Posterior microphthalmos with retinal involvement related to MFRP gene: a report of 10 Brazilian patients.

BACKGROUND: To describe the phenotype and genotype of 10 Brazilian patients with variants in MFRP, posterior microphthalmos and retinal findings. METHODS: Complete ophthalmological evaluation was done at 4 different Brazilian centers. Genetic analysis was performed using commercial next generation sequencing panels for inherited retinal disorders. RESULTS: Ages of the patients ranged from 10 to 65 years and visual acuities from 0,05 to no perception of light. All were hyperopes (+4,25 to + 17,50) with a short axial length (14,4 mm to 18 mm). Common posterior segment features, though not present in all, were optic disc drusen (5/10), foveoschisis (5/10) and retinal pigmentary changes (8/10). Isolated patients presented with macular atrophy, serous retinal detachment, and chorioretinal folds. The most common variant in MFRP found in our patients was a deletion in exon 5 (c.498delC; p.Asn267Thrfs *25), present in all except 2 patients. Other variants found were c.523C>T (p.Gln175*), c.298delG (p.Ala100Argfs *37), c.666del (p.Thr223Argfs *83) and the novel variant c.257C>A (p.Ala86Asp). CONCLUSIONS: This is the first report of Brazilian patients with posterior microphthalmos and pathogenic variants in MFRP and the first describe of the variant p.Ala86Asp in literature. Our cases confirm the previously reported phenotype of high hyperopia, optic disc drusen, alterations in foveal architecture, retinal pigmentary changes with loss of photoreceptor function and visual field constriction. Report of such a rare condition is important to increase awareness to the phenotype of posterior microphthalmia with associated retinal conditions.

Novel compound heterozygous variants in LTBP2 associated with relative anterior microphthalmos.

PURPOSE: Relative anterior microphthalmos (RAM) is a rare congenital defect associated with severe vision impairment that is primarily caused by genetic alterations. The purpose of this study was to identify the causative genetic variants in two Chinese families with RAM with an autosomal recessive inheritance pattern. METHODS: DNA samples were obtained from two probands and their family members. Targeted next-generation sequencing (NGS) was used to screen 425 genes associated with inherited eye diseases to identify possible disease-causing variants in the two patients. Sanger sequencing was subsequently used to validate the results in both families. RESULTS: The targeted NGS panel identified potentially causative novel variants of the latent transforming growth factor beta binding protein 2 (LTBP2) gene in the two RAM families: a missense variant (c.2771C > T; p.Ala924Val) and an intronic variant (c.4582 + 9A > G) in Family A and a different missense variant (c.5239C > A; p.Arg1747Ser) and a synonymous variant (c.951G > A; p.Pro317Pro) in Family B. These four novel variants all cosegregated with the disease phenotype. CONCLUSION: To our knowledge, this is the first study to report novel LTBP2 gene variants related to RAM. Considering the importance of LTBP2 in ocular development, we provide initial insights into the potential pathogenic mechanisms of LTBP2 in RAM.

Insight into small eyes: a practical description from phenotypes presentations to the management.

This narrative review aimed to have an algorithmic approach to microphthalmos by a systematic search. The definition can be related to a number of special phenotypes. In the more challenging cases of complex microphthalmos, relative anterior microphthalmos, and nanophthalmos, the surgeon can approach these cases more safely if they have a deep understanding of the anatomical variations and ideal formulae for intraocular lens computation and knows how to avoid intra- and post-operative complications. In this article, we review the criteria by which we recognize and describe pre-, intra-, and post-operative considerations, as well as discuss the ideal intraocular lenses for microphthalmos, given the intricate varieties of small eye phenotypes.

Efficacy of fitting HydroCone (Toris K) contact lenses for the visual rehabilitation of patients with posterior microphthalmos / Eficácia da adaptação de lentes de contato HydroCone (Toris K) para reabilitação visual de pacientes com microftalmia posterior

ABSTRACT Purpose: To evaluate the efficacy of soft HydroCone silicone hydrogel contact lenses in patients with posterior microphthalmos. Methods: The charts of 13 patients with posterior microphthalmos (26 eyes) who were fitted with soft HydroCone silicone hydrogel contact lenses were reviewed retrospectively. All the patients underwent assessments of uncorrected and best spectacle-corrected visual acuity and cycloplegic refraction. They were fitted with contact lenses according to the parameter values obtained from the topographical analysis and best contact lens-corrected visual acuity measurement. Results: The spherical equivalents of the right and left eyes ranged from 10.00 to 19.25 diopters and from 11.00 to 21.5 diopters, respectively. The mean axial and posterior chamber lengths were shorter than those of the age-matched population. However, the mean values of the anterior segment parameters such as horizontal visible iris diameter, central anterior chamber depth, lens thickness, and central corneal thickness were in the normal range. The mean keratometric measurements revealed increased corneal curvature compared with that in the normal population. The mean best contact lens-corrected visual acuity was significantly higher than the mean best spectacle-corrected visual acuity for both eyes (p=0.045). Conclusion: HydroCone silicon soft contact lenses provided better visual acuity than spectacles in the patients with posterior microphthalmos in this study.

RESUMO Objetivo: Avaliar a eficácia das lentes de contato gelatinosas HydroCone, de hidrogel com silicone, em pacientes com microftalmia posterior. Métodos: Foram revisados retrospectivamente 26 olhos com microftalmia posterior, a partir dos prontuários de 13 pacientes que receberam lentes de contato gelatinosas HydroCone, de hidrogel com silicone. Todos os pacientes foram submetidos ao exame de acuidade visual não corrigida e com melhor correção por óculos e com refração cicloplégica. Todos os pacientes receberam lentes de contato de acordo com os parâmetros obtidos na análise topográfica e foi obtida a melhor acuidade visual corrigida com lentes de contato. Resultados: O equivalente esférico do olho direito variou de 10,00 a 19,25 dioptrias, e o do olho esquerdo de 11,00 a 21,5 dioptrias. Os comprimentos médios axiais e das câmaras posteriores foram menores do que para a população de mesma idade. No entanto, os valores médios dos parâmetros do segmento anterior, como o diâmetro horizontal visível da íris, a profundidade da câmara anterior central, a espessura da lente e a espessura central da córnea estavam dentro da faixa normal. Os valores médios da ceratometria revelaram curvatura corneana aumentada em relação à população normal. A média da melhor acuidade visual corrigida com lentes de contato foi significativamente maior que a média da melhor acuidade visual corrigida com óculos em ambos os olhos (p=0,045). Conclusão: As lentes de contato gelatinosas de silicone HydroCone proporcionam melhor acuidade visual que óculos em pacientes com microftalmia posterior.

Posterior Microphthalmos Pigmentary Retinopathy Syndrome.

Purpose: To report a case of a rare disease entity Posterior Microphthalmos Pigmentary Retinopathy Syndrome (PMPRS) in a 47-year-old female with a brief review of literature. Case Report: A 47-year-old woman presented with a history of defective vision with an associated difficulty in night vision. Clinical workup was done, which included a thorough ocular examination showing diffuse pigmentary mottling of fundus, ocular biometry showing short axial length with normal anterior segment dimensions, electroretinography showing extinguished response, optical coherence tomography showing foveoschisis, and ultrasonography showing thickened sclera-choroidal complex. Findings were consistent with those reported by other authors with PMPRS. Conclusion: Posterior microphthalmia with or without other ocular and systemic associations should be suspected in cases with high hyperopia. It is mandatory to carefully examine the patient at presentation and close follow-ups are needed to maintain visual function.

Microphthalmia, aphakia and agenesis of the optic chiasm and tract in a wild fox squirrel (Sciurusniger).

We describe gross and histopathological features of multiple ocular and neuro-ophthalmic abnormalities in a fox squirrel (Sciurus niger). Ophthalmic findings included severe bilateral microphthalmos, with the right eye more affected than the left. Histopathology confirmed severe microphthalmia, aphakia, disorganized retinal tissue and small optic nerves, as well as agenesis of the optic chiasm and optic tract. This combination of neuro-ophthalmic abnormalities has not been previously described in wild animals.

Choroidal changes in posterior microphthalmos.

PURPOSE: To describe the choroidal variations in posterior microphthalmos (PM). METHODS: In this observational case series, four eyes of two patients diagnosed as PM based on the characteristic clinical features were included. Multimodal retinal imaging with clinical fundus documentation using ultrawide field fundus camera, optical coherence tomography (OCT) and indocyanine green angiography (ICGA) was done for these cases. RESULTS: Multimodal imaging of these cases confirmed the variations in the choroid in PM cases. In both cases, on OCT, the retina and choroid were thick. retinal papillomacular fold (RPMF) was noted in all four eyes. On ICGA, the dye transit time from the arm to choroid and retina were within normal limits. Choroidal vasculature in the far retinal periphery was reduced and was noted as hypocyanescent areas anterior to the equator while the density of choroidal vessels was significantly more posterior to the equator. Vortex veins were not visualised in both cases. CONCLUSION: Choroidal structure and vessels undergo alterations in PM. Further validation of these findings is required in a larger cohort of PM cases.

Retinal arcades in posterior microphthalmos: biometric correlation.

CLINICAL RELEVANCE: Posterior microphthalmos (PM) is a rare developmental disorder characterised by high hyperopia, short axial length, presence of retinal papillomacular fold and relatively normal anterior segment findings. BACKGROUND: The purpose of the study was to compare the retinal arcade distance from fovea between PM cases and to correlate axial shortening in PM eyes with imaging findings. METHODS: This retrospective, comparative case series included 24 eyes of 12 patients with PM as cases and an equal number of age- and sex-matched controls. Retinal findings on optical coherence tomography (OCT), OCT-angiography, Multicolour® image, axial length and corneal biometry were computed, compared and correlated between two groups. RESULTS: Retinal papillomacular fold was noted in all 24 PM eyes. Retinal arcade narrowing was noted in PM (p < 0.001). The central retina (p < 0.001) and choroid (p = 0.003) was thick in PM. Corneal biometry showed shorter axial length (p < 0.001), high keratometry readings (p < 0.001) and small corneal diameters (p = 0.011) in PM. Vessel density (p = 0.031) on OCTA was denser and foveal avascular zone area (p = 0.033) reduced in PM. Strong negative correlation of axial length with spherical equivalent (r = > -0.804;p < 0.001), vessel density (r = > -0.803; p = <0.001) and K1 (r = > -0.76; p < 0.001) and K2 (r = > -0.67; p = 0.001) keratometry readings was noted in PM. Significant positive correlation was noted between axial length and anterior chamber depth (r = 0.75; p < 0.001), foveal avascular zone area (r = 0.56; p = 0.033) and corneal diameter (r = 0.65; p = 0.001). Vessel density on OCT-angiography correlated positively with central corneal thickness (r = 0.552;p = 0.005) and corneal powers K1 (r = 0.709; p = 0.001) and K2 (r = 0.56; p = 0.004) and negatively with corneal diameter (r = > -0.521; p = 0.033). CONCLUSION: Increased choroidal thickening and retinal vascular arcade narrowing were two important, interesting observations noted with PM. Intercorrelation between the axial length, OCT, OCT-angiography and corneal biometry helped in understanding the pathogenesis and the structural and vascular changes in PM eyes.

Clinical characteristics and treatment progress of microphthalmos-anophthalmos-coloboma / 国际眼科杂志(Guoji Yanke Zazhi)

Microphthalmos-anophthalmos-coloboma(MAC)is structurally and clinically correlated congenital ocular malformation. Although MAC is relatively rare, they still become an important cause of blindness in children. At present, the etiology of MAC is not clear; a variety of genetic or environmental factors may cause MAC. Because of its special anatomical structure, MAC has complex clinical manifestations and multiple complications. The complications including cataract, angle-closure glaucoma, uveal effusion, retinal detachment, orbital cyst, which are often accompanied with increased risks for surgery and poor prognosis. By summarizing the clinical features, the common types of ocular complications, and the progress of the treatment, this article will enhance clinicians' cognition of MAC and guide clinicians to formulate personalized and safe treatment plans for patients.

Posterior microphthalmos with achievement of good visual acuity and disappearance of papillomacular retinal folds: a case report.

BACKGROUND: Posterior microphthalmos (PM) is a rare condition with poor visual prognosis even after amblyopia treatment. We report a case of PM with achievement of good visual acuity and disappearance of papillomacular retinal folds (PFs) over a period of 7 years. CASE PRESENTATION: A girl aged 3 years and 5 months was referred to our hospital, after poor visual acuity was identified at a medical checkup for 3-year-olds. She had severe spherical hyperopia: + 17.25 D in the right eye (RE) and + 18 D in the left eye (LE). Her corrected visual acuity was 20/200 in the RE and 20/250 in the LE. PFs were observed in both eyes on optical coherence tomography (OCT), and the diagnosis of PM was made based on the normal corneal diameter and anterior chamber depth. During the course of the disease, a gradual decrease in the height of the PFs was observed on OCT. The corrected visual acuity at age 10 years was 20/20 in the RE and 20/25 in the LE. CONCLUSIONS: The visual prognosis of PM is poor, and only one case with good visual acuity has been reported in the literature. The patient in the present case not only developed good visual acuity, but also showed improvement in macular morphology, which was not noted in previous reports. Early diagnosis of PM and early amblyopia treatment is important for the visual development in PM.

Comparisons of size of foveal avascular zone area among children with posterior microphthalmos, high hyperopia, and normal eyes.

PURPOSE: To determine the area of the surface foveal avascular zone (FAZ) in children with posterior microphthalmos (PM), high hyperopia, and normal eyes using optical coherence tomography (OCT) and OCT angiography (OCTA). METHODS: Thirty-six children were studied including 6 cases 12 eyes of PM (mean age 9.5 ± 5.2 years), 15 cases 30 eyes of high hyperopia (6.9 ± 1.5 years), and 15 cases 30 eyes of healthy individuals (8.7 ± 1.7 years). The B- and C-scan images in all children were recorded by OCT and OCTA with a scanning area of 3.0 × 3.0 mm centered on the fovea. All images were corrected for axial length differences, and the area of the FAZ surface and central macular thickness (CMT) was measured manually and compared. RESULTS: The area of FAZ in the PM group was 0.007 ± 0.003 mm2, which was significantly smaller than that in the high hyperopia eyes at 0.286 ± 0.108 mm2 and healthy eyes at 0.318 ± 0.129 mm2 (both P < 0.001). The CMT in the PM group was 401.58 ± 33.60 mm, which was significantly thicker than in the high hyperopia eyes at 202.93 ± 12.28 mm and the normal eyes at 204.43 ± 18.76 mm. The area of the FAZ and CMT in the hyperopia group did not differ significantly from that of the normal healthy eyes. CONCLUSION: These findings indicate that patients with PM have a hypoplastic macular region, which must be considered in any treatment of these eyes.

Prevalence of complications in eyes with nanophthalmos or microphthalmos: protocol for a systematic review and meta-analysis.

INTRODUCTION: Microphthalmos and nanophthalmos are uncommon ocular conditions, whereby affected eyes have smaller dimensions compared to the normal population. Microphthalmos and nanophthalmos present several challenges to ophthalmologists; they have spontaneous and post-operative sequelae such as high hyperopia, angle-closure glaucoma, uveal effusion syndrome, and retinal detachment. This systematic review and meta-analysis intends to assess the prevalence of both the spontaneous complications associated with nanophthalmos and microphthalmos, as well as the post-surgical complications associated with nanophthalmos or microphthalmos. METHODS AND ANALYSIS: Articles will be searched for, on four online databases: PubMed, EMBASE, Scopus, and Web of Science. Two independent reviewers will identify the studies according to prespecified inclusion and exclusion criteria. All studies included with participants diagnosed with microphthalmos or nanophthalmos in one or both eyes, will be included if they have (i) more than 4 cases and (ii) defined microphthalmos/nanophthalmos as an axial length of < 21 mm or a high lens/eye volume ratio. Nanophthalmos may have an additional diagnostic criterion of posterior wall thickness greater than 1.7 mm. The prevalence of the following complications will be assessed: high hyperopia (spherical equivalent >3D), angle closure glaucoma, uveal effusion syndrome, retinal detachment, and chorioretinal folds. Studies that will be excluded are those that have not adequately defined the criteria for the diagnosis of nanophthalmos or microphthalmos, those studies that have less than five cases, studies with criteria not defined above, and deemed unsuitable, and studies in languages other than English with no published translation. Relevant data will be extracted and assessed for the risk of bias in each article using a modified Joanna Briggs Institute (JBI) assessment tool. The data will then be pooled to determine the prevalence of complications among patients with microphthalmos and nanophthalmos. If the data allows, subgroup analysis will be carried out according to axial length as well as subtype of microphthalmos/nanophthalmos (simple, complex, relative anterior, and posterior). DISCUSSION: Although nanophthalmos is an uncommon condition that affects the eye, its management and complications can be sight-threatening. Thus, it is important to counsel patients and their families correctly (in the case of children) upon diagnosis and prior to any surgical intervention. This can only be done if the overall prevalence of complications is known. REGISTRATION: PROSPERO CRD42021227847.

Recurrent Fetal Anophthalmia Caused by retinoids acid gene 6 mutations: Correlation between prenatal ultrasonography, magnetic resonance imaging, and pathology.

OBJECTIVE: Anophthalmia is an extreme form on the spectrum of anophthalmia-microphthalmia (A/M) syndrome. Most articles define fetal microphthalmia by an ocular diameter (OD) less than fifth percentile. Diagnosis of fetal microphthalmia using only orbital measurements such as interocular distance (IOD), and OD may neglect the presence or morphology of the fetal lens, hence failing to identify abnormalities of the fetal globe. CASE REPORT: We hereby present a case of isolated fetal anophthalmia in two consecutive pregnancies from the same mother. Both fetuses presented as full-sized globes with absence or small size of lens under fetal ultrasound examination. Magnetic resonance imaging and pathology of the second fetus further revealed a thorough view of the underdeveloped globes. Whole exon sequencing (WES) analysis for the parents-fetus trio revealed compound heterozygous mutations of the retinoids acid gene 6 (STRA6). CONCLUSION: Detailed examination for intraocular structures including fetal lens, in addition to orbital measurements by ultrasound is crucial for diagnosis of diseases in the A/M spectrum.

Ophthalmological manifestations of the Schuurs-Hoeijmakers syndrome: a case report / Manifestações oftalmológicas da Síndrome de Schuurs-Hoeijmakers: relato de caso

ABSTRACT This is a case report of a 2-year-old male patient with cognitive delay, facial abnormalities, and microcornea in the right eye, who was referred for ophthalmological investigation. The initial ophthalmological examination revealed hypertelorism, epicanthus, nystagmus, esotropia, and microcornea in the right eye. The examination under anesthesia revealed microphthalmia in the right eye, and iris, retina, and optic nerve coloboma in both eyes. Whole exome sequencing revealed evidence of a heterozygotic pathogenic variant in PACS1. The PACS1 pathogenic variant in association with the clinical findings confirmed the diagnosis of Schuurs-Hoeijmakers syndrome. To our knowledge, this is the first report to describe microcornea and microphthalmia as additional ocular manifestations of Schuurs-Hoeijmakers syndrome.

RESUMO Trata-se de um relato de caso de um paciente do sexo masculino de 2 anos de idade com atraso cognitivo, anormalidades faciais e microcórnea no olho direito encaminhado para investigação oftalmológica. O exame oftalmológico inicial evidenciou hipertelorismo, epicanto, nistagmo, esotropia e microcórnea no olho direito. O exame sob anestesia revelou microftalmia no olho direito e coloboma de íris, retina e nervo óptico em ambos os olhos. Foi realizado sequenciamento completo do exoma que mostrou uma variante patogênica heterozigótica no PACS1. A variante patogênica no PACS1 em associação com os achados clínicos apresentados confirmou o diagnóstico da síndrome de Schuurs-Hoeijmakers). Acredita-se este seja o estudo a descrever microcórnea e microftalmia como manifestações oculares adicionais da síndrome de Schuurs-Hoeijmakers.

Posterior Microphthalmos Pigmentary Retinopathy Syndrome with Angle-Closure Glaucoma: A Case Report.

Purpose: To describe a particular form of posterior microphthalmos pigmentary retinopathy syndrome (PMPRS) with an atypical clinical presentation of pigment retinal dystrophy and an association to an inconstant complication which is angle-closure glaucoma (ACG). Methods: A 40-year-old male patient with ACG on maximal topical treatment was referred to our department for uncontrolled intraocular pressure. Best-corrected visual acuity was 2/10 in the right eye and light perception in the left eye. Intraocular pressure was 36 mmHg bilaterally. He had 360° peripheral anterior synechiae on gonioscopy. Fundus examination revealed total cupping with pale retinal lesions in both eyes and a few pigment deposits in the midperiphery of the right eye. Multimodal imaging was done. Results: Fundus autofluorescence revealed patchy areas of hypoautofluorescence. Optical coherence tomography (OCT) showed bilateral foveoschisis and macular folds. Anterior segment OCT showed a circumferential iridocorneal angle closure. Axial length measured with ultrasound biomicroscopy was 18.4 mm in the right eye and 18.1 in the left eye. Electroretinogram revealed attenuated scotopic responses. The patient was diagnosed with nanophthalmos-retinitis pigmentosa (RP)-foveoschisis syndrome complicated with ACG. A combined surgery with phacoemulsification - anterior vitrectomy - intraocular lens implantation and trabeculectomy was performed in both eyes with a satisfactory outcome. Conclusions: In its typical forms, PMPR syndrome is an association of nanophthalmos - RP - foveoschisis and optic nerve head (ONH) drusen. Incomplete phenotypes may lack ONH drusen or foveoschisis. Patients with PMPRS have to be screened for iridocorneal angle synechia and ACG.

Three Novel Mutations of Microphthalmos Identified in Two Chinese Families.

Genetic alterations are a major cause of microphthalmos, while novel-related genes and mutations in microphthalmos have rarely been explored. To identify the underlying genetic defect responsible for microphthalmos eyes in two three-generation Chinese families, we screened 425 genes involved in common inherited non-syndromic eye diseases with next-generation sequencing-based target capture sequencing of the two probands of two three-generation Chinese families diagnosed with microphthalmos. Variants were filtered and analyzed to identify possible disease-causing variants before Sanger sequencing validation. We enrolled two families with microphthalmos (Family 1: microphthalmos with congenital ocular coloboma and Family 2: simple microphthalmos). Two novel heterozygous mutations, Peroxidasin (PXDN) c.3165C>T (p.Pro1055Pro) and PXDN c.2640C>G (p.Arg880Arg), were found in Family 1, and Crystallin Beta B2 (CRYBB2) c.481G>A (p.Gly161Arg) was found in Family 2, but none of the mutations were found in the unaffected individuals, who were phenotypically normal. Multiple orthologous sequence alignment (MSA) revealed that the CRYBB2 p.Gly161Arg mutation was a deleterious effect mutation. In conclusion, the three novel mutations found in our study extend our current understanding of the genetic basis of microphthalmos and provide early pre-symptomatic diagnosis and emphasize the significance of genetic diagnosis of microphthalmos.

Clinical Congenital Anophthalmos and Microphthalmos-Experiences of Patients and Their Parents after More than 10 Years of Treatment.

Congenital clinical anophthalmos and blind microphthalmos describe the absence of an eye or the presence of a small eye in the orbit. Between 1999 and 2013, 97 children with anophthalmos or microphthalmos were treated with self-inflating, hydrophilic gel expanders at the Rostock Eye Clinic. More than a decade later, this study investigated the perspective of patients and parents regarding the treatment, the surgical outcome, and the emotional and social well-being of the patients. A total of 22 families with 16 patients sighted in the other eye and six patients blind in both eyes participated. Questionnaires were developed, including items on physical, emotional, social, and medical aspects. The patients felt emotionally stable and integrated into their social environment, with no major limitations reported by the majority. These statements were confirmed by most of the parents. Parents (67%) indicated that the success of the operation was already apparent after the first intervention and that the current situation did not play a role in the patients' social environment. The study provided new insights into the therapy results, the postoperative care, and the social and emotional stability of the prosthesis-wearing patients, indicating the chosen expander methods as promising in terms of positive postoperative care.

Long-term follow-up of a case of posterior microphthalmos (PRSS56) with hyperautofluorescent retinal pigment epithelial deposits.

PURPOSE: To report a case of posterior microphthalomos (PM) related to PRSS56 gene mutation with long term follow up with multimodal imaging findings. METHODS: Single retrospective case report. RESULTS: A 43-year old male patient presented in 2009 with bilateral reduced vision. Clinical examination and multimodal imaging showed features consistent with posterior microphthalmos with prominent bilateral horizontal papillomacular retinal folds. Posterior pole hyperautofluorescent RPE deposits were present. Gradual worsening of visual acuity and rod and cone photoreceptor function more so on the left was demonstrated during the 8 years of follow up. CONCLUSION: Hyperautofluorescent RPE deposits may occur in patients with posterior microphthalmos and such patient's may experience only gradual disease progression over long term follow up.