Manabu Kase

Neuronal activity related to vertical eye movement in the region of the interstitial nucleus of Cajal in alert cats

Summary(1) Discharge characteristics of neurons in the region of the interstitial nucleus of Cajal (INC) were studied in alert cats during spontaneous or visually induced eye movement and sinusoidal vertical (pitch) rotation. Activity of a majority of cells (n = 68) was closely related to vertical eye position with or without bursting activity during on-direction saccades. They were called vertical burst-tonic (n = 62) and tonic (n = 6) neurons. Mean discharge rates for individual cells when the eye was near the primary position ranged from 35 to 133 (mean 75) spikes/s with a coefficient of variation (CV) ranging from 0.04 to 0.29 (mean 0.15). Average rate position curves were linear for the great majority of these cells with a mean slope of 3.9 ± 1.2 SD spikes/s/deg. (2) The burst index was defined as the difference in discharge rate between maximal rate during an on-direction saccade and the tonic rate after the saccade. The values of mean burst index for individual cells ranged from 8 to 352 (mean 135) spikes/s. Tonic neurons had a burst index lower than 60 spikes/s and were distributed in the lower end of the continuous histogram, suggesting that burst-tonic and tonic neurons may be a continuous group with varying degrees of burst components. During off-direction saccades, a pause was not always observed, although discharge rate consistently decreased and pauses were seen when saccades were made further in the off-direction toward recruitment thresholds. Significant positive correlation was observed between average discharge rate during off- as well as on-direction saccades and tonic discharge rate after saccades for individual cells, which was not due to cats making saccades mainly from the primary position. (3) During pitch rotation at 0.11 Hz (±10 deg), burst-tonic and tonic neurons had mean phase lag and gain of 128 (±13 SD) deg and 4.2 (±1.7 SD) spikes/s/deg/s2 relative to head acceleration. During pitch rotation of a wide frequency range (0.044–0.495 Hz), the values of phase lag were mostly constant (120–140 deg), while simultaneously recorded vertical VOR showed the mean phase lag of 178 deg. Vertical eye position sensitivity and pitch gain (re head position) showed significant positive correlation. (4) Comparison of the discharge characteristics of vertical burst-tonic and tonic neurons with those of secondary vestibulo-ocular neurons (Perlmutter et al. 1988) and extraocular motoneurons (Delgado-Garcia et al. 1986) in alert cats suggests that signals carried by burst-tonic and tonic neurons are partially processed signals in vertical VOR and saccades, and different from oculomotor signals. (5) The INC region also contained many cells that did not belong to the above groups but whose activity was clearly modulated by pitch rotation (called pitch cells for the present study, n = 44). Many (n = 23) showed some correlation with vestibular quick phases, and some (n = 12) with visually elicited eye movement, although they showed significantly lower and more irregular discharge rates than burst-tonic and tonic neurons (mean discharge rate when the eye was near the primary position 34, range 3–91, spikes/s; mean CV 0.61, range 0.15–1.7). During pitch rotation they showed the mean phase lag and gain of 119(±26 SD) deg and 3.2(±2.1 SD) spikes/s/deg/s2. Some cells showed a much lower phase lag of about 90 deg. (6) More than half the burst-tonic, tonic and pitch cells tested were antidromically activated by stimuli applied to the ponto-medullary medial longitudinal fasciculus at the level of abducens nucleus, while none of them were activated from the inferior olive, suggesting that vertical eye position signals carried by some burst-tonic and tonic neurons are carried to the lower brainstem.

Increased Osteopontin Levels in the Vitreous of Patients with Diabetic Retinopathy

Purpose: Osteopontin (OPN) has diverse functions such as cell adhesion, chemoattraction, immunomodulation, and angiogenesis. The aim of this study is to analyze the OPN levels in vitreous fluid obtained from diabetic retinopathy (DR) and non-DR patients. Methods: Nineteen patients out of 11 with DR and 8 without DR underwent pars plana vitrectomy and vitreous fluid was obtained simultaneously. Two distinct sandwich enzyme-linked immunosorbent assay systems (systems 1 and 2) were applied, which have been developed in our laboratories to quantify the OPN concentrations in vitreous fluid. Results: The non-thrombin-cleaved full-length OPN levels in the vitreous fluid were 921.63 ± 45.38 ng/ml in DR and 632.80 ± 83.43 ng/ml in non-DR using system 1. Also, vitreous thrombin-cleaved and noncleaved OPN levels were increased to 2,109.22 ± 151.651 and 1,651.13 ± 229.82 ng/ml in patients with DR and non-DR using system 2. The vitreous OPN levels were significantly higher in DR than those in non-DR (p < 0.01 by system 1 and p < 0.05 by system 2). Conclusion: Thrombin-cleaved and noncleaved vitreous OPN levels in patients with DR were increased compared with control subjects, suggesting that OPN plays a potential role in the pathogenesis of diabetic retinal ischemia.

Expression of erythropoietin receptor in human epiretinal membrane of proliferative diabetic retinopathy

Purpose: It is widely accepted that intravitreous levels of erythropoietin (Epo) are elevated in patients with ischaemic retinal diseases such as proliferative diabetic retinopathy (PDR). The aim of this study was to examine the expression of Epo and the Epo receptor (EpoR) in epiretinal membranes with and without diabetes. Methods: Eighteen epiretinal membranes (PDR (n = 10), idiopathic epiretinal membranes (IERMs) without diabetes (n = 4) and inner limiting membranes (ILMs) (n = 4)) were obtained during pars plana vitrectomy. Formalin-fixed and paraffin-embedded tissues were examined by immunohistochemistry with anti-Epo and EpoR antibodies. Results: The histopathological findings demonstrated that PDR membranes consisted of a variety of endothelial cells forming a microvascular cavity with red blood cells and non-vascular stromal mononuclear cells. Membranous and cytoplasmic immunoreactivity for EpoR was strongly detected in endothelial cells and stromal cells in all PDR patients. Although microvessels were not observed in IERMs and ILMs, immunoreactivity for EpoR was noted in the cellular component of IERMs, and was weakly detected in ILMs. Epo was not expressed in any membrane. Conclusion: EpoR was strongly expressed in microvessels of all PDR membranes. The in vivo evidence in this study suggests that Epo in the vitreous binds to EpoR in PDR membranes, which subsequently leads to the proliferation of new retinal vessels. EpoR immunoreactivity in non-vascular stromal cells in PDR membranes, and IERMs and ILMs might be indirectly correlated with ischaemia.

Ocular torsion produced by unilateral chemical inactivation of the interstitial nucleus of Cajal in chronically labyrinthectomized cats

Unilateral lesions of the rostral midbrain involving the interstitial nucleus of Cajal (INC) have been known to produce ocular torsion in alert animals including humans, which has been assumed to be the result of an impaired otolith-ocular reflex. We examined the effects of chemical deactivation of the INC using a gamma-aminobutyric acid (GABA) agonist (muscimol) in cats that had received bilateral labyrinthectomy, and compared the results with those in normal cats. Ocular torsion with a magnitude similar to that observed in normal cats appeared in chronically labyrinthectomized cats after unilateral muscimol infusion into the INC, indicating that ocular torsion following unilateral INC deactivation can be produced by a mechanism independent of the otolith-ocular reflex.

Positive association of pigment epithelium-derived factor with total antioxidant capacity in the vitreous fluid of patients with proliferative diabetic retinopathy

Background: Pigment epithelium-derived factor (PEDF), a glycoprotein with potent neuronal differentiating activity, was recently found to inhibit advanced glycation end product (AGE)-induced retinal hyperpermeability and angiogenesis through its antioxidative properties, suggesting that it may exert beneficial effects on diabetic retinopathy by acting as an endogenous antioxidant. However, the inter-relationship between PEDF and total antioxidant capacity in the eye remains to be elucidated. Aims: To determine vitreous PEDF and total antioxidant levels in patients with proliferative diabetic retinopathy (PDR), and to investigate the relationship between them. Methods: Vitreous levels of PEDF and total antioxidant capacity were measured by an ELISA in 39 eyes of 36 patients with diabetes and PDR and in 29 eyes of 29 controls without diabetes. Results: Vitreous levels of total antioxidant capacity were significantly lower in patients with diabetes and PDR than in controls (mean (SD) 0.16 (0.05) vs 0.24 (0.09) mmol/l, respectively, p<0.001). PEDF levels correlated positively with total antioxidant status in the vitreous of patients with PDR (r = 0.37, p<0.05) and in controls (r = 0.41, p<0.05). Further, vitreous levels of PEDF in patients with PDR without vitreous haemorrhage (VH(−)) were significantly (p<0.05) decreased, compared with those in the controls or in patients with PDR with vitreous haemorrhage (VH(+); PDR VH(−), 4.5 (1.1) μg/ml; control, 7.4 (4.1) μg/ml; PDR VH(+) 8.5 (3.6) μg/ml). Conclusion: This study demonstrates that PEDF levels are associated with total antioxidant capacity of vitreous fluid in humans, and suggests that PEDF may act as an endogenous antioxidant in the eye and could play a protective role against PDR.

Retinal vasculitis due to secondary syphilis.

BackgroundRetinal vasculitis is one of the manifestations of ocular syphilis.CaseA 29-year-old man was referred to our hospital with the complaint of sudden visual loss in the left eye lasting more than three weeks.ObservationsOphthalmoscopic examination showed retinal hemorrhages, edema, and sheathing of large retinal arteries and veins. Fluorescein angiography revealed extensive occlusion of the affected retinal arteries, veins, and capillaries. Little evidence of uveitis or vitritis was observed. The fluorescent treponemal antibody-absorption test was positive, and the Treponema pallidum hemagglutination titer was 1 : 10 240. The treatment with penicillin was effective, leading to resolution of the retinal hemorrhages and edema, although occlusion of the retinal vessels persisted.ConclusionsVascular occlusion occurred simultaneously in large retinal arteries, arterioles, and capillaries as well as in segments of retinal veins, resulting in irreversible changes in the vascular walls. Jpn J Ophthalmol 2004;48:65–67

Multisystem degeneration: Drugs and square wave jerks

We studied a 55-year-old woman with macrosquare wave jerks and macrosaccadic oscillations with a vertical component. The oscillations almost completely disappeared after administration of diazepam, clonazepam, thiamylal, or phenobarbital. A disorder of GABAergic tonic inhibitory system from the substantia nigra to superior colliculus probably plays an important role in the pathogenesis of these abnormal ocular movements.

Epiretinal membrane formation in Terson syndrome

Clinical features of epiretinal membranes were examined in 22 eyes of 13 patients with Terson syndrome who were treated with pars plana vitrectomy. The shape and localization of the epiretinal membranes were intraoperatively evaluated and correlated with the presence or absence of posterior vitreous detachment (PVD). Patients with complete PVD, but with no membrane found during surgery, were followed postoperatively. Membrane formation ultimately developed in 13 of the 22 eyes. In eight eyes, PVD was incomplete and the epiretinal membrane was found at the optic disc or along the temporal vascular arcades, displaying retinal folds and vascular tortuosity. Three eyes had massive tractional retinal detachment; five of those with complete PVD developed a thin epiretinal membrane around the posterior pole that became more apparent during long-term follow-up. From these observations, we can classify epiretinal membrane formation in Terson syndrome into two groups: with complete, or with incomplete, PVD. It also appears that multiple pathological processes involving the vitreoretinal interface were responsible for the formation of epiretinal membranes.

Expression of glutamine synthetase and cell proliferation in human idiopathic epiretinal membrane

Background/aim: The mechanisms of the cellular origin and cell proliferation in the idiopathic epiretinal membrane (ERM) are unsolved. The aim of this study was to examine the expression of cell cycle related molecules and glutamine synthetase (GS), which is expressed in Müller cells and their processes, in ERM tissues. Methods: The ERMs were surgically removed using pars plana vitrectomy. Formalin fixed, paraffin embedded ERM tissues were analysed by immunohistochemistry with anti-cyclin D1, p27 (KIP1), proliferating cell nuclear antigen (PCNA), and GS antibodies. Results: The histopathological findings showed that all the ERMs consisted of oval or spindle mononuclear cells with thin collagen-like tissues. Immunoreactivity for GS was detected in collagen-like tissues of ERM, presenting a continuous, isodense pattern. GS immunopositive cells in all cases expressed PCNA in their nuclei. Nuclear immunoreactivity for cyclin D1 was noted in the ERM constituent cells, whereas p27 (KIP1) positive nuclei were not detected. Conclusion: Cyclin D1 and PCNA were expressed in the idiopathic ERM, which was mainly derived from Müller cells and extensions of their processes.

Development of central retinal vein occlusion in dural carotid-cavernous fistula.

We investigated a 46-year-old woman with central retinal vein occlusion complicating dural carotid-cavernous fistula, resulting in severe loss of visual acuity. Venous stasis retinopathy observed on the first examination progressed severely so that central retinal vein occlusion with retinal neovascularization developed 3 months later. A transvascular embolization discontinuing the feeders from the external carotid artery improved the retinal circulation and the visual acuity. These results indicate that the cause of the progression from venous stasis retinopathy to central retinal vein occlusion is the elevation of pressure in the cavernous sinus.