Superselective intraophthalmic artery chemotherapy in a nonhuman primate model: histopathologic findings.

IMPORTANCE: We describe the histopathologic findings in a nonhuman primate (NHP) model of superselective intraophthalmic artery chemotherapy (SSIOAC), detailing ocular and orbital vascular adverse effects. OBJECTIVE: To further document, using comprehensive ocular and orbital histopathology, previously reported toxic effects observed with real-time ophthalmoscopy during SSIOAC in a NHP model. DESIGN: Comparative interventional case series. SETTING: Preclinical trial approved under the guidelines of the Institutional Animal Care and Utilization committee. PARTICIPANTS: Six adult male rhesus macaques (Macacca mulatta). INTERVENTIONS: The right eye of each NHP was treated with 3 cycles of SSIOAC using either melphalan (5 mg/30 mL) or carboplatin (30 mg/30 mL). Both eyes in each animal were enucleated 6 hours after the final procedure, before euthanasia and formalin perfusion of the NHP; we then performed orbital dissection of the arterial vasculature and optic nerves. MAIN OUTCOME MEASURES: Histopathologic examination of the eyes, optic nerves, and orbital vessels of the 6 treated NHPs. RESULTS: We found leukostasis with retinal arteriole occlusion in all treated eyes. Retinal endothelial cells stained positive for 2 inflammatory markers, intercellular adhesion molecule 1 and interleukin 8. Transmission electron microscopy revealed occlusion of the retinal vessels with ultrastructural changes in the endothelial cells and surrounding pericytes. Additional findings included nerve fiber layer infarcts, central retinal artery thrombosis, hypertrophy and occlusion of choroidal arteries with disruption of the internal elastic lamina, patchy choroidal inflammation, and birefringent intravascular foreign bodies. Orbital findings included ophthalmic artery and central retinal artery wall dissection, fracturing of the internal elastic lamina, intimal hyperplasia, and eyelid vessel damage. Optic nerves displayed hemorrhage, leukostasis, and foreign body crystallization. Control eyes, optic nerves, and orbital vessels were normal. CONCLUSIONS AND RELEVANCE: Histopathologic examination of our nonhuman primate model for SSIOAC revealed significant toxic effects in the ocular and orbital vasculature. These findings substantiate previous observations with real-time retinal imaging and parallel reported vascular toxic effects in children with retinoblastoma treated with SSIOAC.

Fluxometria eco-power-doppler da artéria oftálmica externa em gatos (Felis catus Linnaeus, 1758) / Eco-power-doppler arterial flow from the external ophthalmic artery in cats (Felis catus Linnaeus, 1758) / Flujometria por ultrasonido de la arteria oftálmica externaen gatos

RESUMO: Os avanços tecnológicos dos meios diagnósticos benefi ciam a Medicina Veterinária. Para que novas tecnologias sejam utilizadas, são necessárias informações sobre os padrões normais para cada tipo de exame, o que possibilita sua utilização na rotina e destinação, adequadamente, a cada paciente. A fl uxometria ultra-sonográfi ca está começando a ser utilizada em Medicina Veterinária com fi nalidades e propósitos diversos. Para destiná-la a um fi m específi co, o presente trabalho teve por objetivo verifi car a fl uxometria ultra-sonográfi ca da artéria oftálmica externa em gatos. Para tanto, foram utilizados 20 gatos sem raça defi nida, 12 machos e 8 fêmeas, com massa corporal entre 2,0 e 4,0 kg, hígidos, provenientes da Sociedade de Amparo aos Animais de Umuarama ­ PR. Os animais foram anestesiados pela associação de tiletamina e zolazepam, administrada por via intramuscular, na dose de 6,0 mg/kg. A fl uxometria da artéria oftálmica externa foi obtida por meio do equipamento de ultra-sonografi a Toshiba Powervision ATL-HDI 3500, dotado de "eco-doppler", com transdutor setorial de 6,0 MHz, aplicado diretamente sobre a córnea. Cada olho teve o fl uxo de sua artéria aferido pelo programa do próprio aparelho, sendo tomadas três amostras. O índice de resistência vascular foi calculado com base nos valores do fl uxo sistólico e diastólico médio de cada vaso. Os valores foram tabulados e teste t de Student foi aplicado para verifi cação de diferenças entre as médias. No olho direito, obteve-se velocidade de fl uxo de 41,3 ± 14,28 cm/seg para a artéria oftálmica externa, em sístole, e 23,95 ± 11,46 cm/seg, em diástole. No olho esquerdo, 42,75 ± 12,64 cm/seg, em sístole, e 25,45 ± 9,61 cm/seg, em diástole. Não houve diferença signifi cativa entre os olhos. O índice de resistência vascular calculado foi de 0,4175 para a artéria oftálmica externa, no olho direito, e 0,4015 no olho esquerdo, sem diferença signifi cativa entre os olhos. Os resultados apontam para um mecanismo intrínseco de controle do fl uxo, controlado por fatores locais na artéria oftálmica externa, e os valores do índice de resistência denotam uma artéria de baixo fluxo

ABSTRACT: Veterinary medicine is benefi ted by technological advances in diagnosis. In order that new technologies may be used, information about normal standards for each type of examination is necessary, so that they may be used routinely and adequately prescribed for each patient. The Doppler ultrasound is beginning to be used in veterinary medicine for diverse purposes. The objective of this study is to verify the Doppler ultrasound fl ow of the external ophthalmic artery in cats. There were used 20 mixed breed cats, being 12 males and eight females, weighing from 2.0 to 4.0 kg, supplied by the Amparo aos Animais Society, an animal shelter from the city of Umuarama, State of Paraná, Brazil. The animals were anesthetized with 6.0 mg/kg of the association tiletamine plus zolazepam, given by intramuscular route. The fl ow of the external ophthalmic artery was measured through the ultrasound equipment Toshiba Powervision ATL-HDI 3500, with an echo-Doppler and a sectorial transducer of 6.0 MHz, directly applied to the cornea. Each eye had the artery fl ow surveyed by the equipment's own software, in which three samples have been taken. The vascular resistance index was calculated based on the mean values of systolic and diastolic fl ow of each vessel. The values were tabulated and Student t test was applied to verify differences between the averages. In the right eye, the value for the external ophthalmic artery fl ow was 41.30 ± 14.28 cm/sec, in systole, and 23.95 ± 11.46 cm/seg, in diastole. For the left eye, the value was 42.75 ± 12.64 cm/sec, in systole, and 25.45 ± 9.61 cm/sec, in diastole. There were no signifi cant differences between the eyes. The calculated index of vascular resistance was 0.4175 ± 0.0774 for the external ophthalmic artery in the right eye, and 0.4015 ± 0.0719 for the left eye, without signifi cant difference between the eyes. The results point out to an intrinsic mechanism of fl ow control, controlled by local factors in the external ophthalmic artery, and the resistance index values denote a low fl ow artery

RESUMEN: La medicina veterinaria se benefi cia de los adelantos tecnológicos en diagnóstico. El conocimiento de los padrones normales para cada tipo y examen es fundamental para que se puedan usar nuevas tecnologías, posibilitando su empleo rutinario yla indicación adecuada a cada paciente. El objetivo de este estudio fue verifi car la fl ujometría por ultrasonido de la arteria oftálmica externa en gatos. Se emplearon 20 gatos sin raza defi nida, 12 machos y ocho hembras, que provinieron de la Sociedad de Amparo a los Animales de la ciudad de Umuarama, Estado de Paraná, Brasil. Los animales fueron anestesiados con 6.0 mg/kg de la asociación de tiletamina y zolazepam, ministrados por vía intramuscular. El fl ujo de la arteria oftálmica externa fue mensurado por medio del equipo del ultrasonido Toshiba Powervision ATL-HDI 3500, con un eco-doppler y un transductor sectorial de 6.0 MHz, directamenteaplicado a la córnea. Cada ojo tenía el fl ujo de la arteria evaluado por el propio programa del equipo, tomándose tres muestras. El índice de resistencia vascular se calculó basado en los valores promedios de fl ujo sistólico y diastólico de cada vaso. Los valores fueron tabulados y se aplicó el teste t de Student para verifi car diferencias entre los promedios. En el ojo derecho, el valor para el fl ujo de la arteria oftálmica externa fue 41,30 ± 14.28 cm/sec, en sístole, y 23,95 ± 11,46 cm/seg, en diástole. Para el ojo izquierdo, el valor fue 42,75 ± 12,64 cm/seg, en sístole, y 25,45 ± 9,61 cm/sec, en diastole. No se observó diferencia signifi cante entre los ojos. El índice calculado de resistencia vascular fue 0,4175 ± 0,0774 para la arteria oftálmica externa en el ojo derecho, y 0.4015 ± 0.0719 para el ojo izquierdo, sin diferencia signifi cante entre los ojos. Los resultados apuntan para un mecanismo intrínseco de control de fl ujo, controlado por factores locales en la arteria oftálmica externa, y los valores del índice de resistencia denotan una arteria de bajo fl ujo

Ocular blood flow evaluation in injured and healthy fellow eyes.

PURPOSE: To assess if injured eyes develop ocular blood flow disturbances that may contribute to development of traumatic glaucoma. METHODS: Twenty-five eyes of 25 patients hospitalized from January 1997 to July 1999 for blunt (15) or penetrating (10) eye injury and elevated intraocular pressure (IOP) (>23 mm Hg) were controlled at least 24 months after the trauma and underwent visual field examination, pulsatile ocular blood flow (pOBF), and color Doppler imaging (CDI) analysis of ophthalmic artery, central retinal artery, nasal and temporal short posterior ciliary arteries. Uninjured healthy eye was used as control. RESULTS: IOP was significantly higher in injured eyes (15.1+/-3.3 vs 13.0+/-2.7 mmHg; p<0.01), but only 2 eyes (8%) were under medical treatment. pOBF values were significantly lower in injured eyes: 11.25+/-6.56 microL/sec in the trauma eyes and 15.40+/-7.29 in fellow eyes (p=0.002). Resistivity index of all investigated retrobulbar vessels was very significantly higher in injured eyes than in fellow eyes (p<0.0001). There is no significant correlation between IOP and ocular blood flow disturbance. CONCLUSIONS: Long-term follow-up (mean 39+/-12 months) of injured eyes shows, besides a slight but significant increase of IOP, a very significant impairment of ocular blood supply to injured eyes compared to healthy fellow eyes with reduction of pulsatile ocular blood flow and marked increase of resistance to flow in all retrobulbar vessels. These anomalies may be considered an independent risk factor to develop traumatic glaucoma.

Access of autonomic nerves through the optic canal, and their orbital distribution in man.

The notion that autonomic nerves from the internal carotid plexus are transmitted to the orbit with the ophthalmic artery through the optic canal has been variously assumed, disregarded, or denied, but never demonstrated. The objective of this study was to examine the contents of the canal, identify any autonomic nerves, and follow their passage within the orbit. The soft tissues of the optic canal, and the apical tissues of the orbit were removed and examined histologically using 10 cadaver preparations. Additionally, tissues from an orbital exenteration and 10 ocular enucleation or donor specimens were prepared. Some of the latter material was examined with an electron microscope. Numerous autonomic nerves (four to 25, ranging in diameter from 23 to 130 microm) entered the orbit from the internal carotid plexus in the periosteum of the optic canal, the optic nerve dura mater, or the adventitia of the ophthalmic artery. In the orbit they advanced in the loose connective tissue covering the optic nerve dura and joined ciliary nerves close to the eye or entered the eye directly. None were observed to penetrate the dura, apart from a nerve accompanying the central retinal artery. Others were distributed with the ophthalmic artery and its branches. It is concluded that the optic canal is a regular, and often major, route for autonomic nerve distribution to the eye and orbit.

Morphology of the murine optic nerve.

PURPOSE: To study the morphology of the murine optic nerve (ON). METHODS: Eyes of C57/Bl6 and BalbC mice were studied by light and electron microscopy. Microvascular castings of the ON region were prepared by transcardial injection of liquid plastic and studied with a scanning electron microscope. Immunohistochemistry was performed using antibodies against glial fibrillary acidic protein (GFAP), connexin 43, carbonic anhydrase II, and collagen types I and III. RESULTS: The transition between nonmyelinated and myelinated portion of the ON started approximately 0.6 mm behind the globe. A lamina cribrosa was completely absent. Instead, ON axons passed through a scleral hole that was surrounded by a ring of type III and type I collagen fibers. Instead of connective tissue beams within the nerve, layers of elongated astrocytes traversed the ON. All astrocytes stained for GFAP, but not for carbonic anhydrase II. The arterial supply of the nonmyelinated ON derived from branches of the central retinal artery. None of the capillaries derived from choroidal vessels. CONCLUSIONS: The mouse ON head differs from that of other species, because it lacks a lamina cribrosa and a choroidal vascular supply. Studies in glaucomatous mice might help to identify the importance of the lamina cribrosa and the choroidal vascular supply for optic nerve damage in glaucoma.

Corrosion cast demonstration of choroidal vasculature in normal Wistar Kyoto rat.

No previous attempt has been made so to demonstrate the details of the choroid vascularization in the rat. This paper describes the choroidal vascular pattern of the normal Wistar Kyoto rat using the corrosion cast method. 6-month-old normal Wistar Kyoto rats were used. Vascular casts prepared by our previously described technique were observed with a Hitachi S-2360N scanning electron microscope. Corrosion casts of the entire choroidal vasculature showed that the ophthalmic artery branched into two main ciliary arteries: the nasal and temporal arteries, which extend forward to form the iridociliary circle. Further the inferior ciliary artery arises from the temporal ciliary artery. In the posterior eye segment these arteries form four to seven branches supplying the adjacent choriocapillaris. There are different arrangements of choriocapillaris. The larger veins formed four vortex veins, one in each quadrant, draining blood from the anterior region of the choroid or iris. Venous blood from the central region, peripapillary choroid and sometimes optic nerve head is drained by smaller veins, which run more or less directly into the posterior ciliary veins. In conclusion corrosion casts and SEM can show the details of the choroidal vascular architecture. These three-dimensional (3-D) findings of choroidal vessels of the rat are very useful for the study of choroid vascular abnormalities in various pathological conditions.

[Study of blood dynamics of ophthalmic artery in patients with sudden sensorineural hearing loss using color Doppler flow imaging].

OBJECTIVE: To investigate the relationship between the pathogenesis of sudden sensorineural hearing loss (SSHL) and the disorder of blood circulation in inner ear. METHOD: Blood dynamics of the ophthalmic artery were studied quantitatively using color doppler imaging in 34 patients with SSHL. RESULT: Compared with 34 self-controls and 15 normal controls, 28 patients (82.4%) with SSHL had significantly lower blood flow velocities and higher resistance indices (P < 0.05), and there was no significant difference between the self-control group and the normal control group (P > 0.05). CONCLUSION: The study suggested that the blood situations--the decreased blood flow velocities and perfusion and increased resistance of ophthalmic artery in patients with SSHL maybe play a role in the pathogenesis of SSHL.

Microvasculature of the rat optic nerve head.

PURPOSE: To describe the arterial blood supply, capillary bed, and venous drainage of the rat optic nerve head. METHODS: Ocular microvascular castings from 6 Wistar rats were prepared by injection of epoxy resin through the common carotid arteries. After polymerization, tissues were digested with 6 M KOH, and the castings washed, dried, and coated for scanning electron microscopy. RESULTS: Immediately posterior to the globe, the ophthalmic artery trifurcates into the central retinal artery and two posterior ciliary arteries. The central retinal artery directly provides capillaries to the nerve fiber layer and only contributes to capillary beds in the neck of the nerve head. The remainder is supplied by branches of the posterior ciliary arteries that are analogous to the primate circle of Zinn-Haller. Arterioles arising from these branches supply the capillaries of the transitional, or laminar, region of the optic nerve head. These capillaries are continuous with those of the neck and retrobulbar optic nerve head. All optic nerve head capillaries drain into the central retinal vein and veins of the optic nerve sheath. A flat choroidal sinus communicates with the central retinal vein, the choriocapillaris, and with large veins of the optic nerve sheath. CONCLUSIONS: The microvasculature of the rat optic nerve head bears several similarities to that of the primate, with a centripetal blood supply from posterior ciliary arteries and drainage into the central retinal and optic nerve sheath veins. Association of nerve sheath veins with the choroid represents an important difference from the primate.

Microvascular change of the anterior eye segment after tenotomy in the rabbit.

BACKGROUND: The microvascular changes secondary to anterior segment ischemia following tenotomy of the extraocular muscles have not been studied in the rabbit. METHODS: Using scanning electron microscopy of methyl-methacrylate ocular microvascular luminal castings, the anterior eye segment vasculature after tenotomy was documented and compared to that after occlusion of the bilateral long posterior ciliary arteries and that in the eyes that were not subjected to any surgical intervention. RESULTS: Five days and 1 week after the surgical intervention with tenotomy, microvascular change secondary to the anterior segment ischemia was not apparent, but 2 weeks after the tenotomy subtle evidence of ischemia such as new vessels in the iris was observed. Seven weeks after tenotomy, marked microvascular change was observed where corneal new vessels arose from the superior perilimbal arteries. In contrast, we found prominent microvascular changes 2 weeks after the occlusion of the long posterior ciliary arteries. CONCLUSIONS: Tenotomy of the rabbit eye causes microvascular change similar to that in occlusion of the long posterior ciliary arteries. This result suggests that the anterior ciliary artery of the rabbit contributes blood flow to the anterior eye segment and also has a stronger connection with the long posterior ciliary artery than previously reported.

Formation of the ocular arteries in the chick embryo: observations of corrosion casts by scanning electron microscopy.

An investigation was carried out on the formation of the blood vessels that supply the optic cup or eyeball in developing chick embryos ranging in age from Hamburger-Hamilton stage 17 (st17) to st44. Corrosion casts of the vasculature were made by injecting resin and examined by scanning electron microscopy. The optic cup was supplied by branches of the cranial ramus of the circle of Willis (CCW) from st17 to st19. By st23, a branch of the CCW and that of the internal carotid artery became anlagen of two ophthalmic arteries, namely, the cerebral ophthalmic artery (COA) and the internal carotid ophthalmic artery (ICOA) respectively. They were continued by primordia of the long posterior ciliary arteries, which connected with each other to form a ring around the pupil. Between st19 and st26, another branch of the CCW was found, by contrast, to supply the primitive pecten. The distal part of the nasal long posterior ciliary artery began to atrophy at st28, so the temporal long posterior ciliary artery only began to supply the ring artery around the pupil by st30. At the same time, the artery supplying the pecten became anastomosed with the ICOA behind the eyeball to form the definitive pectinate artery. By st30, the ophthalmic branch of the stapedial artery had also formed and connected with the distal part of the ICOA behind the eyeball, as well as with the distal part of the COA by st34. The supraorbital branch of the stapedial artery, which had replaced the CCW to anastomose with the ethmoidal artery by st30, was found to be connected to the COA at st36. The main vascular system supplying the eyeball was complete at st36, and its structure at st40 and st44 was fundamentally similar to that at st36.

Ophthalmic artery flow velocity after physical exercise in healthy men.

This study was conducted to evaluate the effects of physical exercise on blood flow velocity in the ophthalmic artery of healthy men. Color Doppler imaging, which permits rapid noninvasive imaging of the ophthalmic artery, was performed in 11 healthy male adult volunteers to compare pre- and post-exercise measurements of blood flow velocity. After submaximal physical exercise, systolic blood flow velocity (Vmax) and time-averaged blood flow velocity (Vmean) increased significantly, but returned to pre-exercise levels 5-10 minutes after the completion of physical exercise. There were no significant changes in minimum end-diastolic blood flow velocity (Vmin), resistance index (RI) or pulsatility index (PI). The RI and PI parameters are considered to reflect vascular resistance. Our results indicate that submaximal physical exercise increased the blood flow velocity, but did not alter the resistance index of the ophthalmic artery.

Gross and histologic study of the rostral epidural rete mirabile and the cavernous sinus in one-humped camels.

Gross and histologic features of the rostral epidural rete mirabile (carotid rete) and the cavernous sinus in one-humped camels were studied. It was evident that the branches of the carotid rete share a common tunica adventitia with the veins of the cavernous sinus. Transmission electron microscopy of the rostral epidural rete mirabile and the cavernous sinus revealed gap junctions in endothelial cells lining the walls of the arterial rete branches and veins. The internal elastic lamina of rete branches were fenestrated. Some of these structural features could facilitate countercurrent heat exchange between the rete branches and the venous plexus of the cavernous sinus to regulate brain temperature.