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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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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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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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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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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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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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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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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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Andrew T. Hale, P. David Adelson, Gregory W. Albert, Philipp R. Aldana, Tord D. Alden, Richard C. E. Anderson, David F. Bauer, Christopher M. Bonfield, Douglas L. Brockmeyer, Joshua J. Chern, Daniel E. Couture, David J. Daniels, 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, Gregory G. Heuer, Mark Iantosca, Bermans J. Iskandar, Eric M. Jackson, James M. Johnston, Robert F. Keating, Jeffrey R. Leonard, Cormac O. Maher, Francesco T. Mangano, J. Gordon McComb, Thanda Meehan, Arnold H. Menezes, Brent O’Neill, Greg Olavarria, Tae Sung Park, John Ragheb, Nathan R. Selden, Manish N. Shah, Matthew D. Smyth, Scellig S. D. Stone, Jennifer M. Strahle, Scott D. Wait, John C. Wellons, William E. Whitehead, Chevis N. Shannon, David D. Limbrick Jr. and for the Park-Reeves Syringomyelia Research Consortium Investigators

OBJECTIVE

Factors associated with syrinx size in pediatric patients undergoing posterior fossa decompression (PFD) or PFD with duraplasty (PFDD) for Chiari malformation type I (CM-I) with syringomyelia (SM; CM-I+SM) are not well established.

METHODS

Using the Park-Reeves Syringomyelia Research Consortium registry, the authors analyzed variables associated with syrinx radiological outcomes in patients (< 20 years old at the time of surgery) with CM-I+SM undergoing PFD or PFDD. Syrinx resolution was defined as an anteroposterior (AP) diameter of ≤ 2 mm or ≤ 3 mm or a reduction in AP diameter of ≥ 50%. Syrinx regression or progression was defined using 1) change in syrinx AP diameter (≥ 1 mm), or 2) change in syrinx length (craniocaudal, ≥ 1 vertebral level). Syrinx stability was defined as a < 1-mm change in syrinx AP diameter and no change in syrinx length.

RESULTS

The authors identified 380 patients with CM-I+SM who underwent PFD or PFDD. Cox proportional hazards modeling revealed younger age at surgery and PFDD as being independently associated with syrinx resolution, defined as a ≤ 2-mm or ≤ 3-mm AP diameter or ≥ 50% reduction in AP diameter. Radiological syrinx resolution was associated with improvement in headache (p < 0.005) and neck pain (p < 0.011) after PFD or PFDD. Next, PFDD (p = 0.005), scoliosis (p = 0.007), and syrinx location across multiple spinal segments (p = 0.001) were associated with syrinx diameter regression, whereas increased preoperative frontal-occipital horn ratio (FOHR; p = 0.007) and syrinx location spanning multiple spinal segments (p = 0.04) were associated with syrinx length regression. Scoliosis (HR 0.38 [95% CI 0.16–0.91], p = 0.03) and smaller syrinx diameter (5.82 ± 3.38 vs 7.86 ± 3.05 mm; HR 0.60 [95% CI 0.34–1.03], p = 0.002) were associated with syrinx diameter stability, whereas shorter preoperative syrinx length (5.75 ± 4.01 vs 9.65 ± 4.31 levels; HR 0.21 [95% CI 0.12–0.38], p = 0.0001) and smaller pB-C2 distance (6.86 ± 1.27 vs 7.18 ± 1.38 mm; HR 1.44 [95% CI 1.02–2.05], p = 0.04) were associated with syrinx length stability. Finally, younger age at surgery (8.19 ± 5.02 vs 10.29 ± 4.25 years; HR 1.89 [95% CI 1.31–3.04], p = 0.01) was associated with syrinx diameter progression, whereas increased postoperative syrinx diameter (6.73 ± 3.64 vs 3.97 ± 3.07 mm; HR 3.10 [95% CI 1.67–5.76], p = 0.003), was associated with syrinx length progression. PFD versus PFDD was not associated with syrinx progression or reoperation rate.

CONCLUSIONS

These data suggest that PFDD and age are independently associated with radiological syrinx improvement, although forthcoming results from the PFDD versus PFD randomized controlled trial (NCT02669836, clinicaltrials.gov) will best answer this question.