Gregory G. Heuer

Comparison of endoscopic and microscopic removal of pituitary adenomas: single-surgeon experience and the learning curve.

OBJECT The endoscopic endonasal approach for resection of pituitary lesions is an effective surgical option for tumors of the sella turcica. In this study the authors compared outcomes after either purely endoscopic resection or traditional microscope-aided resection. They also attempted to determine the learning curve associated with a surgical team converting to endoscopic techniques. METHODS Retrospective data were collected on patients who were surgically treated for a pituitary lesion at the Hospital of the University of Pennsylvania between July 2003 and May 2008. Age, sex, race, presenting symptoms, length of hospital stay, surgical approach, duration of surgery, tumor pathological features, gross-total resection (GTR) of tumor, recurrence of the lesion, and intraoperative and postoperative complications were noted. All procedures were performed by the same senior neurosurgeon, who was initially unfamiliar with the endoscopic endonasal approach. RESULTS A total of 25 patients underwent microscopic resection and 25 patients underwent endoscopic resection performed by a single skull base team consisting of the same senior neurosurgeon and otorhinolaryngologist (M.S.G. and B.W.O.). In the microscopically treated cohort, there were 8 intra- or postoperative complications, 6 intraoperative CSF leaks, 17 (77%) of 22 patients had GTR on postoperative imaging, 5 patients underwent >or= 2 operations, and 10 (59%) of 17 patients reported total symptom resolution at follow-up. The endoscopically treated group had 7 intraor postoperative complications and 7 intraoperative CSF leaks. Of the patients who had pre- and postoperative imaging studies, 14 (66%) of 21 endoscopically treated patients had GTR; 4 patients had >or= 2 operations, and 10 (66%) of 15 patients reported complete symptom resolution at follow-up. The first 9 patients who were treated endoscopically had a mean surgical time of 3.42 hours and a mean hospital stay of 4.67 days. The next 8 patients treated had a mean surgical time of 3.11 hours and a mean hospital stay of 3.13 days. The final 8 patients treated endoscopically had a mean surgical time of 2.22 hours and a mean hospital stay of 3.88 days. The difference in length of operation between the first 9 and the last 8 patients treated endoscopically was significantly different. There was a trend toward decreased CSF leaks and other complications from the first 2 groups compared with the third group. CONCLUSIONS In this subset of patients, the use of endoscopic endonasal resection results in a similar complication and symptom resolution rate compared with traditional techniques. The authors postulate that the learning curve for endoscopic resection can be </= 17 procedures.

Predictors of Outcome in Childhood Intracerebral Hemorrhage A Prospective Consecutive Cohort Study

Background and Purpose— The purposes of this study were to describe features of children with intracerebral hemorrhage (ICH) and to determine predictors of short-term outcome in a single-center prospective cohort study. Methods— A single-center prospective consecutive cohort study was conducted of spontaneous ICH in children aged 1 to 18 years from January 2006 to June 2008. Exclusion criteria were inciting trauma; intracranial tumor; isolated epidural, subdural, intraventricular, or subarachnoid hemorrhage; hemorrhagic transformation of ischemic stroke; and cerebral sinovenous thrombosis. Hospitalization records were abstracted. Follow-up assessments included outcome scores using the Pediatric Stroke Outcome Measure and Kings Outcome Scale for Childhood Head Injury. ICH volumes and total brain volumes were measured by manual tracing. Results— Twenty-two patients, median age 10.3 years (range, 4.2 to 16.6 years), had presenting symptoms of headache in 77%, focal deficits 50%, altered mental status 50%, and seizures 41%. Vascular malformations caused hemorrhage in 91%. Surgical treatment (hematoma evacuation, lesion embolization or excision) was performed during acute hospitalization in 50%. One patient died acutely. At a median follow-up of 3.5 months (range, 0.3 to 7.5 months), 71% of survivors had neurological deficits; 55% had clinically significant disability. Outcome based on Pediatric Stroke Outcome Measure and Kings Outcome Scale for Childhood Head Injury scores was worse in patients with ICH volume >2% of total brain volume (P=0.023) and altered mental status at presentation (P=0.005). Conclusions— Spontaneous childhood ICH was due mostly to vascular malformations. Acute surgical intervention was commonly performed. Although death was rare, 71% of survivors had persisting neurological deficits. Larger ICH volume and altered mental status predicted clinically significant disability.

STRADα deficiency results in aberrant mTORC1 signaling during corticogenesis in humans and mice

Polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE) is a rare human autosomal-recessive disorder characterized by abnormal brain development, cognitive disability, and intractable epilepsy. It is caused by homozygous deletions of STE20-related kinase adaptor alpha (STRADA). The underlying pathogenic mechanisms of PMSE and the role of STRADA in cortical development remain unknown. Here, we found that a human PMSE brain exhibits cytomegaly, neuronal heterotopia, and aberrant activation of mammalian target of rapamycin complex 1 (mTORC1) signaling. STRADalpha normally binds and exports the protein kinase LKB1 out of the nucleus, leading to suppression of the mTORC1 pathway. We found that neurons in human PMSE cortex exhibited abnormal nuclear localization of LKB1. To investigate this further, we modeled PMSE in mouse neural progenitor cells (mNPCs) in vitro and in developing mouse cortex in vivo by knocking down STRADalpha expression. STRADalpha-deficient mNPCs were cytomegalic and showed aberrant rapamycin-dependent activation of mTORC1 in association with abnormal nuclear localization of LKB1. Consistent with the observations in human PMSE brain, knockdown of STRADalpha in vivo resulted in cortical malformation, enhanced mTORC1 activation, and abnormal nuclear localization of LKB1. Thus, we suggest that the aberrant nuclear accumulation of LKB1 caused by STRADalpha deficiency contributes to hyperactivation of mTORC1 signaling and disruption of neuronal lamination during corticogenesis, and thereby the neurological features associated with PMSE.

Early Progenitor Cell Marker Expression Distinguishes Type II from Type I Focal Cortical Dysplasias

Type I and type II focal cortical dysplasias (FCDs) exhibit distinct histopathologic features that suggest different pathogenic mechanisms. Type I FCDs are characterized by mild laminar disorganization and hypertrophic neurons, whereas type II FCDs exhibit dramatic laminar disorganization and cytomegalic cells (balloon cells). Both FCD types are associated with intractable epilepsy; therefore, identifying cellular or molecular differences between these lesion types that explains the histologic differences could provide new diagnostic and therapeutic insights. Type II FCDs express nestin, a neuroglial progenitor protein that is modulated in vitro by the stem cell proteins c-Myc, sex-determining region Y-box 2 (SOX2), and Octamer-4 (Oct-4) after activation of mammalian target of rapamycin complex 1 (mTORC1). Because mTORC1 activation has been demonstrated in type II FCDs, we hypothesized that c-Myc, SOX2, and Oct-4 expression would distinguish type II from type I FCDs. In addition, we assayed the expression of progenitor cell proteins forkhead box G1 (FOXG1), Kruppel-like factor 4 (KLF4), Nanog, and SOX3. Differential expression of 7 stem cellproteins and aberrant phosphorylation of2mTORC1 substrates, S6 andS6 kinase 1 proteins, clearly distinguished type II from type I FCDs(n = 10 each). Our results demonstrate new potential pathogenic pathways in type II FCDs and suggest biomarkers for diagnostic pathology in resected epilepsy specimens.

Endovascular and surgical treatment of ruptured cerebral aneurysms in pediatric patients.

OBJECTIVEPediatric cerebral aneurysms are rare. There are very few recent studies that focus on the multidisciplinary treatment of ruptured aneurysms. We reviewed our pediatric endovascular and surgical experience with ruptured cerebral aneurysms. METHODSPediatric patients aged 16 years and younger who were admitted with a diagnosis of aneurysmal subarachnoid hemorrhage and treated at the Childrens Hospital of Philadelphia were included in this analysis. RESULTSTwelve patients with 13 aneurysms (4 male patients and 8 female patients; age range, 4 months–16 years; mean age, 5.1 years), were admitted with subarachnoid hemorrhage during the past 12 years. The majority of patients were admitted in good clinical condition; 31% were in Hunt and Hess Grade II, and 31% were in Hunt and Hess Grade III. The remaining patients were in poor clinical condition and were in Hunt and Hess Grade IV (23%) or Grade V (15%). Computed tomography revealed that 15% of the patients were in Fisher Grade 2, 23% were in Fisher Grade 3, and 62% were in Fisher Grade 4. Endovascular techniques were used in the treatment of 5 aneurysms, and microsurgery was used in the treatment of 8 aneurysms. In the endovascular group, aneurysm sizes ranged from 2 to 35 mm (mean, 12.6 mm); 3 aneurysms were in the anterior circulation, and 2 were in the posterior circulation. In the microsurgery group, 6 aneurysms were in the anterior circulation, and 2 were in the posterior circulation; sizes ranged from 3 to 15 mm (mean, 6.8 mm). Sixty-nine percent of the patients were independent at follow-up. CONCLUSIONContemporary endovascular and microsurgical techniques can be used effectively to treat ruptured cerebral aneurysms in pediatric patients. In the time period studied, the techniques were equally effective when used in the appropriate patients.

Fetal Myelomeningocele Repair: The Post-MOMS Experience at the Children's Hospital of Philadelphia

Background: Fetal myelomeningocele (fMMC) repair has become accepted as a standard of care option in selected circumstances. We reviewed our outcomes for fMMC repair from referral and evaluation through surgery, delivery and neonatal discharge. Material and Methods: All patients referred for potential fMMC repair were reviewed from January 1, 2011 through March 7, 2014. Maternal and neonatal data were collected on the 100 patients who underwent surgery. Results: 29% of those evaluated met the criteria and underwent fMMC repair (100 cases). The average gestational age was 21.9 weeks at evaluation and 23.4 weeks at fMMC repair. Complications included membrane separation (22.9%), preterm premature rupture of membranes (32.3%) and preterm labor (37.5%). Average gestational age at delivery was 34.3 weeks and 54.2% delivered at ≥35 weeks. The perinatal loss rate was 6.1% (2 intrauterine fetal demises and 4 neonatal demises); 90.8% of women delivered at the Childrens Hospital of Philadelphia and 3.4% received transfusions. With regard to the neonates, 2 received ventriculoperitoneal shunts prior to discharge; 71.1% of neonates had no evidence of hindbrain herniation on MRI. Of the 80 neonates evaluated, 55% were assigned a functional level of one or more better than the prenatal anatomic level. Conclusion: In an experienced program, maternal and neonatal outcomes for patients undergoing fMMC repair are comparable to results of the MOMS trial.

Barbiturate infusion for intractable intracranial hypertension and its effect on brain oxygenation.

OBJECTIVEBarbiturate-induced coma can be used in patients to treat intractable intracranial hypertension when other therapies, such as osmotic therapy and sedation, have failed. Despite control of intracranial pressure, cerebral infarction may still occur in some patients, and the effect of barbiturates on outcome remains uncertain. In this study, we examined the relationship between barbiturate infusion and brain tissue oxygen (PbtO2). METHODSTen volume-resuscitated brain-injured patients who were treated with pentobarbital infusion for intracranial hypertension and underwent PbtO2 monitoring were studied in a neurosurgical intensive care unit at a university-based Level I trauma center. PbtO2, intracranial pressure (ICP), mean arterial pressure, cerebral perfusion pressure (CPP), and brain temperature were continuously monitored and compared in settings in which barbiturates were or were not administered. RESULTSData were available from 1595 hours of PbtO2 monitoring. When pentobarbital administration began, the mean ICP, CPP, and PbtO2 were 18 ± 10, 72 ± 18, and 28 ± 12 mm Hg, respectively. During the 3 hours before barbiturate infusion, the maximum ICP was 24 ± 13 mm Hg and the minimum CPP was 65 ± 20 mm Hg. In the majority of patients (70%), we observed an increase in PbtO2 associated with pentobarbital infusion. Within this group, logistic regression analysis demonstrated that a higher likelihood of compromised brain oxygen (PbtO2 < 20 mm Hg) was associated with a decrease in pentobarbital dose after controlling for ICP and other physiological parameters (P < 0.001). In the remaining 3 patients, pentobarbital was associated with lower PbtO2 levels. These patients had higher ICP, lower CPP, and later initiation of barbiturates compared with patients whose PbtO2 increased. CONCLUSIONOur preliminary findings suggest that pentobarbital administered for intractable intracranial hypertension is associated with a significant and independent increase in PbtO2 in the majority of patients. However, in some patients with more compromised brain physiology, pentobarbital may have a negative effect on PbtO2, particularly if administered late. Larger studies are needed to examine the relationship between barbiturates and cerebral oxygenation in brain-injured patients with refractory intracranial hypertension and to determine whether PbtO2 responses can help guide therapy.

Selective neurodegeneration in murine mucopolysaccharidosis VII is progressive and reversible.

The mucopolysaccharidoses are caused by inherited deficiencies of lysosomal enzymes involved in the degradative pathway of glycosaminoglycans. Lysosomal storage leads to cellular and organ dysfunction, including mental retardation. Storage lesions are found throughout the diseased brain, but little is known about the cellular and molecular mechanisms that underlie brain dysfunction. In the mouse model of mucopolysaccharidosis VII, we found that specific regions of the brain are vulnerable to neurodegeneration, characterized by the presence of ubiquitin inclusions, neurofilament inclusions, and reactive astrogliosis. The pathological lesions were found predominantly in the hippocampus and cerebral cortex, and they increased progressively with age. Treatment with a recombinant viral vector to correct the enzymatic defect quantitatively reversed the neurodegenerative lesions in targeted regions to normal levels.

Lumbar vertebral hemangioma presenting with the acute onset of neurological symptoms : Case report

Vertebral hemangiomas are common entities that rarely present with neurological deficits. The authors report the unusual case of a large L-3 vertebral hemangioma with epidural extension in a 27-year-old woman who presented with hip flexor and quadriceps weakness, foot drop, and leg pain. The characteristics of the mass on magnetic resonance imaging suggested an aggressive, hypervascular lesion. The patient underwent embolization of the lesion followed by direct intralesional injection of ethanol. Significant resolution of clinical symptoms was observed immediately after the procedure and at her follow-up visits. Follow-up imaging studies obtained 9 months after the procedure also documented a considerable reduction in the size of the hemangioma with minimal loss of vertebral height and a mild kyphosis at the affected level. On repeated imaging studies obtained 21 months postoperatively, the size of the hemangioma and the degree of vertebral body compression were stable. As demonstrated in this case, patients with vertebral hemangiomas can present with acute nerve root compression and signs and symptoms similar to those of disc herniation. Vertebral hemangiomas can be treated effectively with interventional techniques such as embolization and ethanol injection.

Follow-up Imaging to Detect Recurrence of Surgically Treated Pediatric Arteriovenous Malformations

OBJECT The true postoperative incidence of arteriovenous malformation (AVM) recurrence in the pediatric population remains largely unreported. Some literature suggests that delayed imaging studies should be obtained at 6 months to 1 year after negative findings on a postoperative angiogram. The aim of this study was to describe the timing of AVM recurrences after resection and the neuroimaging modalities on which the recurrences were detected. METHODS This study was performed in a retrospective cohort of all pediatric patients treated surgically for AVM resection by a single neurosurgeon between 2005 and 2010. Patients were followed after resection with MR angiography (MRA) or conventional angiography, when possible, at various time points. A visual scale for compactness of the initial AVM nidus was used, and the score was correlated with probability of recurrence after surgery. RESULTS A total of 28 patients (13 female, 15 male) underwent an AVM resection. In 18 patients (64.3%) an intraoperative angiogram was obtained. In 4 cases the intraoperative angiogram revealed residual AVM, and repeat resections were performed immediately. Recurrent AVMs were found in 4 children (14.3%) at 50, 51, 56, and 60 weeks after the initial resection. Recurrence risk was 0.08 per person-year. No patient with normal results on an angiogram obtained at 1 year developed a recurrence on either a 5-year angiogram or one obtained at 18 years of age. All patients with recurrence had a compactness score of 1 (diffuse AVM); a lower compactness score was associated with recurrence (p = 0.0003). CONCLUSIONS All recurrences in this cohort occurred less than 15 months from the initial resection. The authors recommend intraoperative angiography to help ensure complete resection at the time of the surgery. Follow-up vascular imaging is crucial for detecting recurrent AVMs, and conventional angiography is preferred because MRA can miss smaller AVMs. One-year follow-up imaging detected these recurrences, and no one who had negative results on an angiogram obtained at 1 year had a late recurrence. However, not all of the patients have been followed for 5 years or until 18 years of age, so longer follow-up is required for these patients. A lower compactness score predicted recurrent AVM in this cohort.