Bilateral Eye Enucleation Research Articles

Health related quality of life of patients treated with bilateral enucleation for retinoblastoma.

Bilateral enucleation is rarely used to manage retinoblastoma (Rb). We present the health-related quality of life (HQL) and the associated factors among individuals who underwent bilateral surgical enucleation for retinoblastoma. Patients were interviewed via telephone in January 2020. A retinoblastoma registry was used to select patients who underwent bilateral enucleation/exenteration during 33 years. Data included age, gender, literacy, occupation, marital status, and health issues. Patients were asked eight questions on HQL. The responses were graded as 0-10. The percentage proportion of the HQL score was correlated to the determinants. Twenty-one out of 24 participants were interviewed (median age, 23 years). Fourteen participants answered the HQL question themselves, and for 7, their parents answered. Twenty patients (95%) had an ocular prosthesis. The median HQL score was 58 (out of a maximum score of 80) (interquartile range (IQR): 49; 70; minimum, 0 and maximum, 74). The HQL score was positively correlated to: self-reporting than parents reporting (Mann Whitney U (MW) p = 0.05); among students versus individuals in other occupations (MW p = 0.03); interval between eye removal and interview (p = 0.02). Age at enucleation of the second eye (p = 0.001), students (p < 0.001), and self-responders (p < 0.001) were independent predictors of a high HQL score. HQL of individuals having bilateral eye enucleation for retinoblastoma was reasonably good and positively correlated to self-reporting, learning as students to cope and age at 2nd eye removal. Anaplasty services to improve cosmetics seem to benefit such disabled persons.

Bilateral enucleation at birth modifies calcium spike amplitude, but not frequency, in neurons of the somatosensory thalamus and cortex: Implications for developmental cross-modal plasticity

Bilateral eye enucleation at birth (BE) leads to an expansion of the primary somatosensory cortex (S1) in rat pups. Although increased growth of the somatosensory thalamo-cortical afferents (STCAs) in part explains S1 expansion, timing mechanisms governing S1 formation are also involved. In this work, we begin the search of a developmental clock by intending to document the existence of putative clock neurons in the somatosensory thalamus (VPM) and S1 based upon changes of spontaneous spike amplitude; a biophysical property sensitive to circadian regulation; the latter known to be shifted by enucleation. In addition, we also evaluated whether STCAs growth rate and segregation timing were modified, as parameters the clock might time. We found that spontaneous spike amplitude transiently, but significantly, increased or decreased in VPM and S1 neurons of BE rat pups, respectively, as compared to their control counterparts. The growth rate and segregation timing of STCAs was, however, unaffected by BE. These results support the existence of a developmental clock that ticks differently in the VPM and S1 after BE. This observation, together with the fact that STCAs growth rate and segregation timing is unchanged, suggests that S1 expansion in BE rats may in part be controlled at the cortical level.

Photic induction of c-Fos in enkephalin neurons of the rat intergeniculate leaflet innervated by retinal PACAP fibres

The brain's biological clock, located in the suprachiasmatic nucleus (SCN), is synchronised with the cyclic environment by photic and non-photic cues. Photic information to the SCN is mediated by pituitary adenylate-cyclase-activating polypeptide (PACAP)-containing retinal ganglion cells (RGCs), whereas non-photic input originates primarily from neuropeptide Y (NPY) cells in the ipsilateral thalamic intergeniculate leaflet (IGL). RGCs also seem to project to the IGL, indicating a role for this structure in the integration of photic and non-photic inputs related to the resetting of the biological clock. In the present study, we have used anterograde tracing from both eyes, bilateral eye enucleation, double-immunofluorescence histochemistry, high-resolution confocal laser scanning microscopy and three-dimensional computer analysis to show that (1) PACAP-containing RGCs project to the IGL and are the only source for the PACAP-immunoreactive fibres in the IGL; (2) a few NPY-containing neurons in the IGL are innervated by PACAP-containing retinal nerve fibres and the contacts are both axodendritic and axosomatic; (3) most enkephalin-immunoreactive neurons in the IGL are innervated by PACAP-containing retinal afferents and the contacts are mainly axodendritic; (4) light stimulation at various time points activates (as evidenced by c-Fos induction) enkephalin-positive neurons but not NPY-immunoreactive neurons. The findings suggest that PACAP-immunoreactive retinal afferents in the IGL primarily innervate enkephalin-immunoactive neurons and that the enkephalin-containing neurons, which project locally and to the contralateral IGL, are activated by light independent of diurnal time.

Immunoreactive substance P is not part of the retinohypothalamic tract in the rat.

The retinohypothalamic tract (RHT) is a monosynaptic retinofugal pathway mediating information concerning the light/dark cycle from the retina to the brain's biological clock located in the suprachiasmatic nucleus (SCN). Light information, which daily adjusts (entrains) the rhythms of behaviour and physiology generated by the SCN, is mediated by two neurotransmitters, viz. glutamate and pituitary adenylate cyclase activating polypeptide (PACAP), co-stored in the RHT. Substance P (SP) modulates photic- and glutamate-induced phase shifts but data on its possible presence in the RHT are conflicting. By labelling the RHT projection in the SCN with the anterograde tracer cholera toxin subunit B (ChB) and antibodies against PACAP, we have shown that SP immunoreaction is absent from the PACAP/ChB-labelled nerve fibres in the SCN, indicating that the SP-immunoreactive nerve fibres are not part of the RHT but may originate from SP-immunoreactive cell bodies located within the SCN. In the retina, SP immunoreactivity occurs in amacrine cells in the inner nuclear cell layer, in a few displaced amacrine cells in the ganglion cell layer and in a dense plexus of SP-immunoreactive nerve terminals of the inner plexiform layer. Double immunostaining has revealed that SP-immunoreactive cells and fibres in the retina are not identical with the PACAP-immunoreactive ganglion cells that constitute the RHT. These findings together with the demonstration that bilateral eye enucleation does not decrease the number of SP-immunoreactive nerve fibres in the SCN indicate that SP is not a neurotransmitter in the RHT but could be an intrinsic neurotransmitter of the SCN modulating photic input to the clock.

Pituitary adenylate cyclase activating peptide (PACAP) in the retinohypothalamic tract: a daytime regulator of the biological clock.

The retinohypothalamic tract (RHT) relays photic information from the eyes to the brain biological clock in the suprachiasmatic nucleus (SCN). Activation of this pathway by light plays a role in adjusting circadian timing to light exposure at night. Here we report a new signaling pathway by which the RHT regulates circadian timing in the daytime as well. Using dual-immunocytochemistry for PACAP and the in vivo tracer Cholera toxin subunit B (ChB), intense PACAP immunoreactivity (PACAP-IR) was observed in retinal afferents at the rat SCN as well as in the intergeniculate leaflet (IGL) of the thalamus. This PACAP-IR was nearly lost upon bilateral eye enucleation. PACAP afferents originated from ganglion cells distributed throughout the retina. The phase of circadian rhythm measured as SCN neuronal activity in vitro was significantly advanced by application of PACAP-38 during the subjective day, but not at night. The effect is channelled to the clock via a PACAP 1 receptor-cAMP signaling mechanism. Thus, in addition to its role in nocturnal regulation by glutamatergic neurotransmission, the RHT can adjust the biological clock by a PACAP-cAMP-dependent mechanism during the daytime.

Pituitary Adenylate Cyclase-Activating Peptide (PACAP) in the Retinohypothalamic Tract: A Potential Daytime Regulator of the Biological Clock

The retinohypothalamic tract (RHT) relays photic information from the eyes to the suprachiasmatic nucleus (SCN). Activation of this pathway by light plays a role in adjusting circadian timing via a glutamatergic pathway at night. Here we report a new signaling pathway by which the RHT may regulate circadian timing in the daytime as well. We used dual immunocytochemistry for pituitary adenylate cyclase-activating peptide (PACAP) and the in vivo tracer cholera toxin subunit B and observed intense PACAP-immunoreactivity (PACAP-IR) in retinal afferents in the rat SCN as well as in the intergeniculate leaflet (IGL) of the thalamus. This PACAP-IR in the SCN as well as in the IGL was nearly lost after bilateral eye enucleation. PACAP afferents originated from small ganglion cells distributed throughout the retina. The phase of circadian rhythm measured as SCN neuronal activity in vitro was significantly advanced (3.5 +/- 0.4 hr) by application of 1 x 10(-6) M PACAP-38 during the subjective day [circadian time (CT)-6] but not at night (CT14 and CT19). The phase-shifting effect is channeled to the clock via a PACAP-R1 receptor, because mRNA from this receptor was demonstrated in the ventral SCN by in situ hybridization. Furthermore, vasoactive intestinal peptide was nearly 1000-fold less potent in stimulating a phase advance at CT6. The signaling mechanism was through a cAMP-dependent pathway, which could be blocked by a specific cAMP antagonist, Rp-cAMPS. Thus, in addition to its role in nocturnal regulation by glutamatergic neurotransmission, the RHT may adjust the biological clock by a PACAP/cAMP-dependent mechanism during the daytime.

Selective changes in angiotensin II AT 1 and AT 2 receptor subtypes in the rat superior colliculus following eye enucleation

In the brain of young (two weeks old) rats, angiotensin II receptors (AT 2 receptors) are found in brain nuclei which receive and integrate direct visual input from the retina, the suprachiasmatic nuclei (containing only AT 1 receptors), the lateral geniculate nuclei (containing AT 2 receptors) and the superior colliculus (which contains both receptor types with a majority of AT 2). In adult rats, angiotensin II receptors are present in the suprachiasmatic nuclei and the superior colliculus but not in the lateral geniculate. Using quantitative autoradiography we found that, in adult rats, bilateral eye enucleation caused a significant decrease in AT 2 receptor binding, but not in AT 1 receptor binding, and only in the superior colliculus. Unilateral enucleation of 12-day-old pups led to a decrease in AT 2 receptor binding from the contralateral superior colliculus, as early as day 2 postenucleation. Conversely, there was a significant increase in binding to AT 1 receptors in the ipsilateral superior colliculus after seven days. No changes were seen in the lateral geniculate or suprachiasmatic nuclei. Angiotensin II binding to subcellular fractions of tissue from the superior colliculus region of 19-day-old pups suggested that AT 2 receptor sites were present on the plasma membrane of the postsynaptic cell body. Membrane binding studies also showed a significant decrease in AT 2 receptor binding to the same subcellular fractions when 19-day-old pups, enucleated seven days earlier, were compared to sham-operated animals. Our results suggest that expression of AT 1 and AT 2 receptors in the superior colliculus may be regulated by retinal input.

Immunohistochemical localization of calretinin in the rat lateral geniculate nucleus and its retino-geniculate projection

In the present study, we examined the distribution of calretinin-immunoreactive neuronal cell bodies and fibers in the lateral geniculate nucleus of the rat. In normal rats, clusters of immunoreactive cell bodies were found in: (i) the rostral portion of the ventral lateral geniculate nucleus pars medialis (VLGM), (ii) the intergeniculate leaflet (IGL), (iii) the intermediate region between the VLGM and the ventral lateral geniculate nucleus pars lateralis (VLGL), (iv) the caudomedial portion of the VLGM, and (v) the caudolateral portion of the VLGM. In the dorsal lateral geniculate nucleus (DLG), immunoreactive cell bodies were rarely observed. After uni- or bilateral eye enucleation, no significant alteration in the morphological features or distribution of immunoreactive cell bodies was detected in the lateral geniculate nucleus. In normal rats, immunoreactive fibers formed dense plexuses in: (i) the DLG, (ii) the external layer of the VLGL, (iii) the internal layer of the VLGL, (iv) the IGL, (v) the caudomedial portion of the VLGM, and (vi) the optic tract. After unilateral eye enucleation, immunoreactive fibers in the external layer of the VLGL and in the optic tract almost totally disappeared on the contralateral side to the lesion. Unilateral eye enucleation caused a significant decrease of immunoreactive fibers in the DLG and in the internal layer of the VLGL, but a substantial number of immunoreactive fibers still remained there. In the IGL and the caudomedial portion of the VLGM, no observable alteration in the distribution of immunoreactive fibers was detected after uni- or bilateral eye enucleation. In conclusion, (i) subpopulations of neurons of the lateral geniculate nucleus are distinguished by the presence of calretinin immunoreactivity, and (ii) calretinin is a chemical component of subpopulations of the contralateral retino-geniculate pathway, which terminate in the DLG and in the external and internal layers of the VLGL.

Subtance P-immunoreactive innervation from the retina to the suprachiasmatic nucleus in the rat

The present study examined substance P (SP) innervation in the suprachiasmatic nucleus (SCN) of the rat. In the colchicine-untreated rat, SP-immunoreactive fibers formed a dense oval plexus in the ventral part of the SCN. After bilateral eye enucleation, there was a marked reduction in SP-immunoreactive fibers in the ventral part of the SCNs. The SP-immunoreactive neurons in the retinal ganglion cell layer were retrogradely labeled after injection of Fluoro-gold into the SCN. These findings indicate the presence of the SP innervation from the retina to the SCN in the rat. The role of SP in the retino-hypothalamic tract was discussed from the light-dark cycle.

Contrary effect of eye enucleation on VIP-immunoreactive neurons in the suprachiasmatic nucleus and the superior colliculus of the rat

The topographic alternation of vasoactive intestinal peptide (VIP) immunoreactivity after long-term bilateral eye enucleation (80 days) was investigated in the suprachiasmatic nucleus (SCN) and the superior colliculus of the adult rat with the peroxidase-antiperoxidase method. In the SCN, the immunostaining of VIP-immunoreactive (IR) cell bodies increased, and the intensity and density of VIP-IR fibers and terminals were markedly enhanced after eye enucleation. On the other hand, after eye enucleation, no VIP-IR cell bodies and fibers were visible in the stratum griseum superficiale of the superior colliculus, although fusiform-shaped VIP-IR neurons were distributed in the layer of unoperated control rats. The present results, therefore, have revealed that the long-term blockage of retinal input induces changes of VIP immunoreactivity in different manners, according to the target brain areas.

Substance P-like immunoreactive retinal terminals found in two retinorecipient areas of the Japanese monkey

Using peroxidase-antiperoxidase immunocytochemistry, we demonstrated a dense accumulation of substance P-like (SP) immunoreactive terminals in the internal layer of the pregeniculate nucleus and in the pretectal olivary nucleus of the Japanese monkey. These distributions of immunostaining were similar to those for retinofugal terminals in the same nuclei. Bilateral eye enucleation markedly decreased SP immunoreactivity in the nuclei. The reduced immunoreactivity probably reflected the loss of SP-containing retinal ganglion cells that sent axons to the pregeniculate and pretectal olivary nuclei.

The effect of eye enucleation on the number of fibres in the supraoptic decussation of posthatch chicks ( Gallus gallus)

In this study of the young chick we examine the effects of unilateral or bilateral eye enucleation on the number of axons in the supraoptic decussation, a major interhemispheric tract subserving visual function. On posthatch day 25, chicks underwent removal of either one or both eyes. After a survival period of 32 days, electron microscopic examination of the supraoptic decussation revealed a substantial loss of fibres. In the bilaterally enucleated group, a significant decrease in the number of axons occurred in both the dorsal and ventral aspects of the supraoptic decussation. The effect of unilateral enucleation was not as severe. The results indicate that enucleation of the precocial and functioning visual system of the chick leads to a transneuronal loss of axons. The degree of loss may reflect the amount of fibres in the crossed visual projection within the supraoptic decussation.

ECoG effects of peripheral deafferentation of prepyriform and visual cortices in rats

Freely-behaving Wistar albino male rats were prepared for chronic recording of the electrocorticographic (ECoG) activity of neo- and paleocortical areas and of the electromyogram of dorsal neck muscles. The effects of the uni- or bilateral removal of the main olfactory bulbs and adjacent structures on the prepyriform cortex (PPC) ECoG, and the possible ECoG modifications in the area 17 after bilateral eye enucleation were studied. In spite of the fact that the PPC general cycling pattern along the sleep-wakefulness cycle (SWC) was not appreciably affected by the olfactory deafferentation, this experimental maneuver did cause very marked alterations in the PPC ECoG during all of the observed SWC phases. On the other hand, no appreciable ECoG modifications could be detected in area 17 after the visual deafferentation. A comparison of these results with pertinent literature for cats and monkeys allows the formulation of some working hypotheses that deserve experimental testing in the future.

Transsynaptic response of the lateral geniculate nucleus and the pattern of degeneration of the nerve terminals in the Rhesus monkey after eye enucleation

Summary The response of the lateral geniculate neurons to deafferentiation and the anterograde degeneration of the optic terminals have been studied in rhesus monkeys following unilateral and bilateral eye enucleation. The principal features of the transneuronal changes are vacuolation of the perikaryon, chromatolysis, reduction and alterations of mitochondria, nuclear infoldings, proliferation of neurotubules, overall reduction in the cell size, paucity of the dendritic arborization, postsynaptic watery dendrites and profiles with tubulo-vesicular structures. Dark transformation with preservation of filaments was also reported to precede the process of phagocytosis of the filamentous degenerating optic nerve terminals. Other findings related to enucleation were disappearance of axon terminals of other than optic origin, presence of boutons with crowded synaptic vesicles, and glial reaction. ‘Seepage’ of altered substances from the degenerating optic nerve terminals to the postsynaptic site and the multiple mini-traumata induced to the postsynaptic neuron during the phagocytosis of optic nerve terminals engulfed together with fragments of postsynaptic cytoplasm, are considered possible pathogenetic mechanisms of transneuronal degeneration. A chain reaction of transneuronal degeneration may be responsible for the severe reduction of the dendritic arborization.

Ultrastructural and electrophysiological aspects of denervated synapses in the lateral geniculate nucleus

The ultrastructural and electrophysiological alterations taking place in the lateral geniculate mucleus (LGN) were studied in two groups of cats: (I) after bilateral eye enucleation; (II) after electrolytic lesions of the optic tract (OT), or surgical section of the optic chiasm or OT. The study of the fine structure of the optic terminals in the LGN revealed, in both conditions, a progressive decrease in the number of synaptic vesicles together with an increase in the amount of neurofilaments (neurofibrillar hypertrophy). This stage was followed by the appearance of typical images of dark degeneration. The temporal course of this sequence of changes differed in the two cases. In (I) the neurofibrillar hypertrophy was completed in about 72 hr while in (II) it only took 48 hr. The dark degeneration stage appeared at 120 hr in (I) and at 72 hr in (II). The electrophysiological study showed that synaptic transmission ceased at 72–96 hr in (I) while in (II) it only took 48–54 hr. The study of the recovery cycle of the main geniculate synapses during the period of preserved transmission showed a progressive deterioration of synaptic efficiency. The results are interpreted as due to a decrease in the amount of available transmitter for release and to possible alterations in transmitter synthesis. The different temporal course of the alterations in conditions (I) and (II) is related to the length of the axon stump (in (I) ∼- 35 mm; in (II) ∼- 7 mm).

Effects of visual deafferentation on mesencephalic reticular activity in freely behaving cats

Effects of bilateral eye enucleation on maintained and evoked unit activity in the mesencephalic reticular formation (MRF) were studied in freely behaving cats. Recording of MRF units was carried out in the same way as before total visual deafferentation. Three recording conditions were classified: resting arousal, light sleep, and deep sleep. The MRF neurons initially decreased greatly, maintained discharge rates following visual deafferentation, and trended to recover their control level 1 month after deafferentation. Visual deafferentation brought about no notable change in the discharge pattern. Phasic enhancement of unit firing in deep sleep in association with bursts of phasic waves in the central visual system was still observable after deafferentation. Discharge rate and neural responsiveness of visually deafferented MRF neurons shifted between the three states in the same fashion as observed in intact neurons, i.e., light sleep → resting arousal → deep sleep in order of increasing sensitivity. After deafferentation there was much less incidence of MRF responses with longer latency although short-latency responses were well preserved. This phenomenon subsided with a lapse of time. The difference in response latency in the three states was detectable in deafferented MRF neurons. Immediately after visual deafferentation the extent of input convergence on MRF neurons tended to decrease in comparison with controls and this reduction sustained through 1 month. Visual deafferentation did not influence the sampling rate of nonresponding units in the MRF. No uniform relation between the location of units in the MRF and their maintained discharge rates was noted after visual deafferentation.

Temporal course of synaptic degeneration in the lateral geniculate nucleus: Its dependence on axonal stump length

The temporal course of the ultrastructural and functional changes taking place in degenerating optic terminals were studied under three conditions: (a) after bilateral eye enucleation; (b) electrolytic optic tract lesion; and (c) surgical section of the optic chiasm. The ultrastructural study revealed, in (a), the sequence of two typical degenerative patterns: neurofibrillar hypertrophy (72–96 hr) and dark degeneration (120 hr). Synaptic transmission in the LGN ceased at 72–96 hr. The same sequence of ultrastructural patterns was observed in (b), but each stage was completed at an earlier time. Neurofibrillar hypertrophy was total at 48 hr while dark degeneration appeared at 72 hr. Cessation of transmission occurred at 48–54 hr. In (c) the changes were similar in pattern, sequence, and time course to those found in (b). The differential temporal course of the ultrastructural and electrophysiological alterations in conditions (a) and (b) is related to the length of the axon stump (a = 35 mm; b = 7 mm).

Synaptic transmission in the degenerating lateral geniculate nucleus an ultrastructural and electrophysiological study

The functional and anatomical changes taking place at the main (optic) geniculate synapses after bilateral eye enucleation were studied using neurophysiological and ultrastructural techniques. Cessation of synaptic transmission in the lateral geniculate nucleus (LGN) took place between 48 and 72 hours after enucleation in two cats, and between 72 and 96 hours in five cats. During the period in which synaptic transmission was still preserved, the study of the discharges to orthodromic stimulation in the optic radiation and the analysis of the recovery cycle of the main geniculate neurons both indicated that a progressive deterioration of synaptic efficiency was taking place. The ultrastructural study of the main synapses of the LGN revealed, immediately after cessation of transmission, that the synaptic terminals were in the filamentous stage of degeneration. The gradual decrease in number of synaptic vesicles in the optic terminals of the LGN correlates well with the progressive deterioration of synaptic efficiency. It is suggested that these phenomena were due to a decrease in the amount of available transmitter for release at the arrival of each presynaptic spike. Possibly, the rate of transmitter synthesis was also altered.

Effects of bilateral eye enucleation upon single unit activity of the lateral geniculate body in free behaving cats

After both eyes were removed, spontaneous and evoked activities of P type units in the lateral geniculate body (LGB) were studied in the cat during a natural sleep-wakefulness cycle. The eye-removed LGB units were found to discharge spontaneously over a month after the operation. The spontaneous discharge was altered in pattern and rate as the behavioral state shifted from one to another. The pattern of discharge in each state of behavior was found to keep essentially the same characteristics as in the intact cat. The spontaneous discharge rate was highest in deep sleep and decreased from arousal to light sleep as in the case of the intact cat, but the value in each state of behavior was reduced below the control determined with the normal LGB units in the same state, the relative reduction being largest for light sleep and smallest for deep sleep. The firing probability of the deafferented LGB units to antidromic stimulation of the visual cortex was highest during deep sleep and lowest during light sleep.

Discharge patterns of single geniculate neurons during the rapid eye movements of sleep.

Discharge patterns of single geniculate neurons during the rapid eye movements of sleep.