Management of cataract surgery in Lowe syndrome

INTRODUCTION

The Lowe syndrome, also known as oculocerebrorenal syndrome, is a rare systemic disorder which involves several organ systems such as the eyes, the central nervous system and the kidneys

. The prevalence is estimated at 1 in 500 000 children

. It is an X-linked recessive disorder

,showing a key mutation in the

gene. This gene encodes for the enzyme OCRL-1, which is essential for cell functions such as protein trafficking, signaling and actin cytoskeleton polymerization. Dysfunction of this enzyme leads to an accumulation of the substrate phosphatidylinositol-4.5-biphosphate and impairs the intracellular pathways

. Upon birth, Lowe syndrome should be suspected if children show bilateral dense congenital cataract and infantile congenital hypotonia. Furthermore, a positive family history of male relatives is highly indicative. The definite diagnosis is then established on the results of the physical exam findings,laboratory findings and molecular genetic testing.Nervous system abnormalities, already present at birth, show severe central hypotonia and loss of the deep tendon reflexes which may complicate the vital functions (breathing) at birth.Hypotonia can slowly improve with age, but normal motor function and strength will not be achieved. Also, mental retardation is found in the majority of patients and many will develop maladaptive behaviors such as temper tantrums or irritability as well as seizures or febrile convulsions

.

最后一个夜晚，试图再次拨打她的电话。这一次终于拨通，她清晰的声音平淡自若，一如往昔，没有任何情绪流露。只是说刚刚从森林里出来，在当地附近的一个小镇里看病。身体一直不太舒服。

Kidney dysfunction may not be present at birth but rather develop during the first few months of life. Typically, a proximal renal tubular dysfunction of the Fanconi type is found in these patients, which include low molecular-weight proteinuria, aminoaciduria, bicarbonate and potassium wasting,renal tubular acidosis and proteinuria. Chronic renal failure slowly develops due to glomerulosclerosis associated with chronic tubular injury between the second and fourth decade of life

.

Congenital cataract will initially present as bilateral dens lens opacities during physical examination of the newborn

. Next to the congenital cataract, ophthalmic abnormalities include congenital glaucoma, nystagmus and keloids. Glaucoma is found in about 50% of patients

. Therefore, also typical glaucomatous changes such as corneal haze, increased corneal diameter or buphthalmos combined with lens opacities should be suspicious for Lowe syndrome.

Ophthalmic Evaluation The mean age of the children at diagnosis of congenital cataract was 4.07±3.26wk (1-8wk).Lens surgery was performed at the age of 8.98±3.58wk (3-12wk). The mean follow-up was 4.80±5.32y (1.11 to 15.91y).In all children a lensectomy combined with posterior capsulotomy and an anterior vitrectomy was performed. No IOL was implanted at the initial procedure as well as during the followup. Evaluation of the eye characteristics showed a mean eye length, the corneal diameter and the IOP of 17.16±2.01,10.38±0.41, and 10.63±1.49 mm Hg, respectively. In one eye of one child an iris bleeding developed during cataract surgery,whereas no intraoperative complication developed in the remaining eleven eyes (Table 2).

Ophthalmologists often examine babies only a few weeks of age, since parents or pediatricians found bilateral lens opacities. Prompt cataract removal is necessary to allow visual development. Therefore, a good cooperation between ophthalmologists and pediatricians is essential for the initial diagnosis and subsequently treatment and supportive therapy in these patients.

In this study, we evaluated the initial diagnose process, surgical treatment and the postoperative functional development and complications of children with Lowe syndrome.

SUBJECTS AND METHODS

将工程前后海域潮流特征流场分布绘于图4，分析可知：工程海域的潮流周期为12 h，为典型的半日潮。工程海域潮流运动受风向以及近岸辐射状沙洲地形综合影响，其中，南、中、北三个水道的潮流分布呈椭圆状，潮流流向受南北两侧沙洲引导，与深槽方向趋近，且流向受潮汐影响，呈往复流特征。潮流传递呈典型驻波状态。

Bilateral simultaneous cataract surgery was performed under general anesthesia in all cases.

华彩的背后，是鲜为人知的付出。但问起演戏的艰辛，赵多娜不愿多说，别看她在戏里扮演了各种类型的角色，生活中的她，其实很安静，从不拿拍戏的辛苦大肆宣扬。“只要是我认定的事情，我都会很坚持，甚至有点固执。就拿演戏来说，我很享受拍戏的过程，拿它当一辈子的事业来做。可能有时候家人朋友会有一些其它建议，比如女孩子要早点结婚生子，可以转做一些幕后工作等等，但我还是会坚持自己的信念。”赵多娜笃定地说。

Five boys were born at the gestational week 37 to 39, whereas one child was born premature at week 26

and had to be treated at the NICU. The mean birth weight was 2865.17±1007.38 gram (Table 1). In two children a congenital infection was found, whereof in one child an endocarditis and in the other sepsis. At pediatric examination, cerebral hypotonia was observed in all children. Renal changes varied within the study population. One child showed no renal changes, whereas renal calcinosis was found in three children, isolated proteinuria and hydronephrosis in one child each.

测试温度保持常温不变,依次增加980 nm泵浦功率,stokes阶数也随之增加,当泵浦功率增加到600 mW时,产生了如图4所示的30阶稳定stokes线。

Different approaches in the management of pediatric cataract surgery are discussed in literature. Especially, the time point of cataract extraction for uni- and bilateral congenital cataract is discussed with regard to the functional outcome and avoiding postoperative complications

. In Lowe syndrome, both eyes are predominantly affected, making surgery on both eyes necessary.

RESULTS

This study included twelve eyes of six male children. In all children initial diagnosis was made clinically, whereof in three boys at the Ophthalmic Department and in one child at the Neonatology Intensive Care Unit (NICU). Genetic testing in all children confirmed the diagnosis of Lowe syndrome.

During surgery, a complete ophthalmologic examination including ultrasound B-scans (Ocuscan; Alcon Laboratories,Fortworth, Texas, USA) for evaluation of axial eye length and the posterior segment, measurement of intraocular pressure(IOP) and keratometry was performed. Cataract surgery was performed through the aspiration of the soft lens material with a bimanual irrigation-aspiration system. Afterwards, a posterior capsulotomy was done using either a bent needle or the vitrector. All children remained aphakic and glass or contact lenses were prescribed for postoperative visual rehabilitation.Outcome measures included descriptive data (age and gender), information on the cerebral and renal pathologies and the surgical procedure. Anesthesia outcomes, composed of duration of surgery and anesthesia (measured in minutes,min)—that is, total anesthesia time (intubation to extubation),extubation time (time between the end of surgery and extubation), time in the recovery room, and events of oxygen decrease (below 93% was regarded as severe hypoxia)—were recorded. The type intra- (iris bleeding, expulsive bleeding,posterior capsule rupture, intraocular lens (IOL) problems,iris dislocation) and postoperative complications [glaucoma,visual axis obscuration (VAO), synechia, retinal detachment,endophthalmitis or enucleation] were analyzed as well as the number of surgical re-treatments.

Ethical Approval This retrospective, case series was performed at the Department of Ophthalmology, Vienna.Ethics approval for retrospective chart review and analysis was obtained from the local ethics committee (EK: 1116/2019)and adhered to the tenets of the Declaration of Helsinki.Medical records of patients aged 0 to 18y with genetically verified Lowe syndrome who received cataract extraction were included to the study. The Ethics Committee did not ask for informed consent as this was a retrospective chart review.

The initial approach is the cataract removal under general anesthesia. During surgery a complete ophthalmic examination will be carried out including assessment for glaucomatous changes

.

The mean time for cataract surgery per eye was 35.83±8.86min,whereas the total time of surgery was 153.33±22.11min. Four children received an endotracheal tube, whereas two children a larynx mask. The mean extubation time and duration at recovery room was 42.33±22.60min and 130.00±64.37min,respectively. During surgery, a decrease of oxygen saturationbelow 93% was found in only one child. Additionally,no serious complications such as asphyxia, malignant hyperthermia, cardiac and respiratory arrest or seizures were observed during surgery. One child, who showed a short period of insecure respiratory function during extubation,was transferred intubated to the recovery room. Extubation was then performed without complications. Afterwards, this child was brought to the pediatric intensive care unit for postoperative observation. All children left the hospital one to three days after cataract surgery, except the child who was born prematurely. This child remained at the hospital for another 43d because of the need for neonatal care.

CEFTIN在急性细菌性上颌窦炎患者，用于治疗由产β‐内酰胺酶的流感嗜血杆菌或卡他莫拉菌所致鼻窦感染的有效性尚未确定，因为临床试验中这些分离菌数量不足［见临床研究（14.1）］。

During the postoperative follow-up, nystagmus was found in all children. Strabismus was seen in five children, whereof in four children an esotropia and in one child an exotropia. One child developed a VAO during the postoperative follow-up.

Secondary glaucoma developed in five eyes of three children.The maximum IOP was 21.75±10.49 mm Hg (10 to 40 mm Hg)during the follow-up. A trabeculectomy was performed in both eyes of one child four months after lens extraction, whereas a removal of synechia and an iridectomy in one eye of one child one year after lens surgery. In the third child, glaucoma was successfully controlled using topical IOP medication (betablocker).

At the last follow-up, the children showed a visual function of 0.61±0.88 logMAR (0.1-0.4 Snellen). No further surgical interventions were performed during the postoperative followup. However, in two children an examination under general anesthesia was performed for evaluation of glaucomatous changes.

During the follow-up one child, who was born prematurely and showed bronchopulmonary dysplasia, died at the age of 14.93mo due to recurrent respiratory infections (13.2mo after the cataract surgery).

DISCUSSION

From an ophthalmological point of view, Lowe syndrome is mainly characterized by bilateral cataract followed by infantile glaucoma and corneal kelloids. In addition, various diseases of the cerebrovascular system such as generalized hypotonia or intellectual impairment as well as renal changes such as renal tubular sclerosis or proteinuria have been described

. The primary goal is established by the diagnosis

genetic testing in order to initiate adequate treatment and early intervention.In the ophthalmological field, cataract surgery and glaucoma management are the first priorities.

Furthermore, four of the six children presented to the Ophthalmology Department within the first two weeks of life.Children with congenital cataract present very early to eye doctors, which demonstrates the special role of ophthalmologists in the screening process of newborns. Bilateral cataract requires,in general, further pediatric examination, since congenital infections (such as toxoplasmosis, rubella, cytomegalovirus,herpes simplex or other infections,

, syphilis,Varicella-Zoster, HIV or Parvo-B19) or drug exposures have to be ruled out

. Subsequently, a good cooperation and network between ophthalmologists and pediatricians is essential for the timely diagnosis and treatment, especially, if Lowe syndrome is suspected.

Within the demographic results we saw a male predomination of the study population, which is also described in the literature

. About 95% of heterozygous females show specific cortical lens opacities in the shape of snowflakes already during the teenage years. However, cataract surgery is rarely required at a young age in female carriers

.

Statistical Analysis Microsoft Excel

2010 was used for collecting patients’ data, which was then converted to SPSS

version 20 (SPSS, Inc., Chicago, IL, USA) for statistical analysis. Nominal data is given as numbers or percentages,whereas continuous data is given as means±standard deviations(SDs).

At our clinic, bilateral cataracts are treated in one session of general anesthesia but with special care taken

new equipment (two separate phako sets) or change of clothes and gloves. This has the advantage that the children do not need another operation and therefore the total anesthesia time can be significantly reduced. In a retrospective analysis of anesthesia times in pediatric cataract surgery, surgery times per eye and the total anesthesia time were similar to our study results, only extubation time and recovery room time were prolonged

.This may be due to the fact that the anesthetists knew about the suspected diagnosis Lowe syndrome, and therefore general anesthesia was performed more cautiously, or due to the fact that the children took longer to wake up and breathe on their own due to cerebral hypotension or delayed excretion due to the underlying renal pathologies. However, the children could be discharged from the inpatient area relatively quickly after the operation (on average 1-3d). Furthermore, the children did not experience any complications during anesthesia. One child showed prolonged weaning during extubation, but the tube could be removed in the recovery room without further complications.

2)由DSM生成的等高线中含有大量自闭合微短等高线，其来源可分为两种：一种出现在植被和建筑物等地物表面，不属于地形，这是错误的等高线；另一种出现在地表，属于细微的地形，多见于居民地内和乱掘地，这是多余的等高线。应当筛选去掉这些自闭合微短等高线。

Postoperative follow-up examinations revealed various complications such as nystagmus, strabismus and secondary glaucoma. Ma

reported nystagmus strabismus and secondary glaucoma in 69.3%, 35.0%, and 54.7%, respectively.In our retrospective case series, all children showed nystagmus.Strabismus was seen in 83.33% of patients, whereas secondary glaucoma in 50%. All of the above are common postoperative complications in children with congenital cataract. But, due to the generalized muscular hypotonia in Lowe syndrome additional impairment of the ocular motility and fusion reflex resulting in a predisposition towards strabismus may be found. Further, secondary glaucoma in Lowe syndrome is often difficult to treat and might not be controlled with topical treatment and require surgical intervention

.

为了提高基母材之间的焊接强度，通常会采用在其间增加过渡涂层的方法来增加强度，因此针对银铜焊料，选用电镀铜和银来进行基母材的表面处理，镀层厚度10 μm，再制作焊接试样进行试验。不同胎体配方的基母材电镀铜和银的焊接强度汇总表见表9、表10。

In our study, three children showed changes of the IOP two required surgery to control eye pressure. A similar finding was reported by Ma

, 55% of patients underwent glaucoma surgery to control eye pressure sufficiently. Secondary glaucoma is a serious complication following pediatric cataract surgery in any case. One of the main risk factor for the development of secondary glaucoma is, however, the age at cataract surgery

. A delay of cataract surgery was shown to reduce the risk of secondary glaucoma development by 20%for each week of postponement

. Furthermore, secondary glaucoma is associated with decreased visual function

. As a result, timing of cataract surgery in Lowe patients should be adjusted to the timing of bilateral cataracts in general(12wk of life). Especially, since a good visual development is an important base for the general physical and mental development. Next to the vision therapy, many children with Lowe syndrome require supportive therapies in form of physiotherapy or psychotherapy. Therefore, early detection of bilateral cataract and subsequently treatment is essential for the optimal visual prognosis.

Within our case series, one child who was born prematurely showed persistent bronchopulmonary infections and died at the age of 14mo. In literature, the causes of death are related to the underlying renal disease, muscular hypotonia, epileptic seizures and infections, especially in the bronchopulmonary or gastrointestinal tract

.

A bilateral congenital cataract is challenging for the ophthalmologist, anesthesiologist and pediatrician. As a result,an early diagnosis of Lowe syndrome is beneficial for the surgical management to increase the safeness of the surgery.Simultaneous bilateral cataract surgery showed no rise of complications in children with Lowe syndrome. A prolonged extubation time and stay at the recovery room was observed,but the children could be discharged one to three days after surgery.

2.多角度规避、转移PPP的税收风险。在智慧城市建设的PPP项目中，需要从合同流、资金流、物流和信息流视角合理筹划税负，提高社会资本的运营水平。一旦股权出现多重溢价，应当适当停止业务活动，降低税收风险对公司造成的影响。系统性的梳理PPP生命周期中涉及的各项税种以及特殊性处理的税收优惠，为政府和企业双方规避风险，合理节省税务成本。由于PPP项目的基建投资阶段和运营阶段存在一个时间差，因此需要项目方、企业与国税机关三方信息共享，保持实时沟通，分析PPP项目投向的本质，多方面争取税收优惠。而在控制PPP模式专项债务的潜在风险方面，政府应当考虑适当的PPP退税制度，消除民营资本参与PPP项目的顾虑。

The glaucoma screening with IOP measurements is crucial in the postoperative management of Lowe patients, since there seems to be a special association to Lowe syndrome causing an increased prevalence. Especially since a good functional outcome of children with Lowe syndrome is essential for the further general physical development.

ACKNOWLEDGEMENTS

Conflicts of Interest: Eibenberger K, None; Rezar-Dreindl S, None; Pusch F, None; Schmidt-Erfurth U, None; Stifter E, None.

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