Publications

All Publications


  • Neuromodulatory Treatments for Alcohol Use Disorder: A Review. Brain sciences Salib, A. N., Ho, A. L., Sussman, E. S., Pendharkar, A. V., Halpern, C. H. 2018; 8 (6)

    Abstract

    Alcohol use disorder (AUD) is a prevalent condition characterized by chronic alcohol-seeking behaviors and has become a significant economic burden with global ramifications on public health. While numerous treatment options are available for AUD, many are unable to sustain long-term sobriety. The nucleus accumbens (NAcc) upholds an integral role in mediating reward behavior and has been implicated as a potential target for deep brain stimulation (DBS) in the context of AUD. DBS is empirically thought to disrupt pathological neuronal synchrony, a hallmark of binge behavior. Pre-clinical animal models and pilot human clinical studies utilizing DBS for the treatment of AUD have shown promise for reducing alcohol-related cravings and prolonging abstinence. In this review, we outline the various interventions available for AUD, and the translational potential DBS has to modulate functionality of the NAcc as a treatment for AUD.

    View details for PubMedID 29843426

  • Minimally invasive approaches to craniosynostosis. Journal of neurosurgical sciences Pendharkar, A. V., Shahin, M. N., Cavallo, C., Zhao, X., Ho, A. L., Sussman, E. S., Grant, G. A. 2018

    Abstract

    Craniosynostosis (CS) is defined as the premature fusion of one or more calvarial sutures. This carries several consequences, including abnormal/asymmetric cranial vault development, increased intracranial pressure, compromised neurocognitive development, and craniofacial deformity. Definitive management is surgical with the goal of protecting cerebral development by re-establishing normal cranial vault expansion and correcting cosmetic deformity. In today's practice, CS surgery has advanced radically from simple craniectomies to major cranial vault reconstructive (CVR) procedures. More recently there has been considerable interest in endoscopic assisted surgery (EAS). Theoretical benefits include decreased operative time, morbidity, blood loss, postoperative pain, cost and faster recovery times. In this focused review, we summarize the current body of literature reporting clinical outcomes in EAS and review the data comparing EAS and CVR.

    View details for PubMedID 29790726

  • Outpatient spine surgery: defining the outcomes, value, and barriers to implementation. Neurosurgical focus Pendharkar, A. V., Shahin, M. N., Ho, A. L., Sussman, E. S., Purger, D. A., Veeravagu, A., Ratliff, J. K., Desai, A. M. 2018; 44 (5): E11

    Abstract

    Spine surgery is a key target for cost reduction within the United States health care system. One possible strategy involves the transition of inpatient surgeries to the ambulatory setting. Lumbar laminectomy with or without discectomy, lumbar fusion, anterior cervical discectomy and fusion, and cervical disc arthroplasty all represent promising candidates for outpatient surgeries in select populations. In this focused review, the authors clarify the different definitions used in studies describing outpatient spine surgery. They also discuss the body of evidence supporting each of these procedures and summarize the proposed cost savings. Finally, they examine several patient- and surgeon-specific considerations to highlight the barriers in translating outpatient spine surgery into actual practice.

    View details for PubMedID 29712520

  • Propensity-matched comparison of outcomes and cost after macroscopic and microscopic lumbar discectomy using a national longitudinal database. Neurosurgical focus Pendharkar, A. V., Rezaii, P. G., Ho, A. L., Sussman, E. S., Purger, D. A., Veeravagu, A., Ratliff, J. K., Desai, A. M. 2018; 44 (5): E12

    Abstract

    OBJECTIVE There has been considerable debate about the utility of the operating microscope in lumbar discectomy and its effect on outcomes and cost. METHODS A commercially available longitudinal database was used to identify patients undergoing discectomy with or without use of a microscope between 2007 and 2015. Propensity matching was performed to normalize differences between demographics and comorbidities in the 2 cohorts. Outcomes, complications, and cost were subsequently analyzed using bivariate analysis. RESULTS A total of 42,025 patients were identified for the "macroscopic" group, while 11,172 patients were identified for the "microscopic" group. For the propensity-matched analysis, the 11,172 patients in the microscopic discectomy group were compared with a group of 22,340 matched patients who underwent macroscopic discectomy. There were no significant differences in postoperative complications between the groups other than a higher proportion of deep vein thrombosis (DVT) in the macroscopic discectomy cohort versus the microscopic discectomy group (0.4% vs 0.2%, matched OR 0.48 [95% CI 0.26-0.82], p = 0.0045). Length of stay was significantly longer in the macroscopic group compared to the microscopic group (mean 2.13 vs 1.83 days, p < 0.0001). Macroscopic discectomy patients had a higher rate of revision surgery when compared to microscopic discectomy patients (OR 0.92 [95% CI 0.84-1.00], p = 0.0366). Hospital charges were higher in the macroscopic discectomy group (mean $19,490 vs $14,921, p < 0.0001). CONCLUSIONS The present study suggests that the use of the operating microscope in lumbar discectomy is associated with decreased length of stay, lower DVT rate, lower reoperation rate, and decreased overall hospital costs.

    View details for PubMedID 29712527

  • Nurse Telephonic Triage Service for After-hour Patient Calls in Neurosurgery. Annals of surgery Escobedo-Wu, E. L., Dhebar, F., Harsh, G., Steinberg, G., Vyas, A., Katznelson, L., Ho, A. L., Pendharkar, A. V., Sussman, E. S., Rohatgi, N. 2018; 267 (4): e67?e68

    Abstract

    OBJECTIVE: The aim of this study was to report the utilization and experience of the nurse telephonic triage service for after-hour patient calls in Neurosurgery.BACKGROUND: It is challenging for patients to reach their clinicians after-hours in a timely manner. This may result in worse health outcomes for the patients, or inappropriate utilization of emergency rooms and urgent care facilities. Physicians continue to remain overwhelmed with frequent after-hours calls in addition to other clinical responsibilities while on-call.METHODS: In August 2015, our institution launched the Clinical Advice Service (CAS) to provide a patient-centric, nurse-run telephone triage service for after-hour calls from Neurosurgery patients. Clinical protocols were created for use by CAS staff by Neurosurgery clinicians.RESULTS: Between July 2016 and June 2017, CAS has accepted 1021 after-hours calls from Neurosurgery patients. A total of 71.4% of these calls were clinical, and the remaining nonclinical (directions, appointments, general information). CAS escalated 37.3% of the calls to the on-call Neurosurgery physician; 4.8% Neurosurgery patients were triaged to the emergency room by CAS.CONCLUSION: CAS has been able to provide well-coordinated care to Neurosurgery patients while reducing physician workload.

    View details for PubMedID 29064895

  • Improved operative efficiency using a real-time MRI-guided stereotactic platform for laser amygdalohippocampotomy JOURNAL OF NEUROSURGERY Ho, A. L., Sussman, E. S., Pendharkar, A. V., Le, S., Mantovani, A., Keebaugh, A. C., Drover, D. R., Grant, G. A., Wintermark, M., Halpern, C. H. 2018; 128 (4): 1165?72

    Abstract

    OBJECTIVE MR-guided laser interstitial thermal therapy (MRgLITT) is a minimally invasive method for thermal destruction of benign or malignant tissue that has been used for selective amygdalohippocampal ablation for the treatment of temporal lobe epilepsy. The authors report their initial experience adopting a real-time MRI-guided stereotactic platform that allows for completion of the entire procedure in the MRI suite. METHODS Between October 2014 and May 2016, 17 patients with mesial temporal sclerosis were selected by a multidisciplinary epilepsy board to undergo a selective amygdalohippocampal ablation for temporal lobe epilepsy using MRgLITT. The first 9 patients underwent standard laser ablation in 2 phases (operating room [OR] and MRI suite), whereas the next 8 patients underwent laser ablation entirely in the MRI suite with the ClearPoint platform. A checklist specific to the real-time MRI-guided laser amydalohippocampal ablation was developed and used for each case. For both cohorts, clinical and operative information, including average case times and accuracy data, was collected and analyzed. RESULTS There was a learning curve associated with using this real-time MRI-guided system. However, operative times decreased in a linear fashion, as did total anesthesia time. In fact, the total mean patient procedure time was less in the MRI cohort (362.8 ± 86.6 minutes) than in the OR cohort (456.9 ± 80.7 minutes). The mean anesthesia time was significantly shorter in the MRI cohort (327.2 ± 79.9 minutes) than in the OR cohort (435.8 ± 78.4 minutes, p = 0.02). CONCLUSIONS The real-time MRI platform for MRgLITT can be adopted in an expedient manner. Completion of MRgLITT entirely in the MRI suite may lead to significant advantages in procedural times.

    View details for PubMedID 28665249

  • Cervical Stenosis in Adult Arthrogryposis: A Case Report and Review of the Literature. Journal of neurological surgery reports Ho, A. L., Mohole, J., Sussman, E. S., Pendharkar, A. V., Singh, H. 2018; 79 (1): e19?e22

    Abstract

    Arthrogryposis multiplex congenita is a rare, nonprogressive congenital disorder that describes a constellation of conditions characterized by multiple joint contractures. Spinal pathology and deformity are common; however, the majority of the literature on arthrogryposis is focused on pediatric management. There exist very few reports on long-term outcomes and management of adults with arthrogryposis. We present a case of cervical spinal stenosis in an adult female with arthrogryposis that underwent posterior cervical decompression and fusion. A review of spine-related sequelae seen in adults with arthrogryposis and considerations for spinal surgery for these patients is discussed.

    View details for PubMedID 29581933

    View details for PubMedCentralID PMC5860911

  • Diffusion Tensor Imaging in an Infant Undergoing Functional Hemispherectomy: A Surgical Aid. Cureus Ho, A. L., Pendharkar, A. V., Sussman, E. S., Casazza, M., Grant, G. A. 2017; 9 (9): e1697

    Abstract

    Hemispherectomy is a highly effective treatment option for children with severe, unilateral, medically refractory epilepsy. Many patients undergoing hemispherectomy are younger patients with dysmorphic brains, making accomplishing a complete disconnectionchallenging due to anatomic distortion, even with the aid of intraoperative navigation. Diffusion tensor imaging (DTI) has been proposed as a valuable imaging adjunct perioperatively to help guide surgeons intraoperatively, as well as for post-surgical evaluation and confirmation of complete hemispheric disconnection.We present a case of an infant with Otoharra syndrome and hemimegencephaly who underwent a functional hemispherectomy for treatment of severe, refractory seizures. We demonstrate how DTI was utilized both pre-, intra-, and postoperatively to help plan, guide, and confirm surgical disconnection. The application of exquisite DTI for this child led to her being seizure-free, which is a life-changing event with long-lasting benefits and will become even more critical as we now perform these disconnection procedures with a more minimally invasive approach.

    View details for PubMedID 29167751

  • Outpatient vs Inpatient Anterior Cervical Discectomy and Fusion: A Population-Level Analysis of Outcomes and Cost. Neurosurgery Purger, D. A., Pendharkar, A. V., Ho, A. L., Sussman, E. S., Yang, L., Desai, M., Veeravagu, A., Ratliff, J. K., Desai, A. 2017

    Abstract

    Outpatient anterior cervical discectomy and fusion (ACDF) is a promising candidate for US healthcare cost reduction as several studies have demonstrated that overall complications are relatively low and early discharge can preserve high patient satisfaction, low morbidity, and minimal readmission.To compare clinical outcomes and associated costs between inpatient and ambulatory setting ACDF.Demographics, comorbidities, emergency department (ED) visits, readmissions, reoperation rates, and 90-d charges were retrospectively analyzed for patients undergoing elective ACDF in California, Florida, and New York from 2009 to 2011 in State Inpatient and Ambulatory Databases.A total of 3135 ambulatory and 46 996 inpatient ACDFs were performed. Mean Charlson comorbidity index, length of stay, and mortality were 0.2, 0.4 d, and 0% in the ambulatory cohort and 0.4, 1.8 d, and 0.04% for inpatients ( P < .0001). Ambulatory patients were younger (48.0 vs 53.1) and more likely to be Caucasian. One hundred sixty-eight ambulatory patients (5.4%) presented to the ED within 30 d (mean 11.3 d), 51 (1.6%) were readmitted, and 5 (0.2%) underwent reoperation. Among inpatient surgeries, 2607 patients (5.5%) presented to the ED within 30 d (mean 9.7 d), 1778 (3.8%) were readmitted (mean 6.3 d), and 200 (0.4%) underwent reoperation. Higher Charlson comorbidity index increased rate of ED visits (ambulatory operating room [OR] 1.285, P < .05; inpatient OR 1.289, P < .0001) and readmission (ambulatory OR 1.746, P < .0001; inpatient OR 1.685, P < .0001). Overall charges were significantly lower for ambulatory ACDFs ($33 362.51 vs $74 667.04; P < .0001).ACDF can be performed in an ambulatory setting with comparable morbidity and readmission rates, and lower costs, to those performed in an inpatient setting.

    View details for DOI 10.1093/neuros/nyx215

    View details for PubMedID 28498922

  • The effect of socioeconomic status on gross total resection, radiation therapy and overall survival in patients with gliomas. Journal of neuro-oncology Deb, S., Pendharkar, A. V., Schoen, M. K., Altekruse, S., Ratliff, J., Desai, A. 2017

    Abstract

    Socioeconomic status (SES) is associated with survival in many cancers but the effect of socioeconomic status on survival and access to care for patients with gliomas has not been well studied. This study included 50,170 patients from the Surveillance, Epidemiology, and End Results Program at the National Cancer Institute database diagnosed with gliomas of the brain from 2003 to 2012. Patient SES was divided into tertiles and quintiles. Treatment options included radiation, surgery (gross total resection (GTR)/other surgery), and radiation with surgery. Multivariable logistic regression and Cox proportional hazards model were used to analyze data with SAS v9.4. The results were adjusted for age at diagnosis, race, sex, tumor type, and tumor grade. Kaplan-Meier survival curves were constructed according to SES tertiles and quintiles. Patients from a higher SES tertile were significantly more likely to receive surgery, radiation, GTR, and radiation with surgery (OR 1.092, 1.116, 1.103, 1.150 respectively, all p?

    View details for DOI 10.1007/s11060-017-2391-2

    View details for PubMedID 28258423

  • Interventional therapy for brain arteriovenous malformations before and after ARUBA JOURNAL OF CLINICAL NEUROSCIENCE Sussman, E. S., Iyer, A. K., Teo, M., Pendharkar, A. V., Ho, A. L., Steinberg, G. K. 2017; 37: 54-56

    Abstract

    The ARUBA trial (2014) concluded that medical management alone is superior to medical management plus interventional therapy for the treatment of unruptured brain arteriovenous malformations (bAVMs). This sparked considerable controversy among involved healthcare providers. Here, we evaluated the impact of ARUBA on the volume, type, and treatment modality of bAVMs referred to a large tertiary care center. This was achieved by conducting a retrospective review of a prospectively maintained database of all bAVMs treated at Stanford Health Care and Stanford Children's Health from January 2012 through July 2015. The case volume of bAVMs treated at Stanford has been relatively unchanged in the period of time leading up to and after ARUBA. Furthermore, there has been no significant change in the proportion of unruptured AVMs treated. Although differences existed in types of interventions administered, these differences are best explained by variations in the SM grades of AVMs treated during each study period, rather than by underlying changes in treatment strategy. Additional research is warranted to more thoroughly characterize the impact of ARUBA on the treatment patterns of bAVMS.

    View details for DOI 10.1016/j.jocn.2016.10.036

    View details for Web of Science ID 000394396400015

  • Stereotactic radiosurgery for non-vestibular cranial nerve schwanommas JOURNAL OF NEURO-ONCOLOGY D'Astous, M., Ho, A. L., Pendharkar, A., Choi, C. Y., Soltys, S. G., Gibbs, I. C., Tayag, A. T., Thompson, P. A., Adler, J. R., Chang, S. D. 2017; 131 (1): 177-183

    Abstract

    Non-vestibular cranial nerve schwannomas (NVCNS) are rare lesions, representing <10?% of cranial nerve schwannomas. The optimal treatment for NVCNS is often derived from vestibular schwannomas experience. Surgical resection has been referred to as the first line treatment for those benign tumors, but significant complication rates are reported. Stereotactic radiosurgery (SRS) has arisen as a mainstay of treatment for many benign tumors, including schwanommas. We retrospectively reviewed the outcomes of NVCNS treated by SRS to characterize tumor control, symptom relief, toxicity, and the role of hypo-fractionation of SRS dose. Eighty-eight (88) patients, with ninety-five (95) NVCNS were treated with either single or multi-session SRS from 2001 to 2014. Local control was achieved in 94?% of patients treated (median follow-up of 33 months, range 1-155). Complications were seen in 7.4?% of cases treated with SRS. At 1-year, 57?% of patients had improvement or resolution of their symptoms, while 35?% were stable and 8?% had worsening or increased symptoms. While 42?% received only one session, results on local control were similar for one or multiple sessions (p?=?0.424). SRS for NVCNS is a treatment modality that provides excellent local control with minimal complication risk compared to traditional neurosurgical techniques. Tumor control obtained with a multi-session treatment was not significantly different from single session treatment. Safety profile was also comparable for uni or multi-session treatments. We concluded that, as seen in VS treated with CK SRS, radiosurgery treatment can be safely delivered in cases of NVCNS.

    View details for DOI 10.1007/s11060-016-2286-7

    View details for Web of Science ID 000393065400019

  • Outcomes of cervical laminoplasty-Population-level analysis of a national longitudinal database. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia Veeravagu, A., Azad, T. D., Zhang, M., Li, A., Pendharkar, A. V., Ratliff, J. K., Shuer, L. M. 2017

    Abstract

    Cervical laminoplasty is an important alternative to laminectomy in decompressing of the cervical spine. Further evidence to assess the utility of laminoplasty is required. We examine outcomes of cervical laminoplasty via a population level analysis in the United States.We performed a population-level analysis using the national MarketScan longitudinal database to analyze outcomes and costs of cervical laminoplasty between 2007 and 2014. Outcomes included postoperative complications, revision rates, and functional outcomes.Using a national administrative database, we identified 2613 patients (65.6% male, mean 58.5?years) who underwent cervical laminoplasty. Mean length of stay was 3.1?±?2.8?days and mean follow-up was 795.5?±?670.6?days. The overall complication rate was 22.5% (N?=?587), 30-day readmission rate was 7.5% (N?=?195), and mortality rate was 0.08% (N?=?2, elderly patients only). The complication rate was significantly increased in elderly patients (age >65?years) compared to non-elderly patients (OR 0.751, p?

    View details for PubMedID 29153782

  • Diagnostic Utility of Intraoperative Neurophysiological Monitoring for Intramedullary Spinal Cord Tumors: Systematic Review and Meta-Analysis. Clinical spine surgery Azad, T. D., Pendharkar, A. V., Nguyen, V., Pan, J., Connolly, I. D., Veeravagu, A., Popat, R., Ratliff, J. K., Grant, G. A. 2017

    Abstract

    Systematic review and meta-analysis.The aim of this study was to systematically evaluate the diagnostic utility of intraoperative neurophysiological monitoring (IONM) for detecting postoperative injury in resection of intramedullary spinal cord tumors (IMSCT).Surgical management of IMSCT can involve key neurological and vascular structures. IONM aims to assess the functional integrity of susceptible elements in real time. The diagnostic value of IONM for ISMCT has not been systematically evaluated.We performed a systematic review of the PubMed and MEDLINE databases for studies investigating the use of IONM for IMSCT and conducted a meta-analysis of diagnostic capability.Our search produced 257 citations. After application of exclusion criteria, 21 studies remained, 10 American Academy of Neurology grade III and 11 American Academy of Neurology grade IV. We found that a strong pooled mean sensitivity of 90% [95% confidence interval (CI), 84-94] and a weaker pooled mean specificity of 82% (95% CI, 70-90) for motor-evoked potential (MEP) recording changes. Somatosensory-evoked potential (SSEP) recording changes yielded pooled sensitivity of 85% (95% CI, 75-91) and pooled specificity of 72% (95% CI, 57-83). The pooled diagnostic odds ratio for MEP was 55.7 (95% CI, 26.3-119.1) and 14.3 (95% CI, 5.47-37.3) for SSEP. Bivariate analysis yielded summary receiver operative characteristic curves with area under the curve of 91.8% for MEPs and 86.3% for SSEPs.MEPs and SSEPs appear to be more sensitive than specific for detection of postoperative injury. Patients with perioperative neurological deficits are 56 times more likely to have had changes in MEPs during the procedure. We observed considerable variability in alarm criteria and interventions in response to IONM changes, indicating the need for prospective studies capable of defining standardized alarm criteria and responses.

    View details for PubMedID 28650882

  • Laser interstitial thermal therapy for the treatment of epilepsy: evidence to date NEUROPSYCHIATRIC DISEASE AND TREATMENT Shukla, N. D., Ho, A. L., Pendharkar, A. V., Sussman, E. S., Halpern, C. H. 2017; 13: 2469?75

    Abstract

    Medically intractable epilepsy is associated with increased morbidity and mortality. For those with focal epilepsy and correlated electrophysiological or radiographic features, open surgical resection can achieve high rates of seizure control, but can be associated with neurologic deficits and cognitive effects. Recent innovations have allowed for more minimally invasive methods of surgical seizure control such as magnetic resonance-guided laser interstitial therapy (MRgLITT). MRgLITT achieves the goal of ablating seizure foci while preserving neuropsycho-logical function and offering real-time feedback and monitoring of tissue ablation. This review summarizes the utilization of MRgLITT for mesial temporal lobe epilepsy and other seizure disorders. Overall, the efficacy of MRgLITT is comparable to that of open surgery and offers a less invasive approach in patients with significantly less morbidity.

    View details for PubMedID 29026310

  • Interventional therapy for brain arteriovenous malformations before and after ARUBA. Journal of clinical neuroscience Sussman, E. S., Iyer, A. K., Teo, M., Pendharkar, A. V., Ho, A. L., Steinberg, G. K. 2016

    Abstract

    The ARUBA trial (2014) concluded that medical management alone is superior to medical management plus interventional therapy for the treatment of unruptured brain arteriovenous malformations (bAVMs). This sparked considerable controversy among involved healthcare providers. Here, we evaluated the impact of ARUBA on the volume, type, and treatment modality of bAVMs referred to a large tertiary care center. This was achieved by conducting a retrospective review of a prospectively maintained database of all bAVMs treated at Stanford Health Care and Stanford Children's Health from January 2012 through July 2015. The case volume of bAVMs treated at Stanford has been relatively unchanged in the period of time leading up to and after ARUBA. Furthermore, there has been no significant change in the proportion of unruptured AVMs treated. Although differences existed in types of interventions administered, these differences are best explained by variations in the SM grades of AVMs treated during each study period, rather than by underlying changes in treatment strategy. Additional research is warranted to more thoroughly characterize the impact of ARUBA on the treatment patterns of bAVMS.

    View details for DOI 10.1016/j.jocn.2016.10.036

    View details for PubMedID 27810415

  • Stereotactic radiosurgery for non-vestibular cranial nerve schwanommas. Journal of neuro-oncology D'Astous, M., Ho, A. L., Pendharkar, A., Choi, C. Y., Soltys, S. G., Gibbs, I. C., Tayag, A. T., Thompson, P. A., Adler, J. R., Chang, S. D. 2016: -?

    Abstract

    Non-vestibular cranial nerve schwannomas (NVCNS) are rare lesions, representing <10?% of cranial nerve schwannomas. The optimal treatment for NVCNS is often derived from vestibular schwannomas experience. Surgical resection has been referred to as the first line treatment for those benign tumors, but significant complication rates are reported. Stereotactic radiosurgery (SRS) has arisen as a mainstay of treatment for many benign tumors, including schwanommas. We retrospectively reviewed the outcomes of NVCNS treated by SRS to characterize tumor control, symptom relief, toxicity, and the role of hypo-fractionation of SRS dose. Eighty-eight (88) patients, with ninety-five (95) NVCNS were treated with either single or multi-session SRS from 2001 to 2014. Local control was achieved in 94?% of patients treated (median follow-up of 33 months, range 1-155). Complications were seen in 7.4?% of cases treated with SRS. At 1-year, 57?% of patients had improvement or resolution of their symptoms, while 35?% were stable and 8?% had worsening or increased symptoms. While 42?% received only one session, results on local control were similar for one or multiple sessions (p?=?0.424). SRS for NVCNS is a treatment modality that provides excellent local control with minimal complication risk compared to traditional neurosurgical techniques. Tumor control obtained with a multi-session treatment was not significantly different from single session treatment. Safety profile was also comparable for uni or multi-session treatments. We concluded that, as seen in VS treated with CK SRS, radiosurgery treatment can be safely delivered in cases of NVCNS.

    View details for PubMedID 27752881

  • UTILITY OF A GLUCOCORTICOID SPARING STRATEGY IN THE MANAGEMENT OF PATIENTS FOLLOWING TRANSSPHENOIDAL SURGERY ENDOCRINE PRACTICE Jia, X., Pendharkar, A. V., Loftus, P., Dodd, R. L., Chu, O., Fraenkel, M., Katznelson, L. 2016; 22 (9): 1033-1039

    Abstract

    Following transsphenoidal surgery (TSS), it is important to assess for and manage adrenal insufficiency (AI). The goal of this study is to assess the efficacy and safety of a glucocorticoid (GC) sparing protocol to limit GC exposure in patients undergoing TSS.Adult patients undergoing TSS (excluding Cushing disease) with adequate adrenal function prior to surgery underwent TSS without perioperative GC coverage. Following TSS, daily morning fasting serum cortisol levels were tested. GCs were administered at stress doses for serum cortisol <5 mcg/dL, between 5 and 12 mcg/dL in the presence of clinically significant symptoms of AI, or >12 mcg/dL with severe headache, nausea or vomiting, fatigue, anorexia, or hyponatremia. The primary endpoint was the use of GCs in the immediate postoperative period.Of 178 subjects, GCs were administered to 80 (45%) patients for the following indications: 31.3% for serum cortisol <5 mcg/dL; 36.3% for cortisol between 5 and 12 mcg/dL accompanied by symptoms or signs of AI; 8.8% for moderate to severe postoperative hyponatremia; and 7.5% for severe headache, nausea and vomiting, fatigue, or anorexia with cortisol >12 mcg/dL. Logistic regression analysis showed that longer length of hospital stay (odds ratio [OR] 1.22, confidence interval [CI] 1.02-1.45) and the presence of new postoperative anterior pituitary hormone deficiency (OR 3.3, CI 1.26-8.67) were associated with postoperative GC use. By 12 weeks, only 14% of subjects remained on GCs. There were no adverse events related to withholding GCs.Our protocol for managing GC replacement is both safe and effective for limiting GC exposure in patients undergoing TSS.AI = adrenal insufficiency CI = confidence interval FSH = follicle-stimulating hormone GC = glucocorticoid GH = growth hormone IGF-1 = insulin-like growth factor-1 IV = intravenous LH = luteinizing hormone LOS = length of hospital stay OR = odds ratio TSS = transsphenoidal surgery.

    View details for DOI 10.4158/EP161256.OR

    View details for Web of Science ID 000384279900001

    View details for PubMedID 27124693

  • Pituitary Apoplexy Associated with Carotid Compression and a Large Ischemic Penumbra. World neurosurgery Sussman, E. S., Ho, A. L., Pendharkar, A. V., Achrol, A. S., Harsh, G. R. 2016; 92: 581 e7-581 e13

    Abstract

    Pituitary apoplexy is an acute clinical syndrome caused by pituitary gland hemorrhage or infarction. Rarely, this clinical syndrome is associated with cerebral infarction secondary to compression of an internal carotid artery. We report an unusual case of pituitary apoplexy associated with a cerebral infarct with a large ischemic penumbra.The patient presented with headaches and visual disturbance and was found to have pituitary apoplexy. Findings of his neurologic examination showed he had rapidly deteriorated, with obtundation, ophthalmoplegia, and left hemiplegia. Computed tomography perfusion images revealed a right hemispheric infarct with a large ischemic penumbra. Emergent decompressive transsphenoidal resection was performed. The patient had dramatic neurologic recovery, and postoperative imaging revealed salvage of most of the previously identified penumbra.Cerebral perfusion imaging is a useful diagnostic tool for identifying the subset of pituitary apoplexy patients that may benefit from emergent surgical intervention.

    View details for DOI 10.1016/j.wneu.2016.06.040

    View details for PubMedID 27319311

  • The strokes that killed Churchill, Roosevelt, and Stalin. Neurosurgical focus Ali, R., Connolly, I. D., Li, A., Choudhri, O. A., Pendharkar, A. V., Steinberg, G. K. 2016; 41 (1): E7-?

    Abstract

    From February 4 to 11, 1945, President Franklin D. Roosevelt of the United States, Soviet Union Premier Joseph Stalin, and British Prime Minister Winston Churchill met near Yalta in Crimea to discuss how post-World War II (WWII) Europe should be organized. Within 2 decades of this conference, all 3 men had died. President Roosevelt died 2 months after the Yalta Conference due to a hemorrhagic stroke. Premier Stalin died 8 years later, also due to a hemorrhagic stroke. Finally, Prime Minister Churchill died 20 years after the conference because of complications due to stroke. At the time of Yalta, these 3 men were the leaders of the most powerful countries in the world. The subsequent deterioration of their health and eventual death had varying degrees of historical significance. Churchill's illness forced him to resign as British prime minister, and the events that unfolded immediately after his resignation included Britain's mismanagement of the Egyptian Suez Crisis and also a period of mistrust with the United States. Furthermore, Roosevelt was still president and Stalin was still premier at their times of passing, so their deaths carried huge political ramifications not only for their respective countries but also for international relations. The early death of Roosevelt, in particular, may have exacerbated post-WWII miscommunication between America and the Soviet Union-miscommunication that may have helped precipitate the Cold War.

    View details for DOI 10.3171/2016.4.FOCUS1575

    View details for PubMedID 27364260

  • CyberKnife Stereotactic Radiosurgery for Atypical and Malignant Meningiomas. World neurosurgery Zhang, M., Ho, A. L., D'Astous, M., Pendharkar, A. V., Choi, C. Y., Thompson, P. A., Tayag, A. T., Soltys, S. G., Gibbs, I. C., Chang, S. D. 2016; 91: 574-581 e1

    Abstract

    Recurrent World Health Organization (WHO) grade II and III meningiomas have traditionally been treated by surgery alone, but early literature suggests that adjuvant stereotactic radiosurgery may greatly improve outcomes. We present the long-term tumor control and safety of a hypofractionated stereotactic radiosurgery regimen.Prospectively collected data of 44 WHO grade II and 9 WHO grade III meningiomas treated by CyberKnife for adjuvant or salvage therapy were reviewed. Patient demographics, treatment parameters, local control, regional control, locoregional control, overall survival, radiation history, and complications were documented.For WHO grade II patients, recurrence occurred in 41%, with local, regional, and locoregional failure at 60 months recorded as 49%, 58%, and 36%. For WHO grade III patients, recurrence occurred in 66%, with local, regional, and locoregional failure at 12 months recorded as 57%, 100%, and 43%. The 60-month locoregional control rates for radiation naïve and experienced patients were 48% and 0% (P = 0.14). Overall, 7 of 44 grade II patients and 8 of 9 grade III patients had died at last follow-up. The 60-month and 12-month overall survival rates for grade II and III meningiomas were 87% and 50%, respectively. Serious complications occurred in 7.5% of patients.Stereotactic radiosurgery for adjuvant and salvage treatment of WHO grade II meningioma using a hypofractionated plan is a viable treatment strategy with acceptable long-term tumor control, overall survival, and complication rates. Future studies should focus on radiation-naïve patients and local management of malignant meningioma.

    View details for DOI 10.1016/j.wneu.2016.04.019

    View details for PubMedID 27108030

  • Optogenetic modulation in stroke recovery NEUROSURGICAL FOCUS Pendharkar, A. V., Levy, S. L., Ho, A. L., Sussman, E. S., Cheng, M. Y., Steinberg, G. K. 2016; 40 (5)

    Abstract

    Stroke is one of the leading contributors to morbidity, mortality, and health care costs in the United States. Although several preclinical strategies have shown promise in the laboratory, few have succeeded in the clinical setting. Optogenetics represents a promising molecular tool, which enables highly specific circuit-level neuromodulation. Here, the conceptual background and preclinical body of evidence for optogenetics are reviewed, and translational considerations in stroke recovery are discussed.

    View details for DOI 10.3171/2016.2.FOCUS163

    View details for Web of Science ID 000375119300003

    View details for PubMedID 27132527

  • Clinical evaluation of concussion: the evolving role of oculomotor assessments NEUROSURGICAL FOCUS Sussman, E. S., Ho, A. L., Pendharkar, A. V., Ghajar, J. 2016; 40 (4)

    Abstract

    Sports-related concussion is a change in brain function following a direct or an indirect force to the head, identified in awake individuals and accounting for a considerable proportion of mild traumatic brain injury. Although the neurological signs and symptoms of concussion can be subtle and transient, there can be persistent sequelae, such as impaired attention and balance, that make affected patients particularly vulnerable to further injury. Currently, there is no accepted definition or diagnostic criteria for concussion, and there is no single assessment that is accepted as capable of identifying all patients with concussion. In this paper, the authors review the available screening tools for concussion, with particular emphasis on the role of visual function testing. In particular, they discuss the oculomotor assessment tools that are being investigated in the setting of concussion screening.

    View details for DOI 10.3171/2016.1.FOCUS15610

    View details for Web of Science ID 000373476500006

    View details for PubMedID 27032924

  • Junior Seau: An Illustrative Case of Chronic Traumatic Encephalopathy and Update on Chronic Sports-Related Head Injury WORLD NEUROSURGERY Azad, T. D., Li, A., Pendharkar, A. V., Veeravagu, A., Grant, G. A. 2016; 86

    Abstract

    Few neurologic diseases have captured the nation's attention more completely than chronic traumatic encephalopathy (CTE), which has been discovered in the autopsies of professional athletes, most notably professional football players. The tragic case of Junior Seau, a Hall of Fame, National Football League linebacker, has been the most high-profile confirmed case of CTE. Here we describe Seau's case, which concludes an autopsy conducted at the National Institutes of Health that confirmed the diagnosis.Since 1990, Junior Seau had a highly distinguished 20-year career playing for the National Football League as a linebacker, from which he sustained multiple concussions. He committed suicide on May 2, 2012, at age 43, after which an autopsy confirmed a diagnosis of CTE. His clinical history was significant for a series of behavioral disturbances. Seau's history and neuropathologic findings were used to better understand the pathophysiology, diagnosis, and possible risk factors for CTE.This high-profile case reflects an increasing awareness of CTE as a long-term consequence of multiple traumatic brain injuries. The previously unforeseen neurologic risks of American football have begun to cast doubt on the safety of the sport.

    View details for DOI 10.1016/j.wneu.2015.10.032

    View details for Web of Science ID 000369625300104

    View details for PubMedID 26493714

  • National trends in inpatient admissions following stereotactic radiosurgery and the in-hospital patient outcomes in the United States from 1998 to 2011. Journal of radiosurgery and SBRT Ho, A. L., Li, A. Y., Sussman, E. S., Pendharkar, A. V., Iyer, A., Thompson, P. A., Tayag, A. T., Chang, S. D. 2016; 4 (3): 165-176

    Abstract

    This study sought to examine trends in stereotactic radiosurgery (SRS) and in-hospital patient outcomes on a national level by utilizing national administrative data from the Nationwide Inpatient Sample (NIS) database.Using the NIS database, all discharges where patients underwent inpatient SRS were included in our study from 1998 - 2011 as designated by the ICD9-CM procedural codes. Trends in the utilization of primary and adjuvant SRS, in-hospital complications and mortality, and resource utilization were identified and analyzed.Our study included over 11,000 hospital discharges following admission for primary SRS or for adjuvant SRS following admission for surgery or other indication. The most popular indication for SRS continues to be treatment of intracranial metastatic disease (36.7%), but expansion to primary CNS lesions and other non-malignant pathology beyond trigeminal neuralgia has occurred over the past decade. Second, inpatient admissions for primary SRS have declined by 65.9% over this same period of time. Finally, as inpatient admissions for SRS become less frequent, the complexity and severity of illness seen in admitted patients has increased over time with an increase in the average comorbidity score from 1.25 in the year 2002 to 2.29 in 2011, and an increase in over-all in-hospital complication rate of 2.8 times over the entire study period.As the practice of SRS continues to evolve, we have seen several trends in associated hospital admissions. Overall, the number of inpatient admissions for primary SRS has declined while adjuvant applications have remained stable. Over the same period, there has been associated increase in complication rate, length of stay, and mortality in inpatients. These associations may be explained by an increase in the comorbidity-load of admitted patients as more high-risk patients are selected for admission at inpatient centers while more stable patients are increasingly being referred to outpatient centers.

    View details for PubMedID 27795870

    View details for PubMedCentralID PMC5081223

  • Endoscopic Transnasal Approach for Urgent Decompression of the Craniocervical Junction in Acute Skull Base Osteomyelitis. Journal of neurological surgery reports Burns, T. C., Mindea, S. A., Pendharkar, A. V., Lapustea, N. B., Irime, I., Nayak, J. V. 2015; 76 (1): e37-42

    Abstract

    Ventral epidural abscess with osteomyelitis at the craniocervical junction is a rare occurrence that typically mandates spinal cord decompression via a transoral approach. However, given the potential for morbidity with transoral surgery, especially in the setting of immunosuppression, together with the advent of extended endonasal techniques, the transnasal approach could be attractive for selected patients. We present two cases of ventral epidural abscess and osteomyelitis at the craniocervical junction involving C1/C2 that were successfully treated via the endoscopic transnasal approach. Both were treated in staged procedures involving posterior cervical fusion followed by endoscopic transnasal resection of the ventral C1 arch and odontoid process for decompression of the ventral spinal cord and medulla. Dural repairs were successfully performed using multilayered, onlay techniques where required. Both patients tolerated surgery exceedingly well, had brief postoperative hospital stays, and recovered uneventfully to their neurologic baselines. Postoperative magnetic resonance imaging confirmed complete decompression of the foramen magnum and upper C-spine. These cases illustrate the advantages and low morbidity of the endonasal endoscopic approach to the craniocervical junction in the setting of frank skull base infection and immunosuppression, representing to our knowledge a unique application of this technique to osteomyelitis and epidural abscess at the craniocervical junction.

    View details for DOI 10.1055/s-0034-1395492

    View details for PubMedID 26251807

    View details for PubMedCentralID PMC4520966

  • Deep brain stimulation for obesity: rationale and approach to trial design NEUROSURGICAL FOCUS Ho, A. L., Sussman, E. S., Pendharkar, A. V., Azagury, D. E., Bohon, C., Halpern, C. H. 2015; 38 (6)

    Abstract

    Obesity is one of the most serious public health concerns in the US. While bariatric surgery has been shown to be successful for treatment of morbid obesity for those who have undergone unsuccessful behavioral modification, its associated risks and rates of relapse are not insignificant. There exists a neurological basis for the binge-like feeding behavior observed in morbid obesity that is believed to be due to dysregulation of the reward circuitry. The authors present a review of the evidence of the neuroanatomical basis for obesity, the potential neural targets for deep brain stimulation (DBS), as well as a rationale for DBS and future trial design. Identification of an appropriate patient population that would most likely benefit from this type of therapy is essential. There are also significant cost and ethical considerations for such a neuromodulatory intervention designed to alter maladaptive behavior. Finally, the authors present a consolidated set of inclusion criteria and study end points that should serve as the basis for any trial of DBS for obesity.

    View details for DOI 10.3171/2015.3.FOCUS1538

    View details for Web of Science ID 000355539900008

    View details for PubMedID 26030708

  • Deep brain stimulation for vocal tremor: a comprehensive, multidisciplinary methodology NEUROSURGICAL FOCUS Ho, A. L., Erickson-DiRenzo, E., Pendharkar, A. V., Sung, C., Halpern, C. H. 2015; 38 (6)

    Abstract

    Tremulous voice is a characteristic feature of a multitude of movement disorders, but when it occurs in individuals diagnosed with essential tremor, it is referred to as essential vocal tremor (EVT). For individuals with EVT, their tremulous voice is associated with significant social embarrassment and in severe cases may result in the discontinuation of employment and hobbies. Management of EVT is extremely difficult, and current behavioral and medical interventions for vocal tremor result in suboptimal outcomes. Deep brain stimulation (DBS) has been proposed as a potential therapeutic avenue for EVT, but few studies can be identified that have systematically examined improvements in EVT following DBS. The authors describe a case of awake bilateral DBS targeting the ventral intermediate nucleus for a patient suffering from severe voice and arm tremor. They also present their comprehensive, multidisciplinary methodology for definitive treatment of EVT via DBS. To the authors' knowledge, this is the first time comprehensive intraoperative voice evaluation has been used to guide microelectrode/stimulator placement, as well as the first time that standard pre- and post-DBS assessments have been conducted, demonstrating the efficacy of this tailored DBS approach.

    View details for DOI 10.3171/2015.3.FOCUS1537

    View details for Web of Science ID 000355539900006

    View details for PubMedID 26030706

  • Dual-trajectory Approach for Simultaneous Cyst Fenestration and Endoscopic Third Ventriculostomy for Treatment of a Complex Third Ventricular Arachnoid Cyst. Cureus Ho, A. L., Pendharkar, A. V., Sussman, E. S., Ravikumar, V. K., Li, G. H. 2015; 7 (3)

    Abstract

    We present a case of a multiloculated third ventricular arachnoid cyst to describe a novel technique for definitive management of these lesions via direct endoscopic fenestration and CSF diversion utilizing separate trajectories that offers superior visualization and avoids forniceal injury.We present a case of a 33-year-old woman with progressive headache and worsened vision, a known history of a multiloculated third-ventricular arachnoid cyst, and imaging findings consistent with cyst expansion and worsened obstructive hydrocephalus. We then describe the dual-trajectory approach for simultaneous cyst fenestration and endoscopic third ventriculostomy that ultimately resulted in successful treatment of her cyst and hydrocephalus.Dual-trajectory endoscopic approach utilizing double burr holes should be considered when addressing lesions of the third ventricle causing obstructive hydrocephalus.

    View details for DOI 10.7759/cureus.253

    View details for PubMedID 26180677

  • Deep Brain Stimulation for Obesity. Cureus Ho, A. L., Sussman, E. S., Zhang, M., Pendharkar, A. V., Azagury, D. E., Bohon, C., Halpern, C. H. 2015; 7 (3)

    Abstract

    Obesity is now the third leading cause of preventable death in the US, accounting for 216,000 deaths annually and nearly 100 billion dollars in health care costs. Despite advancements in bariatric surgery, substantial weight regain and recurrence of the associated metabolic syndrome still occurs in almost 20-35% of patients over the long-term, necessitating the development of novel therapies. Our continually expanding knowledge of the neuroanatomic and neuropsychiatric underpinnings of obesity has led to increased interest in neuromodulation as a new treatment for obesity refractory to current medical, behavioral, and surgical therapies. Recent clinical trials of deep brain stimulation (DBS) in chronic cluster headache, Alzheimer's disease, and depression and obsessive-compulsive disorder have demonstrated the safety and efficacy of targeting the hypothalamus and reward circuitry of the brain with electrical stimulation, and thus provide the basis for a neuromodulatory approach to treatment-refractory obesity. In this study, we review the literature implicating these targets for DBS in the neural circuitry of obesity. We will also briefly review ethical considerations for such an intervention, and discuss genetic secondary-obesity syndromes that may also benefit from DBS. In short, we hope to provide the scientific foundation to justify trials of DBS for the treatment of obesity targeting these specific regions of the brain.

    View details for DOI 10.7759/cureus.259

    View details for PubMedID 26180683

  • Cushing's disease: predicting long-term remission after surgical treatment NEUROSURGICAL FOCUS Pendharkar, A. V., Sussman, E. S., Ho, A. L., Gephart, M. G., Katznelson, L. 2015; 38 (2)

    Abstract

    Cushing's disease (CD) is a state of excess glucocorticoid production resulting from an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma. The gold-standard treatment for CD is transsphenoidal adenomectomy. In the hands of an experienced neurosurgeon, gross-total resection is possible in the majority of ACTH-secreting pituitary adenomas, with early postoperative remission rates ranging from 67% to 95%. In contrast to the strong data in support of resection, the clinical course of postsurgical persistent or recurrent disease remains unclear. There is significant variability in recurrence rates, with reports as high as 36% with a mean time to recurrence of 15-50 months. It is therefore important to develop biochemical criteria that define postsurgical remission and that may provide prognosis for long-term recurrence. Despite the use of a number of biochemical assessments, there is debate regarding the accuracy of these tests in predicting recurrence. Here, the authors review the various biochemical criteria and assess their utility in predicting CD recurrence after resection.

    View details for DOI 10.3171/2014.10.FOCUS14682

    View details for Web of Science ID 000349263300013

    View details for PubMedID 25639315

  • Utility of Routine Outpatient Cervical Spine Imaging Following Anterior Cervical Corpectomy and Fusion. Cure¯us Desai, A., Pendharkar, A. V., Swienckowski, J. G., Ball, P. A., Lollis, S., Simmons, N. E. 2015; 7 (11)

    Abstract

    Construct failure is an uncommon but well-recognized complication following anterior cervical corpectomy and fusion (ACCF). In order to screen for these complications, many centers routinely image patients at outpatient visits following surgery. There remains, however, little data on the utility of such imaging.The electronic medical record of all patients undergoing anterior cervical corpectomy and fusion at Dartmouth-Hitchcock Medical Center between 2004 and 2009 were reviewed. All patients had routine cervical spine radiographs performed perioperatively. Follow-up visits up to two years postoperatively were analyzed. Sixty-five patients (mean age 52.2) underwent surgery during the time period. Eighteen patients were female. Forty patients had surgery performed for spondylosis, 20 for trauma, three for tumor, and two for infection. Forty-three patients underwent one-level corpectomy, 20 underwent two-level corpectomy, and two underwent three-level corpectomy, using an allograft, autograft, or both. Sixty-two of the fusions were instrumented using a plate and 13 had posterior augmentation. Fifty-seven patients had follow-up with imaging at four to 12 weeks following surgery, 54 with plain radiographs, two with CT scans, and one with an MRI scan. Unexpected findings were noted in six cases. One of those patients, found to have asymptomatic recurrent kyphosis following a two-level corpectomy, had repeat surgery because of those findings. Only one further patient was found to have abnormal imaging up to two years, and this patient required no further intervention.Routine imaging after ACCF can demonstrate asymptomatic occurrences of clinically significant instrument failure. In 43 consecutive single-level ACCF however, routine imaging did not change management, even when an abnormality was discovered. This may suggest a limited role for routine imaging after ACCF in longer constructs involving multiple levels.

    View details for DOI 10.7759/cureus.387

    View details for PubMedID 26719830

    View details for PubMedCentralID PMC4689583

  • Surgical Management of Sacral Chordomas: Illustrative Cases and Current Management Paradigms. Cure¯us Pendharkar, A. V., Ho, A. L., Sussman, E. S., Desai, A. 2015; 7 (8)

    Abstract

    Sacral chordomas represent more than 50% of all sacral tumors. These slow-growing, malignant lesions present insidiously and are often large and intimately involved with sacral neurovascular and pelvic structures. En bloc resection is the only well-established predictor of progression-free survival. Optimal surgical management requires a complex multi-disciplinary approach. Here, we describe two cases of sacral chordoma and review current management paradigms.

    View details for DOI 10.7759/cureus.301

    View details for PubMedID 26430575

  • Use of the NeuroBalloon catheter for endoscopic third ventriculostomy JOURNAL OF NEUROSURGERY-PEDIATRICS Guzman, R., Pendharkar, A. V., Zerah, M., Sainte-Rose, C. 2013; 11 (3): 302-306

    Abstract

    Endoscopic third ventriculostomy (ETV) has become the procedure of choice for treatment of obstructive hydrocephalus. While patient selection is the most critical factor in determining the success of an ETV procedure, the technical challenge lies in the proper site of fenestration and the successful creation of a patent stoma. Positioning of a single balloon catheter at the level or below the floor of the third ventricle to achieve an optimal ventriculostomy can at times be challenging. Here, the authors describe the use of a double-barrel balloon catheter (NeuroBalloon catheter), which facilitates positioning across, as well as dilation of, the floor of the third ventricle. The surgical technique and nuances of using the NeuroBalloon catheter and the experience in more than 1000 cases are described. The occurrence of vascular injury was less than 0.1%, and the risk of balloon rupture was less than 2%. The authors found that the placement and deployment of this balloon catheter facilitate the creation of an adequate ventriculostomy in a few simple steps.

    View details for DOI 10.3171/2012.10.PEDS11159

    View details for Web of Science ID 000315244100011

    View details for PubMedID 23259463

  • Timing of Intra-Arterial Neural Stem Cell Transplantation After Hypoxia-Ischemia Influences Cell Engraftment, Survival, and Differentiation STROKE Rosenblum, S., Wang, N., Smith, T. N., Pendharkar, A. V., Chua, J. Y., Birk, H., Guzman, R. 2012; 43 (6): 1624-?

    Abstract

    Intra-arterial neural stem cell (NSC) transplantation shows promise as a minimally invasive therapeutic option for stroke. We assessed the effect of timing of transplantation on cell engraftment, survival, and differentiation.Mouse NSCs transduced with a green fluorescent protein and renilla luciferase reporter gene were transplanted into animals 6 and 24 hours and 3, 7, and 14 days after hypoxia-ischemia (HI). Bioluminescent imaging was used to assess cell survival at 6 hours and 4 and 7 days after transplantation. Immunohistochemistry was used to assess NSC survival and phenotypic differentiation 1 month after transplantation. NSC receptor expression and brain gene expression were evaluated using real-time reverse transcription-quantitative polymerase chain reaction to elucidate mechanisms of cell migration. Boyden chamber assays were used to assess cell migratory potential in vitro.NSC transplantation 3 days after HI resulted in significantly higher cell engraftment and survival at 7 and 30 days compared with all other groups (P<0.05). Early transplantation at 6 and 24 hours after HI resulted in significantly higher expression of glial fibrillary acidic protein (P=0.0140), whereas late transplantation at 7 and 14 days after HI resulted in higher expression of ?-tubulin (P<0.0001). Corroborating the high cell engraftment 3 days after HI was robust expression of vascular cell adhesion molecule-1, CCL2, and CXCL12 in brain homogenates 3 days after HI.Intra-arterial transplantation 3 days after HI results in the highest cell engraftment. Early transplantation of NSCs leads to greater differentiation into astrocytes, whereas transplantation at later time points leads to greater differentiation into neurons.

    View details for DOI 10.1161/STROKEAHA.111.637884

    View details for PubMedID 22535265

  • The CCR2/CCL2 Interaction Mediates the Transendothelial Recruitment of Intravascularly Delivered Neural Stem Cells to the Ischemic Brain STROKE Andres, R. H., Choi, R., Pendharkar, A. V., Gaeta, X., Wang, N., Nathan, J. K., Chua, J. Y., Lee, S. W., Palmer, T. D., Steinberg, G. K., Guzman, R. 2011; 42 (10): 2923-U387

    Abstract

    The inflammatory response is a critical component of ischemic stroke. In addition to its physiological role, the mechanisms behind transendothelial recruitment of immune cells also offer a unique therapeutic opportunity for translational stem cell therapies. Recent reports have demonstrated homing of neural stem cells (NSC) into the injured brain areas after intravascular delivery. However, the mechanisms underlying the process of transendothelial recruitment remain largely unknown. Here we describe the critical role of the chemokine CCL2 and its receptor CCR2 in targeted homing of NSC after ischemia.Twenty-four hours after induction of stroke using the hypoxia-ischemia model in mice CCR2+/+ and CCR2-/- reporter NSC were intra-arterially delivered. Histology and bioluminescence imaging were used to investigate NSC homing to the ischemic brain. Functional outcome was assessed with the horizontal ladder test.Using NSC isolated from CCR2+/+ and CCR2-/- mice, we show that receptor deficiency significantly impaired transendothelial diapedesis specifically in response to CCL2. Accordingly, wild-type NSC injected into CCL2-/- mice exhibited significantly decreased homing. Bioluminescence imaging showed robust recruitment of CCR2+/+ cells within 6 hours after transplantation in contrast to CCR2-/- cells. Mice receiving CCR2+/+ grafts after ischemic injury showed a significantly improved recovery of neurological deficits as compared to animals with transplantation of CCR2-/- NSC.The CCL2/CCR2 interaction is critical for transendothelial recruitment of intravascularly delivered NSC in response to ischemic injury. This finding could have significant implications in advancing minimally invasive intravascular therapeutics for regenerative medicine or cell-based drug delivery systems for central nervous system diseases.

    View details for DOI 10.1161/STROKEAHA.110.606368

    View details for PubMedID 21836091

  • Intra-arterial injection of neural stem cells using a microneedle technique does not cause microembolic strokes JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Chua, J. Y., Pendharkar, A. V., Wang, N., Choi, R., Andres, R. H., Gaeta, X., Zhang, J., Moseley, M. E., Guzman, R. 2011; 31 (5): 1263-1271

    Abstract

    Intra-arterial (IA) injection represents an experimental avenue for minimally invasive delivery of stem cells to the injured brain. It has however been reported that IA injection of stem cells carries the risk of reduction in cerebral blood flow (CBF) and microstrokes. Here we evaluate the safety of IA neural progenitor cell (NPC) delivery to the brain. Cerebral blood flow of rats was monitored during IA injection of single cell suspensions of NPCs after stroke. Animals received 1 × 10(6) NPCs either injected via a microneedle (microneedle group) into the patent common carotid artery (CCA) or via a catheter into the proximally ligated CCA (catheter group). Controls included saline-only injections and cell injections into non-stroked sham animals. Cerebral blood flow in the microneedle group remained at baseline, whereas in the catheter group a persistent (15?minutes) decrease to 78% of baseline occurred (P<0.001). In non-stroked controls, NPCs injected via the catheter method resulted in higher levels of Iba-1-positive inflammatory cells (P=0.003), higher numbers of degenerating neurons as seen in Fluoro-Jade C staining (P<0.0001) and ischemic changes on diffusion weighted imaging. With an appropriate technique, reduction in CBF and microstrokes do not occur with IA transplantation of NPCs.

    View details for DOI 10.1038/jcbfm.2010.213

    View details for PubMedID 21157474

  • Biodistribution of Neural Stem Cells After Intravascular Therapy for Hypoxic-Ischemia STROKE Pendharkar, A. V., Chua, J. Y., Andres, R. H., Wang, N., Gaeta, X., Wang, H., De, A., Choi, R., Chen, S., Rutt, B. K., Gambhir, S. S., Guzman, R. 2010; 41 (9): 2064-2070

    Abstract

    Intravascular transplantation of neural stem cells represents a minimally invasive therapeutic approach for the treatment of central nervous system diseases. The cellular biodistribution after intravascular injection needs to be analyzed to determine the ideal delivery modality. We studied the biodistribution and efficiency of targeted central nervous system delivery comparing intravenous and intra-arterial (IA) administration of neural stem cells after brain ischemia.Mouse neural stem cells were transduced with a firefly luciferase reporter gene for bioluminescence imaging (BLI). Hypoxic-ischemia was induced in adult mice and reporter neural stem cells were transplanted IA or intravenous at 24 hours after brain ischemia. In vivo BLI was used to track transplanted cells up to 2 weeks after transplantation and ex vivo BLI was used to determine single organ biodistribution.Immediately after transplantation, BLI signal from the brain was 12 times higher in IA versus intravenous injected animals (P<0.0001). After IA injection, 69% of the total luciferase activity arose from the brain early after transplantation and 93% at 1 week. After intravenous injection, 94% of the BLI signal was detected in the lungs (P=0.004) followed by an overall 94% signal loss at 1 week, indicating lack of cell survival outside the brain. Ex vivo single organ analysis showed a significantly higher BLI signal in the brain than in the lungs, liver, and kidneys at 1 week (P<0.0001) and 2 weeks in IA (P=0.007).IA transplantation results in superior delivery and sustained presence of neural stem cells in the ischemic brain in comparison to intravenous infusion.

    View details for DOI 10.1161/STROKEAHA.109.575993

    View details for PubMedID 20616329

  • Ventricular enlargement due to acute hypernatremia in a patient with a ventriculoperitoneal shunt JOURNAL OF NEUROSURGERY Andres, R. H., Pendharkar, A. V., Kuhlen, D., Mariani, L. 2010; 113 (1): 82-84

    Abstract

    Patients requiring CSF shunts frequently have comorbidities that can influence water and electrolyte balances. The authors report on a case involving a ventriculoperitoneal shunt in a patient who underwent intravenous hyperhydration and withdrawal of vasopressin substitution prior to scheduled high-dose chemotherapy regimen for a metastatic suprasellar germinoma. After acute neurological deterioration, the patient underwent CT scanning that demonstrated ventriculomegaly. A shunt tap revealed no flow and negative opening pressure. Due to suspicion of proximal shunt malfunction, the comatose patient underwent immediate surgical exploration of the ventricle catheter, which was found to be patent. However, acute severe hypernatremia was diagnosed during the procedure. After correction of the electrolyte disturbances, the patient regained consciousness and made a good recovery. Although rare, the effects of acute severe hypernatremia on brain volume and ventricular size should be considered in the differential diagnosis of ventriculoperitoneal shunt failure.

    View details for DOI 10.3171/2009.10.JNS09845

    View details for Web of Science ID 000279107300020

    View details for PubMedID 19911884

  • Successful treatment of severe cerebral vasospasm following hemorrhage of an arteriovenous malformation JOURNAL OF NEUROSURGERY-PEDIATRICS Pendharkar, A. V., Guzman, R., Dodd, R., Cornfield, D., Edwards, M. S. 2009; 4 (3): 266-269

    Abstract

    The authors describe the case of a 13-year-old boy who presented with an intraventricular hemorrhage caused by a left trigonal arteriovenous malformation. After an initial recovery, the patient experienced complete right-sided paresis on posthemorrhage Day 6. Severe cerebral vasospasm was found on MR angiography and confirmed on conventional cerebral angiography. Intraarterial nicardipine injection and balloon angioplasty were successfully performed with improved vasospasm and subsequent neurological recovery. Cerebral vasospasm should be considered in the differential diagnosis for neurological deterioration following an arteriovenous malformation hemorrhage, and aggressive treatment can be administered to prevent ischemia and further neurological deficits.

    View details for DOI 10.3171/2009.4.PEDS09126

    View details for Web of Science ID 000269223300012

    View details for PubMedID 19772412

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