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PURPOSE: The purpose of this study was to investigate changes in the mechanical properties of capsular tissue using shear wave elastography (SWE) and a durometer under various tensile loads, and to explore the reliability and correlation of SWE and durometer measurements to evaluate whether SWE technology could be used to assess tissue changes during capsule tensile loading. METHODS: The inferior glenohumeral joint capsule was harvested from 10 fresh human cadaveric specimens. Tensile loading was applied to the capsular tissue using 1-, 3-, 5-, and 8-kg weights. Blinded investigators measured tissue stiffness and hardness during loading using SWE and a durometer, respectively. Intraobserver reliability was established for SWE and durometer measurements using intraclass correlation coefficients (ICCs). The Pearson product-moment correlation was used to assess the associations between SWE and durometer measurements. RESULTS: The ICC3,5 for durometer measurements was 0.90 (95% confidence interval [CI], 0.79 to 0.96; P<0.001) and 0.95 (95% CI, 0.88 to 0.98; P<0.001) for SWE measurements. The Pearson correlation coefficient values for 1-, 3-, and 5-kg weights were 0.56 (P=0.095), 0.36 (P=0.313), and -0.56 (P=0.089), respectively. When the 1- and 3-kg weights were combined, the ICC3,5 was 0.72 (P<0.001), and it was 0.62 (P<0.001) when the 1-, 3-, and 5-kg weights were combined. The 8-kg measurements were severely limited due to SWE measurement saturation of the tissue samples. CONCLUSION: This study suggests that SWE is reliable for measuring capsular tissue stiffness changes in vitro at lower loads (1 and 3 kg) and provides a baseline for the non-invasive evaluation of effects of joint loading and mobilization on capsular tissues in vivo.
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PURPOSE: To describe a patient with BRAF mutation-positive cutaneous melanoma who developed acute exudative polymorphous vitelliform maculopathy during vemurafenib and pembrolizumab treatment for metastatic melanoma. METHODS: Retrospective case report documented with wide-field fundus imaging, spectral domain optical coherence tomography, and fundus autofluorescence imaging. RESULTS: A 55-year-old woman with bilateral ductal breast carcinoma and BRAF mutation-positive metastatic cutaneous melanoma complained of bilateral blurred vision within 5 days of starting vemurafenib (BRAF inhibitor). She had been on pembrolizumab (program death receptor antibody) and intermittently on dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor), and had a normal ophthalmologic examination. On presentation three weeks after the introduction of vemurafenib, her visual acuity had declined to 20/40 in both eyes. Her examination showed diffuse elevation of the fovea with multifocal yellow-white, crescent-shaped subretinal deposits within the macula of both eyes and bilateral neurosensory retinal detachments by spectral domain optical coherence tomography. Discontinuation of vemurafenib and introduction of difluprednate and dorzolamide led to a gradual resolution (over four months) of the neurosensory detachments with recovery of vision. CONCLUSION: This case report suggests that acute exudative polymorphous vitelliform maculopathy may be directly associated with the use of BRAF inhibitors as treatment for metastatic cutaneous melanoma, or indirectly by triggering autoimmune-paraneoplastic processes. Future identification of similar associations is required to unequivocally link vemurafenib and/or pembrolizumab to acute exudative polymorphous vitelliform maculopathy in metastatic melanoma.
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Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos/efectos adversos , Melanoma/tratamiento farmacológico , Síndromes Paraneoplásicos Oculares/inducido químicamente , Neoplasias Cutáneas/tratamiento farmacológico , Vemurafenib/efectos adversos , Distrofia Macular Viteliforme/inducido químicamente , Enfermedad Aguda , Femenino , Humanos , Melanoma/secundario , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias Cutáneas/secundarioRESUMEN
PURPOSE: To assess the potential ocular toxicity of a combined BRAF inhibition (BRAFi) + MEK inhibition (MEKi) + hydroxychloroquine (HCQ) regime used to treat metastatic BRAF mutant melanoma. METHODS: Patients with stage IV metastatic melanoma and BRAF V600E mutations (n = 11, 31-68 years of age) were included. Treatment was with oral dabrafenib, 150 mg bid, trametinib, 2 mg/day, and HCQ, 400 mg to 600 mg bid. An ophthalmic examination, spectral domain optical coherence tomography, near-infrared and short-wavelength fundus autofluorescence, and static perimetry were performed at baseline, 1 month, and q/6 months after treatment. RESULTS: There were no clinically significant ocular events; there was no ocular inflammation. The only medication-related change was a separation of the photoreceptor outer segment tip from the apical retinal pigment epithelium that could be traced from the fovea to the perifoveal retina noted in 9/11 (82%) of the patients. There were no changes in retinal pigment epithelium melanization or lipofuscin content by near-infrared fundus autofluorescence and short-wavelength fundus autofluorescence, respectively. There were no inner retinal or outer nuclear layer changes. Visual acuities and sensitivities were unchanged. CONCLUSION: BRAFi (trametinib) + MEKi (dabrafenib) + HCQ causes very frequent, subclinical separation of the photoreceptor outer segment from the apical retinal pigment epithelium without inner retinal changes or signs of inflammation. The changes suggest interference with the maintenance of the outer retinal barrier and/or phagocytic/pump functions of the retinal pigment epithelium by effective MEK inhibition.
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Antineoplásicos/efectos adversos , Inhibidores Enzimáticos/efectos adversos , Hidroxicloroquina/efectos adversos , Imidazoles/efectos adversos , Mácula Lútea/patología , Melanoma/tratamiento farmacológico , Oximas/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Piridonas/efectos adversos , Pirimidinonas/efectos adversos , Enfermedades de la Retina , Adulto , Anciano , Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Hidroxicloroquina/uso terapéutico , Imidazoles/uso terapéutico , MAP Quinasa Quinasa 1/antagonistas & inhibidores , Masculino , Melanoma/genética , Persona de Mediana Edad , Oximas/uso terapéutico , Células Fotorreceptoras/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Piridonas/uso terapéutico , Pirimidinonas/uso terapéutico , Enfermedades de la Retina/inducido químicamente , Enfermedades de la Retina/patología , Epitelio Pigmentado de la Retina/patologíaRESUMEN
Importance: A better pathophysiologic understanding of the neurodevelopmental abnormalities observed in neonates exposed in utero to Zika virus (ZIKV) is needed to develop treatments. The retina as an extension of the diencephalon accessible to in vivo microcopy with spectral-domain optical coherence tomography (SD-OCT) can provide an insight into the pathophysiology of congenital Zika syndrome (CZS). Objective: To quantify the microstructural changes of the retina in CZS and compare these changes with those of cobalamin C (cblC) deficiency, a disease with potential retinal maldevelopment. Design, Setting, and Participants: This case series included 8 infants with CZS and 8 individuals with cblC deficiency. All patients underwent ophthalmologic evaluation at 2 university teaching hospitals and SD-OCT imaging in at least 1 eye. Patients with cblC deficiency were homozygous or compound heterozygotes for mutations in the methylmalonic aciduria and homocystinuria type C (MMACHC) gene. Data were collected from January 1 to March 17, 2016, for patients with CZS and from May 4, 2015, to April 23, 2016, for patients with cblC deficiency. Main Outcomes and Measures: The SD-OCT cross-sections were segmented using automatic segmentation algorithms embedded in the SD-OCT systems. Each retinal layer thickness was measured at critical eccentricities using the position of the signal peaks and troughs on longitudinal reflectivity profiles. Results: Eight infants with CZS (5 girls and 3 boys; age range, 3-5 months) and 8 patients with cblC deficiency (3 girls and 5 boys; age range, 4 months to 15 years) were included in the analysis. All 8 patients with CZS had foveal abnormalities in the analyzed eyes (8 eyes), including discontinuities of the ellipsoid zone, thinning of the central retina with increased backscatter, and severe structural disorganization, with 3 eyes showing macular pseudocolobomas. Pericentral retina with normal lamination showed a thinned (<30% of normal thickness) ganglion cell layer (GCL) that colocalized in 7 of 8 eyes with a normal photoreceptor layer. The inner nuclear layer was normal or had borderline thinning. The central retinal degeneration was similar to that of cblC deficiency. Conclusions and Relevance: Congenital Zika syndrome showed a central retinal degeneration with severe GCL loss, borderline inner nuclear layer thinning, and less prominent photoreceptor loss. The findings provide the first, to date, in vivo evidence in humans for possible retinal maldevelopment with a predilection for retinal GCL loss in CZS, consistent with a murine model of the disease and suggestive of in utero depletion of this neuronal population as a consequence of Zika virus infection.
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Infecciones Virales del Ojo/diagnóstico , Complicaciones Infecciosas del Embarazo , Degeneración Retiniana/diagnóstico , Células Ganglionares de la Retina/patología , Infección por el Virus Zika/diagnóstico , Adolescente , Anticuerpos Antivirales/sangre , Niño , Preescolar , Infecciones Virales del Ojo/congénito , Infecciones Virales del Ojo/virología , Femenino , Humanos , Lactante , Masculino , Células Fotorreceptoras de Vertebrados/patología , Embarazo , Degeneración Retiniana/congénito , Degeneración Retiniana/virología , Células Ganglionares de la Retina/virología , Estudios Retrospectivos , Tomografía de Coherencia Óptica , Agudeza Visual , Deficiencia de Vitamina B 12/diagnóstico , Virus Zika/inmunología , Infección por el Virus Zika/congénito , Infección por el Virus Zika/virologíaAsunto(s)
Fóvea Central/patología , Síndrome POEMS/diagnóstico , Enfermedades de la Retina/etiología , Segmento Externo de las Células Fotorreceptoras Retinianas/patología , Humanos , Masculino , Persona de Mediana Edad , Síndrome POEMS/complicaciones , Enfermedades de la Retina/diagnóstico , Tomografía de Coherencia Óptica/métodosRESUMEN
PURPOSE: To describe in detail the retinal structure and function of a group of patients with cobalamin C (cblC) disease. METHODS: Patients (n = 11, age 4 months to 15 years) with cblC disease (9/11, early onset) diagnosed by newborn screening underwent complete ophthalmic examinations, fundus photography, near-infrared reflectance imaging, and spectral-domain optical coherence tomography (SD-OCT). Electroretinograms (ERGs) were performed in a subset of patients. RESULTS: Patients carried homozygous or compound heterozygote mutations in the methylmalonic aciduria and homocystinuria type C (MMACHC) gene. Late-onset patients had a normal exam. All early-onset patients showed a maculopathy; older subjects had a retina-wide degeneration (n = 4; >7 years of age). In general, retinal changes were first observed before 1 year of age and progressed within months to a well-established maculopathy. Pseudocolobomas were documented in three patients. Measurable visual acuities ranged from 20/200 to 20/540. Nystagmus was present in 8/11 patients; 5/6 patients had normal ERGs; 1/6 had reduced rod-mediated responses. Spectral-domain OCT showed macular thinning, with severe ganglion cell layer (GCL) and outer nuclear layer (ONL) loss. Inner retinal thickening was observed in areas of total GCL/ONL loss. A normal lamination pattern in the peripapillary nasal retina was often seen despite severe central and/or retina-wide disease. CONCLUSIONS: Patients with early-onset cblC and MMACHC mutations showed an early-onset, unusually fast-progressing maculopathy with severe central ONL and GCL loss. An abnormally thickened inner retina supports a remodeling response to both photoreceptor and ganglion cell degeneration and/or an interference with normal development in early-onset cblC.
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Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Degeneración Retiniana/etiología , Células Ganglionares de la Retina/patología , Adolescente , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Niño , Preescolar , Electrorretinografía , Femenino , Humanos , Lactante , Masculino , Degeneración Retiniana/diagnóstico , Índice de Severidad de la Enfermedad , Tomografía de Coherencia Óptica/métodos , Agudeza VisualRESUMEN
The efficacy of proteasome inhibition for myeloma is limited by therapeutic resistance, which may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation. Preclinical studies demonstrate that autophagy inhibition with hydroxychloroquine augments the antimyeloma efficacy of the proteasome inhibitor bortezomib. We conducted a phase I trial combining bortezomib and hydroxychloroquine for relapsed or refractory myeloma. We enrolled 25 patients, including 11 (44%) refractory to prior bortezomib. No protocol-defined dose-limiting toxicities occurred, and we identified a recommended phase 2 dose of hydroxychloroquine 600 mg twice daily with standard doses of bortezomib, at which we observed dose-related gastrointestinal toxicity and cytopenias. Of 22 patients evaluable for response, 3 (14%) had very good partial responses, 3 (14%) had minor responses, and 10 (45%) had a period of stable disease. Electron micrographs of bone marrow plasma cells collected at baseline, after a hydroxychloroquine run-in, and after combined therapy showed therapy-associated increases in autophagic vacuoles, consistent with the combined effects of increased trafficking of misfolded proteins to autophagic vacuoles and inhibition of their degradative capacity. Combined targeting of proteasomal and autophagic protein degradation using bortezomib and hydroxychloroquine is therefore feasible and a potentially useful strategy for improving outcomes in myeloma therapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Autofagia , Ácidos Borónicos/uso terapéutico , Hidroxicloroquina/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Inhibidores de Proteasoma/uso terapéutico , Pirazinas/uso terapéutico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Autofagia/efectos de los fármacos , Ácidos Borónicos/farmacocinética , Ácidos Borónicos/farmacología , Bortezomib , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Hidroxicloroquina/farmacocinética , Hidroxicloroquina/farmacología , Masculino , Persona de Mediana Edad , Inhibidores de Proteasoma/farmacología , Pirazinas/farmacocinética , Pirazinas/farmacología , RecurrenciaRESUMEN
Elevated intraocular pressure-induced interlamellar stromal keratitis (PISK) is an entity of interface haze usually occurring weeks to months after laser in situ keratomileusis (LASIK) that is associated with elevated intraocular pressures and worsening with steroid treatment. There is evidence that this interface haze is the result of abnormal fluid dynamics that occur in the cornea after LASIK. We present a case of pressure-induced interlamellar stromal keratitis occurring 9 years after LASIK in the setting of anterior uveitis. This case emphasizes the importance of considering such diagnoses as pressure-induced interlamellar stromal keratitis in the differential diagnosis when presented with a patient with corneal haze and a history of LASIK.
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Sustancia Propia/patología , Presión Intraocular , Queratitis/etiología , Queratomileusis por Láser In Situ/efectos adversos , Hipertensión Ocular/etiología , Adulto , Humanos , Masculino , Agudeza VisualRESUMEN
OBJECTIVE: To discuss the manifestation of pseudotumor cerebri during the course of correcting the hypercortisolism of Cushing's disease. METHODS: We describe the clinical, biochemical, and neuro-ophthalmologic findings in a patient in whom pseudotumor cerebri developed during correction of the hypercortisolism of Cushing's disease. In addition, we review the relationship between pseudotumor cerebri and Cushing's disease in the literature. RESULTS: A 44-year-old woman with Cushing's disease underwent total adrenalectomy after two unsuccessful transsphenoidal operations. She developed daily headaches 2 weeks postoperatively while taking 60 mg of hydrocortisone daily. She noticed a visual floater 8 weeks postoperatively, and a prompt ophthalmologic evaluation revealed papilledema. We diagnosed pseudotumor cerebri on the basis of symptoms and signs of intracranial hypertension, unremarkable findings on neuroimaging and cerebrospinal fluid analysis, and a substantially increased cerebrospinal fluid pressure. After 8 weeks of treatment with furosemide, the headaches and papilledema resolved, and the patient was able to reduce her dose of hydrocortisone to 30 mg daily. Pseudotumor cerebri has been associated with adrenocortical insufficiency and gluco- corticoid withdrawal and can lead to loss of vision. A literature review revealed 6 previous patients in whom pseudotumor cerebri developed in association with Cushing's disease. In all but one case, the pseudotumor cerebri manifested 2 to 4 weeks after treatment of hypercortisolism or cessation of hydrocortisone replacement. CONCLUSION: Symptoms of intracranial hypertension such as headache occurring in a patient recently withdrawn from exogenous or endogenous corticosteroids should prompt consideration of the presence of pseudotumor cerebri.