Assessment of the volume of intraorbital structures using the numerical segmentation image technique (NSI): the extraocular muscles

INTRODUCTION: In recent years the use of computer systems has allowed numerical analysis of medical images to be introduced and has speeded up the conversion of numerical data into clinically valuable information. The creation of a software application that could almost automatically calculate the volume of anatomical structures imaged by MRI has seemed possible. The aim of our study was to determine the clinical usefulness of an numerical segmentation image technique (NSI) software application in estimating the volume of extraocular muscles. MATERIAL AND METHODS: The study group was formed of 45 patients (90 orbits). All the patients underwent MRI examinations of the orbits by a 1.5 T scanner using a head coil. The degree of exophthalmos was determined clinically and radiologically in relation to the interzygomatic line. The quantitative assessment of all eye muscles was carried out using the NSI application, a new software program introduced by the authors. RESULTS: A close correlation between muscle volume and the degree of exophthalmos was revealed and confirmed by statistical analysis (r = 0.543, p = 3.13396E-08) in agreement with other papers. CONCLUSIONS: The NSI software program is an application which offers a reliable and precise estimation of eye muscle volume. It is therefore useful in the diagnosis of the pathological processes leading to exophthalmos. It has special clinical value for monitoring discrete volume changes of muscles during treatment.     

Rationale of treatment in Graves ophthalmopathy.

Graves ophthalmopathy is a chronic and multisystem disorder caused by an autoimmune process, characterized by the presence of antibodies that stimulate a general fibroblastic reaction (thyroid gland and lower extremities), and involves orbital fat tissue and muscles. The clinical findings and therapy for the treatment of the exophthalmos, such as changes in extrinsic eye motility, diplopia, optic nerve involvement, and lid retraction, were analyzed, and the various types of surgical treatment currently available for Graves ophthalmopathy were evaluated. The aim was to choose the best option to treat each case.The surgical techniques were transpalpebral decompression by removal of intraorbital fat, three-wall osseous expansion, and zygomatic osteotomy. Adjunctive procedures were lengthening of the levator muscle of the upper eyelid, lengthening of the retractor of the lower eyelid (if necessary), and surgery of the extrinsic muscles to correct diplopia. All these techniques were useful in treating the disease, which is characterized by chronic evolution and, at times, a "malignant" outcome. A total of 39 orbits were treated using different techniques of decompression and secondary adjunctive procedures. Results were analyzed after a minimum 6-month follow-up. It was evident that surgery greatly reduced the degree of exophthalmos and improved eye motility, diplopia, and visual acuity.Close cooperation among a team of specialists, including an endocrinologist, ophthalmologist, neuroradiologist, surgeon, anesthesiologist, and radiotherapist, is essential to manage and to quantify the postoperative results of this complex disorder.The authors' experience and application of different surgical strategies, as based on clinical data and histopathological classification, are presented.     

Intraocular and intraorbital compartment pressure changes following orbital bone grafting: a clinical and laboratory study

Visual loss is an uncommon but catastrophic complication after intraorbital bone grafting for the reconstruction of acute traumatic defects or long-standing enophthalmos. Increased intraocular or intraorbital compartment pressure may be pathogenic in this setting. A two-part study was designed to test the null hypothesis that intraocular and intraorbital compartment pressure values remain constant despite orbital volume reduction with graft material. Laboratory study: Intraocular and intraorbital compartment pressures were measured during sequential orbital volume reduction in New Zealand White rabbits that had been randomized to one of three groups: intact orbits (n = 10), acute orbital wall defects (n = 8), and chronic (3 months) orbital wall defects (n = 11). Intraocular pressure was significantly (p<0.05) elevated in all three groups of orbits undergoing orbital volume reduction compared with control, nonoperated orbits. Intraorbital compartment pressure values did not change significantly from control levels throughout the grafting sequence. Although no significant differences existed between groups in the maximum levels of intraocular pressure attained, the chronic group demonstrated a greater rate of rise and slower rate of decline. Clinical study: Using applanation tonometry, intraocular pressure was measured before and serially after orbital floor exploration and intraorbital placement of split calvarial bone grafts in 19 patients who presented with orbital-zygomatic complex fractures that required surgery. A separate group of 16 patients with orbital-zygomatic complex fractures that required exploration of the orbital floor but not bone grafting was used for comparison. A significant (p<0.05) elevation of intraocular pressure was observed immediately after bone grafting compared with nongrafted orbits, but values returned to normal within 30 minutes and remained stable through the third postoperative day. There were no cases of visual impairment in any patients in either group as the result of surgical treatment. These data indicate that orbital volume reduction with graft material results in significant, temporary elevation of intraocular pressure. No significant elevations of intraorbital compartment pressure were detected in the rabbit orbits. Data from this study may have direct relevance in defining guidelines for "tolerable" changes in orbital tissue and globe pressures after surgery.     

A quantitative analysis of orbital soft tissue in Graves' disease based on B-mode ultrasonography

Using B-mode ultrasonography, an attempt was made to measure the volume of extraocular muscles and retrobulbar fat in 31 patients (62 orbits) with Graves' disease. None of the patients had exophthalmometric measurements greater than 21 mm or had eye symptoms. The mean value of muscle volume of Graves' patients was significantly larger than that of normal controls (6.48 +/- 2.70 cm3 and 3.25 +/- 1.30 cm3, respectively, p less than 0.001). All of the patients had extraocular muscle swelling, although 2 of them had no extraocular muscle change for their unilateral eye. The extraocular muscle volume increased as the degree of the proptosis increased. The fat volume tended to increase in parallel with the degree of the proptosis. In the Graves' group with obvious proptosis (Hertel reading: 19--21 mm), the fat volume increased more significantly than in any other group. The ratio of extraocular muscle volume to retrobulbar fat volume was significantly higher in Graves' disease, but it did not increase as the degree of the proptosis increased. A significant correlation between proptosis and muscle volume plus fat volume was observed. No significant difference of the extraocular muscle volume was observed between the patients untreated and treated with antithyroid drugs. The data show a uniform enlargement of the extraocular muscles in Graves' disease and also suggest an involvement of increased retrobulbar fat volume in a group of obvious exophthalmos. The degree of the proptosis is in aclose proportion ot the quantitative change of the orbital soft tissue.     

Treatment of exophthalmos

Current procedures for Graves' exophthalmos fail to achieve complete correction. The standard orbital decompressions were therefore modified to maximize the degree of volumetric increase behind the axis of the globe. In 15 orbits, the preoperative exophthalmos averaged 9.5 mm, whereas the postoperative exophthalmos was 4.1 mm. Postoperative CT study demonstrated that the remaining posterior orbital wall, combined with the persistently increased intraocular muscle volume, blocked retrodisplacement of the globe, despite adequate total volumetric increase. The increased muscle volume varied from 2 to 5 cc. Despite this residual exophthalmos, the modified four-wall expansion provides excellent aesthetic results with visual improvement and resolution of chemosis and exposure keratitis.     

Quantification of volume of tissue damage in stroke using T2- weighed MRI images

We have developed a quantitative technique for scoring of the severity of ischemic damage of the brain using quantitative data of the T2-weighted MRI images of brain in stroke. The principle of the method is the assumption that T2 signal increases proportionally to the severity of ischemic damage of cerebral tissue up to the level equal to intraventricular liquor signal in the case of postinfarction cystic degeneration. Depicting the mean T2-signal from the intraventricular liquor region as Iliq, the signal from ischemic brain area as Iinsult, and from the intact brain as Inorm, obviously, the volume quota of damaged tissue in the total volume of the stroke region is represented by the ratio (Iinsult - Inorm)/(Iliq - Inorm). The total volume of damaged tissue (VDT, cub.cm) in the stroke region is then the following sum taken over all slices i, where the stroke damage can be: VDT = sigma i d.Si.[(Iinsult - Inorm)/(Iliq - Inorm)]i, where d is the slice thickness, Si--area of the ischemic region in the slice i. The quota of damaged tissue in the physical volume of the stroke region is henceforth the following ratio: Q = [sigma i d.Si.[(Iinsult - Inorm)/(Iliq - Inorm)]i]/[sigma i d.Si]. The technique was applied in retrospective analysis of routine MRI studies in 15 patients referred because of acute ischemic stroke. The studies were performed using low-field MRI tomograph Magnetom-Open (Siemens Medical) with field strength 0.22 T. In patients studied during the first day after occurrence of ischemic insult with the minimal degree of acute neurologic deficit, who later have demonstrated clinically full recovery, the VDT was below 20 cm3, and Q was below 10%. In cases with VDT > 25 cm3 and Q > 20% the full regress was not observed in any patient. Henceforth, the quantification of cerebral damage in stroke using quantitative indices based on measurement of T2-parameters over ischemic and intact zones of the brain are of independent prognostic clinical value and improve clinical usefulness of the MRI in ischemic brain stroke.     

The direct effect of intraorbital pressure on orbital growth in the anophthalmic piglet.

Tissue expanders placed within the orbit can have a positive effect on orbital and ipsilateral midfacial growth. To date, there is no precise method for controlling and monitoring expansion to induce normal growth in the developing facial skeleton. The present study was undertaken to determine the optimal physiologic pressure required to stimulate normal orbital growth and to determine whether above-normal growth could be achieved with higher intraorbital pressures. Using a neonatal swine model, an accurate method of monitoring intraorbital pressure, precisely controlling intraorbital expansion, and achieving normal orbital growth was explored. Sixteen male, 3-week-old Yorkshire piglets were randomly divided into three surgical groups. In each group, the left orbit was the experimental side, and the contralateral right orbit served as an untreated control. Group 1 (n = 6) underwent enucleation only. Group 2 (n = 5) underwent enucleation and orbital expansion at a near-normal physiologic pressure of 20 mmHg. Group 3 (n = 5) underwent enucleation and orbital expansion at a supernormal pressure of 60 mmHg. Spherical tissue expanders (10 cc) with a separate injection port were utilized as the orbital expanders. Pressure was monitored by an electronic manometer that was calibrated daily. Morphology of the orbits was documented by photography, the dimensions of the orbits were quantitated by three-dimensional mechanical digitization, and orbital volumes were calculated. In the unexpanded, anophthalmic control group, a significant reduction in radial growth after evisceration was seen. In group 2, the orbit stimulated with a consistent pressure of 20 mmHg, just above the physiologic normal pressure of 17 mmHg, showed an increase in radial dimension of 8 percent compared with the unoperated side. In the high-pressure group of 60 mmHg, an increase of 16 percent in the radius was observed over the 4-week period. This led to a corresponding increase in orbital volumes with increased pressure. Utilizing a paired t test, these differences in the radial and volumetric growth of the orbit were statistically significant (p < 0.005). The results obtained demonstrated a direct relationship between intraorbital pressure and the growth of the bony orbit in the radial dimension. On the basis of this study, we concluded that orbital expansion maintained at normal physiologic pressure can stimulate normal orbital growth in the neonatal facial skeleton. In addition, application of above-normal pressures for expansion can induce accelerated orbital growth.     

Treatment of ocular motility disturbances in Graves' disease with botulinum toxin A

The aim of this study was to evaluate the efficacy of botulinum toxin-A injections on motility disturbance in patients with dysthyroid eye disease. In 36 patients (52 orbits) with active phase of Grave's ophthalmopathy with motility disturbance, botulinum toxin-A injections were applied. Ocular motility was measured before and after treatment in four main directions (elevation, depression, abduction and adduction) with F?rster perimeter. In all patients 20 units of botulinum toxin-A in one single injection was applied in the projection of the inferior rectus muscle. Statistically, the degree of upgaze increased notably in all three groups, but mostly in the first group where it amounted up to 5.8-6.0 (z = 10.0;p = 0.68). We could not prove notable increase of the motility grade in the adduction in none of the groups of the tested patients. Due to the fact that eyeball motility can be objectively measured, effect of the applied therapy can be clearly evaluated.     

Orbital volume measurements in enophthalmos using three-dimensional CT imaging

The purpose of this study was to investigate enophthalmos by measuring the volume of various orbital structures using off-line computer techniques on images generated by a CT scanner. Eleven patients with enophthalmos had CT scans of the orbits consisting of 30 to 40 adjacent 1.5-mm slices. The data from the scans were analyzed on a Nova 830 stand-alone computer system using software programs that allowed measurement of total bony orbital volume, total soft-tissue volume, globe volume, orbital fat volume, neuromuscular tissue volume, and apex-to-globe distance in the horizontal plane. These data were analyzed comparing the volumes in the normal eye with the volumes in the enophthalmic eye in each patient. The analysis demonstrated a statistically significant increase in bony orbital volume in the enophthalmic eye, but the total soft-tissue volume, fat volume, neuromuscular tissue volume, and globe volume were the same as in the normal eye. The apex-to-globe distance, a measure of the degree of enophthalmos, was less in the enophthalmic eye than in the normal eye. These results suggest that in the majority of patients, the cause of posttraumatic enophthalmos is increased bony orbital volume rather than by soft-tissue loss or fat necrosis. (Several patients showed no volume discrepancies, and it is likely that cicatricial contracture is responsible for the enophthalmos in these cases.) This study suggests that the objective of surgery for correction of enophthalmos in patients with a volume discrepancy should be to decrease the volume of the bony orbit and to increase the anterior projection of the globe.     

Fetal Eye Movements on Magnetic Resonance Imaging

Objectives

Eye movements are the physical expression of upper fetal brainstem function. Our aim was to identify and differentiate specific types of fetal eye movement patterns using dynamic MRI sequences. Their occurrence as well as the presence of conjugated eyeball motion and consistently parallel eyeball position was systematically analyzed.

Methods

Dynamic SSFP sequences were acquired in 72 singleton fetuses (17–40 GW, three age groups [17–23 GW, 24–32 GW, 33–40 GW]). Fetal eye movements were evaluated according to a modified classification originally published by Birnholz (1981): Type 0: no eye movements; Type I: single transient deviations; Type Ia: fast deviation, slower reposition; Type Ib: fast deviation, fast reposition; Type II: single prolonged eye movements; Type III: complex sequences; and Type IV: nystagmoid.

Results

In 95.8% of fetuses, the evaluation of eye movements was possible using MRI, with a mean acquisition time of 70 seconds. Due to head motion, 4.2% of the fetuses and 20.1% of all dynamic SSFP sequences were excluded.Eye movements were observed in 45 fetuses (65.2%). Significant differences between the age groups were found for Type I (p = 0.03), Type Ia (p = 0.031), and Type IV eye movements (p = 0.033). Consistently parallel bulbs were found in 27.3–45%.

Conclusions

In human fetuses, different eye movement patterns can be identified and described by MRI in utero. In addition to the originally classified eye movement patterns, a novel subtype has been observed, which apparently characterizes an important step in fetal brainstem development. We evaluated, for the first time, eyeball position in fetuses. Ultimately, the assessment of fetal eye movements by MRI yields the potential to identify early signs of brainstem dysfunction, as encountered in brain malformations such as Chiari II or molar tooth malformations.     

The development of the eye in Astyanax mexicanus (Characidae,Pisces), its blind cave derivative,Anoptichthys Jordani (Characidae,Pisces), and their crossbreds

The development of the eye of the characin Astyanax mexicanus, of its blind derivative Anoptichthys jordani, and crossbreds of both forms was studied at different ontogenetic stages by means of scanning- and transmission-electron microscopy. Astyanax exhibits a form of eye development resembling that in other characid species. A severe reduction of the eye could be observed in Anoptichthys starting with the second day of ontogeny. This degenerational process is characterized by the following features: 1) An overgrowth of epidermal tissue that gradually covers the surface of the eyeball; 2) the sinking of the eyeball below the surface of the integument; 3) the formation of epidermal channels from the body surface to the disappearing surface of the eyeball; 4) a severe degeneration of the retinal sensory cells; and 5) a small number of pigment granules in the pigment epithelial cells. The progeny of crosses between Astyanax and Anoptichthys show varying degrees of these degenerational signs. Taste buds and the lateral line organ display identical features in all crosses analyzed with the scanning electron microscope.     

Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain

We present a technique for automatically assigning a neuroanatomical label to each voxel in an MRI volume based on probabilistic information automatically estimated from a manually labeled training set. In contrast to existing segmentation procedures that only label a small number of tissue classes, the current method assigns one of 37 labels to each voxel, including left and right caudate, putamen, pallidum, thalamus, lateral ventricles, hippocampus, and amygdala. The classification technique employs a registration procedure that is robust to anatomical variability, including the ventricular enlargement typically associated with neurological diseases and aging. The technique is shown to be comparable in accuracy to manual labeling, and of sufficient sensitivity to robustly detect changes in the volume of noncortical structures that presage the onset of probable Alzheimer's disease.     

High-resolution magnetic resonance imaging tracks changes in organ and tissue mass in obese and aging rats

Magnetic resonance imaging (MRI) has the ability to discriminate between various soft tissues in vivo. Whole body, specific organ, total adipose tissue (TAT), intra-abdominal adipose tissue (IAAT), and skeletal muscle (SM) weights determined by MRI were compared with weights determined by dissection and chemical analysis in two studies with male Sprague-Dawley rats. A 4.2-T MRI machine acquired high-resolution, in vivo, longitudinal whole body images of rats as they developed obesity or aged. Weights of the whole body and specific tissues were determined using computer image analysis software, including semiautomatic segmentation algorithms for volume calculations. High correlations were found for body weight (r = 0.98), TAT (r = 0.99), and IAAT (r = 0.98) between MRI and dissection and chemical analyses. MRI estimated the weight of the brain, kidneys, and spleen with high accuracy (r > 0.9), but overestimated IAAT, SM, and liver volumes. No differences were detected in organ weights using MRI and dissection measurements. Longitudinal MRI measurements made during the development of obesity and aging accurately represented changes in organ and tissue mass.     

Thyroid-Associated Ophthalmopathy: Preliminary Study Using T2 Mapping to Characterize Intraorbital Optic Nerve Changes Before Dysthyroid Optic Neuropathy

ObjectiveTo evaluate the performance of T2 mapping in detecting intraorbital optic nerve (ON) changes in patients with thyroid-associated ophthalmopathy (TAO) before the onset of dysthyroid optic neuropathy (DON).MethodsThirty-five patients with TAO and without DON (21 active, 14 inactive) and 21 healthy controls (HCs) were enrolled. Magnetic resonance imaging-derived parameters of T2 relaxation time (T2RT) at the intraorbital ON, extraocular muscle (EOM), orbital fat, exophthalmos, summed thickness of EOMs, orbital fat thickness, and clinical variables were compared. Correlations between T2RT at the ON and other variables were assessed.ResultsPatients with TAO showed significantly higher T2RTs at the intraorbital ON than HCs (P < .001). Patients with active TAO had significantly higher T2RTs than those with inactive TAO and HCs (P < .001). Differences between patients with inactive TAO and HCs were insignificant (P > .05/3). T2RT at the intraorbital ON was positively correlated with clinical activity score, modified NOSPECS score, T2RT at EOM, exophthalmos, and summed thickness of EOMs in the TAO group (P ≤ .003) and negatively correlated with visual acuity (P = .033) and visual field indices (P = .030) in patients with active TAO. A T2RT cutoff of 82.9 ms for the intraorbital ON distinguished active TAO and healthy eyes optimally (area under the curve, 0.800; sensitivity, 85.7%; specificity, 64.3%).ConclusionT2RT detects disturbance in the intraorbital ON in patients with TAO, especially active TAO, before DON develops. T2 mapping has a potential for noninvasive evaluation of ON changes in patients with TAO.     

A congenital orbital defect with periorbital-dural tissue adhesion

This case demonstrates a previously unreported congenital orbital deformity. The patient was born with a unilateral exophthalmos. The etiology of the defect was demonstrated by CT scan as a convex bowing of the right superomedial orbital wall behind the axis of the eye. At surgery, this convexity was revealed to be a small bony defect through which the periorbital tissue and dura mater adhered. This sort of orbital deformity, although subtle, must be considered in the differential diagnosis of congenital unilateral exophthalmos.     

Use of magnetic resonance imaging in the study of goat mammary glands in vivo

A technique is described for the in-vivo determination of mammary gland size and gross composition in goats by using nuclear magnetic resonance imaging (MRI). The volume of test objects determined with MRI had an error of +0.4 +/- 1.6% of the actual volume. In lactating goats the in-vivo MRI estimate of mammary parenchymal volume was significantly greater than, but highly significantly correlated with, the weight of parenchyma determined post mortem (for the whole udder, r = 0.88, P less than 0.001; for individual glands, r = 0.85, P less than 0.001). MRI-determined estimates of the volume of fluid within the mammary gland were within 1.2% of the volume of milk removed from the udders after imaging. The spin-lattice (T1) relaxation time of the whole udder correlated closely with the volume of fluid within the udder. The T1 relaxation time of parenchymal tissue measured in vivo did not differ significantly from that determined immediately after post-mortem excision.     

介入室X线电视系统下眶内及眶周金属异物摘出术的临床观察

目的:探讨在介入室X线电视系统下摘出眶内及眶周金属异物的临床效果。方法:选择2002年7月至2012年7月我院收治的金属异物患者86例86只眼,在介入室X线电视系统直视引导下,根据影像学特点制定个体化手术方法,经皮肤或结膜进路摘出眶内及眶周金属异物。结果:86例均成功取出异物,其中一次手术取出83例(96.5%),二次手术取出3例(3.5%)。随访2~18(9.2±5.3)月。末次随访时视力达术前水平62例(72.1%),视力提高21例(24.4%)。术前及术后末次随访时眼球运动障碍分别为34例(39.5%)和16例(18.6%),术前及术后末次随访时外伤性上睑下垂分别为5例(5.8%)和3例(3.5%)。结论:在介入室X线电视系统下摘出眶内及眶周金属异物对眶内及眶周组织损伤小,手术时间短,疗效满意,便于操作,值得推广。     

Computer-assisted secondary reconstruction of unilateral posttraumatic orbital deformity

Until now, computer-assisted surgery has not been practiced as part of the surgical routine of posttraumatic orbital reconstruction. The purpose of this study was to investigate the use of a navigation system for computer-assisted preoperative planning with virtual reconstruction to obtain symmetry of the orbits and intraoperative control of virtual contours in comparison with the clinically achieved surgical results. A further objective of the computer-assisted orbital analysis was to use an ideal measurement for the two-dimensional and three-dimensional changes following orbital reconstruction and to check the equality of the postoperative values for the affected orbits in comparison with those of the unaffected sides. Patients with unilateral posttraumatic orbital defects (n = 18) underwent computer-assisted surgery and preoperative planning using a spiral computed tomography database. Surgical procedures were preplanned with virtual correction by mirroring an individually defined three-dimensional segment from the unaffected side onto the deformed side, creating an ideal unilateral reconstruction. These computer-models were intraoperatively used as virtual templates to navigate the preplanned contours and the globe projection using the Stryker-Leibinger navigation system. Individual noninvasive registration with an overall inaccuracy of approximately 1 mm was achieved by using a maxillary occlusal splint with four markers. The mirroring of the unaffected side allowed an ideal virtual reconstruction. A mean decrease in enlarged orbital volume of 4.0 (SD +/- 1.9) cm was achieved, as was a mean increase in the sagittal globe projection of 5.88 (SD +/- 2.98) mm. With a paired Student test, the decrease between the preoperative and postoperative differences of the affected and unaffected sides was proved significant for orbital volume, globe projection, and computed tomography-based Hertel scale changes (p < 0.01). In 15 of 18 cases, simultaneous malar bone advancement resulted primarily in an additional increase in orbital volume before intraorbital augmentation with calvarial split-bone grafts could be performed. Intraorbital bony augmentation included one (n = 1), two (n = 7), three (n = 8), and all four (n = 2) orbital walls. Computer-assisted preoperative planning enables the surgeon to predict reconstructive surgical steps before the operation. Highly vulnerable structures such as the optic nerve can be detected and avoided intraoperatively, and virtually preplanned bone graft positions and/or orbital frame contours can be checked. Computer-assisted preoperative planning and surgery thus advance the difficult surgical field of orbital reconstruction, particularly through a greater exploitation of radiologic information without additional radiation to the patient.     

Bayesian estimation of probabilistic atlas for tissue segmentation

Automatic anatomical brain image segmentation is still a challenge. In particular, algorithms have to address the partial volume effect (PVE) as well as the variability of the gray level of internal brain structures which may appear closer to gray matter (GM) than white matter (WM). Atlas based segmentation is one solution as it brings prior information. For such tasks, probabilistic atlases are very useful as they take account of the PVE information. In this paper, we provide a detailed analysis of a generative statistical model based on dense deformable templates that represents several tissue types observed in medical images. The inputs are gray level data whereas our atlas is composed of both an estimation of the deformation metric and probability maps of each tissue (called class). This atlas is used to guide the tissue segmentation of new images. Experiments are shown on brain T1 MRI datasets. This method only requires approximate pre-registration, as the latter is done jointly with the segmentation. Note however that an approximate registration is a reasonable pre-requisite given the application.