Neurodevelopmental outcome at 2 years after neuroendoscopic lavage in neonates with posthemorrhagic hydrocephalus

Philine Behrens cand med1, Anna Tietze Dr med2, Elisabeth Walch Dr med3, Petra Bittigau PD, Dr med3, Christoph Bührer Dr med4, Matthias Schulz PD, Dr med1, Annette Aigner PhD5, and Ulrich-Wilhelm Thomale Prof Dr med1
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  • 1 Pediatric Neurosurgery,
  • | 2 Neuroradiology,
  • | 3 Pediatric Neurology,
  • | 4 Neonatology, and
  • | 5 Institute of Biometry and Clinical Epidemiology, Charité—Universitätsmedizin Berlin, Germany
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OBJECTIVE

A standardized guideline for treatment of posthemorrhagic hydrocephalus in premature infants is still missing. Because an early ventriculoperitoneal shunt surgery is avoided due to low body weight and fragility of the patients, the neurosurgical treatment focuses on temporary solutions for CSF diversion as a minimally invasive approach. Neuroendoscopic lavage (NEL) was additionally introduced for early elimination of intraventricular blood components to reduce possible subsequent complications such as shunt dependency, infection, and multiloculated hydrocephalus. The authors report their first experience regarding neurodevelopmental outcome after NEL in this patient cohort.

METHODS

In a single-center retrospective cohort study with 45 patients undergoing NEL, the authors measured neurocognitive development at 2 years with the Bayley Scales of Infant Development, 2nd Edition, Mental Developmental Index (BSID II MDI) and graded the ability to walk with the Gross Motor Function Classification System (GMFCS). They further recorded medication with antiepileptic drugs (AEDs) and quantified ventricular and brain volumes by using 3D MRI data sets.

RESULTS

Forty-four patients were alive at 2 years of age. Eight of 27 patients (30%) assessed revealed a fairly normal neurocognitive development (BSID II MDI ≥ 70), 28 of 36 patients (78%) were able to walk independently or with minimal aid (GMFCS 0–2), and 73% did not require AED treatment. Based on MR volume measurements, greater brain volume was positively correlated with BSID II MDI (rs = 0.52, 95% CI 0.08–0.79) and negatively with GMFCS (rs = −0.69, 95% CI −0.85 to −0.42). Based on Bayesian logistic regression, AED treatment, the presence of comorbidities, and also cerebellar pathology could be identified as relevant risk factors for both neurodevelopmental outcomes, increasing the odds more than 2-fold—but with limited precision in estimation.

CONCLUSIONS

Neuromotor outcome assessment after NEL is comparable to previously published drainage, irrigation, and fibrinolytic therapy (DRIFT) study results. A majority of NEL-treated patients showed independent mobility. Further validation of outcome measurements is warranted in an extended setup, as intended by the prospective international multicenter registry for treatment of posthemorrhagic hydrocephalus (TROPHY).

ABBREVIATIONS

AED = antiepileptic drug; BSID II MDI = Bayley Scales of Infant Development, 2nd Edition, Mental Developmental Index; CI = confidence interval; CrI = credible interval; CSF = cerebrospinal fluid; DRIFT = drainage, irrigation, and fibrinolytic therapy; GMFCS = Gross Motor Function Classification System; IQR = interquartile range; IVH = intraventricular hemorrhage; NEL = neuroendoscopic lavage; OR = odds ratio.

OBJECTIVE

A standardized guideline for treatment of posthemorrhagic hydrocephalus in premature infants is still missing. Because an early ventriculoperitoneal shunt surgery is avoided due to low body weight and fragility of the patients, the neurosurgical treatment focuses on temporary solutions for CSF diversion as a minimally invasive approach. Neuroendoscopic lavage (NEL) was additionally introduced for early elimination of intraventricular blood components to reduce possible subsequent complications such as shunt dependency, infection, and multiloculated hydrocephalus. The authors report their first experience regarding neurodevelopmental outcome after NEL in this patient cohort.

METHODS

In a single-center retrospective cohort study with 45 patients undergoing NEL, the authors measured neurocognitive development at 2 years with the Bayley Scales of Infant Development, 2nd Edition, Mental Developmental Index (BSID II MDI) and graded the ability to walk with the Gross Motor Function Classification System (GMFCS). They further recorded medication with antiepileptic drugs (AEDs) and quantified ventricular and brain volumes by using 3D MRI data sets.

RESULTS

Forty-four patients were alive at 2 years of age. Eight of 27 patients (30%) assessed revealed a fairly normal neurocognitive development (BSID II MDI ≥ 70), 28 of 36 patients (78%) were able to walk independently or with minimal aid (GMFCS 0–2), and 73% did not require AED treatment. Based on MR volume measurements, greater brain volume was positively correlated with BSID II MDI (rs = 0.52, 95% CI 0.08–0.79) and negatively with GMFCS (rs = −0.69, 95% CI −0.85 to −0.42). Based on Bayesian logistic regression, AED treatment, the presence of comorbidities, and also cerebellar pathology could be identified as relevant risk factors for both neurodevelopmental outcomes, increasing the odds more than 2-fold—but with limited precision in estimation.

CONCLUSIONS

Neuromotor outcome assessment after NEL is comparable to previously published drainage, irrigation, and fibrinolytic therapy (DRIFT) study results. A majority of NEL-treated patients showed independent mobility. Further validation of outcome measurements is warranted in an extended setup, as intended by the prospective international multicenter registry for treatment of posthemorrhagic hydrocephalus (TROPHY).

ABBREVIATIONS

AED = antiepileptic drug; BSID II MDI = Bayley Scales of Infant Development, 2nd Edition, Mental Developmental Index; CI = confidence interval; CrI = credible interval; CSF = cerebrospinal fluid; DRIFT = drainage, irrigation, and fibrinolytic therapy; GMFCS = Gross Motor Function Classification System; IQR = interquartile range; IVH = intraventricular hemorrhage; NEL = neuroendoscopic lavage; OR = odds ratio.

In Brief

A neurodevelopmental outcome analysis and brain volumetry study was performed in children who underwent neuroendoscopic lavage due to hydrocephalus after interventricular hemorrhage in the neonatal period. This is the first outcome analysis for a cohort of patients who underwent neuroendoscopic lavage for posthemorrhagic hydrocephalus in neonates.

Despite continuous progress in neonatal care, a relevant rate of premature infants (25%–30%) still develop intraventricular hemorrhage (IVH).1,2 In most cases, IVH in neonates is caused by germinal matrix rupture within the first 72 hours after preterm delivery, which leads to a primary destruction of neuronal and glial precursor cells in the parenchyma to a varying extent.3 According to the Papile classification, IVH is classified into the following categories: grade I, with isolated subependymal hemorrhage without ventricular involvement; grade II, with IVH including ≤ 50% of ventricular volume; grade III, with IVH extending into > 50% of the ventricular volume; and grade IV, in which parenchymal hemorrhage is additionally observed.4,5

In general, the outcome of patients is mainly determined by possible comorbidities of prematurity, such as the extent of bleeding resulting in possible secondary brain damage that includes the development of posthemorrhagic ventricular dilatation or even posthemorrhagic hydrocephalus.6,7 Hydrocephalus causes white matter shearing forces by massive enlargement of the ventricles, and consecutive intracranial pressure may result in compression-related brain tissue injury.6 Shunt dependency is observed in 38%–87% of cases and may be associated with secondary treatment complications.1 In addition, the accumulation of intraventricular blood triggers an immune response recruiting cytotoxic substances, which might cause further neuronal damage.8

The primary focus of neurosurgical treatment of IVH-related hydrocephalus in this patient cohort is the diversion of CSF by a temporizing measure, because an early ventriculoperitoneal shunt implantation may be associated with higher shunt failure rates due to low body weight and the amount of blood and its degradation products in the CSF.9,10 Different approaches, directed toward reduction of the shunt dependency rate and improved neurological outcome (e.g., by repeated lumbar or ventricular tapping or the use of acetazolamide and furosemide to reduce CSF production), did not yield any beneficial effect.10 In a clinical trial comparing ventricular access devices and ventriculosubgaleal shunts, no differences were found with respect to shunt infection, surgical revision, or mortality rate.9 These results were reinforced by a meta-analysis showing a similar range of outcomes for ventriculosubgaleal shunts and ventricular access devices regarding obstruction, infection, revision, arrest of hydrocephalus, good neurodevelopmental outcome, and death. Interestingly, external ventricular drain implantation showed a lower infection and higher arrested hydrocephalus rate compared with the other methods, but also a relevant higher surgical revision rate.1

More invasive methods were directed at the early elimination of blood products from the ventricles. The efficacy of the drainage, irrigation, and fibrinolytic therapy (DRIFT) study to prevent hydrocephalus through early removal of intraventricular blood, cytokines, and iron resulted in no differences between groups regarding shunt dependency or death, but a 35% versus 8% rate of secondary hemorrhage in the standard versus the DRIFT group.10 In addition, an analysis performed 2 years after inclusion showed a reduction of severe cognitive disability indicated by the Bayley Scales of Infant Development, 2nd Edition, Mental Developmental Index (BSID II MDI) and a nonsignificantly lower rate of epilepsy in the DRIFT group.7 The 10-year follow-up further confirmed improved cognitive function in the DRIFT group compared with the standard group.11

Neuroendoscopic lavage (NEL), on the other hand, represents a single intervention procedure, is minimally invasive, and is a far more controlled technique to achieve the elimination of intraventricular blood products, because it obviates the use of fibrinolytic agents, thereby decreasing the risk for secondary hemorrhage.12 Its feasibility has been confirmed in previous studies and a reduction of shunt frequency, CSF infections, and the development of a multiloculated hydrocephalus were shown.2,4,12 However, developmental outcome measures are still missing for the assessment of NEL. Thus, the aim of this research was to evaluate the neurodevelopmental and motor outcomes, as well as the ventricular and brain volume measurements 2 years after NEL in a single-center retrospective study. Potential clinical risk factors for impaired neuromotor outcomes were investigated.

Methods

This retrospectively analyzed cohort study was approved by the institutional research ethics board. In a database review we included all consecutively treated patients who underwent the intervention of NEL at our institution between September 2010 and May 2016 (n = 45). The indication for surgery and the surgical technique were described previously4,12 and are described more in detail in the supplemental material.

Clinical baseline data were derived from the in-house database, such as gestational age, body weight at birth, IVH grade, comorbidities, time from hemorrhage to NEL, and the use of antiepileptic drugs (AEDs). We included only patients who were alive at the intended follow-up of 2 years, and thereby excluded 1 patient who died from bronchopulmonary dysplasia at the age of 2 months and 3 weeks. At the follow-up of 2 years corrected age, taking the calculated birthday after premature birth into account, patients’ families visited the hospital again and we performed neurodevelopmental assessment by using BSID II MDI, the Gross Motor Function Classification System (GMFCS), and MRI as described below.

BSID II MDI

The BSID II MDI score was assessed in the Pediatric Care Center for Complex Chronic Diseases. The BSID II MDI is designed to measure the developmental progress of infants between 1 month and 42 months. It helps to quantify the following aspects in a playful and interactive examination: memory, learning ability, problem-solving, early concept of numbers, generalization, categorization, language, and communicative competences. According to the developmental classification, scores ≥ 85 indicate a normal range of development, whereas scores between 70 and 84 indicate the risk for subsequent developmental delay, and values < 70 indicate a manifest delay in development. Scores from 50 to 55 indicate severe cognitive disabilities, whereas values < 50 are not measurable.

GMFCS

Possible cerebral palsy is quantified by evaluating the ambulatory ability in the Pediatric Care Center for Complex Chronic Diseases by using the GMFCS, which focuses on self-initiated movement.13,14 According to the expanded and revised version of the GMFCS, 5 different levels of cerebral palsy (1–5) are differentiated and are additionally adapted to the specific age. Because the infants of this study population were assessed at 2 years, the indicative factors for a child’s movement between the 2nd and 4th birthday were evaluated (Table 1).

TABLE 1.

Evaluation of GMFCS between 2nd and 4th birthday in patients with neonatal posthemorrhagic hydrocephalus

LevelAbilities
0• Free walking without spasticity
1• Free walking, moving in and out of sitting position without assistance
2• Walking with limitations/preferred with assistance holding on to furniture
• Moving in and out of sitting without assistance
3• Walking with handheld mobility device
• W-sitting, assuming of sitting position with adult support
4• No walking, powered mobility required
• Trunk support required for sitting
• Creeping or crawling
5• No independent movement
• Limited head and trunk control

Based on data from Palisano and colleagues.13,14

Ventricular and Total Intracranial Brain Volume

The ventricular and brain volumes were quantified by using a semiautomated CSF and brain tissue segmentation tool (ITK-SNAP; an open software program that can be downloaded at http://www.itksnap.org15). High-resolution 3D T1-weighted MRI data as part of the clinical MRI protocol were acquired on a 1.5-T system (Genesis Signa; GE Healthcare) until 2015 and subsequently on a 3-T system (Magnetom Skyra; Siemens Healthineers).

For tissue-type segmentation (i.e., the quantification of brain parenchyma and the ventricular system), 3D T1-weighted MRI data were loaded into the ITK-SNAP tool and tissue classes were manually defined using a built-in presegmentation step. At least 10 seed points were then placed into the region of interest (CSF and brain tissue) and the evolution tool was used to let these seeds automatically evolve or contract to include CSF and brain tissue, respectively. Either incomplete segmentation or oversegmentation occurred in all cases, and the volumes were manually corrected slice by slice. Finally, the volume calculation tool was used to compute the number of voxels and, considering the voxel size, the volume was calculated (Fig. 1).

FIG. 1.
FIG. 1.

Illustration of CSF and brain tissue segmentation. Figure is available in color online only.

Statistical Analysis

We report absolute and relative frequencies for categorical variables and median with interquartile range (IQR) for ordinal and continuous variables, for the whole cohort, as well as neurodevelopmental and motor outcomes. Associations among brain volume, ventricular volume, and neurodevelopment were assessed with Spearman correlation coefficients, reported along with 95% confidence intervals (CIs) calculated via z-transformation. Risk factors for worse neurodevelopment, defined as BSID II MDI < 70 or GMFCS > 2, were investigated with Bayesian logistic regression models with a weakly informative prior distribution to deal with complete separation,16 i.e., the situation in which combinations of variables are not present or occur very rarely in the data. Because missing follow-up data are expected to be associated with the condition of a patient, these analyses were performed on multiply imputed data for all patients present at follow-up (i.e., 42 observations). Subsequently, the odds ratio (OR) estimates and 95% credible intervals (CrIs) were pooled by drawing 100,000 samples from each posterior distribution of the coefficients of all imputed data sets and deriving the mean and 2.5% and 97.5% quantiles. Based on the same analyses, we also report unadjusted effect estimates as sensitivity analyses and assess risk factors for shunt dependency. Due to the small sample size and the issue of complete separation, all results have to be interpreted with care, and the focus should be on effect estimates rather than on statistical significance, where variables changing the odds of the outcome by more than 50% are deemed relevant in this setting.

Statistical analyses were performed using R software,17 as well as additional R packages for data handling and plotting,18 Spearman correlation,19 Bayesian logistic regression,20 and multiple imputation,21 where the latter was based on the classification and regression tree algorithm with 100 imputed data sets.

Results

Patient Characteristics

Of 44 eligible patients, 2 were lost to follow-up. Of the 42 patients with at least one 2-year follow-up appointment, 36 were assessed with GMFCS, 27 with BSID II MDI, and 29 received ventricular and supratentorial volume measurements on MRI volume data sets acquired at a median of 25.1 months (IQR 22.3–30.3 months) after surgery. The information about AED therapy was available based on hospital records for 41 patients. Thirty of 41 patients (73%) did not require AED treatment. Basic patient characteristics are given in Table 2.

TABLE 2.

Patient characteristics by outcome parameter at 2-year follow-up

BSID II MDI ScoreGMFCS Score
CharacteristicTotal, n = 42≥70, n = 12<70, n = 15≤2, n = 28>2, n = 8
Gestational wk
 Median (IQR)27 (25–32)28 (26.8–39)26 (24–30)30 (26–35.2)24.5 (23.8–27)
Birth weight in g
 Median (IQR)1168.5 (809.5–2082.5)1275 (844–3276.2)930 (711.5–1350)1208.5 (847.5–2822.5)849.5 (601.8–1330)
IVH grade
 II4 (10%)2 (17%)0 (0%)4 (14%)0 (0%)
 III17 (40%)4 (33%)6 (40%)13 (46%)2 (25%)
 IV21 (50%)6 (50%)9 (60%)11 (39%)6 (75%)
Wks from hemorrhage to NEL
 Median (IQR)2.6 (2–3.7)2.6 (2.2–3.7)3 (2.4–3.8)2.6 (2–3.4)2.7 (2.4–4.4)
Body weight in g at NEL
 Median (IQR)1610 (1248.8–2406.2)1690 (1473.8–3323.8)1580 (1286–1922.5)1630 (1256.2–3027.5)1642.5 (1390–1913.8)
Initial infection
 No36 (86%)10 (83%)14 (93%)23 (82%)7 (88%)
 Yes6 (14%)2 (17%)1 (7%)5 (18%)1 (12%)
VP shunt
 No17 (40%)4 (33%)5 (33%)11 (39%)3 (38%)
 Yes25 (60%)8 (67%)10 (67%)17 (61%)5 (62%)
Shunt revision
 No12 (48%)3 (38%)6 (60%)7 (41%)3 (60%)
 Yes13 (52%)5 (62%)4 (40%)10 (59%)2 (40%)
Ventricular vol in ml
 Median (IQR)170.9 (94.3–226.2)123.9 (94.3–225.2)218.4 (172.6–339)123.9 (60.1–208.5)301.4 (221.4–491)
Brain vol in ml
 Median (IQR)932.7 (739–1020.5)939.8 (838.7–1041.1)693.3 (645.1–910.8)962.7 (906.9–1036.5)653 (621.8–704.8)
Cerebellar pathology
 None36 (86%)12 (100%)10 (67%)26 (93%)4 (50%)
 Isolated 4th V3 (7%)0 (0%)3 (20%)1 (4%)2 (25%)
 Cerebellar atrophy*6 (14%)0 (0%)5 (33%)2 (7%)4 (50%)
AEDs
 No30 (71%)11 (92%)7 (47%)23 (82%)3 (38%)
 Yes11 (26%)1 (8%)8 (53%)5 (18%)5 (62%)
Comorbidities
 No29 (69%)12 (100%)7 (47%)24 (86%)2 (25%)
 Yes13 (31%)0 (0%)8 (53%)4 (14%)6 (75%)

VP = ventriculoperitoneal; 4th V = fourth ventricle.

Unless otherwise indicated, values are expressed as the number of patients (%).

Two of 6 patients with cerebellar atrophy also had isolated fourth ventricle.

Basic clinical data from missing patients showed that the 2 patients who were lost to follow-up had a higher birth weight than those with some follow-up appointments (1465 g vs 1168.5 g), and both were classified with an IVH grade of IV. In our final cohort of 42 patients, 6 patients received systemic antibiotics due to increased infectious parameters in serum. Of those, 2 patients showed positive germ cultures in CSF. For 3 of them, the BSID II MDI score was missing but not the GMFCS score. Patients without a BSID II MDI assessment tended to have lower GMFCS values (median GMFCS of level 0 vs level 2) and a lower body weight at NEL (1375 g vs 1615 g), and their proportion of IVH grade IV was lower (40% vs 56%), as was the proportion of shunt dependency (47% vs 67%). Patients without a GMFCS assessment had similar birth weight (1174 g vs 1169 g), but lower body weight at NEL (1338 g vs 1630 g). Their proportion of IVH grade IV was higher (66.7% vs 47.2%), as was the proportion of comorbidities (50.0% vs 27.8%). Forty percent of those without a BSID II MDI assessment also did not have a GMFCS assessment (Supplemental Table S1).

Outcome Measures

Of the 36 patients assessed with the GMFCS, 13 (36%) showed no cerebral palsy—representing a normal gait. They were classified with level 0 in the Spearman correlation analysis (Table 3). Four patients (11%) were able to walk freely with spasticity (level 1); 11 patients (31%) preferred to walk with assistance (level 2); 3 patients (8%) used a handheld mobility device (level 3); and another 3 patients (8%) tended to creep and crawl or needed powered mobility and trunk support while sitting (level 4). Only 2 patients (6%) were not able to move independently (level 5) (Fig. 2).

TABLE 3.

Comparisons between neurodevelopment, ventricular volume, and brain volume in patients with hydrocephalus

Outcome MeasureGMFCS ScoreVentricular VolBrain Vol
BSID II MDI−0.69 (−0.85 to −0.42)−0.37 (−0.7 to −0.1)0.52 (0.08 to 0.79)
GMFCS score0.51 (0.15 to 0.76)−0.69 (−0.85 to −0.40)
Ventricular vol−0.47 (−0.72 to −0.13)

Values are expressed as the Spearman correlation coefficient (95% CI).

FIG. 2.
FIG. 2.

Stacked bar chart showing the relative distribution in assessed outcome for BSID II MDI neurodevelopmental score (n = 27) and GMFCS score (n = 36), respectively, during 2 years of follow-up. GMFCS 0 = no spasticity. Figure is available in color online only.

Of 27 patients assessed with BSID II MDI, 8 patients (30%) reached a score ≥ 85, which indicates a neurocognitive development within normal range at the corrected age of 2 years. Four patients (15%) showed minor developmental delay, as indicated by a score between 70 and 84, whereas 3 (11%) presented with moderate developmental delay at a score range from 55 to 69, and 12 children (44%) had severe cognitive disability, indicated by a score < 55 at the time of investigation (Fig. 2).

Brain and Ventricular Volume

The median brain volume of the 29 patients was 932.7 ml (IQR 739–1020.5 ml) and the median ventricular volume was 170.9 ml (IQR 94.3–226.2 ml). Brain volume measures showed a positive correlation with BSID II MDI and a negative one with GMFCS; the association appears stronger with GMFCS. The association of both BSID II MDI and GMFCS scores with ventricular volume is weaker compared with their association with brain volume (Fig. 3, Table 3). On MRI no multiloculated hydrocephalus with CSF communication disturbances was observed. However, 3 patients developed an isolated fourth ventricle and were treated with endoscopic stented aqueductoplasty. In addition, we observed 6 patients with severe cerebellar atrophy, of whom 2 had an isolated fourth ventricle.

FIG. 3.
FIG. 3.

Scatterplots of brain volume versus BSID II MDI neurodevelopmental score (left) and GMFCS score (right). GMFCS 0 = no spasticity. (For Spearman correlation coefficient, see Table 3.)

Neurodevelopmental and Motor Outcomes

Based on 42 patients for whom some follow-up was observed, older gestational age, time from hemorrhage to NEL, and also shunt dependency had negligible associations with the neurodevelopmental and motor outcome measures used after 2 years. An IVH grade of III or IV might have a relevant detrimental effect regarding both outcomes, but given the few observations in patients with grade II, this effect could not be estimated with sufficient precision in any model.

The use of AEDs, the presence of comorbidities, and also cerebellar pathology could be identified as relevant risk factors for both neurodevelopmental and motor outcomes. Adjusting for all other factors, AEDs increased the odds of worse neurocognitive and ambulatory outcomes approximately 3-fold (OR 3.06, 95% CrI 0.52–20.53 and OR 2.68, 95% CrI 0.46–16.69, respectively), and comorbidities increased the odds approximately 2.5-fold (OR 2.45, 95% CrI 0.34–24.24 and OR 2.47, 95% CrI 0.36–16.77, respectively). Without adjustment for confounding, these effects were even stronger and could be estimated with higher precision, resulting in smaller CrIs. A cerebellar pathology independently increases the odds of worse neurocognitive and ambulatory outcomes almost 2-fold (OR 1.92, 95% CrI 0.16–48.12 and OR 1.69, 95% CrI 0.25–11.59, respectively), although with very low precision in estimation. Without adjustment, these effects are more pronounced with OR estimates above 5—but still with high uncertainty in the actual effect (Fig. 4).

FIG. 4.
FIG. 4.

OR estimates with 95% CrIs based on Bayesian multiple (A) and univariate (B) logistic regression models with multiply imputed data. Outcome parameters are neurodevelopmental score BSID II MDI < 70 and GMFCS > 2. Figure is available in color online only.

Shunt Dependency

In the cohort, 26 of 44 patients (59%) became shunt dependent. Time from hemorrhage to NEL was not relevantly lower for patients without a shunt (median age 2.4 weeks [IQR 1.9–3.1 weeks] vs 3.1 weeks [IQR 2.3–3.8 weeks]; Supplemental Fig. S1B). Adjusting for baseline parameters (gestational week, IVH grade, comorbidities, and infection), the time from hemorrhage to NEL, and also the gestational age and comorbidities had negligible effects on the outcome. A higher IVH grade might increase the odds of shunt dependency relevantly (OR 4.45, 95% CrI 0.55–36.29), as might the presence of infections at baseline (OR 4.16, 95% CrI 0.58–29.70) (Supplemental Fig. S1A).

Discussion

After introducing NEL in our department in 2010 as a routine technique for treating decompensated posthemorrhagic hydrocephalus in neonates, we herewith present functional outcome measurements as relevant parameters to validate the effectiveness of such a technique for the first time. Almost one-third of children in our study who underwent NEL after IVH showed a neurocognitive development within normal range, and three-quarters showed the ability to walk freely or with minor aid. More than two-thirds did not suffer from treatment-dependent epilepsy. However, 44% of the infants had a severe cognitive disability and more than 1 in 5 patients could not walk or constantly needed a mobility device. We found a positive correlation between brain volume and ambulatory ability, which was less pronounced for the cognitive outcome. Ventricular volume measurements correlated less clearly with outcome parameters compared with brain volume measurements. In logistic regression analysis, the treatment with AEDs, the presence of comorbidities at baseline, and a cerebellar pathology were associated with impaired outcome after 2 years.

The indication for intervention in our cohort was similar to the inclusion criteria of the DRIFT study.7 A direct comparison of the baseline parameters at the time of treatment is presented in Table 4. There is no indication of major differences, but there was a tendency for body weight in our cohort to be higher at NEL. Because a more detailed comparison of the two studies is not possible, we can only speculate about the reasons for the different outcomes in the NEL and DRIFT groups. One explanatory factor might be the single intervention in the NEL group in a controlled environment of the operating room, as opposed to repeated procedures performed over several days by changing staff on the neonatal intensive care unit in the DRIFT group. This safety measure is mainly reflected in a higher rate of secondary IVH, which was 35% in the DRIFT group compared with 8% in the NEL group. It is, however, not confirmed by either the mortality rate (6% vs 5%) or the infection rate—the latter was 0% in the DRIFT group compared with 3.6% in a bicenter experience in which the NEL technique was used.4

TABLE 4.

Comparison of baseline characteristics between the DRIFT study and the current NEL study

CharacteristicNEL CohortDRIFT Cohort
No. of patients4234
Median gestational age in wks (IQR)27 (23–41)27 (24–34)
Median birth weight in g (IQR)1168 (520–3490)1066 (640–2100)
Male sex64%71%
Parenchymal hemorrhagic infarction50%53%
Median age at intervention in days (IQR)21 (8–77)20 (7–28)

Based on data (DRIFT cohort) from Whitelaw et al.10

Comparing the BSID II MDI from our NEL study cohort with the results of the previously published randomized controlled DRIFT study,7 fewer surviving children in the DRIFT group had a normal cognitive development (BSID II MDI score ≥ 85) 2 years after intervention than in our NEL group (23% vs 30%). Also, more children showed minor (BSID II MDI score 70–84) and moderate (BSID II MDI score 55–69) developmental delays in the DRIFT group (minor: 26% vs 15%; moderate: 20% vs 11%). However, only 31% of the surviving children in the DRIFT group suffered from severe cognitive disability (BSID II MDI score < 55) compared with 44% in the NEL group. Taking into account the higher mortality of 6% in the DRIFT group compared with 2% in our present NEL cohort, we may summarize that the DRIFT outcome results are not relevantly different from the results presented here.10 The comparison of neurocognitive and ambulatory outcomes after NEL with those reported for the control group of the DRIFT study (BSID II MDI score ≥ 85: 28% vs 30%; BSID II MDI score 70–84: 9% vs 15%; BSID II MDI score 55–69: 3% vs 11%; BSID II MDI score < 55: 59% vs 44%) indicates a benefit from NEL for avoiding severe disability.

Results regarding ambulatory function are more difficult to compare with the DRIFT group, in which the GMFCS was not used. However, the ability to walk was described to be normal in 17% of the DRIFT group, which might correspond to the 36% of NEL patients without spasticity. Similarly, 44% in the DRIFT group were described as unable to walk without assistance, whereas the remaining patients had normal or abnormal gait with reduced mobility.7 This subgroup might best be compared with GMFCS 3–4 in our study, in which it represents 22% of the NEL cohort. Overall, this indicates that in this single-center study NEL resulted in better gait ability after 2 years; however, such a conclusion must be interpreted cautiously due to different study setups. Interestingly, in the DRIFT study there were no clear differences with respect to gait ability in the DRIFT cohort compared with the patients treated with standard care (normal or nonfluent gait 42% vs 45%; reduced or no mobility 58% vs 55%).

The rate of shunt dependency in the DRIFT study was rather low compared with our cohort after applying NEL (38% vs 60%). Here it is important to state that the indication for shunt insertion remains a subjective decision made mainly by the treating neurosurgical team, because all states of marginally compensated hydrocephalus may be left without shunting and will eventually reach a steady state. This makes shunt independence a fragile parameter; some patients with a shunt might end up with better outcomes given that brain parenchyma can be preserved by avoiding high intracranial pressure periods compared with patients without a shunt. Nevertheless, it is debatable whether low gestational age as well as the presence of an early infection is associated with higher odds of shunt dependency.4 These factors may be taken into account when deciding about shunt surgery and consulting the parents.

The DRIFT study did not measure brain or ventricular volume as outcome parameters. There are only limited data in the literature about brain volume development at 2 years after neonatal posthemorrhagic hydrocephalus. The technique of automated volume segmentation for hydrocephalic radiographic imaging was reported previously.15,22–25 In a mixed hydrocephalus cohort in which endoscopic third ventriculostomy and choroid plexus cauterization (ETV-CPC) were used for treatment, after 12 months a median CSF volume of 311 ml was measured, which is relevantly larger than the values in our cohort. Brain volume measurements are only presented as relative values in this study.24 It was shown that decreased CSF volume is observed in patients with shunts; however, a correlation of brain volume with outcome was not investigated. The same study did not find significant differences in outcome between individuals with and without shunts.

Previous studies have shown that IVH and posthemorrhagic hydrocephalus are highly correlated with deep gray matter and cerebellar volume, as well as with presumed microstructural white matter integrity,26 and that periventricular leukomalacia in infants is associated with their visual function.27 In fact, we found a stronger correlation between brain tissue volume and motor and developmental outcome than between ventricular volumes and these outcome measures. Studies of normative brain volume growth have determined the brain volume at 2 years to be between 900 and 1350 ml.28 In spite of the prematurity and various comorbidities in our cohort, approximately 50% of patients have brain volumes above the 3rd percentile as defined by Peterson and colleagues. Our data may underline the importance of brain tissue volume measurement rather than ventricular size as an outcome surrogate, because the latter will not detect any brain volume changes indirectly when external CSF spaces are additionally enlarged. Further investigations are necessary to verify the importance of brain volume measures in relation to neurodevelopmental outcome.

Limitations of the Study

The low prevalence of neonatal posthemorrhagic hydrocephalus is reflected by the small sample size in our study. Because we rely on data from a retrospective cohort, in which outcome parameters were measured on a routine basis depending on whether families actually received follow-up at our institution, we were not able to collect all information on outcome parameters after 2 years in the NEL cohort. Due to the fact that, first, measurements of BSID II MDI scores, GMFCS scores, ventricular volume, and brain volume are correlated with each other to a moderate to high extent, and, second, baseline information was associated with whether or not observations of the outcome parameters were missing at follow-up, a multiple imputation approach appears to be appropriate and uses the available information most efficiently. However, results have to be interpreted with care; e.g., we acknowledge that patients with missing GMFCS scores tended to have higher IVH grades and more comorbidities, potentially resulting in worse ambulatory outcome. Furthermore, brain volume measurements will not detect any microstructural changes that also may be linked to posthemorrhagic and hydrocephalus-derived brain injury.

Regarding the validity of the neurocognitive evaluation by BSID II MDI, a child’s lack of familiarity with the tasks possibly leads to a lower cognitive score in general and may also reflect only a developmental delay, but will not give sufficient information about the developmental potential. Additionally, a family’s low socioeconomic status could negatively influence the neurocognitive outcome, e.g., through less extensive support by parents, which could compensate for neurodevelopmental deficits. However, because we did not assess socioeconomic status in our cohort study, this influence could not be explored.

Conclusions

NEL seems to be associated with similar neurodevelopmental and motor outcomes as are seen after other techniques of eliminating intraventricular blood components in neonatal posthemorrhagic hydrocephalus. Our results emphasize the relevance of using different neurodevelopmental and motor outcome parameters for the evaluation of neurosurgical procedures in neonates, especially because the patient’s ability to walk freely seems to be more positively affected in comparison to BSID II MDI measurements. We describe the outcome after the NEL in neonatal posthemorrhagic hydrocephalus for the first time and, although our small sample size does not allow us to draw solid conclusions, it may, however, contribute to the ongoing debate of how to manage posthemorrhagic hydrocephalus surgically. The neurodevelopmental outcome and brain volume should be further investigated in an extended setup in order to allow a comparison between different surgical procedures used for this patient cohort.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Thomale, Tietze, Schulz. Acquisition of data: Thomale, Behrens, Tietze, Walch, Bittigau, Schulz. Analysis and interpretation of data: Thomale, Behrens, Tietze, Bührer, Schulz, Aigner. Drafting the article: Thomale, Behrens, Tietze, Bührer, Aigner. Critically revising the article: Thomale, Behrens, Tietze, Walch, Bittigau, Bührer, Aigner. Reviewed submitted version of manuscript: Thomale, Behrens, Tietze, Walch, Bittigau, Bührer, Aigner. Approved the final version of the manuscript on behalf of all authors: Thomale. Statistical analysis: Thomale, Bührer, Aigner. Administrative/technical/material support: Thomale, Aigner. Study supervision: Thomale, Aigner.

Supplemental Information

Online-Only Content

Supplemental material is available with the online version of the article.

References

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  • 4

    d’Arcangues C, Schulz M, Bührer C, et al. Extended experience with neuroendoscopic lavage for posthemorrhagic hydrocephalus in neonates. World Neurosurg. 2018;116:e217e224.

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    Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr. 1978;92(4):529534.

    • Search Google Scholar
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    Whitelaw A, Jary S, Kmita G, et al. Randomized trial of drainage, irrigation and fibrinolytic therapy for premature infants with posthemorrhagic ventricular dilatation: developmental outcome at 2 years. Pediatrics. 2010;125(4):e852e858.

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    Gram M, Sveinsdottir S, Cinthio M, et al. Extracellular hemoglobin—mediator of inflammation and cell death in the choroid plexus following preterm intraventricular hemorrhage. J Neuroinflammation. 2014;11:200.

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    Whitelaw A, Evans D, Carter M, et al. Randomized clinical trial of prevention of hydrocephalus after intraventricular hemorrhage in preterm infants: brain-washing versus tapping fluid. Pediatrics. 2007;119(5):e1071e1078.

    • Search Google Scholar
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    Luyt K, Jary S, Lea C, et al. Ten-year follow-up of a randomised trial of drainage, irrigation and fibrinolytic therapy (DRIFT) in infants with post-haemorrhagic ventricular dilatation. Health Technol Assess. 2019;23(4):1116.

    • Search Google Scholar
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  • 12

    Schulz M, Bührer C, Pohl-Schickinger A, et al. Neuroendoscopic lavage for the treatment of intraventricular hemorrhage and hydrocephalus in neonates. J Neurosurg Pediatr. 2014;13(6):626635.

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    Palisano R, Rosenbaum P, Bartlett D, et al. GMFCS E&R Gross Motor Function Classification System Expanded and Revised. CanChild Centre for Childhood Disability Research; 2007.

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    Palisano R, Rosenbaum P, Walter S, et al. Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol. 1997;39(4):214223.

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    Yushkevich PA, Piven J, Hazlett HC, et al. User-guided 3D active contour segmentation of anatomical structures: significantly improved efficiency and reliability. Neuroimage. 2006;31(3):11161128.

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    • Search Google Scholar
    • Export Citation
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    Klimont M, Flieger M, Rzeszutek J, et al. Automated ventricular system segmentation in paediatric patients treated for hydrocephalus using deep learning methods. Biomed Res Int. 2019;2019:3059170.

    • Search Google Scholar
    • Export Citation
  • 24

    Kulkarni AV, Schiff SJ, Mbabazi-Kabachelor E, et al. Endoscopic treatment versus shunting for infant hydrocephalus in Uganda. N Engl J Med. 2017;377(25):24562464.

    • Search Google Scholar
    • Export Citation
  • 25

    Mandell JG, Langelaan JW, Webb AG, Schiff SJ. Volumetric brain analysis in neurosurgery: Part 1. Particle filter segmentation of brain and cerebrospinal fluid growth dynamics from MRI and CT images. J Neurosurg Pediatr. 2015;15(2):113124.

    • Search Google Scholar
    • Export Citation
  • 26

    Brouwer MJ, de Vries LS, Kersbergen KJ, et al. Effects of posthemorrhagic ventricular dilatation in the preterm infant on brain volumes and white matter diffusion variables at term-equivalent age. J Pediatr. 2016;168:4149.e1.

    • Search Google Scholar
    • Export Citation
  • 27

    Cioni G, Bertuccelli B, Boldrini A, et al. Correlation between visual function, neurodevelopmental outcome, and magnetic resonance imaging findings in infants with periventricular leucomalacia. Arch Dis Child Fetal Neonatal Ed. 2000;82(2):F134F140.

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    Peterson M, Warf BC, Schiff SJ. Normative human brain volume growth. J Neurosurg Pediatr. 2018;21(5):478485.

Supplementary Materials

Illustration from Aldave (pp 572–577). Images created by Katherine Relyea and printed with permission from Baylor College of Medicine.

  • View in gallery

    Illustration of CSF and brain tissue segmentation. Figure is available in color online only.

  • View in gallery

    Stacked bar chart showing the relative distribution in assessed outcome for BSID II MDI neurodevelopmental score (n = 27) and GMFCS score (n = 36), respectively, during 2 years of follow-up. GMFCS 0 = no spasticity. Figure is available in color online only.

  • View in gallery

    Scatterplots of brain volume versus BSID II MDI neurodevelopmental score (left) and GMFCS score (right). GMFCS 0 = no spasticity. (For Spearman correlation coefficient, see Table 3.)

  • View in gallery

    OR estimates with 95% CrIs based on Bayesian multiple (A) and univariate (B) logistic regression models with multiply imputed data. Outcome parameters are neurodevelopmental score BSID II MDI < 70 and GMFCS > 2. Figure is available in color online only.

  • 1

    Badhiwala JH, Hong CJ, Nassiri F, et al. Treatment of posthemorrhagic ventricular dilation in preterm infants: a systematic review and meta-analysis of outcomes and complications. J Neurosurg Pediatr. 2015;16(5):545555.

    • Search Google Scholar
    • Export Citation
  • 2

    Etus V, Kahilogullari G, Karabagli H, Unlu A. Early endoscopic ventricular irrigation for the treatment of neonatal posthemorrhagic hydrocephalus: a feasible treatment option or not? A multicenter study. Turk Neurosurg. 2018;28(1):137141.

    • Search Google Scholar
    • Export Citation
  • 3

    Christian EA, Melamed EF, Peck E, et al. Surgical management of hydrocephalus secondary to intraventricular hemorrhage in the preterm infant. J Neurosurg Pediatr. 2016;17(3):278284.

    • Search Google Scholar
    • Export Citation
  • 4

    d’Arcangues C, Schulz M, Bührer C, et al. Extended experience with neuroendoscopic lavage for posthemorrhagic hydrocephalus in neonates. World Neurosurg. 2018;116:e217e224.

    • Search Google Scholar
    • Export Citation
  • 5

    Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr. 1978;92(4):529534.

    • Search Google Scholar
    • Export Citation
  • 6

    Cherian S, Whitelaw A, Thoresen M, Love S. The pathogenesis of neonatal post-hemorrhagic hydrocephalus. Brain Pathol. 2004;14(3):305311.

    • Search Google Scholar
    • Export Citation
  • 7

    Whitelaw A, Jary S, Kmita G, et al. Randomized trial of drainage, irrigation and fibrinolytic therapy for premature infants with posthemorrhagic ventricular dilatation: developmental outcome at 2 years. Pediatrics. 2010;125(4):e852e858.

    • Search Google Scholar
    • Export Citation
  • 8

    Gram M, Sveinsdottir S, Cinthio M, et al. Extracellular hemoglobin—mediator of inflammation and cell death in the choroid plexus following preterm intraventricular hemorrhage. J Neuroinflammation. 2014;11:200.

    • Search Google Scholar
    • Export Citation
  • 9

    Limbrick DD Jr, Mathur A, Johnston JM, et al. Neurosurgical treatment of progressive posthemorrhagic ventricular dilation in preterm infants: a 10-year single-institution study. J Neurosurg Pediatr. 2010;6(3):224230.

    • Search Google Scholar
    • Export Citation
  • 10

    Whitelaw A, Evans D, Carter M, et al. Randomized clinical trial of prevention of hydrocephalus after intraventricular hemorrhage in preterm infants: brain-washing versus tapping fluid. Pediatrics. 2007;119(5):e1071e1078.

    • Search Google Scholar
    • Export Citation
  • 11

    Luyt K, Jary S, Lea C, et al. Ten-year follow-up of a randomised trial of drainage, irrigation and fibrinolytic therapy (DRIFT) in infants with post-haemorrhagic ventricular dilatation. Health Technol Assess. 2019;23(4):1116.

    • Search Google Scholar
    • Export Citation
  • 12

    Schulz M, Bührer C, Pohl-Schickinger A, et al. Neuroendoscopic lavage for the treatment of intraventricular hemorrhage and hydrocephalus in neonates. J Neurosurg Pediatr. 2014;13(6):626635.

    • Search Google Scholar
    • Export Citation
  • 13

    Palisano R, Rosenbaum P, Bartlett D, et al. GMFCS E&R Gross Motor Function Classification System Expanded and Revised. CanChild Centre for Childhood Disability Research; 2007.

    • Search Google Scholar
    • Export Citation
  • 14

    Palisano R, Rosenbaum P, Walter S, et al. Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol. 1997;39(4):214223.

    • Search Google Scholar
    • Export Citation
  • 15

    Yushkevich PA, Piven J, Hazlett HC, et al. User-guided 3D active contour segmentation of anatomical structures: significantly improved efficiency and reliability. Neuroimage. 2006;31(3):11161128.

    • Search Google Scholar
    • Export Citation
  • 16

    Gelman A, Jakulin A, Pittau M, et al. A weakly informative default prior distribution for logistic and other regression models. Ann Appl Stat. 2009;2(4):13601383.

    • Search Google Scholar
    • Export Citation
  • 17

    R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing; 2019.

  • 18

    Wickham H, Averick M, Bryan J, et al. Welcome to Tidyverse. J Open Source Softw. 2019;4(43):1686.

  • 19

    Signorell A, Aho K, Alfons A, et al. DescTools: Tools for Descriptive Statistics. R package; 2020.

  • 20

    Gelman A, Hill J. Data Analysis Using Regression and Multilevel/Hierarchical Models. Cambridge University Press; 2006

  • 21

    van Buuren S, Groothuis-Oudshoorn K. mice: Multivariate imputation by chained equations in R. J Stat Softw. 2011;45(3):167.

  • 22

    Cherukuri V, Ssenyonga P, Warf BC, et al. Learning based segmentation of CT brain images: application to postoperative hydrocephalic scans. IEEE Trans Biomed Eng. 2018;65(8):18711884.

    • Search Google Scholar
    • Export Citation
  • 23

    Klimont M, Flieger M, Rzeszutek J, et al. Automated ventricular system segmentation in paediatric patients treated for hydrocephalus using deep learning methods. Biomed Res Int. 2019;2019:3059170.

    • Search Google Scholar
    • Export Citation
  • 24

    Kulkarni AV, Schiff SJ, Mbabazi-Kabachelor E, et al. Endoscopic treatment versus shunting for infant hydrocephalus in Uganda. N Engl J Med. 2017;377(25):24562464.

    • Search Google Scholar
    • Export Citation
  • 25

    Mandell JG, Langelaan JW, Webb AG, Schiff SJ. Volumetric brain analysis in neurosurgery: Part 1. Particle filter segmentation of brain and cerebrospinal fluid growth dynamics from MRI and CT images. J Neurosurg Pediatr. 2015;15(2):113124.

    • Search Google Scholar
    • Export Citation
  • 26

    Brouwer MJ, de Vries LS, Kersbergen KJ, et al. Effects of posthemorrhagic ventricular dilatation in the preterm infant on brain volumes and white matter diffusion variables at term-equivalent age. J Pediatr. 2016;168:4149.e1.

    • Search Google Scholar
    • Export Citation
  • 27

    Cioni G, Bertuccelli B, Boldrini A, et al. Correlation between visual function, neurodevelopmental outcome, and magnetic resonance imaging findings in infants with periventricular leucomalacia. Arch Dis Child Fetal Neonatal Ed. 2000;82(2):F134F140.

    • Search Google Scholar
    • Export Citation
  • 28

    Peterson M, Warf BC, Schiff SJ. Normative human brain volume growth. J Neurosurg Pediatr. 2018;21(5):478485.

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