Normative parameters of the Evans Index using Computer Tomography in the Saudi population.

OBJECTIVES: To calculate The Evans Index (EI) in normal Individuals. Ventricular enlargement is referred to as hydrocephalus. Computer tomography (CT) scans are commonly used to investigate such intracranial pathologies. The EI is an important parameter for diagnosing hydrocephalus. METHODS: We included all patients who underwent Computer tomography (CT) scan of the brain that was reported as normal. The mean EI was calculated for the whole sample stratified by age, gender, and ethnicity. Patients with an initial report indicating any intracranial pathology, such as hydrocephalus, tumors, hemorrhages, or neurodegenerative disorders, were excluded. RESULTS: A total of 1,330 brain CT scans carried out at our institution were reviewed retrospectively from August 2021 to December 2021. A total of 423 CT scans were screened after excluding 25 patients with abnormal imaging findings and 14 repeated images for the same patients. A total of 384 patients were included. The mean EI for the entire sample was 0.2550±0.0277. There was a minimal but statistically significant difference based on gender, with a mean EI of 0.2588±0.0274 for males and 0.2517±0.0276 for females (p=0.012). There was no statistically significant difference between Saudi and non-Saudi patients. EI increased progressively with age in both genders. CONCLUSION: Our EI values were similar to many of those reported in other countries, which supports the use of the 0.3 cutoff for the diagnosis of hydrocephalus, regardless of gender, age, or ethnicity.

Spinal magnetic resonance imaging artifacts in lumboperitoneal shunt surgery using adjustable valve implantation on the paravertebral spinal muscles.

BACKGROUND: Adjustable shunt valves that have been developed for managing hydrocephalus rely on intrinsically magnetic components ; thus, artifacts with these valves on magnetic resonance imaging (MRI) are inevitable. No studies on valve-induced artifacts in lumboperitoneal shunt (LPS) surgery have been published. Therefore, this study aimed to evaluate valve-induced artifacts in LPS. METHODS: We retrospectively reviewed all MRIs obtained between January 2023 and June 2023 in patients with an implanted Codman CERTAS Plus adjustable shunt valve (Integra Life Sciences, Princeton, New Jersey, USA). The valve was placed <1 cm subcutaneously on the paravertebral spinal muscle of the back, with its long axis perpendicular to the body axis. The scans were performed using a Toshiba Medical Systems 1.5 Tesla scanner. The in-plane artifact sizes were assessed as the maximum distance of the artifact from the expected region of the back. RESULTS: All spinal structures or spinal cords can be recognized, even with valve-induced artifacts. The median maximum valve-induced artifact distance on T1-weighted axial imaging was 25.63 mm (mean, 25.98 mm ; range, 22.24-30.94 mm). The median maximum valve-induced artifact distance on T2-weighted axial imaging was 25.56 mm (mean, 26.27 mm ; range, 21.83-29.53 mm). CONCLUSION: LPS surgery with adjustable valve implantation on paravertebral muscles did not cause valve-induced artifacts in the spine and spinal cord. We considered that LPS could simplify the postoperative care of these patients. J. Med. Invest. 71 : 154-157, February, 2024.

Advanced Imaging of Shunt Valves in Cranial CT Scans with Photon-Counting Scanner.

This brief report aimed to show the utility of photon-counting technology alongside standard cranial imaging protocols for visualizing shunt valves in a patient's cranial computed tomography scan. Photon-counting CT scans with cranial protocols were retrospectively surveyed and four types of shunt valves were encountered: proGAV 2.0®, M.blue®, Codman Certas®, and proSA®. These scans were compared with those obtained from non-photon-counting scanners at different time points for the same patients. The analysis of these findings demonstrated the usefulness of photon-counting technology for the clear and precise visualization of shunt valves without any additional radiation or special reconstruction patterns. The enhanced utility of photon-counting is highlighted by providing superior spatial resolution compared to other CT detectors. This technology facilitates a more accurate characterization of shunt valves and may support the detection of subtle abnormalities and a precise assessment of shunt valves.

Optic nerve sheath diameter correlates with both success and failure of hydrocephalus treatment in pediatric patients with pineal region lesions.

BACKGROUND: Pineal region lesions in children are heterogenous pathologies often symptomatic due to occlusive hydrocephalus and thus elevated intracranial pressure (ICP). MRI-derived parameters to assess hydrocephalus are the optic nerve sheath diameter (ONSD) as a surrogate for ICP and the frontal occipital horn ratio (FOHR), representing ventricle volume. As elevated ICP may not always be associated with clinical signs, the adjunct of ONSD could help decision making in patients undergoing treatment. The goal of this study is to assess the available magnetic resonance imaging (MRI) of patients with pineal region lesions undergoing surgical treatment with respect to pre- and postoperative ONSD and FOHR as an indicator for hydrocephalus. METHODS: Retrospective data analysis was performed in all patients operated for pineal region lesions at a tertiary care center between 2010 and 2023. Only patients with pre- and postoperative MRI were selected for inclusion. Clinical data and ONSD at multiple time points, as well as FOHR were analyzed. Imaging parameter changes were correlated with clinical signs of hydrocephalus before and after surgical treatment. RESULTS: Thirty-three patients with forty operative cases met the inclusion criteria. Age at diagnosis was 10.9 ± 4.6 years (1-17 years). Hydrocephalus was seen in 80% of operative cases preoperatively (n = 32/40). Presence of hydrocephalus was associated with significantly elevated preoperative ONSD (p = 0.006). There was a significant decrease in ONSD immediately (p < 0.001) and at 3 months (p < 0.001) postoperatively. FOHR showed a slightly less pronounced decrease (immediately p = 0.006, 3 months p = 0.003). In patients without hydrocephalus, no significant changes in ONSD were observed (p = 0.369). In 6/6 patients with clinical hydrocephalus treatment failure, ONSD increased, but in 3/6 ONSD was the only discernible MRI change with unchanged FOHR. CONCLUSIONS: ONSD measurements may have utility in evaluating intracranial hypertension due to hydrocephalus in patients with pineal region tumors. ONSD changes appear to have value in assessing hydrocephalus treatment failure.

Neuroendoscopic access to the third ventricle in patients with narrow foramen of monro without stenosis/obstruction: role of foraminoplasty.

OBJECT: One of the critical steps for the success of intraventricular neuroendoscopic procedures is the entry into the third ventricle and passage of the endoscopy system through the foramen of Monro (FM). A diameter larger than that of the instrument used is considered a prerequisite for safely performing the technique, as damage to this structure can lead to alterations in the fornix and vascular structures. When the foramen diameter is narrow and there is no obstruction/stenosis, the role of foraminoplasty in reducing the risk of complications has not been adequately assessed in the literature. METHODS: A review of endoscopic procedures conducted at our center since 2018 was undertaken. Cases in which preoperative imaging indicated a FM diameter < 6 mm and foraminoplasty technique was applied were examined to determine the technical and functional success of the procedure. The technical success was determined by completing the neuroendoscopic procedure with the absence of macroscopic lesions in the various structures comprising the foramen and without complications in the follow-up imaging tests. Functional success was defined as the absence of cognitive/memory alterations during the 3-month postoperative follow-up. Additionally, a review of the various forms of foraminoplasty described in the literature is conducted. RESULTS: In our cohort, six patients were identified with a preoperative FM diameter < 6 mm without obstruction or stenosis. Foraminoplasty was planned for these cases to facilitate various intraventricular neuroendoscopic procedures. In all instances, the technique was successfully performed without causing macroscopic damage to the structures comprising the foramen. Follow-up visits included various cognitive tests to assess potential sequelae related to microscopic damage to the fornix. None of the patients exhibited anomalies. CONCLUSION: Foraminoplasty in patients with a narrow FM without signs of stenosis/obstruction is a useful technique to reduce the risk of complications during the passage of the endoscopy system through this structure, enabling the safe performance of neuroendoscopic procedures.

Three-Dimensional Visualization of Shunt Valves with Photon Counting CT and Comparison to Traditional X-ray in a Simple Phantom Model.

This study introduces an application of innovative medical technology, Photon Counting Computer Tomography (PC CT) with novel detectors, for the assessment of shunt valves. PC CT technology offers enhanced visualization capabilities, especially for small structures, and opens up new possibilities for detailed three-dimensional imaging. Shunt valves are implanted under the skin and redirect excess cerebrospinal fluid, for example, to the abdominal cavity through a catheter. They play a vital role in regulating cerebrospinal fluid drainage in various pathologies, which can lead to hydrocephalus. Accurate imaging of shunt valves is essential to assess the rate of drainage, as their precise adjustment is a requirement for optimal patient care. This study focused on two adjustable shunt valves, the proGAV 2.0® and M. blue® (manufactured by Miethke, Potsdam, Germany). A comprehensive comparative analysis of PC CT and traditional X-ray techniques was conducted to explore this cutting-edge technology and it demonstrated that routine PC CT can efficiently assess shunt valves' adjustments. This technology shows promise in enhancing the accurate management of shunt valves used in settings where head scans are already frequently required, such as in the treatment of hydrocephalus.

Multimodal radionuclide shuntography for device patency: New procedural tips for anuncommon historical technique.

Cerebrospinal fluid (CSF) shunting is an established long-term treatment option for hydrocephalus, and is one of the most commonly performed neurosurgical procedures in western countries.Despite advances in CSF shunt design and management, its failure rates remain high and is most commonly due to obstruction and infection.Cerebrospinal fluidshunt failure diagnosis should be prompt and accurate in establishing timely if its revision is appropriate. Radionuclide shuntography with technetium-99m-diethylenetriaminepetaacetic acid (99mTc-DTPA) is a useful technique for evaluation CSF shunts and management of patients presenting with shunt-related problems, in particular it can avoid unnecessary replacement interventions. Although its execution and interpretation require specific skills, we suggest its execution for the evaluation of device's patency. We here describe the radionuclide shuntography performed with recent hybrid multimodal technologies, with a procedure customized to a complicated patient with hydrocefalus and neoplastic disease. We suggest considering radionuclide shuntography in association with conventional imaging and strongly recommend the additional performance of single photon emission computed tomography/computed tomography (SPECT/CT) because it also provides valuable information to complete the interpretation of planar images.

Quantitative noninvasive measurement of cerebrospinal fluid flow in shunted hydrocephalus.

OBJECTIVE: Standard MRI protocols lack a quantitative sequence that can be used to evaluate shunt-treated patients with a history of hydrocephalus. The objective of this study was to investigate the use of phase-contrast MRI (PC-MRI), a quantitative MR sequence, to measure CSF flow through the shunt and demonstrate PC-MRI as a useful adjunct in the clinical monitoring of shunt-treated patients. METHODS: The rapid (96 seconds) PC-MRI sequence was calibrated using a flow phantom with known flow rates ranging from 0 to 24 mL/hr. Following phantom calibration, 21 patients were scanned with the PC-MRI sequence. Multiple, successive proximal and distal measurements were gathered in 5 patients to test for measurement error in different portions of the shunt system and to determine intrapatient CSF flow variability. The study also includes the first in vivo validations of PC-MRI for CSF shunt flow by comparing phase-contrast-measured flow rate with CSF accumulation in a collection burette obtained in patients with externalized distal shunts. RESULTS: The PC-MRI sequence successfully measured CSF flow rates ranging from 6 to 54 mL/hr in 21 consecutive pediatric patients. Comparison of PC-MRI flow measurement and CSF volume collected in a bedside burette showed good agreement in a patient with an externalized distal shunt. Notably, the distal portion of the shunt demonstrated lower measurement error when compared with PC-MRI measurements acquired in the proximal catheter. CONCLUSIONS: The PC-MRI sequence provided accurate and reliable clinical measurements of CSF flow in shunt-treated patients. This work provides the necessary framework to include PC-MRI as an immediate addition to the clinical setting in the noninvasive evaluation of shunt function and in future clinical investigations of CSF physiology.

Feasibility of assessing non-invasive intracranial compliance using FSI simulation-based and MR elastography-based brain stiffness.

Intracranial compliance (ICC) refers to the change in intracranial volume per unit change in intracranial pressure (ICP). Magnetic resonance elastography (MRE) quantifies brain stiffness by measuring the shear modulus. Our objective is to investigate the relationship between ICC and brain stiffness through fluid-structure interaction (FSI) simulation, and to explore the feasibility of using MRE to assess ICC based on brain stiffness. This is invaluable due to the clinical importance of ICC, as well as the fast and non-invasive nature of the MRE procedure. We employed FSI simulation in hydrocephalus patients with aqueductal stenosis to non-invasively calculate ICP which is the basis of the calculation of ICC and FSI-based brain stiffness. The FSI simulated parameters used have been validated with experimental data. Our results showed that there is no relationship between FSI simulated-based brain stiffness and ICC in hydrocephalus patients. However, MRE-based brain stiffness may be sensitive to changes in intracranial fluid dynamic parameters such as cerebral perfusion pressure (CPP), cerebral blood flow (CBF), and ICP, as well as to mechano-vascular changes in the brain, which are determining parameters in ICC assessment. Although optimism has been found regarding the assessment of ICC using MRE-based brain stiffness, especially for acute-onset brain disorders, further studies are necessary to clarify their direct relationship.

[Possibilities of dynamic phase contrast MRI of cerebrospinal fluid for performing a tap test in a patient with idiopathic normotensive hydrocephalus]. / Vozmozhnosti dinamicheskoi fazovo-kontrastnoi MR-likvorografii pri vypolnenii tap-testa u patsienta s idiopaticheskoi normotenzivnoi gidrotsefaliei.

Idiopathic normotensive hydrocephalus (iNH) is a widespread disease in elderly patients. The effectiveness of iNG treatment and the subsequent quality of patients' lives directly depends on timely and early diagnosis. The criteria for diagnosing iNG that are used in neuroimaging can also be found in patients without clinical manifestations of this disease, and the widely used tap-test is an invasive technique with a rather low sensitivity. The need for early diagnosis and initiation of treatment before the development of irreversible damage to brain structures determines the relevance of the search for an accessible, minimally invasive, accurate and safe diagnostic method. The article presents a clinical observation of the use of phase-contrast MRI of cerebrospinal fluid (CSF) in a female patient with a positive response to the tap test with a quantitative analysis of changes in CSF flow parameters and ALVI and Evans indices depending on the time after CSF evacuation. Phase-contrast MRI of CSF with a quantitative assessment of CSF flow parameters in combination with an assessment of the ALVI index has the potential to increase the accuracy of diagnosing iNH and is of scientific interest for further research.

Clinical and magnetic resonance imaging findings in a French bulldog puppy with genetically confirmed congenital hypothyroidism.

A 7-month-old male French bulldog was referred for abnormal mentation and gait. Physical examination revealed a dome shaped calvarium and persistent bregmatic fontanelle. Neurological examination revealed proprioceptive ataxia, pelvic limb paraparesis and strabismus with moderate ventriculomegaly, thinning of the cerebral parenchyma, and widened cerebral sulci on magnetic resonance imaging. Masses were identified in the region of the thyroid, which appeared heterogeneous and hyperintense in T1-weighted and T2-weighted compared with the adjacent muscle signal masses were identified. Radiological diagnosis was hydrocephalus "ex vacuo" and goiter. Blood test revealed abnormally low total thyroxine (TT4), free thyroxine (FT4), and normal thyrotropin concentration. A diagnosis of congenital hypothyroidism was confirmed by positive genetic test for thyroid peroxidase mutation. Thyroxine supplementation treatment rapidly improved clinical signs.

A female case of L1 syndrome that may have developed due to skewed X inactivation.

BACKGROUND: Heterozygous L1CAM variants cause L1 syndrome with hydrocephalus and aplasia/hypoplasia of the corpus callosum. L1 syndrome usually has an X-linked recessive inheritance pattern; however, we report a rare case occurring in a female child. CASE PRESENTATION: The patient's family history was unremarkable. Fetal ultrasonography revealed enlarged bilateral ventricles of the brain and hypoplasia of the corpus callosum. The patient was born at 38 weeks and 4 days of gestation. Brain MRI performed on the 8th day of life revealed enlargement of the brain ventricles, marked in the lateral and third ventricles with irregular margins, and hypoplasia of the corpus callosum. Exome sequencing at the age of 2 years and 3 months revealed a de novo heterozygous L1CAM variant (NM_000425.5: c.2934_2935delp. (His978Glnfs * 25). X-chromosome inactivation using the human androgen receptor assay revealed that the pattern of X-chromosome inactivation in the patients was highly skewed (96.6 %). The patient is now 4 years and 11 months old and has a mild developmental delay (developmental quotient, 56) without significant progression of hydrocephalus. CONCLUSION: In this case, we hypothesized that the dominant expression of the variant allele arising from skewed X inactivation likely caused L1 syndrome. Symptomatic female carriers may challenge the current policies of prenatal and preimplantation diagnoses.

Prenatal phenotype of a homozygous nonsense MPDZ variant in a fetus with severe congenital hydrocephalus.

The fetal phenotype of MPDZ-associated congenital hydrocephalus type 2 with or without brain or eye anomalies (HYC2) (OMIM 615219) is not well described in the literature. The present case shows not previously published clinical fetal features that are detected during routine second trimester ultrasound screening at 21 weeks of gestation such as bilateral ventriculomegaly, lean cavum septum pellucidum, suspicion of hypoplastic corpus callosum, and suspicion of gyration disorder with normal fossa posterior. Combination of clinical features and a gene panel for congenital malformation syndromes detected a homozygous, likely pathogenic nonsense variant in the MPDZ gene. HYC2 is a rare autosomal recessive disorder with prenatal onset. Clinical presentation is highly variable, varying from stillbirth and severe neurodevelopmental problems with death in infancy to adult patients. Other reported associated congenital anomalies are mainly heart defects and ophthalmologic abnormalities. The present case so far is the first prenatally well described case of HYC2 in an ongoing pregnancy.

Structural Alterations of the Corpus Callosum in Children With Infantile Hydrocephalus.

This study investigates structural alterations of the corpus callosum in children diagnosed with infantile hydrocephalus. We aim to assess both macrostructural (volume) and microstructural (diffusion tensor imaging metrics) facets of the corpus callosum, providing insights into the nature and extent of alterations associated with this condition. Eighteen patients with infantile hydrocephalus (mean age = 9 years) and 18 age- and sex-matched typically developing healthy children participated in the study. Structural magnetic resonance imaging and diffusion tensor imaging were used to assess corpus callosum volume and microstructure, respectively. Our findings reveal significant alterations in corpus callosum volume, particularly in the posterior area, as well as distinct microstructural disparities, notably pronounced in these same segments. These results highlight the intricate interplay between macrostructural and microstructural aspects in understanding the impact of infantile hydrocephalus. Examining these structural alterations provides an understanding into the mechanisms underlying the effects of infantile hydrocephalus on corpus callosum integrity, given its pivotal role in interhemispheric communication. This knowledge offers a more nuanced perspective on neurologic disorders and underscores the significance of investigating the corpus callosum's health in such contexts.

Follow-up outcome analysis of 324 cases of early-onset and late-onset mild fetal ventriculomegaly: a retrospective cohort study.

BACKGROUND: Mild fetal ventriculomegaly (VM) is a nonspecific finding common to several pathologies with varying prognosis and is, therefore, a challenge in fetal consultation. We aimed to perform a constant, detailed analysis of prenatal findings and postnatal outcomes in fetuses with early-onset and late-onset mild ventriculomegaly, and provide a new evidence basis and new perspective for prenatal counseling. METHODS: This is a retrospective cohort study of women with a diagnosis of mild fetal VM between January 2018 and October 2020. The population was divided into two groups according to the gestational ages (GAs) at initial diagnosis: the early-onset group (diagnosed at/before 24+6 weeks) and the late-onset group (diagnosed after 24+6 weeks). Clinical data and pregnancy outcomes were obtained from hospital records. The children's neurodevelopment status was assessed using the Ages and Stages Questionnaire, Third Edition (ASQ-3) and telephone interviews. RESULTS: Our study cohort comprised 324 fetuses, out of which 94 (29%) were classified as early-onset group and 230 (71%) late-onset group. Early-onset group was more likely to have concurrent additional abnormalities, whereas in the late-onset group, isolated enlargement was more common (P = 0.01). Unilateral enlargement was more common in the late-onset group (P = 0.05), and symmetrical enlargement in the early-onset group (P < 0.01). In addition, early-onset mild VM cases were more likely to have intrauterine progression (P = 0.03), and many had a higher proportion of complex multisystem abnormalities. Compared with the late-onset group, the early-onset group was more often associated with congenital brain structure malformations. Approximately 11% of fetuses with mild VM had postnatal neurodevelopmental delay/disorders, and the risk was higher in the early-onset group (19.4% vs. 7.4%). Regression analysis showed that the GA at first diagnosis, non-isolated, and intrauterine progression significantly correlated with neurodevelopmental abnormalities. CONCLUSIONS: Early-onset and late-onset mild VM had significantly different ultrasound features and outcomes. Early-onset mild VM may have more complex potential abnormalities and are more likely to predict poor prognosis than the late-onset.

Delayed hydrocephalus and visual field defect due to perianeurysmal inflammation after treating a large unruptured aneurysm with flow diverter and coil: A case report.

Flow diverter (FD) placement is increasingly used to treat large supraclinoid aneurysms. Here, we report a case of hydrocephalus following FD placement. One patient in her 60 s underwent FD placement combined with coil embolization. Within 1 month, the patient started to show visual field defects and symptoms of hydrocephalus, which worsened within another month. We report that hydrocephalus developed acutely, without high protein levels in the cerebrospinal fluid, and as a complication using a Surpass Streamline. Although the precise mechanisms are unclear, our report suggests a different mechanism for the development of hydrocephalus after FD placement combined with coil embolization.

Expanding the phenotypic spectrum of LIG4 pathogenic variations: neuro-histopathological description of 4 fetuses with stenosis of the aqueduct.

Severe ventriculomegaly is a rare congenital brain defect, usually detected in utero, of poor neurodevelopmental prognosis. This ventricular enlargement can be the consequence of different mechanisms: either by a disruption of the cerebrospinal fluid circulation or abnormalities of its production/absorption. The aqueduct stenosis is one of the most frequent causes of obstructive ventriculomegaly, however, fewer than 10 genes have been linked to this condition and molecular bases remain often unknown. We report here 4 fetuses from 2 unrelated families presenting with ventriculomegaly at prenatal ultra-sonography as well as an aqueduct stenosis and skeletal abnormalities as revealed by fetal autopsy. Genome sequencing identified biallelic pathogenic variations in LIG4, a DNA-repair gene responsible for the LIG4 syndrome which associates a wide range of clinical manifestations including developmental delay, microcephaly, short stature, radiation hypersensitivity and immunodeficiency. Thus, not only this report expands the phenotype spectrum of LIG4-related disorders, adding ventriculomegaly due to aqueduct stenosis, but we also provide the first neuropathological description of fetuses carrying LIG4 pathogenic biallelic variations.

A re-evaluation of the Endoscopic Third Ventriculostomy Success Score: a Hydrocephalus Clinical Research Network study.

OBJECTIVE: The Hydrocephalus Clinical Research Network (HCRN) conducted a prospective study 1) to determine if a new, better-performing version of the Endoscopic Third Ventriculostomy Success Score (ETVSS) could be developed, 2) to explore the performance characteristics of the original ETVSS in a modern endoscopic third ventriculostomy (ETV) cohort, and 3) to determine if the addition of radiological variables to the ETVSS improved its predictive abilities. METHODS: From April 2008 to August 2019, children (corrected age ≤ 17.5 years) who underwent a first-time ETV for hydrocephalus were included in a prospective multicenter HCRN study. All children had at least 6 months of clinical follow-up and were followed since the index ETV in the HCRN Core Data Registry. Children who underwent choroid plexus cauterization were excluded. Outcome (ETV success) was defined as the lack of ETV failure within 6 months of the index procedure. Kaplan-Meier curves were constructed to evaluate time-dependent variables. Multivariable binary logistic models were built to evaluate predictors of ETV success. Model performance was evaluated with Hosmer-Lemeshow and Harrell's C statistics. RESULTS: Seven hundred sixty-one children underwent a first-time ETV. The rate of 6-month ETV success was 76%. The Hosmer-Lemeshow and Harrell's C statistics of the logistic model containing more granular age and etiology categorizations did not differ significantly from a model containing the ETVSS categories. In children ≥ 12 months of age with ETVSSs of 50 or 60, the original ETVSS underestimated success, but this analysis was limited by a small sample size. Fronto-occipital horn ratio (p = 0.37), maximum width of the third ventricle (p = 0.39), and downward concavity of the floor of the third ventricle (p = 0.63) did not predict ETV success. A possible association between the degree of prepontine adhesions on preoperative MRI and ETV success was detected, but this did not reach statistical significance. CONCLUSIONS: This modern, multicenter study of ETV success shows that the original ETVSS continues to demonstrate good predictive ability, which was not substantially improved with a new success score. There might be an association between preoperative prepontine adhesions and ETV success, and this needs to be evaluated in a future large prospective study.