Introduction: Open spina bifida (OSB) manifests as myelomeningocele (MMC) or myeloschisis (MS). Both lesions theoretically leak cerebrospinal fluid (CSF) and produce different degrees of Chiari II malformation (CHMII). However, it is not entirely clear whether these forms of OSB have different clinical manifestations. This study aimed to evaluate the clinical and/or radiological differences between MS and MMC in patients who underwent prenatal OSB repair. Methods: A total of 71 prenatal repairs were performed with the open technique at the Public Hospital of Rancagua, Chile, between 2012 and 2022. We performed follow-up magnetic resonance imaging (MRI) of fetuses that qualified for prenatal OSB repair surgery. We examined the correlations between various anthropomorphic measurements and clinical and imaging variables, such as the type of lesion and dimensions such as ventricle atrium diameter, degree of severity of CHMII, need for CSF shunt at 12 months, and walking at 30 months. Results: This study included 71 fetuses with OSB for which 38 MRI examinations were analyzed; 61% (43/71) of lesions were MMC and 39% (28/71) were MS. Grade 3 (severe) Chiari II malformations were found in 80% (12/15) of MS and 43% (10/23) of MMC (p < 0.05). Fetuses with an atrial diameter less than 13.48 mm had a lower probability of requiring a CSF shunt at 12 months (p < 0.05). MMC was associated with a significantly higher frequency of clubfoot at birth (p < 0.05), whereas MS was significantly associated with more severe CHMII (p < 0.05). Although the correlations were not significant, we observed clear trends that more children with MS required shunts at 12 months and could walk at 30 months compared to children with MMC. Conclusions: MS and MMC are distinct subtypes of OSB. Further studies of larger cohorts that include biomolecular and histological analysis are required to better understand the differences between these lesions. The findings of this study may enable healthcare providers to better advise parents and prepare healthcare teams earlier for the management of patients undergoing prenatal repair of OSB.

Neural tube defects (NTDs) are a group of anomalies that include anencephaly, encephalocele, craniorachischisis, iniencephaly, and spina bifida (SB) [1]. SB, one of the more serious malformations in humans, is the most frequent NTD with a worldwide incidence of 18.6 per 10,000 live births [2, 3]. SB is classified as open spina bifida (OSB) or closed spina bifida (CSB). In OSB, the placode is exposed to the environment, and the margins are demarcated with a transition to skin. In CSB, the neural malformation is covered by overlying healthy functional skin that acts as a mechanical barrier to the underlying cerebrospinal fluid (CSF) interface [4].

NTD malformations have been described using several confusing nomenclatures in the scientific literature [5‒8]. The terms myelomeningocele (MMC), open dysraphism, OSB, and CSB are often used interchangeably to describe OSB. It has been stated that the only known difference between a newborn with MMC versus a newborn with myeloschisis (MS) is the presence of a cystic component in MMC [5]. However, emerging evidence in the literature has demonstrated several dissimilarities and distinct clinical implications between MS and MMC [9‒11]. Thus, early recognition of the differences between these lesions may have a major impact on the management of these patients. Further research is required to define the precise features and outcomes of MS and MMC. Therefore, in the present work, we investigated the clinical and radiological differences between MMC and MS in fetuses with prenatally corrected OSB and examined the postnatal outcomes.

Between January 2012 and December 2022, 71 mothers and fetuses underwent prenatal OSB repair at the Libertador Bernardo O’Higgins Regional Hospital (HRLBO), Rancagua, Chile, according to the classic open technique described by the Management of Myelomeningocele Study (MOMS) [12]. Fetuses that qualified as candidates for intrauterine surgery according to the inclusion and exclusion criteria defined by the MOMS were included in this retrospective study. Data were collected from the fetal magnetic resonance imaging (MRI) scans and on various anthropomorphic measures. Lesion size, in the case of MMC, was calculated as described by Corroenne [13] using:
MMCvolumecm3=lengthcm×widthcm×depthcm×0.52
In the case of MS, the area of an ellipse was determined, i.e.,
MSareacm2=lengthcm2×widthcm2×π
In addition, the degree of hindbrain herniation was assessed to determine the characteristics of Chiari II malformation (CHMII) [14]. Moreover, based on Nagaraj et al. [9], we classified narrowing of the fossa from grade 1 to 3 (shown in Fig. 1), with a higher grade corresponding to greater severity of narrowing. Grade 1 is defined as a lesion in which the fossa shows no cerebellar ectopia, with a patent cisterna magna and a visible fourth ventricle; grade 2 exhibits cerebellar ectopia and an absent fourth ventricle, but the cisterna magna is visible; and grade 3 is defined as cerebellar ectopia with no visible fourth ventricle or cisterna magna. The occipital atrium was measured to determine fetal hydrocephalus (shown in Fig. 2a).
Fig. 1.

Different Chiari II grades detected on fetal MRI. Images show distinct patients with Chiari II grade 1, 2, or 3. White arrows indicate cisterna magna, and black arrows show the fourth ventricle.

Fig. 1.

Different Chiari II grades detected on fetal MRI. Images show distinct patients with Chiari II grade 1, 2, or 3. White arrows indicate cisterna magna, and black arrows show the fourth ventricle.

Close modal
Fig. 2.

Fetal MRI obtained at gestational week 25 showing the occipital atrium and clubfoot. a Measurement of occipital atrium diameter. b Presence of clubfoot in a patient with MMC. Patient clubfoot (black arrow) and MMC lesion (white arrow) are shown.

Fig. 2.

Fetal MRI obtained at gestational week 25 showing the occipital atrium and clubfoot. a Measurement of occipital atrium diameter. b Presence of clubfoot in a patient with MMC. Patient clubfoot (black arrow) and MMC lesion (white arrow) are shown.

Close modal

The vertebral anatomical level of the injury was also evaluated. For statistical analysis, the first cervical vertebra C1 was arbitrarily considered as level 1, T1 as level 8, and the fifth lumbar (L5) as level 24. We considered the upper boundary of the lesion as the beginning and the lower boundary as the ending of the extension of injury, respectively, i.e., the vertebral count involved counting from top to bottom, in a cephalon caudal fashion (online suppl. Fig. 2; for all online suppl. material, see https://doi.org/10.1159/000538099).

Finally, we also analyzed data on various clinical variables such as the presence of clubfoot at birth, the requirement for a shunt at 12 months, and gait status at 30 months. The MRI images were mostly obtained using the resonator at the HRLBO. Fetal acquisitions were performed from 22 weeks of gestation onwards on a 1.5 T Siemens Aera MRI scanner with a field of view (FOV) of 70–45 cm at 33 mT/m. The neuroaxis protocol was a Haste sequence performed in three planes (axial, coronal, and sagittal) to obtain 11–23 4-mm-thick slices with no spacing between slices using a FOV of 300 mm, TR of 1,000–1,200 ms, TE of 120 ms, oversampling at 100%, and a matrix of 256 × 256 and a TrueFISP sequence of 11–23 4-mm-thick slices obtained in three planes (axial, coronal, and sagittal) with no spacing between slices using a FOV of 300 mm, TR of 4.5 ms, TE of 2.48 ms, oversampling at 50%, and a matrix of 320 × 256.

The Student’s t test was used to compare continuous variables between the MMC and MS groups; the χ2 test or Fisher’s test, as appropriate, was used to examine the differences in categorical variables between groups. Pearson correlation coefficients (r) were calculated to assess the strength and direction of the linear relationships among these variables. A two-tailed p value was used to determine the statistical significance of each correlation. A p value <0.05 was considered significant. Statistical analyses were performed using GraphPad Prism® (version 9.4.1).

Authorization to conduct this study was obtained from the management of HRLBO with the prior approval of the Scientific Ethical Committee of the San Juan de Dios Hospital, Santiago, Chile. The research protocol underwent review (approval number Protocol No. 236). An e-mail was sent to the mothers of the children to request informed consent for the study.

A total of 71 fetuses with OSB born from January 2012 to December 2022 were included in this study (Table 1). Thirty-eight fetal MRI scans performed between 23 and 25 weeks of gestation were available. Overall, 61% (43/71) of the fetuses had MMC-type lesions, and 39% (28/71) had MS. Hindbrain herniation was present in 100% of cases. There was no significant difference in sex between the groups with MMC and MS.

Table 1.

Description of the study population in Hospital Libertador Bernardo O’Higgins, Rancagua, Chile

CharacteristicOverall group, n (%)MMC, n (%)MS, n (%)
Patients, n 71   
 Female 35 (49) 20 (57) 15 (43) 
 Male 36 (51) 23 (64) 13 (36) 
Type of injury 
 MMC 43 (61)   
 MS 28 (39)   
Lesion size* 
 MS lesion, cm2 3.21±1.95   
 MMC lesion, cm3 6.39±9.19   
Lesion level 38 23 15 
 Thoracic 1 (2) 0 (0) 1 (100) 
 L1–L2 9 (24) 7 (78) 2 (22) 
 L3 10 (26) 5 (50) 5 (50) 
 L4 9 (24) 7 (78) 2 (22) 
 L5 9 (24) 4 (44) 5 (56) 
 Lesion level L3 or lower 28 (73) 12 (43) 16 (57) 
Lesion extension** 38 23 15 
 2 2 (5) 1 (50) 1 (50) 
 3 1 (3) 1 (100) 
 4 10 (26) 6 (60) 4 (40) 
 5 14 (36) 8 (57) 6 (43) 
 6 4 (11) 2 (50) 2 (50) 
 7 6 (16) 6 (100) 
 11 1 (3) 1 (100) 
Patients with CHMII reported 38   
 Grade 1 2 (5) 2 (9) 0 (0) 
 Grade 2 14 (37) 11 (48) 3 (20) 
 Grade 3 22 (58) 10 (43) 12 (80) 
Patients with shunt requirement at 12 months 61   
 Yes 21 (34) 12 (57) 9 (43) 
 No 40 (66) 24 (60) 16 (40) 
Patients with walking status reported at 30 months 47   
 Yes 17 (36) 7 (41) 10 (59) 
 No 30 (64) 20 (67) 10 (33) 
Patients with clubfoot reported 67   
 Yes 35 (52) 26 (74) 9 (26) 
 No 32 (48) 15 (47) 17 (53) 
CharacteristicOverall group, n (%)MMC, n (%)MS, n (%)
Patients, n 71   
 Female 35 (49) 20 (57) 15 (43) 
 Male 36 (51) 23 (64) 13 (36) 
Type of injury 
 MMC 43 (61)   
 MS 28 (39)   
Lesion size* 
 MS lesion, cm2 3.21±1.95   
 MMC lesion, cm3 6.39±9.19   
Lesion level 38 23 15 
 Thoracic 1 (2) 0 (0) 1 (100) 
 L1–L2 9 (24) 7 (78) 2 (22) 
 L3 10 (26) 5 (50) 5 (50) 
 L4 9 (24) 7 (78) 2 (22) 
 L5 9 (24) 4 (44) 5 (56) 
 Lesion level L3 or lower 28 (73) 12 (43) 16 (57) 
Lesion extension** 38 23 15 
 2 2 (5) 1 (50) 1 (50) 
 3 1 (3) 1 (100) 
 4 10 (26) 6 (60) 4 (40) 
 5 14 (36) 8 (57) 6 (43) 
 6 4 (11) 2 (50) 2 (50) 
 7 6 (16) 6 (100) 
 11 1 (3) 1 (100) 
Patients with CHMII reported 38   
 Grade 1 2 (5) 2 (9) 0 (0) 
 Grade 2 14 (37) 11 (48) 3 (20) 
 Grade 3 22 (58) 10 (43) 12 (80) 
Patients with shunt requirement at 12 months 61   
 Yes 21 (34) 12 (57) 9 (43) 
 No 40 (66) 24 (60) 16 (40) 
Patients with walking status reported at 30 months 47   
 Yes 17 (36) 7 (41) 10 (59) 
 No 30 (64) 20 (67) 10 (33) 
Patients with clubfoot reported 67   
 Yes 35 (52) 26 (74) 9 (26) 
 No 32 (48) 15 (47) 17 (53) 

Distinct parameters as type of injury, lesion size, lesion level, lesion extension, Chiari II grade malformation (CHMII), shunt requirement, and clubfoot presence are shown with their respective percentage.

*The value is expressed as mean ± standard deviation (SD).

**The extension was determined by vertebrae count.

First, the associations between the MRI findings of MMC and MS lesions and clinical findings were evaluated (Table 2). Patients with MS were five times more likely to have grade 3 CHMII on fetal MRI than patients with MMC (OR 5.2, 95% CI 1.154–20.03, p = 0.0435). Patients with MMC were three times more likely to have clubfoot at birth than patients with MS (OR 3.274, 95% CI, 1.156–9.379, p = 0.0262). Patients with MS were almost three times more likely to be able to walk at 30 months than patients with MMC, though this trend was not significant (OR 2.857, 95% CI 0.8754–10.38, p = 0.1273).

Table 2.

Statistical relations of imaging and clinical findings in MMC and MS lesions

Chiari II grade 3Clubfoot presence at birthShunt requirement at 12 months oldWalking status at 30 months old
MS, n (%) 12 (55) 9 (26) 9 (43) 10 (59) 
MMC, n (%) 10 (45) 26 (74) 12 (57) 7 (41) 
OR [95% CI] 5.2 [1.154–20.03] 3.274 [1.156–9.379] 1.125 [0.3732–3.184] 2.857 [0.8754–10.38] 
p value 0.0435* 0.0262* >0.9999 (ns) 0.1273 (ns) 
Chiari II grade 3Clubfoot presence at birthShunt requirement at 12 months oldWalking status at 30 months old
MS, n (%) 12 (55) 9 (26) 9 (43) 10 (59) 
MMC, n (%) 10 (45) 26 (74) 12 (57) 7 (41) 
OR [95% CI] 5.2 [1.154–20.03] 3.274 [1.156–9.379] 1.125 [0.3732–3.184] 2.857 [0.8754–10.38] 
p value 0.0435* 0.0262* >0.9999 (ns) 0.1273 (ns) 

Chiari II grade 3, clubfoot, shunt requirement, and ability to march are distributed by type of lesion. Effect size is shown in odds ratios (OR), with a 95% of confidence interval and p value, respectively. *, correponds to p value below 0.05.

Concerning the degree of hindbrain herniation on MRI, the most severe degree of herniation, i.e., grade 3, was observed in 80% (12/15) of cases of MS and 43% (10/23) of cases of MMC (Table 1). Regarding lesion size, the size of the sacs formed by MMCs tended to be larger as the severity of CHMII decreased (p = 0.1167; Fig. 3a); thus, the size of the sac was inversely proportional to the severity of CHMII. In contrast, in MS, the area of the lesions was directly proportional to the severity of CHMII (p = 0.025; Fig. 3b).

Fig. 3.

Relationship between lesion size and severity Chiari II. a Relationship between MMC lesion volume (cm3) and Chiari II 1, 2, or 3. b Relationship between MS lesion area (cm2) and Chiari II 2 or 3. No patients with MS had Chiari II grade 1 in this study.

Fig. 3.

Relationship between lesion size and severity Chiari II. a Relationship between MMC lesion volume (cm3) and Chiari II 1, 2, or 3. b Relationship between MS lesion area (cm2) and Chiari II 2 or 3. No patients with MS had Chiari II grade 1 in this study.

Close modal

Comparison of the atrium diameters between groups revealed that an atrium diameter of up to 13.48 mm was more related to MMC than MS (online Suppl. Fig. 1). Furthermore, assessment of hydrocephalus based on the occipital atrial diameter revealed that fetuses with an atrium diameter of less than 13.48 mm were significantly less likely to have a shunt placed at 12-month-old than fetuses with a larger occipital atrial diameter (OR 14, CI 95%, 2.405–64.88, p = 0.006; Table 3). Shunts were inserted in 21/61 (34%) of the children at 12 months (Table 1). There was no significant relationship between the requirement for a shunt and the type of lesion (OR 1.12, CI 95%, 0.3732–3.184, p > 0.999). Overall, 20/38 (53%) of the children could walk at 30 months (Table 1). The type of lesion (MMC/MS), atrial diameter, and grade of CHMII were not related to the ability to walk (Tables 2, 3). Although no significant association was found between the type of lesion and the requirement for a shunt (p > 0.999) or gait status, children with MS tended to be more likely to have better gait status at 30 months compared to the children with MMC (p = 0.1273; Table 2).

Table 3.

Clinical and imagenological parameters to determine whether the patients have more or less possibility to require shunt

ParameterShunt requirementOR [95% CI]p value
Atrium diameter >13.48 mm Yes 14 [2.405–64.88] 0.006** 
Chiari II grade 3 No 1.4 [0.3151–5.436] 0.717 (ns) 
March No 2.25 [0.3713–12.79] 0.617 (ns) 
Clubfoot No 0.88 [0.2051–3.794] >0.999 (ns) 
ParameterShunt requirementOR [95% CI]p value
Atrium diameter >13.48 mm Yes 14 [2.405–64.88] 0.006** 
Chiari II grade 3 No 1.4 [0.3151–5.436] 0.717 (ns) 
March No 2.25 [0.3713–12.79] 0.617 (ns) 
Clubfoot No 0.88 [0.2051–3.794] >0.999 (ns) 

Effect size is shown in odds ratios (OR), with a 95% of confidence interval and p value, respectively. **, corresponds to a p value below 0.01.

Additionally, for patients with MS, larger lesion extension and a higher cephalic location of the upper lesion boundary were associated with a larger occipital atrium diameter (p = 0.009 and p = 0.018, respectively, online suppl. Fig. 2). In both types of lesions, there was a correlation between a higher cephalic location of the upper lesion boundary and increased lesion extension (p > 0.001; online suppl. Fig. 2). On the other hand, neither MS nor MMC lesions significantly correlated with the location or extension of the lesion (measured by vertebral count), the degree of CHMII (p > 0.05 for location and extension at both lesions), or walking status (p = 0.0537 and p = 0.6072, respectively; online suppl. Fig. 2, 3). However, when the extension of the lesion was measured by length (mm), we observed a significant direct correlation between extension of the lesion and the degree of CHMII in MS (p = 0.043), but not in MMC (online suppl. Fig. 2, 4).

There is a serious problem with the nomenclature for SB as several synonyms are used for each pathology; this issue makes it very complex for medical practitioners to differentiate between MMC and MS, which are distinct entities. OSB can present as a classic MMC with a large sac or an MS with a clear and distinct functional placode-skin interface; however, a wide spectrum of anato-histological variations is observed between these two manifestations [5‒7]. This retrospective study identified clinical and imageological findings that may help healthcare providers to differentiate between MMC and MS (Fig. 4). Overall, MMC was the predominant form of OSB in our cohort and was associated with a significantly higher frequency of clubfoot at birth, whereas MS was significantly associated with more severe MCHII.

Fig. 4.

Relationship between MMC and MS with different clinical and radiological outcomes. Patients with MS developed Chiari II grade 3 more frequently (p = 0.0435) and had a higher tendency to march. Patients with MMC developed clubfoot more frequently (p = 0.0262) and were more likely to have atrium diameters over 13.48 mm. Shunt requirement is independent of the lesion type and is associated with a fetal atrium diameter over 13.48 mm (p = 0.006).

Fig. 4.

Relationship between MMC and MS with different clinical and radiological outcomes. Patients with MS developed Chiari II grade 3 more frequently (p = 0.0435) and had a higher tendency to march. Patients with MMC developed clubfoot more frequently (p = 0.0262) and were more likely to have atrium diameters over 13.48 mm. Shunt requirement is independent of the lesion type and is associated with a fetal atrium diameter over 13.48 mm (p = 0.006).

Close modal

A small number of authors have previously described the differences between MS and MMC. MMC occurred in 67% of cases in the Children’s Hospital of Philadelphia post-MOMS series [15]. Schindelmann et al. [7] studied 99 autopsies of patients with OSB and recorded 23% cases of MMC. In our series, 61% of cases that underwent OSB fetal surgery were MMC. Oliver et al. [10] studied the relationship between the sac size of MMC on MRI and clubfoot. They reported that MMC was associated with a higher rate of clubfoot (28.4 vs. 16.5%, p < 0.02) and greater impairment of function of the lower extremities compared to MS (34.9 vs. 19.0%, p < 0.002), and suggested that these findings could be explained by root traction under the MMC placode. We also observed that MMC was significantly associated with clubfoot compared to MS (74 vs. 26%, p < 0.0262).

Nagaraj et al. [16] evaluated 119 fetal MRIs of patients with OSB and detected MS in 29.4% of cases. All cases of MS (35/35) exhibited grade 3 CHMII. In addition, the authors found that a larger MMC sac size was associated with a lower severity of CHMII. We also observed an inverse relationship between the sac size and severity of CHMII, though this trend was not significant (p = 0.1167). Nagaraj et al. [16] suggested that the presence of the MMC sac may protect against herniation of the hindbrain.

We found a clear tendency that patients with MMC tended to have an atrium diameter up to 13.48 mm (online suppl. Fig. 1). Additionally, in our series, an atrium diameter up to 13.48 mm had good predictive value for the requirement for a shunt. Similarly, Tulipan et al. reported that an atrium diameter of 15 mm was associated with the need for a shunt [17].

Wilson et al. [11] found lower limb function at one year old was better in the MS group than the MMC group (p = 0.059), although this trend did not reach statistical significance. In agreement with that finding, we observed a trend that patients with MS were more likely to be able to walk at 30 months than patients with MMC (OR 2.857, 95% CI 0.8754–10.38, p = 0.1273). Based on the anatomical relationships, we argue that the greater traction of the nerve roots in MMC may lead to a poorer gait, and vice versa in MS. Further analysis of larger cohorts is required to confirm the significance of these relationships.

Similarly to OSB, CHMII exists as a spectrum ranging of manifestations from open dysraphic lesions that present classic features of brain stigmata to lesions that leak CSF but do not present herniation of the hindbrain, or CSB lesions that indeed manifest MCHII [9, 18‒20]. Osaka et al. [21] studied 92 human embryos and four fetuses with MS and observed that CHMII was not present in any embryos but was present in two fetuses [21]. Most series have demonstrated reversion of hindbrain herniation after prenatal OSB correction. Thus, it appears that the development of CHMII is a dynamic process and that the severity of CHMII increases during pregnancy, indicating a process of “developing CHMII” [18]. Based on this finding, we believe there is an evolution in the formation of CHMII. Moreover, we suggest a probable causality exists in relation to the type of OSB lesion and the genesis of this brain malformation. The cause of CHMII has been debated for many years. The most widely accepted theory is that hindbrain herniation develops secondary to a pressure gradient [22]. McLone and Días [23] propose that, under normal anatomical conditions, there is a temporary period of spinal neurocele occlusion just before neural tube closure in the human embryo. Their theory suggests that occlusion is a transient process that causes brief closure of the neural tube lumen [14] that is essential for normal physiological development of the brain structures. In OSB, such as MS and MMC, hydrocephalus is initially not present at a significant degree but progressively develops after surgical closure since the closure prevents external CSF leakage [5]. By repairing the OSB prenatally, the site of CSF leakage is eliminated, which often leads to accelerated ventricular enlargement after closure. Thus, this may explain why MS lesions are associated with more severe CHMII than MMC, as less effective transient occlusion of the neurocele or higher CSF leakage could occur in MS. On the contrary, the partial maintenance of CSF hydrostatic pressure in patients with MMC may beneficially contribute to temporary occlusion of the neural tube, which is essential for normal brain structure formation. Despite several previous studies and our work supporting this explanation, further neuroanatomic research is needed to confirm this hypothesis [10, 16, 20].

Regarding the vertebral level of the injury, we also observed that a higher upper boundary and more extensive lesions in MS correlated with a larger occipital atrium diameter. According to McLone’s theory of temporary incomplete occlusion of the neurocele [23], this finding could be attributed to greater CSF leakage leading to less favorable ventricular anatomy due to a higher grade of MCHII. Despite that, we did not observe a significant association between the degree of Chiari II malformation and lesion extension measured by vertebrae count but did observe a significant correlation between the degree of Chiari II malformation and lesion extension measured by length (mm), which reaffirms the previously stated theory. Thus, McLone’s theory explains why a MS lesion that leaks more CSF is correlated with more severe MCHII; this may also explain why MS lesions – being more extensive – have a larger atrium diameter. Since there is more extensive OSB lesion in MS, greater CSF efflux is present, which leads to poor temporary closure of the neurocele, which prevents normal development of the posterior fossa. As a consequence, deformation of the posterior fossa interferes with the physiological circulation of CSF, resulting in a dilated ventricular anatomy. This hypothesis requires further study involving an examination of the correlations between more precise and comprehensive fetal MRI anthropometric measurements (e.g., cephalo-caudal length, extent, level of the dysraphic lesion, craniometric measurements) and histological studies in animal models. To date, we have not found any literature that correlates the aforementioned factors.

Batty et al. [18] found 23% (15/65) of fetuses with OSB did not show CHMII on MRI. Rethmann et al. [20] evaluated 18 cases of MMC and nine cases of MS and reported that cerebellar herniation was significantly more severe in MS than in MMC (p < 0.001). They stated that not all open defects are associated with CHMII. In contrast, Hüsler et al. [19] analyzed 16 fetuses via ultrasound and MRI and, surprisingly, found that four fetuses with CSB developed herniation of the hindbrain during pregnancy. These cases had a combination of defects (OEIS complex) and/or a large myelocystocele sac, i.e., lesions with functional skin. In our series of 42 patients with closed SB, one female with an OEIS complex and a huge megasac with functional skin presented a clear CHMII. Thus, it could be hypothesized that CSB with a large CSF container, i.e., a large meningocele, myelocystocele, or an OEIS complex with functional skin, can somehow induce dysfunctional occlusion of the temporal neural tube, in the context of McLone’s hypothesis on the genesis of CHMII. Alternatively, a large cele in cystic MMC OSB could function as a buffer or protector against the formation of CHMII, at least the most severe forms. This suggests that a lack of skin indemnity is not necessarily needed to induce CHMII, but rather that the genesis of CHMII lies in the degree of malocclusion of the neural tube and probably its duration of exposure during development.

Further research is required to determine the precise mechanisms involved in the physiological occlusion/distension of the neurocele. The evidence reported herein strongly supports that the major determining factor in the development of the CHMII is hydrostatic pressure, where presumably low pressure fails to activate the signaling required to induce temporal occlusion of the neurocele. Other open questions include the critical volume or hydrostatic pressure of CSF necessary to generate, or not, this failure during embryogenesis, and the mechanism by which CSF pressure is translated in the neuroepithelial cells to reach some manifestation of the MHC spectrum. It is tempting to speculate that mechanotransduction by primary cilia [24] in neuroepithelial cells leading to changes in the expression of cell junction proteins may be implicated. In addition, the possibility of abnormal concentrations of morphogens in the CSF cannot be ruled out.

This work is not without limitations. The main weakness is the low number of MRI scans analyzed; analysis of a larger dataset including all of the patients treated at our center would have increased the statistical power of our study; however, this was not possible due to data loss. Another weakness of this work is the lack of complete follow-up of all children and their mothers. We are a national reference center that covers a linear distance of 4,270 km, and the complex geography of the region makes communication and feedback between mothers and treating physicians in isolated and distant regions of our country difficult. Moreover, our center covers a large rural population, with limited socioeconomic resources, low rates of schooling, and minimal access to communication. However, we are actively collecting information to strengthen our database of patients and their mothers, with the aim of improving our work as a clinical team and obtaining more robust results. Our next goal is to study whether the differences between MMC and MS affect neurosurgical outcomes, such as the duration of surgery, skin complications, and the need for hysterotomy enlargement.

Based on the present work, we conclude that MS and MMC exhibit distinct pathomorphological features and clinical outcomes. Patients with MS were more likely to have more severe CHMII and tended to be more likely to be able to walk at 30 months. In contrast, MMC was associated with clubfoot at birth and an atrial diameter up to 13.48 mm. These data further indicate that MS and MMC are different subtypes of OSB. Further analyses of larger cohorts that include more extensive biomolecular and histological analysis are required to better understand the differences between these types of OSB. The findings of this work can be used as input to better advise parents and prepare healthcare teams for the timely management of patients who undergo prenatal surgery for OSB. Overall, this information may improve decision-making during surgical programming, refine suspicion of the development of hydrocephalus and planning of the need for gait rehabilitation, and thus make better use of resources, especially in countries with limited funding, like ours.

We thank the Fetal Medicine team of the HRLBO including the neurosurgery, anesthesia, gynecologic, obstetric, and imageology services, the MRI unit, the Research Department of the HRLBO, and the Histology Institute, Faculty of Medicine, Universidad Austral de Chile. Special gratitude to our families for their patience and constant support, and finally to all the mothers and fathers who have trusted us.

The study was conducted in accordance with the local legislation and institutional requirements. This study protocol was reviewed and approved by the “Comité científico del Hospital San Juan de Dios” of Hospital San Juan de Dios (Santiago, Chile), approval number (236), and written informed consent was obtained from all participants. Research was performed as stated by the guidelines for human studies and was conducted ethically in accordance with the World Medical Association’s Declaration of Helsinki. The article avoids providing identifying information, and participants’ identifiable attributes were anonymized.

The authors have no conflicts of interest to declare.

This work was not funded.

José Miguel Müller, Renatto Anfossi, Álvaro Santibañez, Rodrigo Zapata, Silvana Echeverría, Juan Pablo Jara, Aura Jimenez, and Carolina B. Lindsay: experimental design and data analysis. Jose Miguel Müller: writing the manuscript. Jose Miguel Müller, Edgardo Corral, and Renatto Anfossi: conception of the research and analysis of the data.

All data generated or analyzed during this study are included in this article and its supplementary material files. Further inquiries can be directed to the corresponding author.

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