Nomogram model for predicting oculomotor nerve palsy in patients with intracranial aneurysm

INTRODUCTION

Intracranial aneurysm (IA) is a common cerebrovascular condition with a rupture rate of 13%-25%

. Because of the following subarachnoid hemorrhage (SAH) and its complications, the mortality rate of ruptured IA is 27%-45%

.Regrettably, the early diagnostic rate for IA is relatively low due to the lack of specificity of the presenting symptoms.Choosing the optimal treatment time and measures for unruptured IA is controversial. Some scholars held that unruptured IA with a diameter less than 5 mm could be treated conservatively

. However, it has been reported that the rupture rate of small- and medium-sized aneurysms in the Japanese was significantly higher than that in Europeans and Americans

. Although the rupture rate of a small aneurysm has been reported to be low, it can cause life-threatening SAH once ruptured

. To the best of our knowledge, the clinical treatment principles for small aneurysms have not been established. A considerable number of IA patients are in the stage of clinical follow-up due to differences in medical conditions and clinician’s treatment principles

.

Oculomotor nerve palsy (ONP) is a common neuroophthalmologic condition with manifestations of ptosis,exotropia, eye movement restrictions, dilated pupil, loss of pupillary light reflex, and diplopia. The etiology of ONP is complex, such as diabetes mellitus, IA, tumors, painful ophthalmoplegia, pituitary lesions, cavernous sinus lesions,central nervous system infections, and SAH

. Recent reports indicated that 29.8% of ONP was caused by IA, a potentially life-threatening condition with a high morbidity and mortality rate

. Thus this study aimed to explore the predictive factors of ONP in patients with IA. Moreover, we also established a nomogram for individualized prediction of ONP prognosis with IA.

SUBJECTS AND METHODS

Variables with normal and skewed distribution were presented as mean±standard deviation(SD) and median (range), respectively. Student

-test and the Mann-Whitney

test were used to compare two groups, as appropriate. Chi-square test was carried out for dichotomous data, and non-parametric test was employed for hierarchical data. Univariate and multivariate analyses of influencing factors were performed by logistic regression analysis.Variables were significantly related to ONP, and the degree of ONP in the univariate analysis (

<0.05) was subsequently selected for multivariate Logistic regression analysis. A twosided

value less than 0.05 was considered to be statistically significant.

辅导员是与学生接触最为频繁的教师，其一言一行对于学生各方面的成长来说，都可能产生重要影响。辅导员必须做到言行一致、公平正义，才能被同学信服，才能成为学生内心的榜样。针对一些辅导员道德素质低下的现象，学校必须严格控制，加强对辅导员的素质训练，确保学生权利平等。同时，辅导员应明确自身职责，学生才是其工作的主体，要切实发挥好自身的作用。

旅游者在旅行、游览过程中依据自己的需求和爱好表现出一定的旅游行为特征.在相同旅游条件下，不同旅游个体表现出不同的旅游行为.

The study was approved by the Clinical Research Ethics Committee of Shanghai Changhai Hospital and Peking University International Hospital. Informed consent was waived due to the retrospective nature of the study.

IA is a common cerebrovascular condition that is predominantly caused by injury of vascular intima associated with wall shear stress

. When ruptured, they could easily generate SAH that may cause high morbidity and mortality.

RESULTS

The clinical data of 329 IA patients collected (124 males and 205 females, 81 with ONP and 248 without ONP) were presented in Table 1. There were significant differences with regard to gender, location of the aneurysm, diameter of aneurysm and cerebral infarction between the ONP group and non-ONP group (all

<0.05).

The results of the univariate and multivariate analysis were shown in Table 2.By univariate analysis, female gender, PCoA aneurysm and aneurysm diameter were identified to be predictive factors of ONP. Nonetheless, only PCoA aneurysm [hazard ratio(HR)=17.13, 95% confidence interval (CI): 7.93-37.01,

<0.001] and aneurysm diameter (≥15 mm; HR=1.31, 95%CI:1.21-1.41,

<0.001) were independent risk factors of ONP by multivariate analysis.

In conclusion, early recognition and evaluation of ONP is important to rule out potential PCoA aneurysms. Especially,more attention should be paid to PCoA aneurysm and aneurysm diameter. The nomogram we established for individualized prediction of the prognosis of ONP with IA has a good predictive accuracy and clinical diagnostic value,which provided important clinical evidence for clinicians in the diagnosis and selection of therapeutic schedule. Ultimately it contributed to reducing the incidence rate of ONP and rupture rate of IA and improving the quality and survival of life.

The calibration curve was conducted to evaluate the performance of the nomogram in ONP, which indicated that the nomogram possessed favourable calibration and discriminative ability supported by a fair uniformity between prediction and observation of the nomogram (Figure 3). The ROC curve showed the high diagnostic utility of the nomogram(Figure 4), as indicated by an AUC of 0.863. Furthermore the clinical practicality of nomogram was established by the DCA which showed satisfactory net benefits among most of the threshold probabilities in both groups and was superior in predicting ONP than conventional predictive methods. All these data supported that the nomogram we established provided constructive guidance for clinical decision-making (Figure 5).

We further categorized ONP patients into the complete and partial ONP group based on the degree of ONP (35 complete ONP and 46 partial ONP). Patients with partial ONP tended to have PCoA more than complete ONP (

=0.01). The results of univariate and multivariate analysis of ONP severity were shown in Table 3. The results indicated that PCoA aneurysm(HR=3.38, 95%CI: 1.27-8.98,

=0.015) was an independent risk factor of ONP severity.

Consecutive patients diagnosed with IA from January 2012 to December 2019 were retrospectively identified by searching the electronic medical system. We confirmed the diagnosis of IA by imaging scans(computed tomography, magnetic resonance imaging) or cerebral angiography (Figure 1). The exclusion criteria were as follows: 1) presence of other intracranial lesions or neurological conditions; 2) concomitant eye diseases other than ONP, such as strabismus, glaucoma, fundus ophthalmopathy,and optic neuropathy; 3) ONP caused by other conditions, such as cerebrovascular infarction, hemorrhagic disease, diabetes, intracranial inflammation, trauma or congenital ONP. Also we retrieved clinical characteristics which included patient age, sex, concomitance with ONP or not, ONP degree, number of aneurysms, aneurysm diameter and location, the time span from symptom onset to treatment,presence of SAH or not, history of hypertension and cerebral infarction. Complete ONP was defined as complete ptosis of the upper eyelid, paralysis of the external ocular muscle,dilated pupil, and disappearance of direct or interfacial light reflection. By contrast, incomplete ptosis or partial vision,inner vision, impaired vision or incomplete pupil dilation and reduced light reflex constituted partial ONP. IA diameter was calibrated by the distance from the midpoint of the aneurysm neck plane to the furthest point of the aneurysm in digital subtraction angiography images.

俗话说，“眼过千遍，不如手过一遍”。对于经典篇目和句段，不仅要能达到“准确背诵，不错一字”，还要能做到字词准确，标点精准，以达到经典入心的效果。

DISCUSSION

To further facilitate individualized prediction of ONP, a nomogram were established using the rms package in R,version 3.5.1 based on the results of multivariate Logistic regression analysis. In order to verify the prediction ability of the nomogram, a calibration curve was performed to evaluate the calibration ability of nomogram according to the consistency between the nomogram prediction and observed real outcomes. Subsequently, the area under the curve (AUC)was calculated with the receiver-operating characteristic curve (ROC). In order to evaluate the clinical utility of the nomogram, decision curve analysis (DCA) was performed by rmda package of R to analyze the net benefit of the nomogram we established.

The oculomotor nerve is the third cranial nerve that emerges from the interpeduncular fossa in the midbrain. It travels between the posterior cerebral artery and the superior cerebellar artery that parallels to the PCoA before finally enters the cavernous sinus. Any IA adjacent to the oculomotor nerve may predispose to the development of ONP. This study revealed the correlation between IA and ONP. More importantly, we established an individualized prediction model for assessing the risk of ONP in patients with IA, which may have important clinical significance for guiding clinicians to make appropriate medical decisions and reduce the risk of disability or mortality.The present study showed that PCoA aneurysm was an independent risk factor for ONP and its severity. Of the total 329 IA patients, 81 were having ONP, which is consistent with previous studies reporting that IA, especially PCoA aneurysms is a common cause of ONP. For example, it has been noted that approximately 7%-23% of patients with PCoA aneurysms will develop ONP

. The intimate relationship between PCoA aneurysm and ONP may be closely related to the anatomy and structure of the oculomotor nerve. First, the oculomotor nerve travels on the lower lateral side of the PCoA and is closely surrounded by the arachnoid membrane, thus the puffed aneurysm could directly compresses the adjacent oculomotor nerve. The persistent throbbing of the aneurysm causes chronic damages to the oculomotor nerve with nerve venous congestion and oedema. Furthermore, ruptured aneurysms can directly stimulate the oculomotor nerve or produce a progressive effect

. ONP is an important and clinically useful indicator of PCoA aneurysm on the verge of rupture

. SAH occurs in about 50% of PCoA aneurysm patients with ONP, of which only 15% presented with ONP prior to aneurysm rupture. It is reported that an unruptured PCoA aneurysm has similar morphologic and hemodynamic characteristics with a ruptured PCoA aneurysm in ONP patients

. The degree of ONP in the early period is a useful predictor of ONP recovery in both ruptured and unruptured aneurysms

. The outcome for complete ONP is generally worse than partial ONP

. This study alerted clinicians to pay more attention to ONP once they have encountered IA patients,especially those with PCoA aneurysms. IA patients with ONP(especially complete ONP) should be given more vigilance and timely treatment to avoid the life-threatening rupture of aneurysms.

Currently, the relationships between aneurysm diameter and ONP occurrence have not been thoroughly established.Chalouhi

found that the diameters of PCoA aneurysms with ONP were larger than those without ONP. Previous reports

indicated that aneurysms with a diameter greater than 4 or 7 mm were inclined to generate ONP. In line with these reports, our study showed that IA diameter was an independent predictive factor for ONP. It was reported that 54% of ruptured aneurysms ranged from 5 to 10 mm in diameter

. Aneurysms larger than 7 mm in diameter tended to rupture

, the risk of which can be reduced by 59% if active treatment is initiated

. Other risk factors for aneurysm rupture include location, genetics, smoking and others

. Clinicians can better assess the risk based on the aneurysms’ diameter and thus take more active therapeutic measures.

Nomogram provides individualized risk assessment based on clinical variables. This study has established a practical and internally validated nomogram for predicting the prognosis of ONP with IA. The nomogram showed that PCoA aneurysm and IA diameters were independent risk factors for ONP.The calibration curve indicated that the nomogram possessed favourable calibration and discriminative ability, which was further validated by the high AUC. In addition, the DCA proved that the nomogram was beneficial to the clinical decision by demonstrating better net benefit for predicting the prognosis of ONP. The nomogram we established has demonstrated adequate discriminative and diagnostic value to predict the occurrence of ONP individually.

This study suffers several limitations. First, the small sample size and the retrospective nature of the design would limit study robustness. Prospective studies with larger sample size and longer follow-up is required in the future. Second, all the patients included were Chinese that limited the study’s extrapolation result to patients with other ethnicities. A heterogeneous patient population that represented different genetic backgrounds in multi-centers would further validate our study results. Third, additional risk factors, such as tumor orientation and tumor morphology, may also influence study results.

为了确诊，通常采用一些辅助检查手段，如穿刺，穿刺液为清亮透明的粘稠液体。常规涂片粘液蛋白呈轻度嗜酸性。病理检查时，在显微镜下可见囊肿大多无上皮衬里，初期腔内为多发性小间隙，里面充满粘液蛋白，周围有一层肉芽组织围绕；晚期由于囊腔扩大或融合成一个腔隙，腔内见有大量泡沫细胞，囊壁的肉芽组织逐渐被纤维组织所代替。

We established the nomogram for predicting the prognosis of ONP according to the independent risk factor identified by the multivariate logistic regression analysis. A score of 0-100 was assigned to each variable, which was transformed to the coefficients of the independent risk factor. The sum of corresponding scores of different variables was added to reach the total score, which corresponded to the risk axis that denoted the risk of individual ONP. The greater the influence of the variables, the higher the nomogram score. The nomogram we established suggested that aneurysm diameter had the greatest impact on ONP, followed by location (Figure 2). In a representative case, a 56-year-old man with PCoA aneurysm(21 points) that measured 25 mm (50 points), leading to a sum score of 71 points that could be converted to >90% probability of ONP.

优秀数学教师首先应体现于对教学内容的深刻理解和对教学活动的深入思考[6]．中央民族大学何伟对中国“三区三州”深度贫困地区的212名小学和101名初中数学骨干教师和教研员分别进行了数学教学知识测试，从学科知识（一般内容知识——CCK、特殊内容知识——SCK）和教学内容知识（内容和学生知识——KCS、内容和教学知识——KCT）两个方面的测试结果发现，“三区三州”数学教师的教学知识上存在较大问题，在某些知识点上，教师的得分率甚至只有30%左右．表明当地数学教师的教学知识还比较贫乏，教学质量亟待提升．

ACKNOWLEDGEMENTS

The authors thank Hong Liu and Ji-Fang Qu for their support and help in writing the manuscript.

3）由项目单位对监理人员直接进行管理。传统的监理模式中，项目单位会将监理工作直接交给监理单位，通过监理单位内部管理提高监理质量。这一监理模式存在一定的安全隐患，而新的管理方法必须打破传统的管理模式，监理工作人员直接接受项目单位的管理，并由项目单位进行工作发放。

Conception and design: Zhao SH;Provision of study materials or patients: Cui YY and Wang B;Collection and assembly of data: Cui YY and Jiang B; Data analysis and interpretation: Cui YY, Jiang B, and Wang B;Manuscript writing: All authors; Final approval of manuscript:All authors.

中国的探月工程——嫦娥工程是人类探月史上的重要篇章，对人类进一步了解月球做出了重要贡献。本书主要介绍宇宙太空的知识和嫦娥探月的历程，包括即将开展的嫦娥四号、嫦娥五号及火星探测任务的介绍。书中设有翻翻页、小册子、大立体等70余组互动机关，让小朋友在互动参与的过程中了解中国探月工程，开启他们的航天梦想。

Supported by National Natural Science Foundation of China (No.81970822).

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