Carlos A. Bagley, Markus J. Bookland, Jonathan A. Pindrik, Tolga Ozmen, Ziya L. Gokaslan, and Timothy F. Witham
Spinal column metastatic disease clinically affects thousands of cancer patients every year. Local chemotherapy represents a new option in the treatment of metastatic disease of the spine. Despite the clinical impact of metastatic spine disease, the literature currently lacks an accurate animal model for the effective dosing of local chemotherapeutic agents within the vertebral column.
Female Fischer 344 rats, weighing 150 to 200 g each, were used in this study. After induction of anesthesia, a transabdominal approach to the ventral vertebral body of L-6 was performed. A small hole was drilled and 5 μL of ReGel (blank polymer), OncoGel (paclitaxel and ReGel) 1.5%, OncoGel 3.0%, or OncoGel 6.0% were immediately injected to determine drug toxicity. Based on these results, efficacy studies were performed by intratumoral injection of 5 μL of ReGel, OncoGel 3.0%, and OncoGel 6.0% on Day 6 in a CRL-1666 breast adenocarcinoma metastatic spine tumor model. Hind limb function was tested pre- and postoperatively using the Basso-Beattie-Bresnahan rating scale. Histological analysis of the spinal cord and vertebral column was performed when the animal died or was killed.
There were no signs of toxicity observed in association with any of the agents under study. No increased benefit was seen in the blank polymer group compared with the control group (tumor only). OncoGel 3.0% and OncoGel 6.0% were effective in delaying the onset of paralysis in the respective study groups.
These findings demonstrate the potential benefit of OncoGel in cases of subtotal resections of metastatic spinal column tumors. OncoGel 6.0% is the most efficacious drug concentration and offers the best therapeutic option in this experimental model. These results provide promise for the development of local chemotherapeutic means to treat spinal metastases.
Jonathan Pindrik, Brandon G. Rocque, Anastasia A. Arynchyna, James M. Johnston, and Curtis J. Rozzelle
Endoscopic third ventriculostomy (ETV) with choroid plexus (CP) cauterization (CPC) represents a viable treatment option for congenital hydrocephalus in infants younger than 2 years. Imaging studies complement clinical data in the evaluation of treatment success or failure. The objectives of this study were to investigate novel radiographic markers—cerebrospinal fluid (CSF) turbulence and CP visualization—and their ability to reflect or predict clinical outcomes following ETV/CPC.
Hydrocephalic patients younger than 2 years who were initially treated by ETV/CPC at the senior authors' institution between March 2013 and February 2014 were retrospectively reviewed. Clinical data, as well as the visualization of CSF turbulence and CP on pre- and postoperative fast-sequence MRI, were recorded. Radiographic images were reviewed by a blinded observer based on specific criteria for the visualization of CSF turbulence and CP. Data were collected and analyzed using descriptive statistics, including Fisher's exact test for comparisons. The research team obtained appropriate institutional review board approval for this study, without the need for informed consent.
Among the 32 patients (53% male and 47% female) studied, 18 of 32 (56%) responded favorably to initial or repeat ETV/CPC, with 13 of 32 (41%) patients requiring 1 surgery. Of the 19 (59%) patients whose initial ETV/CPC failed, 8 of 19 (42%) patients underwent repeat ETV/CPC, with 5 of 8 (63%) patients responding favorably. Radiographic CSF turbulence appeared more frequently following ETV/CPC failure than after ETV/CPC success (55% vs 18%, respectively; p = 0.02). The sensitivity and specificity of CSF turbulence as a radiographic marker for ETV/CPC failure were 80% and 58%, respectively. The radiographic depiction of CP disappearance following ETV/CPC from pre- to postoperative imaging occurred in 20 of 30 patients (67%). Among the patients who responded unsuccessfully to ETV/CPC and ultimately required secondary shunt insertion, 71% (10 of 14 patients) demonstrated CP persistence on postoperative imaging. In contrast, 6% (1 of 18) of patients who were treated successfully by ETV/CPC demonstrated the presence of CP on follow-up imaging. This difference reached statistical significance (p = 0.0001). The visualization of CP persistence despite ETV/CPC reflected treatment failure with 91% sensitivity and 81% specificity. The sensitivity of either or both radiographic markers to suggest ETV/CPC failure was 77%, while their specificity (both markers absent, thereby indicating ETV/CPC success) was 81%.
Radiographic markers correlate with clinical outcomes following the treatment of infantile hydrocephalus with ETV/CPC. Specifically, CSF turbulence may indicate ongoing pathological CSF flow dynamics, while CP absence following ETV/CPC may predict shunt independence. Future studies that incorporate prospective review and formal intra- and interobserver reliability estimates may help corroborate the utility of these radiographic markers.
Jonathan Pindrik, Thierry A. G. M. Huisman, Mahadevappa Mahesh, Aylin Tekes, and Edward S. Ahn
Despite its diagnostic utility, head CT scanning imparts risks of radiation exposure. Children with shunt-treated hydrocephalus exhibit increased risks of radiation toxicity due to the higher vulnerability of developing, immature tissues and frequent scanning. Several methods have been used to achieve dose reduction, including modifications of CT scanner tube current and potential. This retrospective study explores the use of a newly defined limited sequence of axial head CT slices to evaluate children with shunted hydrocephalus and decrease radiation exposure from diagnostic CT scans.
Consistent sequences of 7 axial slices were extracted from previously performed standard head CT scans in children with shunted hydrocephalus. Chronologically distinct limited sequences of each patient were blindly, retrospectively reviewed by 2 pediatric neuroradiologists and 1 pediatric neurosurgeon. Limited-sequence CT evaluation focused on the adequacy of portraying the ventricular system, changes in ventricular size, and visualization of the proximal catheter. Reviewers assessed all original full series head CT scans at least 4 months later for comparison. Adequacy and accuracy of the limited-sequence CT compared with the gold standard head CT was investigated using descriptive statistics. Effective dose (ED) estimates of the limited-sequence and standard head CT scans were compared using descriptive statistics and the Mann-Whitney test.
Two serial head CT scans from each of 50 patients (age range 0–17 years; mean age 5.5 years) were reviewed both in standard and limited-sequence forms. The limited-sequence CT adequately portrayed the ventricular system in all cases. The inaccuracy rate for assessing changes in ventricular size by majority assessment (2 of 3 reviewers evaluating inaccurately) was 3 (6%) of 50. In 1 case, the inaccurate assessment would not have altered clinical management, corresponding to a 2 (4%) of 50 clinically relevant inaccuracy rate. As compared with the gold standard complete head CT series, the limited-sequence CT exhibited high sensitivity (100%) and specificity (91%) for portraying changes in ventricular caliber. Additionally, the limited-sequence CT displayed the ventricular catheter in 91.7% of scans averaged across 3 observers. Among all scans reviewed, 97 pairs of standard head CT and complementary limited-sequence CT scans contained adequate dosing information to calculate the effective dose (ED). The ED50 of the limited-sequence CT (0.284 mSv) differed significantly from the ED50 of the standard head CT (4.27 mSv) (p < 0.0001). The limited-sequence CT reflected a median absolute reduction of 4.10 mSv and a mean percent reduction of 91.8% in ED compared with standard head CT.
Limited-sequence head CT scanning provided adequate and accurate diagnostic information in children with shunted hydrocephalus. Techniques including minimization of axial slice quantity and modification of CT scanner parameters can achieve significant dose reduction, maintaining a balance between diagnostic utility and patient safety.
Carlos A. Bagley, Jonathan A. Pindrik, Markus J. Bookland, Joaquin Q. Camara-Quintana, and Benjamin S. Carson
Achondroplasia is the most common hereditary form of dwarfism, and is characterized by short stature, macrocephaly, and a myriad of skeletal abnormalities. In the pediatric population, stenosis and compression at the level of the cervicomedullary junction commonly occurs. The goal in this study was to assess the outcomes in children with achondroplasia who underwent cervicomedullary decompression.
Forty-three pediatric patients with heterozygous achondroplasia and foramen magnum stenosis underwent 45 cervicomedullary decompressions at the authors’ institution over an 11-year period. After surgical decompression, complete resolution or partial improvement in the preoperative symptoms was observed in all patients. There were no deaths in the treated patients. The surgical morbidity rate was low and usually consisted of a cerebrospinal fluid (CSF) leak in patients in whom the dura mater had been opened (either intentionally or accidentally). This problem was successfully managed in all cases with local measures (wound oversewing) or CSF diversion.
In this review the authors demonstrate that decompression of the cervicomedullary junction in the setting of achondroplasia may be accomplished safely with significant clinical benefit and minimal morbidity.
Carlos A. Bagley, Markus J. Bookland, Jonathan A. Pindrik, Tolga Ozmen, Ziya L. Gokaslan, Jean-Paul Wolinsky, and Timothy F. Witham
Spinal column metastatic disease affects thousands of cancer patients every year. Radiation therapy frequently represents the primary treatment for this condition. Despite the enormous clinical impact of spinal column metastatic disease, the literature currently lacks an accurate animal model for testing the efficacy of irradiation on spinal column metastases.
After anesthesia was induced, female Fischer 344 rats underwent a transabdominal approach to the ventral vertebral body (VB) of L-6. A 2- to 3-mm-diameter bur hole was drilled for the implantation of a section of CRL-1666 breast adenocarcinoma. After the animals had recovered from the surgery, they underwent fractionated, single-port radiotherapy beginning on postoperative Day 7. Each group of animals underwent five daily fractions of radiation treatment. Group I animals received a total dose of 10 Gy in 200-cGy daily fractions, Group II animals received a total dose of 20 Gy in 400-cGy daily fractions, and Group III animals received a total dose of 30 Gy in 600-cGy daily fractions. A control group of rats with implanted VB lesions did not receive radiation. To test the effects of radiation toxicity alone, additional rats without implanted tumors received radiation treatments in the same fractions as the rats with tumors. Hindlimb function in all rats was rated before and after radiation treatment using the Basso-Beattie-Bresnahan locomotor rating scale. Histological analysis of spinal cord and vertebral column sections was performed after each animal's death.
Functional assessments demonstrated a statistically significant delay in the onset of paresis between the three treatment groups and the control group (tumor implanted but no radiotherapy). The rats in the three treatment groups, however, did not exhibit any significant differences related to hindlimb function. A dose-dependent relationship was found for the percentage of animals who had become paralyzed at the time of death, with all members of the control group and no members of the 30-Gy group exhibiting paralysis. The results of this study do not indicate any overall survival benefit for any level of radiation dose.
These findings demonstrate the efficacy of focal spinal irradiation in delaying the onset of paralysis in a rat metastatic spine tumor model, but without a clear survival benefit. Because of the dose-related toxicity observed in the rats treated with 30 Gy, this effect was most profound for the 20-Gy group. This finding parallels the observed clinical course of spinal column metastatic disease in humans and provides a basis for the future comparison of novel local and systemic treatments to augment the observed effects of focal irradiation.
Pablo F. Recinos, Jonathan A. Pindrik, Mazen I. Bedri, Edward S. Ahn, George I. Jallo, and Violette Renard Recinos
The aim of this study was to examine the feasibility and safety of ventriculoperitoneal (VP) shunt placement using a periumbilical approach for distal peritoneal access. By using this minimally invasive approach, the authors hypothesized that the cosmetic outcomes would be better than could be achieved by using a traditional minilaparotomy and that clinical results would be comparable.
A periumbilical approach was used for distal catheter insertion during a first-time VP shunt placement in 20 patients (8 males and 12 females). Median age at time of surgery was 3.0 months (range 7 days–11.9 years) and mean follow-up time was 17.8 months (range 1.2–28.0 months). The median weight of the patients was 3.99 kg (range 1.95–57.0 kg). A single incision was made along the natural crease inferior to the umbilicus. The linea alba was exposed and a 1-mm incision made while the patient was temporarily held in a Valsalva maneuver. A peritoneal trocar was then inserted through the fascial incision and the distal catheter was passed into the peritoneal space.
The incision line in all patients healed well, did not require operative revision, and was described as minimally visible by the patients' families. Mean operative time was 35 minutes. Eight patients required revision surgery. One distal failure occurred when the distal shunt tubing retracted and became coiled in the neck; this was repaired by conversion to a minilaparotomy for distal replacement. There was 1 shunt infection (5%) requiring shunt removal and replacement. One patient had significant skin thinning around the valve and proximal catheter, which required replacement of the entire shunt system, and another patient underwent a conversion to a ventriculoatrial shunt due to poor peritoneal absorption. In the remaining 4 patients who required operative revision, the peritoneal portion of the shunt was not involved.
The periumbilical approach for peritoneal access during VP shunt placement is technically feasible, has low infection rates, and has cosmetically appealing results. It may be considered as an alternative option to standard VP shunt placement techniques.
Aaron M. Yengo-Kahn, John C. Wellons III, Todd C. Hankinson, Jason S. Hauptman, Eric M. Jackson, Hailey Jensen, Mark D. Krieger, Abhaya V. Kulkarni, David. D. Limbrick Jr., Patrick J. McDonald, Robert P. Naftel, Jonathan A. Pindrik, Ian F. Pollack, Ron Reeder, Jay Riva-Cambrin, Curtis J. Rozzelle, Mandeep S. Tamber, William E. Whitehead, John R. W. Kestle, and for the Hydrocephalus Clinical Research Network
Treating Dandy-Walker syndrome–related hydrocephalus (DWSH) involves either a CSF shunt-based or endoscopic third ventriculostomy (ETV)–based procedure. However, comparative investigations are lacking. This study aimed to compare shunt-based and ETV-based treatment strategies utilizing archival data from the Hydrocephalus Clinical Research Network (HCRN) registry.
A retrospective review of prospectively collected and maintained data on children with DWSH, available from the HCRN registry (14 sites, 2008–2018), was performed. The primary outcome was revision-free survival of the initial surgical intervention. The primary exposure was either shunt-based (i.e., cystoperitoneal shunt [CPS], ventriculoperitoneal shunt [VPS], and/or dual-compartment) or ETV-based (i.e., ETV alone or with choroid plexus cauterization [CPC]) initial surgical treatment. Primary analysis included multivariable Cox proportional hazards models.
Of 8400 HCRN patients, 151 (1.8%) had DWSH. Among these, the 102 patients who underwent shunt placement (79 VPSs, 16 CPSs, 3 other, and 4 multiple proximal catheter) were younger (6.6 vs 18.8 months, p < 0.001) and more frequently had 1 or more comorbidities (37.3% vs 14.3%, p = 0.005) than the 49 ETV-treated children (28 ETV-CPC). Fifty percent of the shunt-based and 51% of the ETV-based treatments failed. Notably, 100% (4/4) of the dual-compartment shunts failed. Adjusting for age, baseline ventricular size, and comorbidities, ETV-based treatment was not significantly associated with earlier failure compared with shunt-based treatment (HR for failure 1.32, 95% CI 0.77–2.26; p = 0.321). Complication rates were low: 4.9% and 6.1% (p = 0.715) for shunt- and ETV-based procedures, respectively. There was no difference in survival between ETV-CPC– and ETV-based treatment when adjusting for age (HR for failure 0.86, 95% CI 0.29–2.55, p = 0.783).
In this North American, multicenter, prospective database review, shunt-based and ETV-based primary treatment strategies of DWSH appear similarly durable. Pediatric neurosurgeons can reasonably consider ETV-based initial treatment given the similar durability and the low complication rate. However, given the observational nature of this study, the treating surgeon might need to consider subgroups that were too small for a separate analysis. Very young children with comorbidities were more commonly treated with shunts, and older children with fewer comorbidities were offered ETV-based treatment. Future studies may determine preoperative characteristics associated with ETV treatment success in this population.