiasmatic nucleus to the contralateral optic nerve, these results suggest that T cells infiltrating the area of the contralateral suprachiasmatic nucleus prior to the arrival of virus at this site prevent virus spread into the optic nerve of the inoculated eye.

Laser flare intensity in diabetics: correlation with retinopathy and aqueous protein concentration.

The laser flare intensity in diabetics, measured with the scattering of a light beam, was evaluated and compared with actual aqueous protein concentration obtained during surgery. Measurement of the laser flare intensity in 120 diabetics and 108 normal subjects was performed with the laser flare cell meter (FC1000 Kowa, Tokyo). Aqueous protein concentration in 26 diabetics and six controls who underwent intraocular surgery was measured by the method of Bradford. No significant difference in the laser flare intensity was found between normal subjects and diabetics without retinopathy. A significant increase in the laser flare intensity was observed after six decades in diabetics with background retinopathy and all with proliferative retinopathy. The laser flare intensity correlated with the duration of diabetes mellitus. There was a significant linear relation between the laser flare intensity and actual aqueous protein concentration. The linear regression formula was X = Y1.39 x 1.02 (X = protein concentration, mg/dl; Y = flare intensity, photon counts/ms). The precise value of the laser flare intensity provides a new indicator to evaluate the diabetic change in the function of the ocular barrier.