Nathan T. Zwagerman

Toll-like receptor-4 and cytokine cascade in stroke after exercise

Abstract Objectives: As part of the innate immune system, activation of Toll-like receptor-4 by inflammatory mediators causes the release of inflammatory cytokines, leading to cellular damage. Exercise for 3 weeks has been shown to provide neuroprotection against ischemia/reperfusion insults by decreasing inflammation. This study explores the expression of Toll-like receptor-4 in brain parenchyma during an ischemic stroke after exercise, in association with brain injury. Methods: Adult male Sprague-Dawley rats were studied in four groups (control, exercise, stroke and stroke after exercise). Exercise consisted of 30 minutes of treadmill running daily for 3 weeks. Using an intraluminal filament, a stroke was induced by 2 hour middle cerebral artery occlusion. Nissl staining was used to determine brain infarct volume. Brain Toll-like receptor-4 messenger RNA expression and protein levels were determined by real time reverse transcriptase polymerase chain reaction and Western blot, respectively. Results: Exercise significantly (p<0·05) decreased Toll-like receptor-4 messenger RNA and protein expression, in association with significantly (p<0·05) reduced brain infarct volume. The stroke group had significantly (p<0·05) increased levels of Toll-like receptor-4 expression compared to the control, whereas the exercise/stroke group was significantly (p<0·05) attenuated. Conclusion: Exercise reduced Toll-like receptor-4 expression within brain tissue in response to ischemia/reperfusion insult. This is the first paper, to our knowledge, indicating the correlation between exercise, Toll-like receptor-4 expression and reduced brain infarct volume.

Preischemic exercise reduces brain damage by ameliorating metabolic disorder in ischemia/reperfusion injury

Physical exercise preconditioning is known to ameliorate stroke‐induced injury. In addition to several other mechanisms, the beneficial effect of preischemic exercise following stroke is due to an upregulated capacity to maintain energy supplies. Adult male Sprague‐Dawley rats were used in exercise and control groups. After 1–3 weeks of exercise, several enzymes were analyzed as a gauge of the direct effect of physical exercise on cerebral metabolism. As a measure of metabolic capacity, an ADP/ATP ratio was obtained. Glucose transporters (GLUT1 and GLUT3) were monitored to assess glucose influx, and phosphofructokinase (PFK) was measured to determine the rate of glycolysis. Hypoxia‐induced factor‐1α (HIF‐1α) and 5′AMP‐activated protein kinase (AMPK) levels were also determined. These same analyses were performed on preconditioned and control rats following an ischemic/reperfusion (I/R) insult. Our results show that GLUT1, GLUT3, PFK, AMPK, and HIF‐1α were all increased following 3 weeks of exercise training. In addition, the ADP/ATP ratio was chronically elevated during these 3 weeks. After I/R injury, HIF‐1α and AMPK were significantly higher in exercised rats. The ADP/ATP ratio was reduced in preconditioned rats in the acute phase after stroke, suggesting a lower level of metabolic disorder. GLUT1 and GLUT3 were also increased in the acute phase in exercise rats, indicating that these rats were better able to increase rates of metabolism immediately after ischemic injury. In addition, PFK expression was increased in exercise rats showing an enhanced glycolysis resulting from exercise preconditioning. Altogether, exercise preconditioning increased the rates of glucose metabolism, allowing a more rapid and more substantial increase in ATP production following stroke.

Onyx embolization of infectious intracranial aneurysms

Background Infectious intracranial aneurysms (IIAs) are rare and potentially devastating. First-line management involves intravenous antibiotics, with surgical or endovascular management reserved for cases of failed medical treatment or aneurysmal rupture. Endovascular therapy has become the primary approach for treating these small, distally located aneurysms. Liquid embolic agents are well suited for use because of their ability to fill the aneurysm and parent vessel. We present our experience in treating these aneurysms via Onyx embolization and review the literature. Methods We retrospectively reviewed the endovascular treatment of IIAs at our institution from 2010 to 2012. Eight patients with 16 IIAs ranging in size from 1 to 16 mm underwent treatment. Seven of the patients initially presented after aneurysmal rupture. Onyx was pushed until the aneurysm and parent artery were filled. Confirmation of aneurysmal occlusion was made by repeat cerebral angiography. Results One symptomatic stroke occurred after embolization. Fourteen of the 16 aneurysms have been evaluated with follow-up angiography and remain occluded. Conclusions Treatment of IIAs using an endovascular approach with Onyx is safe and effective.

The development of Moyamoya syndrome after proton beam therapy.

The development of Moyamoya syndrome (MMS) after cranial irradiation for pediatric tumors has been well established. However, information on the development of MMS after proton beam radiotherapy is sparse. We present the case of a 2‐year‐old child who developed radiation‐induced MMS after treatment with proton beam therapy. Pediatr Blood Cancer 2014; 61:1490–1492.

Lateral Orbitotomy Approach for Lesions Involving the Middle Fossa: A Retrospective Review of Thirteen Patients

Background Classically used for treatment of orbital lesions, the lateral orbitotomy with cantholysis can be combined with a temporal craniectomy for lesions involving the middle cranial fossa. Objective To present a single-center experience with the lateral orbitotomy approach for lesions involving the middle fossa. Metuods Twenty-five patients underwent lateral orbitotomies from April 2012 to July 2015. Excluding patients with solely intraorbital pathologies, 13 patients’ clinical and radiographic records were retrospectively reviewed. Results Signs/symptoms in the 13 patients (ages 28-81) included proptosis (69%), decreased visual acuity (31%), diplopia (54%), and afferent pupillary defect (69%). Pathologies were meningioma (8), esthesioneuroblastoma, lymphoma, chordoma, Ewings sarcoma, and squamous cell carcinoma. Surgical goals were maximal safe resection in 8 patients, palliative debulking in 3 patients, and cavernous sinus biopsy in 2 patients. In 8 patients for whom maximal resection was the goal, 2 had gross total resection, while 6 had near-total resection. All patients (3) for whom palliation was the goal had symptomatic improvement. Both cavernous sinus biopsies obtained diagnostic tissue without complications. All patients with proptosis (n = 9) and diplopia (n = 7), and 2 of 4 patients with decreased visual acuity had improvement in their symptoms. No patient reported worsening of their symptoms. Mean follow-up was 12 mo (2-30 mo). Complications included oculorrhea (1), pseudomeningocele (2), transient ptosis (2), and forehead numbness (1). Conclusion The lateral orbitotomy is a promising approach for carefully selected lesions with involvement of both the lateral orbit and middle cranial fossa. It provides minimally invasive access for biopsy, decompression, or resection.

Endoscopic transnasal skull base surgery: pushing the boundaries

The endoscopic endonasal approach (EEA) has significantly evolved since its initial uses in pituitary and sinonasal surgery. The literature is filled with reports and case series demonstrating efficacy and advantages for the entire ventral skull base. With competence in ‘minimally invasive’ parasellar approaches, larger and more complex approaches were developed to utilize the endonasal corridor to create maximally invasive endoscopic skull base procedures. The challenges of these more complex endoscopic procedures include a long learning curve and navigating in a narrow corridor; reconstruction of defects presented new challenges and early experience revealed a significantly higher risk of cerebrospinal fluid leak. Despite these challenges, there are many benefits to the EEA including avoidance of brain and neurovascular retraction, improved visualization, a direct corridor onto many tumors and the two-surgeon approach. Most importantly, the EEA provides a midline corridor to directly access tumors, which displace critical neurovascular structures laterally, giving it an inherent advantage of minimizing any manipulation of these structures and thus decreasing their potential injury.

The impact of mode of delivery on infant neurologic outcomes in myelomeningocele

BACKGROUND Controversy exists regarding the optimal route of delivery for fetuses who are diagnosed prenatally with myelomeningocele. Current recommendations are based partly on antiquated studies with questionable methods. All studies that have been published to date suffer from nonstandardized outcome measures, selection bias, and small sample size. The larger studies are >15 years old. OBJECTIVE The purpose of this study was to provide information for evidence-based decision-making regarding the impact of route of delivery on motor outcomes for pediatric patients with prenatally were diagnosed myelomeningocele in a well-defined retrospective cohort. STUDY DESIGN Medical records were reviewed retrospectively for all neonates who had been diagnosed with a myelomeningocele at birth from 1995-2015 within the University of Pittsburgh Medical Center system, as identified through the Childrens Hospital of Pittsburgh Neurosurgery Department operative database. Records were matched with maternal records with the use of the Center for Assistance in Research that used eRecord. Data from 72 maternal-neonatal pairs were analyzed for multiple variables. The primary outcome measure was the difference between the functional and anatomic motor levels in the child at the age of 2 years, stratified by mode of delivery and presence or absence of labor. The sample size necessary to detect a difference between the groups with power of 0.8 and significance of .05 was calculated to be 52 subjects total (26 per group). RESULTS Functional levels were slightly better than predicted by anatomic levels for all pediatric patient groups, regardless of mode of delivery or presence of labor. Anatomic levels were slightly lower (better), and defects were smaller for those infants who underwent vaginal delivery or a trial of labor, likely attributable to selection bias. Attempts to correct for this selection bias did not change the results. No other outcomes that were analyzed were associated significantly with mode of delivery or presence of labor. CONCLUSION No benefit to motor function from delivery by cesarean section or avoidance of labor was demonstrated statistically in this mother-infant cohort.

Facial necrosis after endovascular Onyx‑18 embolization for epistaxis

Background: Evolution in techniques and equipment has expanded the role, effectiveness, and safety of endovascular transarterial embolization for the treatment of severe epistaxis. Risks from this treatment approach include major ischemic complications. To date, there have been only a few reports of soft tissue necrosis following endovascular embolization for severe epistaxis; none involve the use of Onyx-18. Case Description: We report the case of a 52-year-old woman who presented with epistaxis that was refractory to medical and surgical management, which lead to endovascular intervention and embolization with Onyx-18. The patient subsequently developed nasal ala and facial necrosis as a result of the procedure. Conclusion: We report the use of Onyx-18 for the endovascular embolization of a patient with severe epistaxis and subsequent complications. In cases of severe epistaxis that warrant intervention in the form of embolization, ischemic complications are rare; however, ischemic complications may be unavoidable and should factor into the discussion regarding procedural risks.

Endoscopic endonasal resection of the odontoid process: clinical outcomes in 34 adults

OBJECTIVE Treatment of odontoid disease from a ventral corridor has consisted of a transoral approach. More recently, the endoscopic endonasal approach (EEA) has been used to access odontoid pathology. METHODS A retrospective review was conducted of patients who underwent an EEA for odontoid pathology from 2004 to 2013. During our analysis, the mean follow-up duration was 42.6 months (range 1-80 months). Patient outcomes, complications, and postoperative swallowing function were assessed either by clinic visit or phone contact. RESULTS Thirty-four patients underwent an EEA for symptomatic odontoid pathology. The most common pathology treated was basilar invagination (n = 17). Other pathologies included odontoid fractures, os odontoideum, and metastatic carcinoma. The mean patient age was 71.5 years. Thirty-one patients underwent a posterior fusion. All 34 patients experienced stability or improvement in symptoms and all had successful radiographic decompression. The overall complication rate was 76%. Nearly all of these complications were transient (86%) and the overall complication rate excluding mild transient dysphagia was only 44%. Twenty-one patients (62%) suffered from transient postoperative dysphagia: 15 cases were mild, transient subjective dysphagia (6 of whom had documented preoperative dysphagia), whereas 6 other patients required tube feedings for decreased oral intake, malnutrition, and dysphagia in the perioperative setting (5 of these patients had documented preoperative dysphagia). Sixteen patients had documented preoperative dysphagia and 6 of these had lower cranial nerve dysfunction. Postoperatively, 6 (37.5%) of 16 patients with preoperative dysphagia and 4 (67%) of 6 with lower cranial nerve dysfunction had significant dysphagia/respiratory complications. Eighteen patients had no documented preoperative dysphagia and only 2 had significant postoperative dysphagia/respiratory complications (11%). The rates of these complications in patients without preoperative dysphagia were lower than in those with any preoperative dysphagia (p = 0.07) and especially those with preexisting lower cranial neuropathies (p = 0.007). Dysphagia was also significantly more common in patients who underwent occipitocervical fixation (19/26, 73%) than in patients who underwent cervical fusion alone or no fusion (2/8, 25%; p = 0.02). All patients with perioperative dysphagia had improved at follow-up and all patients were tolerating oral diets. No patient suffered from velopalatal insufficiency. Two patients had intraoperative CSF leaks. One of these patients underwent a negative exploratory surgery for a questionable postoperative CSF leak. One patient developed infection in the resection bed requiring debridement and antibiotics. One patient died 8 days following surgery from an unknown cause. The 90-day perioperative mortality rate was 2.9%. CONCLUSIONS A completely EEA can be performed for compressive odontoid disease in all cases of neoplastic, degenerative, or invaginative atlantoaxial disease with satisfactory outcomes and low morbidity. Transient perioperative dysphagia and respiratory complications are common, usually as an exacerbation and reflection of underlying disease or occipitocervical fusion rather than the EEA, emphasizing the importance of avoiding transoral surgery.

Histopathological examination of spine tumors after treatment with radiosurgery

OBJECTIVE Increased survival time after diagnosis of neoplastic disease has resulted in a gradual increase in spine tumor incidence. Radiosurgery is frequently a viable alternative to operative management in a population with severe medical comorbidities. The authors sought to assess the histopathological consequences of radiosurgery in the subset of patients progressing to operative intervention. METHODS Eighteen patients who underwent radiosurgery for spine tumors between 2008 and 2014 subsequently progressed to surgical treatment. A histopathological examination of these cases was performed. Indications for surgery included symptomatic compression fractures, radiographic instability, and symptoms of cord or cauda equina compression. Biopsy samples were obtained from the tumor within the radiosurgical zone in all cases and were permanently fixated. Viable tumor samples were stained for Ki 67. RESULTS Fifteen patients had metastatic lesions and 3 patients had neurofibromas. The mean patient age was 57 years. The operative indication was symptomatic compression in 10 cases (67%). The most frequent metastatic lesions were breast cancer (4 cases), renal cell carcinoma (3), prostate cancer (2), and endometrial cancer (2). In 9 (60%) of the 15 metastatic cases, histological examination of the lesions showed minimal evidence of inflammation. Viable tumor at the margins of the radiosurgery was seen in 9 (60%) of the metastatic cases. Necrosis in the tumor bed was frequent, as was fibrotic bone marrow. Vascular ectasia was seen in 2 of 15 metastatic cases, but sclerosis with ectasia was frequent. No evidence of malignant conversion was seen in the periphery of the lesions in the 3 neurofibroma cases. In 1 case of neurofibroma, the lesion demonstrated some small areas of remnant tumor in the radiosurgical target zone. CONCLUSIONS This case series demonstrates important histopathological characteristics of spinal lesions treated by SRS. Regions with the highest exposure to radiation appear to be densely necrotic and show little evidence of tumor growth, whereas peripheral regions distant from the radiation dosage are more likely to demonstrate viable tumor in malignant and benign neoplasms. Physiological tissue appears to be similarly affected. With additional investigation, a more homogenized field of hypofractionated radiation exposure may allow for tumor obliteration with relative preservation of critical anatomical structures.