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Mandeep S. Tamber and James T. Rutka

The purpose of this review is to highlight some of the pertinent concepts and controversies surrounding the diagnosis and treatment of pediatric supratentorial high-grade gliomas. Unlike the adult counterparts, pediatric high-grade gliomas are likely derived from distinct cytogenetic and molecular alterations. Surgery has been shown to play a role in extending patient survival. Some success is associated with the provision of chemotherapy. Radiotherapy remains an important adjunct in children older than age 3 years. The challenges involved in improving the poor prognosis of children in whom these very aggressive tumors have been diagnosed will be discussed, as well as some of the novel approaches being investigated to improve patient survival and quality of life.

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Ann Marie Flannery, Ann-Christine Duhaime, Mandeep S. Tamber and Joanna Kemp

Object

This systematic review was undertaken to answer the following question: Do technical adjuvants such as ventricular endoscopic placement, computer-assisted electromagnetic guidance, or ultrasound guidance improve ventricular shunt function and survival?

Methods

The US National Library of Medicine PubMed/MEDLINE database and the Cochrane Database of Systematic Reviews were queried using MeSH headings and key words specifically chosen to identify published articles detailing the use of cerebrospinal fluid shunts for the treatment of pediatric hydrocephalus. Articles meeting specific criteria that had been delineated a priori were then examined, and data were abstracted and compiled in evidentiary tables. These data were then analyzed by the Pediatric Hydrocephalus Systematic Review and Evidence-Based Guidelines Task Force to consider evidence-based treatment recommendations.

Results

The search yielded 163 abstracts, which were screened for potential relevance to the application of technical adjuvants in shunt placement. Fourteen articles were selected for full-text review. One additional article was selected during a review of literature citations. Eight of these articles were included in the final recommendations concerning the use of endoscopy, ultrasonography, and electromagnetic image guidance during shunt placement, whereas the remaining articles were excluded due to poor evidence or lack of relevance.

The evidence included 1 Class I, 1 Class II, and 6 Class III papers. An evidentiary table of relevant articles was created.

Conclusions

Recommendation: There is insufficient evidence to recommend the use of endoscopic guidance for routine ventricular catheter placement. Strength of Recommendation: Level I, high degree of clinical certainty.

Recommendation: The routine use of ultrasound-assisted catheter placement is an option. Strength of Recommendation: Level III, unclear clinical certainty.

Recommendation: The routine use of computer-assisted electromagnetic (EM) navigation is an option. Strength of Recommendation: Level III, unclear clinical certainty.

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Mandeep S. Tamber, Paul Klimo Jr., Catherine A. Mazzola and Ann Marie Flannery

Object

The objective of this systematic review was to answer the following question: What is the optimal treatment strategy for CSF shunt infection in pediatric patients with hydrocephalus?

Methods

The US National Library of Medicine and the Cochrane Database of Systematic Reviews were queried using MeSH headings and key words relevant to the objective of this systematic review. Abstracts were reviewed, after which studies meeting the inclusion criteria were selected and graded according to their quality of evidence (Classes I–III). Evidentiary tables were constructed that summarized pertinent study results, and based on the quality of the literature, recommendations were made (Levels I–III).

Results

A review and critical appraisal of 27 studies that met the inclusion criteria allowed for a recommendation for supplementation of antibiotic treatment using partial (externalization) or complete shunt hardware removal, with a moderate degree of clinical certainty. However, a recommendation regarding whether complete shunt removal is favored over partial shunt removal (that is, externalization) could not be made owing to severe methodological deficiencies in the existing literature. There is insufficient evidence to recommend the use of intrathecal antibiotic therapy as an adjunct to systemic antibiotic therapy in the management of routine CSF shunt infections. This also holds true for other clinical scenarios such as when an infected CSF shunt cannot be completely removed, when a shunt must be removed and immediately replaced in the face of ongoing CSF infection, or when the setting is ventricular shunt infection caused by specific organisms (for example, gram-negative bacteria).

Conclusions

Supplementation of antibiotic treatment with partial (externalization) or complete shunt hardware removal are options in the management of CSF shunt infection. There is insufficient evidence to recommend either shunt externalization or complete shunt removal as the preferred surgical strategy for the management of CSF shunt infection. Therefore, clinical judgment is required. In addition, there is insufficient evidence to recommend the combination of intrathecal and systemic antibiotics for patients with CSF shunt infection when the infected shunt hardware cannot be fully removed, when the shunt must be removed and immediately replaced, or when the CSF shunt infection is caused by specific organisms. The potential neurotoxicity of intrathecal antibiotic therapy may limit its routine use.

Recommendation: Supplementation of antibiotic treatment with partial (externalization) or with complete shunt hardware removal is an option in the management of CSF shunt infection. Strength of Recommendation: Level II, moderate degree of clinical certainty.

Recommendation: There is insufficient evidence to recommend either shunt externalization or complete shunt removal as a preferred surgical strategy for the management of CSF shunt infection. Therefore, clinical judgment is required. Strength of Recommendation: Level III, unclear degree of clinical certainty.

Recommendation: There is insufficient evidence to recommend the combination of intrathecal and systemic antibiotics for patients with CSF shunt infection in whom the infected shunt hardware cannot be fully removed or must be removed and immediately replaced, or when the CSF shunt infection is caused by specific organisms. The potential neurotoxicity of intrathecal antibiotic therapy may limit its routine use. Strength of Recommendation: Level III, unclear degree of clinical certainty.

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Joanna Kemp, Ann Marie Flannery, Mandeep S. Tamber and Ann-Christine Duhaime

Object

The objective of this guideline was to answer the following question: Do the entry point and position of the ventricular catheter have an effect on shunt function and survival?

Methods

Both the US National Library of Medicine/MEDLINE database and the Cochrane Database of Systematic Reviews were queried using MeSH headings and key words specifically chosen to identify published articles detailing the use of CSF shunts for the treatment of pediatric hydrocephalus. Articles meeting specific criteria that had been delineated a priori were then examined, and data were abstracted and compiled in evidentiary tables.

Results

The search yielded 184 abstracts, which were screened for potential relevance to the clinical question of the effect of ventricular catheter entry site on shunt survival. An initial review of the abstracts identified 14 papers that met the inclusion criteria, and these were recalled for full-text review. After review of these articles, only 4 were noted to be relevant for an analysis of the impact of entry point on shunt survival; an additional paper was retrieved during the review of full-text articles and was included as evidence to support the recommendation. The evidence included 1 Class II paper and 4 Class III papers. An evidentiary table was created including the relevant articles.

Conclusion

Recommendation: There is insufficient evidence to recommend the occipital versus frontal point of entry for the ventricular catheter; therefore, both entry points are options for the treatment of pediatric hydrocephalus. Strength of Recommendation: Level III, unclear degree of clinical certainty.

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Xiao Zhu, Michael M. McDowell, William C. Newman, Gary E. Mason, Stephanie Greene and Mandeep S. Tamber

Nivolumab is an immune checkpoint inhibitor (ICI) currently undergoing Phase III clinical trials for the treatment of glioblastoma. The authors present the case of a 10-year-old girl with glioblastoma treated with nivolumab under compassionate-use guidelines. After the first dose of nivolumab the patient developed hemiparesis, cerebral edema, and significant midline shift due to severe tumor necrosis. She was managed using intravenous dexamethasone and discharged on a dexamethasone taper. The patient's condition rapidly deteriorated after the second dose of nivolumab, demonstrating hemiplegia, seizures, and eventually unresponsiveness with a fixed and dilated left pupil. Computed tomography of her brain revealed malignant cerebral edema requiring emergency decompressive hemicraniectomy. Repeat imaging demonstrated increased size of the lesion, reflecting immune-mediated inflammation and tumor necrosis. The patient remained densely hemiplegic, but became progressively more interactive and was ultimately extubated. She resumed nivolumab several weeks later, but again her condition deteriorated with headache, vomiting, swelling at the craniectomy site, and limited right-sided facial movement following the sixth dose. MRI demonstrated severe midline shift and uncal herniation despite her craniectomy. Her condition gradually declined, and she died several days later under “do not resuscitate/do not intubate” orders. To the authors' knowledge, this represents the first case of malignant cerebral edema requiring operative intervention following nivolumab treatment for glioblastoma in a pediatric patient.

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Abhaya V. Kulkarni, Jay Riva-Cambrin, Samuel R. Browd, James M. Drake, Richard Holubkov, John R. W. Kestle, David D. Limbrick, Curtis J. Rozzelle, Tamara D. Simon, Mandeep S. Tamber, John C. Wellons III and William E. Whitehead

Object

The use of endoscopic third ventriculostomy (ETV) with choroid plexus cauterization (CPC) has been advocated as an alternative to CSF shunting in infants with hydrocephalus. There are limited reports of this procedure in the North American population, however. The authors provide a retrospective review of the experience with combined ETV + CPC within the North American Hydrocephalus Clinical Research Network (HCRN).

Methods

All children (< 2 years old) who underwent an ETV + CPC at one of 7 HCRN centers before November 2012 were included. Data were collected retrospectively through review of hospital records and the HCRN registry. Comparisons were made to a contemporaneous cohort of 758 children who received their first shunt at < 2 years of age within the HCRN.

Results

Thirty-six patients with ETV + CPC were included (13 with previous shunt). The etiologies of hydrocephalus were as follows: intraventricular hemorrhage of prematurity (9 patients), aqueductal stenosis (8), myelomeningocele (4), and other (15). There were no major intraoperative or early postoperative complications. There were 2 postoperative CSF infections. There were 2 deaths unrelated to hydrocephalus and 1 death from seizure. In 18 patients ETV + CPC failed at a median time of 30 days after surgery (range 4–484 days). The actuarial 3-, 6-, and 12-month success for ETV + CPC was 58%, 52%, and 52%. Time to treatment failure was slightly worse for the 36 patients with ETV + CPC compared with the 758 infants treated with shunts (p = 0.012). Near-complete CPC (≥ 90%) was achieved in 11 cases (31%) overall, but in 50% (10 of 20 cases) in 2012 versus 6% (1 of 16 cases) before 2012 (p = 0.009). Failure was higher in children with < 90% CPC (HR 4.39, 95% CI 0.999–19.2, p = 0.0501).

Conclusions

The early North American multicenter experience with ETV + CPC in infants demonstrates that the procedure has reasonable safety in selected cases. The degree of CPC achieved might be associated with a surgeon's learning curve and appears to affect success, suggesting that surgeon training might improve results.

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Mony Benifla, Francesco Sala, John Jane Jr., Hiroshi Otsubo, Ayako Ochi, James Drake, Shelly Weiss, Elizabeth Donner, Ayataka Fujimoto, Stephanie Holowka, Elysa Widjaja, O. Carter Snead III, Mary Lou Smith, Mandeep S. Tamber and James T. Rutka

Object

The authors undertook this study to review their experience with cortical resections in the rolandic region in children with intractable epilepsy.

Methods

The authors retrospectively reviewed the medical records obtained in 22 children with intractable epilepsy arising from the rolandic region. All patients underwent preoperative electroencephalography (EEG), MR imaging, prolonged video-EEG recordings, functional MR imaging, magnetoencephalography, and in some instances PET/SPECT studies. In 21 patients invasive subdural grid and depth electrode monitoring was performed. Resection of the epileptogenic zones in the rolandic region was undertaken in all cases. Seizure outcome was graded according to the Engel classification. Functional outcome was determined using validated outcome scores.

Results

There were 10 girls and 12 boys, whose mean age at seizure onset was 3.2 years. The mean age at surgery was 10 years. Seizure duration prior to surgery was a mean of 7.4 years. Nine patients had preoperative hemiparesis. Neuropsychological testing revealed impairment in some domains in 19 patients in whom evaluation was possible. Magnetic resonance imaging abnormalities were identified in 19 patients. Magnetoencephalography was performed in all patients and showed perirolandic spike clusters on the affected side in 20 patients. The mean duration of invasive monitoring was 4.2 days. The mean number of seizures during the period of invasive monitoring was 17. All patients underwent resection that involved primary motor and/or sensory cortex. The most common pathological entity encountered was cortical dysplasia, in 13 children. Immediately postoperatively, 20 patients had differing degrees of hemiparesis, from mild to severe. The hemiparesis improved in all affected patients by 3–6 months postoperatively. With a mean follow-up of 4.1 years (minimum 2 years), seizure outcome in 14 children (64%) was Engel Class I and seizure outcome in 4 (18%) was Engel Class II. In this series, seizure outcome following perirolandic resection was intimately related to the child's age at the time of surgery. By univariate logistic regression analysis, age at surgery was a statistically significant factor predicting seizure outcome (p < 0.024).

Conclusions

Resection of rolandic cortex for intractable epilepsy is possible with expected morbidity. Accurate mapping of regions of functional cortex and epileptogenic zones may lead to improved seizure outcome in children with intractable rolandic epilepsy. It is important to counsel patients and families preoperatively to prepare them for possible worsened functional outcome involving motor, sensory and/or language pathways.

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Ann Marie Flannery, Catherine A. Mazzola, Paul Klimo Jr., Ann-Christine Duhaime, Lissa C. Baird, Mandeep S. Tamber, David D. Limbrick Jr., Dimitrios C. Nikas, Joanna Kemp, Alexander F. Post, Kurtis I. Auguste, Asim F. Choudhri, Laura S. Mitchell and Debby Buffa

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Jay Riva-Cambrin, John R. W. Kestle, Richard Holubkov, Jerry Butler, Abhaya V. Kulkarni, James Drake, William E. Whitehead, John C. Wellons III, Chevis N. Shannon, Mandeep S. Tamber, David D. Limbrick Jr., Curtis Rozzelle, Samuel R. Browd, Tamara D. Simon and The Hydrocephalus Clinical Research Network

OBJECT

The rate of CSF shunt failure remains unacceptably high. The Hydrocephalus Clinical Research Network (HCRN) conducted a comprehensive prospective observational study of hydrocephalus management, the aim of which was to isolate specific risk factors for shunt failure.

METHODS

The study followed all first-time shunt insertions in children younger than 19 years at 6 HCRN centers. The HCRN Investigator Committee selected, a priori, 21 variables to be examined, including clinical, radiographic, and shunt design variables. Shunt failure was defined as shunt revision, subsequent endoscopic third ventriculostomy, or shunt infection. Important a priori–defined risk factors as well as those significant in univariate analyses were then tested for independence using multivariate Cox proportional hazard modeling.

RESULTS

A total of 1036 children underwent initial CSF shunt placement between April 2008 and December 2011. Of these, 344 patients experienced shunt failure, including 265 malfunctions and 79 infections. The mean and median length of follow-up for the entire cohort was 400 days and 264 days, respectively. The Cox model found that age younger than 6 months at first shunt placement (HR 1.6 [95% CI 1.1–2.1]), a cardiac comorbidity (HR 1.4 [95% CI 1.0–2.1]), and endoscopic placement (HR 1.9 [95% CI 1.2–2.9]) were independently associated with reduced shunt survival. The following had no independent associations with shunt survival: etiology, payer, center, valve design, valve programmability, the use of ultrasound or stereotactic guidance, and surgeon experience and volume.

CONCLUSIONS

This is the largest prospective study reported on children with CSF shunts for hydrocephalus. It confirms that a young age and the use of the endoscope are risk factors for first shunt failure and that valve type has no impact. A new risk factor—an existing cardiac comorbidity—was also associated with shunt failure.

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John R. W. Kestle, Richard Holubkov, D. Douglas Cochrane, Abhaya V. Kulkarni, David D. Limbrick Jr., Thomas G. Luerssen, W. Jerry Oakes, Jay Riva-Cambrin, Curtis Rozzelle, Tamara D. Simon, Marion L. Walker, John C. Wellons III, Samuel R. Browd, James M. Drake, Chevis N. Shannon, Mandeep S. Tamber, William E. Whitehead and The Hydrocephalus Clinical Research Network

OBJECT

In a previous report by the same research group (Kestle et al., 2011), compliance with an 11-step protocol was shown to reduce CSF shunt infection at Hydrocephalus Clinical Research Network (HCRN) centers (from 8.7% to 5.7%). Antibiotic-impregnated catheters (AICs) were not part of the protocol but were used off protocol by some surgeons. The authors therefore began using a new protocol that included AICs in an effort to reduce the infection rate further.

METHODS

The new protocol was implemented at HCRN centers on January 1, 2012, for all shunt procedures (excluding external ventricular drains [EVDs], ventricular reservoirs, and subgaleal shunts). Procedures performed up to September 30, 2013, were included (21 months). Compliance with the protocol and outcome events up to March 30, 2014, were recorded. The definition of infection was unchanged from the authors' previous report.

RESULTS

A total of 1935 procedures were performed on 1670 patients at 8 HCRN centers. The overall infection rate was 6.0% (95% CI 5.1%–7.2%). Procedure-specific infection rates varied (insertion 5.0%, revision 5.4%, insertion after EVD 8.3%, and insertion after treatment of infection 12.6%). Full compliance with the protocol occurred in 77% of procedures. The infection rate was 5.0% after compliant procedures and 8.7% after noncompliant procedures (p = 0.005). The infection rate when using this new protocol (6.0%, 95% CI 5.1%–7.2%) was similar to the infection rate observed using the authors' old protocol (5.7%, 95% CI 4.6%–7.0%).

CONCLUSIONS

CSF shunt procedures performed in compliance with a new infection prevention protocol at HCRN centers had a lower infection rate than noncompliant procedures. Implementation of the new protocol (including AICs) was associated with a 6.0% infection rate, similar to the infection rate of 5.7% from the authors' previously reported protocol. Based on the current data, the role of AICs compared with other infection prevention measures is unclear.