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David Satzer and Daniel J. Guillaume

Object

Brainstem dysfunction occurs in a minority of patients with myelomeningocele (MMC), most of whom have Chiari Type II malformation. Some surgeons advocate early identification of these patients for craniocervical decompression to avoid significant mortality. The auditory brainstem response has been found to be abnormal in most children with MMC. The present study examines whether failure of routine newborn hearing screening (NHS) predicts brainstem dysfunction in MMC patients.

Methods

The charts of 40 newborns with MMC and 50 newborns without MMC who stayed in the neonatal intensive care unit were reviewed. Results of NHS, brainstem symptoms, birth demographics, and surgical history were retrospectively examined. Differences in the presence and onset of brainstem symptoms by NHS result were assessed.

Results

Failure of NHS was more common among newborns with MMC who developed brainstem symptoms (31%, 4 of 13 patients) than among newborns without MMC (0%, 0 of 50 patients; p = 0.001). Among the 40 newborns with MMC, brainstem symptoms were more common in those who failed NHS (80%, 4 of 5 patients) than in those who passed (26%, 9 of 35 patients; p = 0.031). Respiratory symptom onset occurred later in patients who failed NHS (median 16 months) than among those who passed (median 0 months; p = 0.022). The positive and negative predictive values of NHS for brainstem dysfunction in MMC were 0.80 and 0.74, respectively.

Conclusions

Results of NHS may help predict future brainstem dysfunction in patients with MMC and may be useful to incorporate into prognostic assessment and surgical decision making.

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Daniel J. Guillaume and Su-Chun Zhang

✓ The primary therapeutic goal of embryonic stem cell (ESC) research is cell replacement therapy. During the last decade, great strides have been made in developing in vitro protocols for differentiating human ESCs into neuroepithelial progenitors. More recent progress has been made in further directing them into becoming cells with specialized regional and neurotransmitter identities, such as midbrain dopaminergic and spinal motor neurons. Along with directed differentiation, other current efforts are aimed at efficient enrichment, avoidance of immune rejection, demonstration of functional integration, genetic modification to regulate neurotransmitter and factor release, directed axon growth, in vivo cell tracking, and measures to ensure safety. This review will focus on the potential of ESCs as a source of transplantable cells for use in cell replacement therapy.

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Bharathi D. Jagadeesan, Andrew W. Grande, Daniel J. Guillaume, David R. Nascene, and Ramachandra P. Tummala

Dural sinus malformations (DSMs) are rare congenital malformations that can be midline or lateral in location. Midline DSMs have been reported to have a worse prognosis than lateral DSMs and have traditionally been more difficult to manage. The authors report 2 unusual manifestations of midline DSMs and their management with percutaneous transfontanelle embolization. The first patient (Case 1) presented at 21 days of life with a large midline DSM and multiple highflow dural and pial arteriovenous shunts. The child developed congestive cardiac failure and venous congestion with intracranial hemorrhage and seizures within a few weeks. The second patient (Case 2) presented with a large midline DSM found on prenatal imaging that was determined to be a purely venous malformation on postnatal evaluation. This large malformation resulted in consumptive coagulopathy and apneic episodes from brainstem compression. The patient in Case 1 was treated initially with endovascular embolization and eventually with curative percutaneous-transfontanelle embolization. The patient in Case 2 was treated with percutaneous transfontanelle embolization in combination with posterior fossa decompression and cranial expansion surgery.

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Mark P. Piedra, Eric M. Thompson, Nathan R. Selden, Brian T. Ragel, and Daniel J. Guillaume

Object

The object of this study was to determine if early cranioplasty after decompressive craniectomy for elevated intracranial pressure in children reduces complications.

Methods

Sixty-one consecutive cases involving pediatric patients who underwent autologous cranioplasty after decompressive craniectomy for raised intracranial pressure at a single academic children's hospital over 15 years were studied retrospectively.

Results

Sixty-one patients were divided into early (< 6 weeks; 28 patients) and late (≥ 6 weeks; 33 patients) cranioplasty cohorts. The cohorts were similar except for slightly lower age in the early (8.03 years) than the late (10.8 years) cranioplasty cohort (p < 0.05). Bone resorption after cranioplasty was significantly more common in the late (42%) than the early (14%) cranioplasty cohort (p < 0.05; OR 5.4). No other complication differed in incidence between the cohorts.

Conclusions

After decompressive craniectomy for raised intracranial pressure in children, early (< 6 weeks) cranioplasty reduces the occurrence of reoperation for bone resorption, without altering the incidence of other complications.

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Daniel J. Guillaume, Stephen L. Huhn, Nathan R. Selden, and Robert D. Steiner

✓ Successful cellular replacement in the diseased human central nervous system (CNS) faces numerous hurdles. In this first installment of a 2-part review, the authors report on the preclinical challenges involved in preparing for a major Phase I trial investigating the safety of human neural stem cell transplantation in a lysosomal storage disorder. Specifically, they discuss choice of the ideal disease for treatment, best donor cell type and source for implantation, the in vitro and in vivo methods used to estimate safety and efficacy, the challenges to noninvasive tracking of cells after transplantation, and the unique issues related to the immunology of CNS cellular transplantation.

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Bharathi D. Jagadeesan, Haralabos Zacharatos, David R. Nascene, Andrew W. Grande, Daniel J. Guillaume, and Ramachandra P. Tummala

A 5-month-old infant was to be treated with elective transarterial embolization for a vein of Galen aneurysmal malformation (VGAM). A team of endovascular surgical neuroradiologists, pediatric interventional radiologists, and pediatric cardiologists attempted conventional femoral arterial access, which was unsuccessful given the small caliber of the femoral arteries and superimposed severe vasospasm. Thereafter, eventual arterial access was achieved by navigating from the venous to the arterial system across the patent foramen ovale following a right femoral venous access. Embolization was then successfully performed. At a later date, the child underwent successful transvenous balloon-assisted embolization and eventual arterial embolization with cure of the VGAM.

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Nathan R. Selden, Daniel J. Guillaume, Robert D. Steiner, and Stephen L. Huhn

✓ Cellular replacement therapy attempts to improve functioning of the diseased human central nervous system (CNS). In this second installment of a 2-part review, the authors discuss the major challenges to the translation of in vitro and animal studies of neural stem cell (NSC) therapy in the clinical setting. This analysis details the problems unique to the design of clinical trials using human NSCs, outlines patient selection practices, describes surgical techniques for cellular transplantation, and reviews the regulatory issues and ethical concerns in trials involving neurologically impaired children.

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Daniel J. Guillaume, Kristin Knight, Carol Marquez, Dale F. Kraemer, Dianna M. E. Bardo, and Edward A. Neuwelt

Object

Cerebrospinal fluid shunting has previously been associated with hearing loss. Although the mechanism for this is unclear, it is thought that changes in CSF pressure can affect cochlear physiology via endolymph expansion in the setting of a patent cochlear aqueduct. Patients undergoing radiation and cisplatin chemotherapy are at risk for hearing loss. The authors hypothesized that the incidence and severity of hearing loss in patients undergoing radiation and chemotherapy for medulloblastoma would be greater in those with shunts than in those without shunts.

Methods

Baseline and longitudinal audiology data were collected in 33 patients with medulloblastoma who were receiving radiation and cisplatin chemotherapy. Additional data included age, sex, details of shunt placement and revision, and details of chemotherapy and radiation. Hearing sensitivity and peripheral auditory function measures included pure tone audiometry, immittance audiometry, and distortion product evoked otoacoustic emissions. Ototoxicity was determined according to the American Speech-Language-Hearing Association criteria. Severity of hearing loss was determined using the Brock hearing loss grades. Incidence of hearing loss and association with shunting was determined.

Results

Thirteen (39.4%) of the 33 patients evaluated had undergone shunt placement. Hearing loss occurred in 14 (70%) of 20 patients without shunts and in 13 (100%) of 13 patients with shunts. The difference between the rates of hearing loss in patients with shunts versus those without the devices was highly significant (p = 0.0008). The odds ratio for hearing loss in patients with a CSF shunt compared with those without a shunt was 23.49 (95% CI 4.21–131.15). Age, side of shunt, evidence of dissemination, diameter of cochlear aqueduct, and treatment protocol did not have a significant effect on shunt-related ototoxicity.

Conclusions

This study suggests an independent association between CSF shunting and hearing loss in children undergoing treatment for medulloblastoma, laying the foundation for a prospective study evaluating hearing loss in children with shunts who are not treated with ototoxic therapy.

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Nathan R. Selden, Amira Al-Uzri, Stephen L. Huhn, Thomas K. Koch, Darryn M. Sikora, Mina D. Nguyen-Driver, Daniel J. Guillaume, Jeffrey L. Koh, Sakir H. Gultekin, James C. Anderson, Hannes Vogel, Trenna L. Sutcliffe, Yakop Jacobs, and Robert D. Steiner

Object

Infantile and late-infantile neuronal ceroid lipofuscinoses (NCLs) are invariably fatal lysosomal storage diseases associated with defects in lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT-1) or tripeptidyl peptidase 1 (TPP1) activity. Previous preclinical studies have demonstrated that human CNS stem cells (HuCNS-SCs) produce both PPT-1 and TPP1 and result in donor cell engraftment and reduced accumulation of storage material in the brain when tested in an NCL mouse model.

Methods

HuCNS-SC transplantation was tested in an open-label dose-escalation Phase I clinical trial as a potential treatment for infantile and late-infantile NCL. Study design included direct neurosurgical transplantation of allogeneic HuCNS-SCs into the cerebral hemispheres and lateral ventricles accompanied by 12 months of immunosuppression.

Results

Six children with either the infantile or late-infantile forms of NCL underwent low- (3 patients) and high- (3 patients) dose transplantation of HuCNS-SCs followed by immunosuppression. The surgery, immunosuppression, and cell transplantation were well tolerated. Adverse events following transplantation were consistent with the underlying disease, and none were directly attributed to the donor cells. Observations regarding efficacy of the intervention were limited by the enrollment criteria requiring that patients be in advanced stages of disease.

Conclusions

This study represents the first-in-human clinical trial involving transplantation of a purified population of human neural stem cells for a neurodegenerative disorder. The feasibility of this approach and absence of transplantation-related serious adverse events support further exploration of HuCNS-SC transplantation as a potential treatment for select subtypes of NCL, and possibly for other neurodegenerative disorders. Clinical trial registration no.: NCT00337636 (ClinicalTrials.gov).

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Alexander T. Yahanda, P. David Adelson, S. Hassan A. Akbari, Gregory W. Albert, Philipp R. Aldana, Tord D. Alden, Richard C. E. Anderson, David F. Bauer, Tammy Bethel-Anderson, Douglas L. Brockmeyer, Joshua J. Chern, Daniel E. Couture, David J. Daniels, Brian J. Dlouhy, Susan R. Durham, Richard G. Ellenbogen, Ramin Eskandari, Timothy M. George, Gerald A. Grant, Patrick C. Graupman, Stephanie Greene, Jeffrey P. Greenfield, Naina L. Gross, Daniel J. Guillaume, Todd C. Hankinson, Gregory G. Heuer, Mark Iantosca, Bermans J. Iskandar, Eric M. Jackson, James M. Johnston, Robert F. Keating, Mark D. Krieger, Jeffrey R. Leonard, Cormac O. Maher, Francesco T. Mangano, J. Gordon McComb, Sean D. McEvoy, Thanda Meehan, Arnold H. Menezes, Brent R. O’Neill, Greg Olavarria, John Ragheb, Nathan R. Selden, Manish N. Shah, Chevis N. Shannon, Joshua S. Shimony, Matthew D. Smyth, Scellig S. D. Stone, Jennifer M. Strahle, James C. Torner, Gerald F. Tuite, Scott D. Wait, John C. Wellons III, William E. Whitehead, Tae Sung Park, and David D. Limbrick Jr.

OBJECTIVE

Posterior fossa decompression with duraplasty (PFDD) is commonly performed for Chiari I malformation (CM-I) with syringomyelia (SM). However, complication rates associated with various dural graft types are not well established. The objective of this study was to elucidate complication rates within 6 months of surgery among autograft and commonly used nonautologous grafts for pediatric patients who underwent PFDD for CM-I/SM.

METHODS

The Park-Reeves Syringomyelia Research Consortium database was queried for pediatric patients who had undergone PFDD for CM-I with SM. All patients had tonsillar ectopia ≥ 5 mm, syrinx diameter ≥ 3 mm, and ≥ 6 months of postoperative follow-up after PFDD. Complications (e.g., pseudomeningocele, CSF leak, meningitis, and hydrocephalus) and postoperative changes in syrinx size, headaches, and neck pain were compared for autograft versus nonautologous graft.

RESULTS

A total of 781 PFDD cases were analyzed (359 autograft, 422 nonautologous graft). Nonautologous grafts included bovine pericardium (n = 63), bovine collagen (n = 225), synthetic (n = 99), and human cadaveric allograft (n = 35). Autograft (103/359, 28.7%) had a similar overall complication rate compared to nonautologous graft (143/422, 33.9%) (p = 0.12). However, nonautologous graft was associated with significantly higher rates of pseudomeningocele (p = 0.04) and meningitis (p < 0.001). The higher rate of meningitis was influenced particularly by the higher rate of chemical meningitis (p = 0.002) versus infectious meningitis (p = 0.132). Among 4 types of nonautologous grafts, there were differences in complication rates (p = 0.02), including chemical meningitis (p = 0.01) and postoperative nausea/vomiting (p = 0.03). Allograft demonstrated the lowest complication rates overall (14.3%) and yielded significantly fewer complications compared to bovine collagen (p = 0.02) and synthetic (p = 0.003) grafts. Synthetic graft yielded higher complication rates than autograft (p = 0.01). Autograft and nonautologous graft resulted in equal improvements in syrinx size (p < 0.0001). No differences were found for postoperative changes in headaches or neck pain.

CONCLUSIONS

In the largest multicenter cohort to date, complication rates for dural autograft and nonautologous graft are similar after PFDD for CM-I/SM, although nonautologous graft results in higher rates of pseudomeningocele and meningitis. Rates of meningitis differ among nonautologous graft types. Autograft and nonautologous graft are equivalent for reducing syrinx size, headaches, and neck pain.