Association between sacubitril/valsartan initiation and changes in left ventricular ejection fraction: Insights from ARIADNE registry.

AIMS: We tested the hypothesis that initiation versus non-initiation of sacubitril/valsartan is associated with a more favorable subsequent change in left ventricular ejection fraction (LVEF) in a real-world setting. METHODS: A prospective, non-randomized, double-arm, open-label, cohort study had been conducted across 687 centers in 17 European countries enrolling HFrEF patients aged ≥18 years with symptoms of HF (New York Heart Association [NYHA] II-IV) and "reduced LVEF". For the current analysis, 2602 patients with LVEF measured at baseline and follow-up were chosen, of which 860 (33%, mean age 67 years, 26% women) were started on sacubitril/valsartan at baseline and 1742 (67%, 68 years, 23% women) were not. Patients started on sacubitril/valsartan had higher NYHA class and lower LVEF. RESULTS: LVEF increased from mean 32.7% to 38.1% in the sacubitril/valsartan group versus from 35.9% to 38.7% in the non-sacubitril/valsartan group (mean difference in increase 2.6%, p < 0.001). LVEF increased from baseline in 64% versus 53% of patients and increased by ≥5% (absolute %) in 50% versus 35% of patients in the sacubitril/valsartan versus non-sacubitril/valsartan groups, respectively. In the overall cohort, initiation of sacubitril/valsartan was independently associated with any increase in LVEF (adjusted odds ratio [OR] 1.49 [1.26-1.75]) and with increase by ≥5% (OR 1.65 [1.39-1.95]). CONCLUSION: Initiating versus not initiating sacubitril/valsartan was independently associated with a greater subsequent increase in LVEF in this real-world setting. Reverse cardiac remodeling may be one mechanism of benefit of sacubitril/valsartan.

Outcomes with sacubitril/valsartan in outpatients with heart failure and reduced ejection fraction: The ARIADNE registry.

AIMS: ARIADNE aimed to assess the association between effects of sacubitril/valsartan and no sacubitril/valsartan treatment and clinical characteristics, functional capacity, and clinical outcomes (cause-specific mortality and hospitalizations) in outpatients with heart failure (HF) with reduced ejection fraction (HFrEF). METHODS: ARIADNE was a prospective European registry of 9069 patients with HFrEF treated by office-based cardiologists or selected primary care physicians. Of the 8787 eligible for analysis, 4173 patients were on conventional HF treatment (non-S/V group), whereas 4614 patients were either on sacubitril/valsartan treatment at enrolment or started sacubitril/valsartan within 1 month of enrolment (S/V group). We also generated a restricted analysis set (rS/V) including only those 2108 patients who started sacubitril/valsartan treatment within the month prior to or after enrolment. RESULTS: At the baseline, average age of patients enrolled in the study was 68 years, and 23.9% (2099/8787) were female. At the baseline, the proportions of patients with New York Heart Association (NYHA) Class III symptoms were 30.9 (1288/4173), 42.8 (1974/4614), and 48.2% (1015/2108), in non-S/V, S/V, and rS/V groups, respectively. After 12 months of treatment, the proportion of patients with NYHA Class III at baseline who improved to Class II was 32.0% (290/907) in the non-S/V group vs. 46.3% (648/1399) in S/V group and 48.7% (349/717) in rS/V group. The overall mortality rate was 5.0 per 100 patient-years. Rates of HF hospitalizations were high (20.9, 20.3, and 21.2 per 100 patient-years in the non-S/V, S/V, and rS/V groups, respectively). Emergency room visits without hospitalization occurred in 3.9, 3.2, and 3.9% of patients in the non-S/V, S/V, and rS/V groups, respectively. CONCLUSIONS: This large HFrEF European registry provides a contemporary outcome profile of outpatients with HFrEF treated with or without sacubitril/valsartan. In a real-world setting, sacubitril/valsartan was associated with an improvement of symptoms in patients with HFrEF compared with the conventional HFrEF treatment.

Utilization of sacubitril/valsartan in patients with heart failure with reduced ejection fraction: real-world data from the ARIADNE registry.

AIMS: To compare baseline characteristics of patients with heart failure with reduced ejection fraction (HFrEF) initiated on sacubitril/valsartan compared with patients continued on conventional heart failure (HF)-treatment in a European out-patient setting. METHODS AND RESULTS: Between July 2016 and July 2019, ARIADNE enrolled 8787 outpatients aged ≥18 years with HFrEF from 17 European countries. Choice of therapy was solely at the investigators' discretion. In total, 4173 patients were on conventional HF-treatment (non-S/V group), while 4614 patients were on sacubitril/valsartan either at enrolment or started sacubitril/valsartan within 1 month of enrolment (S/V group). Of these, 2108 patients started sacubitril/valsartan treatment ±1 month around enrolment [restricted S/V (rS/V) group]. The average age of the patients was 68 years. Patients on S/V were more likely to have New York Heart Association (NYHA) class III or IV symptoms (50.3%, 44.6%, 32.1% in rS/V, S/V, and non-S/V, respectively) and had lower left ventricular ejection fraction (LVEF; 32.3%, 32.7%, and 35.4% in rS/V, S/V, and non-S/V, respectively; P < 0.0001). The most frequently received HF treatments were angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB; ∼84% in non-S/V), followed by ß-blockers (∼80%) and mineralocorticoid receptor antagonists (MRAs; 53%). The use of triple HF therapy (ACEI/ARB/angiotensin receptor neprilysin inhibitor with ß-blockers and MRA) was higher in the S/V groups than non-S/V group (48.2%, 48.2%, and 40.2% in rS/V, S/V, and non-S/V, respectively). CONCLUSION: In this large multinational HFrEF registry, patients receiving sacubitril/valsartan tended to be younger with lower LVEF and higher NYHA class. Fewer than half of the patients received triple HF therapy.

Individualised treatment targets in patients with type-2 diabetes and hypertension.

AIM: Patients with type-2 diabetes mellitus (T2DM) are at high risk of cardiovascular events, accentuated in the presence of hypertension. At present, it is unclear to what extent the guidelines for the management of T2DM, advocating reduction in HbA1c levels to below target levels, are being adhered to in clinical practice. METHODS: DIALOGUE was a prospective, observational, non-interventional registry performed across multiple centres in Germany. Patients aged 18 years or older who had T2DM and hypertension for whom the treating physician considered blood glucose lowering medication as inadequate and/or not safe/tolerable and chose to add a further oral drug or switch drug treatment were included. Patients were assigned a treatment target HbA1c value (≤ 6.5% [strict]; > 6.5 to ≤ 7.0% [intermediate]; > 7.0 to ≤ 7.5% [lenient]). RESULTS: 8568 patients with T2DM and hypertension were enrolled. 6691 (78.1%) had 12-month follow-up. Patients who were assigned a strict HbA1c treatment target (n = 2644) were younger, had shorter diabetes duration, and less comorbidity in comparison to those with intermediate (n = 2912) or lenient targets (n = 1135). Only 53.1% of patients achieved their HbA1c treatment target (46.2% [strict], 56.8% [intermediate], 59.4% [lenient]). There was little sign of treatment intensification for patients that had not achieved their HbA1c target. CONCLUSIONS: Achievement of treatment targets was poor, leaving many patients with sub-optimal blood glucose levels. The apparent reluctance of physicians to intensify antidiabetic drug therapy is alarming, especially considering the evidence pointing to an association of hyperglycaemia and microvascular complications in patients with T2DM.

Achievement of individualized treatment targets in patients with comorbid type-2 diabetes and hypertension: 6 months results of the DIALOGUE registry.

BACKGROUND: Patients with type-2 diabetes mellitus (T2DM) and hypertension have increased risk of cardiovascular disease (CVD). We studied individualized treatment targets and their achievement in clinical practice. METHODS: DIALOGUE is a prospective, multi-center registry in patients with both T2DM and hypertension. RESULTS: Patients (n = 6,586) had a baseline fasting glucose (8.5 ± 2.8 mmol/l), postprandial glucose (10.9 ± 3.4 mmol/l), and HbA1c (7.8 ± 2.1%) levels indicated poor glycemic control. Baseline systolic and diastolic BP were 140.3 ± 15.7 and 82.6 ± 9.5, respectively. Patients were categorized by HbA1c treatment goals: ≤6.5% (strict), >6.5 to ≤7.0% (medium), and >7.0 to ≤7.5% (loose). When considering systolic BP (SBP) targets (≤130 mmHg [strict], >130 to ≤135 mmHg [medium], and >135 to ≤140 mmHg [loose]), patients with strict SBP treatment goals displayed similar characteristics to those with strict HbA1c targets. Although approximately 70% of patients received both strict HbA1c and SBP targeting, overall treatment goals remained unmet in all HbA1c target groups at the 6-month follow-up. SBP targets were not reached in the strict and medium groups, but were achieved in the loose treatment group. Specific predictors for choosing loose SBP or HbA1c treatment goals were identified, including SBP/HbA1c levels and various comorbidities. CONCLUSIONS: Individualized glucose and BP targets were selected by treating physicians based on patient characteristics and overall comorbidity. While treatment goals were not consistently met using various antidiabetic and antihypertensive therapies, our analyses indicated that the strictly targeted patient populations maintained lower overall HbA1c and SBP levels at 6 months.

Vildagliptin versus insulin in patients with type 2 diabetes mellitus inadequately controlled with sulfonylurea: results from a randomized, 24 week study.

OBJECTIVE: There is limited evidence to guide the selection of second-line anti-hyperglycemic agents in patients with type 2 diabetes mellitus (T2DM) who are inadequately controlled with sulfonylurea monotherapy and are intolerant to metformin. We compared the efficacy and safety of vildagliptin 50 mg qd and Neutral Protamine Hagedorn (NPH) insulin qd in such patients. METHODS: This was a 24 week, multicenter, randomized, open-label study. The co-primary endpoints were (i) proportion of patients achieving HbA1c <7.0% without any confirmed hypoglycemic events (HEs) or weight gain ≥3% (composite endpoint); (ii) rate of confirmed HEs. Treatment satisfaction was assessed using the TSQM-9 questionnaire at study end. RESULTS: A total of 162 patients were randomly assigned to vildagliptin (n = 83) and NPH insulin (n = 79). Similar proportion of patients achieved the composite endpoint in vildagliptin versus NPH insulin group (35.4% versus 34.2%; OR 0.985; 95% CI 0.507, 1.915; p = 0.96). After 24 weeks, 48.8% of patients in the vildagliptin group and 60.8% in the NPH insulin group achieved HbA1c <7.0%; 13.4% in the vildagliptin group and 29.1% in the insulin group had at least one confirmed HE; while 11.0% in the vildagliptin group and 22.8% in the insulin group experienced weight gain. The rate of confirmed HEs was significantly lower in patients receiving vildagliptin versus NPH insulin (1.3 versus 5.1 events per year). The TSQM-9 score for 'convenience' at week 24 increased significantly more with vildagliptin than with NPH insulin. CONCLUSIONS: Addition of vildagliptin and NPH insulin resulted in a similar number of patients reaching HbA1c target without HEs or weight gain in T2DM patients inadequately controlled with sulfonylurea. The addition of vildagliptin to sulfonylurea could be considered as a treatment option prior to intensification with insulin, with the advantages of a lower HE rate and greater patient convenience. Study results are limited by a higher drop-out rate in the vildagliptin arm.

Radiation damage reveals promising interaction position.

High-resolution structural data of protein inhibitor complexes are the key to rational drug design. Synchrotron radiation allows for atomic resolutions but is frequently accompanied by radiation damage to protein complexes. In this study a human aldose reductase mutant complexed with a bromine-substituted inhibitor was determined to atomic resolution [Protein Data Bank (PDB) code 3onc]. Though the radiation dose was moderate, a selective disruption of a bromine-inhibitor bond during the experiment was observed while the protein appears unaffected. A covalent bond to bromine is cleaved and the displaced atom is not scattered throughout the crystal but can most likely be assigned as a bromide to an additional difference electron density peak observed in the structure. The bromide relocates to an adjacent unoccupied site where promising interactions to protein residues stabilize its position. These findings were verified by a second similar structure determined with considerably higher radiation dose (PDB code 3onb).

Ligand-induced fit affects binding modes and provokes changes in crystal packing of aldose reductase.

BACKGROUND: Flexibility is a common feature of proteins. For human aldose reductase, a variety of conformers have been observed in crystalline complexes with different inhibitors. METHODS: A study of crystal structures and isothermal titration calorimetry was performed on wild type and mutated aldose reductase. RESULTS AND CONCLUSIONS: Though the interaction to the mutated residue Thr113 does not directly alter the binding mode of zopolrestat to aldose reductase, a shift of its basic scaffold is induced which affects the interaction with a flexible loop and introduces disorder. With the related inhibitor IDD393, two distinct binding site conformations result in two different crystal forms: While a backbone flip of the same residues as for zopolrestat is present in both crystal forms, a considerable side-chain movement of a phenylalanine is observed for only one crystal form. In consequence, residual mobility of adjacent amino acids is increased and some crystal contacts are prevented which reinforces different crystal packing. The structure of a benzothiazepine reveals a protein conformer, where this phenylalanine is further relocated resulting in the same altered crystal packing. Differences in the thermodynamic signature recorded for the various complexes relate to the structural differences. GENERAL SIGNIFICANCE: Crystal structures are accepted as "gold standard" for the interpretation of protein geometry, however, they are only one possible structure and can be influenced by crystal packing. In reverse, ligand binding can affect protein conformation and determine crystal packing. The phenomenon of such "polymorphic forms" is well appreciated, however rarely understood at the molecular level.

Temporizing treatment of hyperacute subdural hemorrhage by subdural evacuation port system placement.

An acute subdural hematoma (SDH) requiring surgical intervention is treated with craniotomy or craniectomy, in part because it is generally accepted that coagulated blood present in the acute phase cannot be adequately evacuated by less-invasive means such as bur hole drainage. However, a hyperacute SDH in the first few hours after trauma can have mixed-density components on CT scans that are thought to represent subdural blood that is not yet fully coagulated. The authors report a case in which a hyperacute SDH in a patient receiving antiplatelet therapy was treated with the novel technique of temporizing subdural evacuation port system (SEPS) placement. Placement of an SEPS in the intensive care unit allowed for rapid surgical treatment of the patient's elevated intracranial pressure (ICP) by drainage of 70 ml of fresh subdural blood. After initial SEPS-induced stabilization, the patient underwent operative treatment of the SDH by craniotomy. The combined approach of emergency SEPS placement followed by craniotomy resulted in a dramatic recovery, with improvement from coma and extensor posturing to a normal status on neurological evaluation 5 weeks later. In appropriately selected cases, patients with a hyperacute SDH may benefit from SEPS placement to quickly treat elevated ICP, as a bridge to definitive surgical treatment by craniotomy.

Tracing the detail: how mutations affect binding modes and thermodynamic signatures of closely related aldose reductase inhibitors.

Improvements on the computational methods for affinity prediction from the structure of protein-ligand complexes require a better understanding of the nature of molecular interactions and biomolecular recognition principles. In the present contribution, the binding of two chemically closely related human aldose reductase inhibitors had been studied by high-resolution X-ray analysis (0.92-1.35 Çº) and isothermal titration calorimetry against a series of single-site mutants of the wild-type protein. A crucial threonine thought to be involved in a short bromine-to-oxygen halogen bond to the inhibitors in the wild type has been mutated to the structurally similar residues alanine, cysteine, serine and valine. Overall, structurally, the binding mode of the inhibitors is conserved; however, small but significant geometrical adaptations are observed as a consequence of the spatial and electronic changes at the mutation site. They involve the opening of a central bond angle and shifts in consequence of the lost or gained halogen bonds. Remarkably, the tiny structural changes are responded by partly strong modulation of the thermodynamic profiles. Even though the free energy of binding is maximally perturbed by only 7 kJ/mol, much stronger modulations and shifts in the enthalpy and entropy signatures are revealed, which indicate a pronounced enthalpy/entropy compensation. However, an explanatory correlation can be detected when facing these perturbances against the small structural changes. This also provides deeper insights into how single-site mutations can alter the selectivity profile of closely related ligands against a target protein.

The role of early follow-up computed tomography imaging in the management of traumatic brain injury patients with intracranial hemorrhage.

BACKGROUND: The purpose of this study was to investigate whether routine follow-up computed tomography (CT) for patients with head injury, in the absence of clinical indications, alters patient management. METHODS: Nonpenetrating head injury patients admitted to San Francisco General Hospital during an 18-month period were reviewed. Patients not surgically treated at presentation and with a routine follow-up head CT within 24 hours were included. Surgical and nonsurgical interventions after repeat CT were assessed. Clinical and imaging parameters were correlated with progressive hemorrhagic injury (PHI) and with delayed development of surgical lesions. RESULTS: PHI was identified in 49 (42%) of 116 patients. None of these patients required a nonoperative intervention in response to the PHI. Six of these patients developed a neurologic change concurrent with routine follow-up imaging and required operative intervention. Thus, no patient underwent an intervention in response to a worsening head CT in the absence of clinical findings. Of the six patients who developed a surgical lesion, two had increased intracranial pressure, one had a change in pupillary examination, three had worsening mental status, and one had change in the motor examination. Univariate risk factors for development of a delayed surgical lesion included 5 to 10 mm of midline shift (p = 0.001), basal cistern effacement (p = 0.01), and higher Marshall score (p = 0.01) on initial CT imaging. CONCLUSIONS: Although PHI is common with head injury, delayed interventions in the absence of clinical indicators are uncommon. Our data suggest that early follow-up CT imaging in the setting of head trauma is not routinely indicated. We suggest that assessment, based on the severity of findings on initial brain imaging and serial clinical examinations, should guide the need for follow-up imaging in the setting of head trauma.

Myelomeningocele: characterization of a surgically induced sheep model and its central nervous system similarities and differences to the human disease.

OBJECTIVE: The purpose of this study was to determine how closely the surgically induced sheep myelomeningocele (MMC) model resembles the central nervous system derangements seen in human disease, and identify which aspects of MMC are the result of the early neuronal developmental defect, and which are secondary to the cerebrospinal fluid (CSF) drainage. STUDY DESIGN: An MMC-like lesion was created surgically in 16 fetal sheep at 75 days' gestation: 5 died in utero, 7 underwent no fetal repair, 4 were repaired (2-layer closure or biological glue) at 100 days' gestation. MMC sheep were delivered at term and allowed to survive up to 17 days for analysis of behavioral status and feeding behavior. Animals not repaired in utero were repaired at birth. All lambs were sacrificed and analyzed for hindbrain herniation, hydrocephalus, and other CNS derangements. RESULTS: Hindbrain herniation was observed in 43% of animals not repaired in utero, and in 1 lamb repaired with Bioglue. No animal developed hydrocephalus or other CNS derangements. CONCLUSION: Although this sheep MMC-like model reproduces the CSF leak, but not the developmental defect seen in humans, it suggests CSF leak contributes to hindbrain herniation seen in humans. This model may be useful to develop new minimally invasive techniques to halt CSF leak in utero.

Fetal magnetic resonance imaging enhances detection of spinal cord anomalies in patients with sonographically detected bony anomalies of the spine.

OBJECTIVE: Although fetal magnetic resonance imaging (MRI) is being increasingly used to evaluate sonographically suspected abnormalities, its utility in the evaluation of the spinal canal is not well studied. Because it is not susceptible to the limitations of fetal position, oligohydramnios, and shadowing from bony structures, we hypothesize that fetal MRI is better suited to assess the contents of the spinal canal compared with prenatal sonography. The purpose of this investigation was to determine whether fetal MRI could detect spinal abnormalities in cases in which they had not been originally suspected on prenatal sonography. METHODS: Fetal spine MR images were retrospectively reviewed over a 42-month period. Corresponding sonographic images were then rereviewed to determine whether there were findings in retrospect that might have suggested the cord abnormalities. Cases of myelomeningocele were counted as a spinal cord abnormality only if fetal MRI showed a cord anomaly other than the myelomeningocele. RESULTS: Of 33 cases referred for bony anomalies of the spine, fetal MRI showed additional abnormalities involving the spinal cord in 3 patients. These included diastematomyelia in 2 cases and segmental spinal dysgenesis in the third case. One case of diastematomyelia occurred in association with a lumbosacral myelomeningocele. The spinal cord anomalies were not visible on any of the prenatal sonograms, even in retrospect. CONCLUSIONS: Additional spinal cord anomalies were detected in 10% of cases reviewed. Fetal MRI can be useful in assessing the spinal cord in fetuses with bony spinal anomalies. Our findings suggest that fetuses with sonographically diagnosed bony abnormalities of the spine may benefit from further evaluation with fetal MRI.

Neurophysiological monitoring for safe surgical tethered cord syndrome release in adults.

BACKGROUND: Release of tethered spinal cord by sectioning of the filum terminale carries a significant risk of injury to the neighboring motor and sensory nerve roots. Intraoperative neurophysiological monitoring techniques can help to minimize these adverse neurologic outcomes. METHODS: We performed a retrospective review of 67 consecutive patients undergoing tethered cord release. We excluded 52 pediatric patients which limited our study to 15 adult patients treated during a four year period, including patients with a thick filum, low lying conus, myelomeningocele, filum tumor, spinal cord malformation, and/or lipoma. Clinical outcomes were determined from postoperative follow-up visits. Two patients were lost to follow up and were excluded from the clinical outcome analysis. Electrical stimulation of the filum terminale and lumbo-sacral nerve roots in conjunction with electromyogram (EMG) recording was performed intraoperatively. RESULTS: The mean electrical threshold for EMG response during stimulation of the filum terminale was 37.1 volts (V), range 15 to 100 V. In comparison, the lowest threshold obtained by direct stimulation of the ventral nerve roots was a mean of 1.46 V, with a range of 0.1 to 7 V. More than 70% of the patients studied demonstrated a filum to motor root threshold ratio of 100:1 or greater. No patient developed new neurologic symptoms or signs postoperatively. Bowel and bladder function improved in 46% of patients, back pain in 39% and motor function in 31%. Eight percent reported decline in bladder control and worsening back pain postoperatively. CONCLUSIONS: The often dramatic difference in the threshold of the filum terminale and adjacent motor nerve roots (100:1) helps to identify, isolate, and safely section the filum terminale. Tethered cord release using intraoperative neurophysiological monitoring is safe and in the majority of cases leads to improvement or at least, stabilization of neurologic function. Monitoring prevented intraoperative nerve root injury that might have resulted in immediate onset of new neurologic deficits caused by the surgical procedure.

Central neurocytoma: a review.

Central neurocytomas are rare intraventricular neoplasms of the central nervous system, compromising 0.25-0.5% of brain tumors. The diagnosis and management of these tumors remains controversial since most clinical series are small. Typically, patients with central neurocytomas have a favorable prognosis, but in some cases the clinical course is more aggressive. Although histological features of anaplasia do not predict biologic behavior, proliferation markers including MIB-1 might be more useful in predicting relapse. The most important therapeutic modality is surgery, and a safe maximal resection confers the best long-term outcome. In cases of a subtotal resection,'standard external beam radiation can be added or radiation can be delayed until tumor progression occurs. Smaller residual tumor volumes or recurrences can be treated with more conformal radiation or focused radiosurgery. Re-operation for recurrence should be considered if the procedure can be safely performed. Chemotherapy may be useful for recurrent central neurocytomas that cannot be resected and have been radiated, although long-term responses have not been reported for chemotherapy. Overall, this paper reviews the findings of the larger studies and highlights some of the important case reports that contribute to the current management of central neurocytomas.

The role of PCV chemotherapy in the treatment of central neurocytoma: illustration of a case and review of the literature.

BACKGROUND: Most central neurocytomas follow a benign clinical course. However, more aggressive variants have been described requiring additional surgical resection, radiation, or chemotherapy. Chemotherapy has rarely been used as an adjuvant therapy for central neurocytomas. METHODS: We report a case of a 20-year-old girl who underwent four subtotal resections, over the course of 3 years, for a large central neurocytoma that continued to progress. She was not a candidate for stereotactic radiosurgery, given the large tumor size. To avoid radiation injury in a young patient, she was treated with six cycles of chemotherapy including procarbazine, CCNU, and vincristine. Procarbazine was stopped after 2 cycles because of the development of a rash. Serial magnetic resonance imaging was used to follow treatment response. RESULTS: Her tumor started to decrease in size after 2 cycles of chemotherapy and continued to shrink until it stabilized after 5 cycles of chemotherapy. A small area of residual tumor with minimal enhancement persisted along the left lateral ventricle and remained stable for at least 16 months after the completion of chemotherapy. CONCLUSIONS: To our knowledge, this is only the fourth report describing the use of chemotherapy for progression of central neurocytomas as a treatment alternative to radiation therapy. The use of procarbazine, CCNU, and vincristine has not been previously described for the treatment of a central neurocytoma and presents an additional treatment option.

In utero surgery for hydrocephalus.

INTRODUCTION: Neonatal hydrocephalus is one of the most common congenital anomalies affecting the nervous system. DISCUSSION: Currently, ultrasonography allows for early detection of fetal ventriculomegaly and presents the family with several treatment options: termination of pregnancy, early delivery and neonatal shunting, and delivery at term followed by shunting. Despite ventricular decompression after birth, the cognitive outcome is variable as prolonged in utero hydrocephalus has a detrimental effect. In the early 1980s, fetal intervention was explored with the intention of improving outcome. However, patient selection was poor. Fetal ventriculomegaly from other conditions was not adequately distinguished from fetal hydrocephalus. In addition, fetal surgical techniques were not advanced. Consequently, the results were poor and a de facto moratorium on fetal shunting was imposed. However, recent improvements in fetal imaging, such as magnetic resonance imaging, and advances in fetal surgical techniques offer the possibility that properly selected fetuses with hydrocephalus can benefit from an in utero intervention.

In utero repair of myelomeningocele: experimental pathophysiology, initial clinical experience, and outcomes.

HYPOTHESIS: Experimental work raises the possibility that in utero repair of myelomeningocele (MMC) may improve lower extremity, bladder, and bowel function, ameliorate the Arnold-Chiari malformation, and decrease the need for postnatal shunting. DESIGN: We previously developed fetal lamb models to create and reverse lower extremity damage and the Arnold-Chiari malformation in utero. We then applied our extensive experience with fetal surgery, including fetal endoscopic (fetoscopic) surgical manipulation, to develop techniques for MMC repair. SETTING: A tertiary referral center. PATIENTS: All patients treated between 1998 and 2002 for a prenatally diagnosed MMC. INTERVENTIONS: Either fetoscopic MMC repair, fetoscopic patch repair, or limited maternal hysterotomy and microsurgical 3-layered fetal MMC repair was performed. MAIN OUTCOME MEASURES: Gestational age at delivery, survival, neurologic outcome, and need for ventricular shunting at 1 year. RESULTS: Complete fetoscopic repair was accomplished in 1 fetus. Two other fetuses underwent partial fetoscopic procedures. The remaining 10 patients underwent limited maternal hysterotomy and microsurgical 3-layered fetal MMC repair. Four of 13 patients died, and the mean gestational age at delivery of 11 fetuses born alive was 31 weeks. Five of 9 required ventricular shunting by age 1 year. In 2 patients, lower extremity function improved by more than 2 vertebral levels compared with prenatal ultrasonography. Five of 10 patients who lived longer than 3 weeks required postnatal wound revision within 7 days after birth. CONCLUSIONS: Fetoscopic repair, although feasible, does not yet yield optimal surgical results. Open surgical repair before 22 weeks' gestation is physiologically sound and technically feasible. One third of patients appear to be spared the need for a shunt at age 1 year, but improvement in distal neurologic function is less clear. Additionally, fetal mortality is associated with this procedure. Our results complement the data published by groups at Children's Hospital of Philadelphia, in Pennsylvania, and Vanderbilt University, Nashville, Tenn. A National Institutes of Health-sponsored prospective randomized trial is now underway at these 3 centers to compare fetal repair with postnatal repair.