The Evolution of 5-Aminolevulinic Acid Fluorescence Visualization: Time for a Headlamp/Loupe Combination.

BACKGROUND: The use of 5-aminolevulinic acid (5-ALA) for intraoperative protoporphyrin IX fluorescent imaging in the resection of malignant gliomas has been demonstrated to improve tumor visualization, increase the extent of resection, and extend progression-free survival. The current technique for visualization of 5-ALA consists of excitation and emission filters built into the operating microscope. However, there are notable limitations to this process, including low quantum yield, expense, and masking of surrounding anatomy. METHODS: We present 3 cases in which 3 separate methods were employed for visualizing fluorescence. The devices reported are 1) a low-cost blue light flashlight, 2) a low-cost headlamp, and 3) the first reported case of the new Designs for Vision REVEAL Fluorescence-Guided Surgery (FGS) 5-ALA fluorescent headlight and loupes. The aim of the study is to provide confirmation that tumor fluorescence can be observed using commercially available products other than the microscope. RESULTS: We demonstrate through 3 intraoperative cases that a variety of devices can produce visible fluorescence of the high-grade tumor and allow for simultaneous real-time visualization of the adjacent brain parenchyma and vasculature. The REVEAL FGS system appears to offer increased fluorescence emission compared with all other methods, including the microscope. CONCLUSIONS: Our study demonstrates the feasibility of using blue/ultraviolet light supplied by a commercially available, inexpensive flashlight or headlamp to visualize 5-ALA fluorescence in high-grade gliomas. We also provide the first documentation of the intraoperative use of the new Designs for Vision REVEAL FGS 5-ALA fluorescent headlight and loupes and report on the experience. Lack of an operative microscope capable of fluorescent illumination should not be a limiting factor in performing fluorescent-guided glioma resection.

The critical importance of a vascularized flap in preventing recurrence after endoscopic repair of spontaneous cerebrospinal fluid leaks and meningoencephaloceles.

OBJECTIVE: Spontaneous CSF leaks into the anterior skull base nasal sinuses are often associated with meningoencephaloceles and occur in patients with idiopathic intracranial hypertension (IIH). Endonasal endoscopic repair has become the primary method of choice for repair. The authors sought to evaluate the success rate of endoscopic closure and to identify predictive factors for CSF leak recurrence. METHODS: A consecutive series of endonasally repaired anterior skull base meningoencephaloceles was drawn from a prospectively acquired database. Lumbar punctures were not performed as part of a treatment algorithm. All patients had at least 5 months of follow-up. Chart review and phone calls were used to determine the timing and predictors of recurrence. Demographic information and details of operative technique were correlated with recurrence. Two independent radiologists reviewed all preoperative imaging to identify radiographic markers of IIH, as well as the location and size of the meningoencephalocele. RESULTS: From a total of 54 patients there were 5 with recurrences (9.3%), but of the 39 patients in whom a vascularized nasoseptal (n = 31) or turbinate (n = 8) flap was used there were no recurrences (p = 0.0009). The mean time to recurrence was 24.8 months (range 9-38 months). There was a trend to higher BMI in patients whose leak recurred (mean [± SD] 36.6 ± 8.6) compared with those whose leak did not recur (31.8 ± 7.4; p = 0.182). Although the lateral recess of the sphenoid sinus was the most common site of meningoencephalocele, the fovea ethmoidalis was the most common site in recurrent cases (80%; p = 0.013). However, a vascularized flap was used in significantly more patients with sphenoid (78.3%) defects than in patients with fovea ethmoidalis (28.6%) defects (Fisher's exact test, p = 0.005). Radiographic signs of IIH were equally present in all patients whose leak recurred (75%) compared with patients whose leak did not recur (63.3%); however, an enlarged Meckel cave was present in 100% (2/2) of patients whose leaks recurred compared with 13.3% (4/30) of patients whose leaks did not recur (p = 0.03). The average meningoencephalocele diameter tended to be larger (1.73 ± 1.3 cm) in patients with recurrence compared to those without recurrence (1.2 ± 0.66 cm; p = 0.22). A ventriculoperitoneal shunt was already in place in 3 patients, placed perioperatively in 5, and placed at recurrence in 2, none of whose leaks recurred. CONCLUSIONS: Recurrence after endonasal repair of spontaneous CSF leaks from meningoencephaloceles can be dramatically reduced with the use of a vascularized flap. Although failures of endonasal repair tend to occur in patients who have higher BMI, larger brain herniations, and no CSF diversion, the lack of vascularized flap was the single most important risk factor predictive of failure.

Utility of Head Computed Tomography Scans Before Outpatient Follow-up for Low-Risk Mild Traumatic Brain Injury.

BACKGROUND: Neurosurgeons are frequently consulted for traumatic brain injuries (TBIs) resulting in intracranial hemorrhage (ICH). After inpatient confirmation of hemorrhage stability, outpatient head computed tomography (CT) is often performed to assess for hemorrhage resolution. Our objective was to assess the practice patterns and clinical utility of routine outpatient head CT scans for patients with mild TBI (mTBI). MATERIALS AND METHODS: A retrospective review was performed on all adult mTBI patients with ICH who presented to a level I trauma center over a 4-year period. A combination of the patient's initial clinical evaluation and CT findings was used to identify mTBI patients at low risk for neurologic deterioration and neurosurgical intervention. Findings from the outpatient follow-up clinical evaluation and head CT were assessed. Patients without outpatient follow-up within 3 months were excluded. RESULTS: Forty-nine patients met inclusion criteria for the study. Thirty-two had an outpatient head CT before their follow-up appointment. Twenty-one patients had at least 1 neurologic finding at the earliest follow-up appointment. All patients except those with a subdural hematoma (SDH) had smaller or resolving ICH on outpatient CT scans. Seven patients with an SDH had unchanged or expanded hemorrhage on outpatient imaging, 2 of whom had traumatic brain injury-related hospitalizations and 1 of whom underwent neurosurgical intervention due to an enlarging SDH. CONCLUSIONS: Routine outpatient head CT scans before follow-up for low-risk mTBI patients without an SDH appears to have limited clinical utility. In low-risk mTBI patients with an SDH, obtaining an outpatient head CT is reasonable to monitor for resolution.

Assessing the efficacy of mild traumatic brain injury management.

OBJECTIVE: Intracranial hemorrhage (ICH) is frequently found on computed tomography (CT) after mild traumatic brain injury (mTBI) prompting transfer to centers with neurosurgical coverage and repeat imaging to confirm hemorrhage stability. Studies suggest routine repeat imaging has little utility in patients with minimal ICH, no anticoagulant/antiplatelet use, and no neurological decline. Additionally, it is unclear which mTBI patients benefit from transfer for neurosurgery consultation. The authors sought to assess the clinical utility and cost effectiveness of routine repeat head CTs and transfer to tertiary centers in patients with low-risk, mTBI. METHODS: Retrospective evaluation of patients receiving a neurosurgical consultation for TBI during a 4-year period was performed at a level 1 trauma center. Patients were stratified according to risk for neurosurgical intervention based on their initial clinical evaluation and head CT. Only patients with low-risk, mTBI were included. RESULTS: Of 531 patients, 119 met inclusion criteria. Eighty-eight (74.0 %) received two or more CTs. Direct cost of repeat imaging was $273,374. Thirty-seven (31.1 %) were transferred to our facility from hospitals without neurosurgical coverage, costing $61,384. No patient had neurosurgical intervention or mTBI-related in-hospital mortality despite enlarging ICH on repeat CT in three patients. Two patients had mTBI related 30-day readmission for seizure without ICH expansion. CONCLUSION: Routine repeat head CT or transfer of low-risk, mTBI patients to a tertiary center did not result in neurosurgical intervention. Serial neurological examinations may be a safe, cost-effective alternative to repeat imaging for select mTBI patients. A large prospective analysis is warranted for further evaluation.

5-Aminolevulinic acid radiodynamic therapy for treatment of high-grade gliomas: A systematic review.

INTRODUCTION: Radiodynamic therapy (RDT) involves administration of a radiosensitizing agent and its subsequent activation by ionizing radiation for destruction of neoplastic cells. MATERIALS AND METHODS: A comprehensive evaluation of the literature was performed to review the history of RDT using porphyrins for solid tumors, the cellular mechanisms of action, immunomodulatory effects, and both preclinical and clinical studies for use in high-grade gliomas (HGGs). This manuscript was prepared in accordance with the PRISMA guidelines. RESULTS: A total of 271 articles were considered for initial review. After removal of duplicates, articles not unrelated to specific topic, and exclusion of commentary articles, a total of 11 articles were subject to full analysis that included in vivo, in vitro, and human studies. Porphyrins such as 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) selectively accumulate in neoplastic cells and are currently used for fluorescent-guided surgical resection and photodynamic therapy (PDT) of HGG and other brain tumors. 5-ALA is also shown to act as a radiosensitizer by increasing oxidative stress in neoplastic cell mitochondria and enhancing the host immune response. Postoperative radiation therapy is currently the standard of care for treatment of HGG. CONCLUSION: RDT remains a promising adjuvant therapy for HGGs and requires further investigation. Clinical trials of 5-ALA RDT for HGG are needed to evaluate the optimum timing, dosing and effectiveness.

Robotic Skull Base Surgery.

Robotic surgery has become more common in otolaryngologic surgery since the introduction of the da Vinci robotic system, but has played a limited role in anterior and central skull base surgery, largely because of technical limitations of existing robots. Current robotic technology has been used in creative ways to access the skull base, but was not designed to navigate these complex anatomic constraints. Novel robots should target many of the limitations of current robotic technology, such as maneuverability, inability to suture, lack of haptic feedback, and absent integration with image guidance.

A New Treatment Opportunity for DIPG and Diffuse Midline Gliomas: 5-ALA Augmented Irradiation, the 5aai Regimen.

Prognosis for diffuse intrinsic pontine glioma (DIPG) and generally for diffuse midline gliomas (DMG) has only marginally improved over the last ~40 years despite dozens of chemotherapy and other therapeutic trials. The prognosis remains invariably fatal. We present here the rationale for a planned study of adding 5-aminolevulinic acid (5-ALA) to the current irradiation of DIPG or DMG: the 5aai regimen. In a series of recent papers, oral 5-ALA was shown to enhance standard therapeutic ionizing irradiation. 5-ALA is currently used in glioblastoma surgery to enable demarcation of overt tumor margins by virtue of selective uptake of 5-ALA by neoplastic cells and selective conversion to protoporphyrin IX (PpIX), which fluoresces after excitation by 410 nm (blue) light. 5-ALA is also useful in treating glioblastomas by virtue of PpIX's transfer of energy to O2 molecules, producing a singlet oxygen that in turn oxidizes intracellular DNA, lipids, and proteins, resulting in selective malignant cell cytotoxicity. This is called photodynamic treatment (PDT). Shallow penetration of light required for PpIX excitation and resultant energy transfer to O2 and cytotoxicity results in the inaccessibility of central structures like the pons or thalamus to sufficient light. The recent demonstration that keV and MeV photons can also excite PpIX and generate singlet O2 allows for reconsideration of 5-ALA PDT for treating DMG and DIPG. 5-ALA has an eminently benign side effect profile in adults and children. A pilot study in DIPG/DMG of slow uptitration of 5-ALA prior to each standard irradiation session-the 5aai regimen-is warranted.

Resolution of Symptomatic Lumbar Synovial Cyst After Traumatic Event.

BACKGROUND: Synovial cysts are most commonly found in the lumbar spine and are associated with low back pain and radiculopathy. Frequent use of imaging modalities has led to an increase in intraspinal synovial cyst identification. Treatment typically ranges from conservative measures to surgical decompression, but spontaneous resolution has previously been reported. Here, we present the first report of symptomatic lumbar synovial cyst resolution after a traumatic fall. CASE DESCRIPTION: We present a case of a symptomatic synovial cyst between the fourth (L4) and fifth (L5) lumbar vertebrae identified on magnetic resonance imaging (MRI). The patient presented with right paramedian back pain and right-sided L5 radiculopathy. She underwent unsuccessful trials of antiinflammatory agents and physical therapy. Less than 1 year since initial diagnosis, the patient sustained a mechanic fall followed by resolution of prior symptoms. A subsequent lumbar MRI revealed complete resolution of the intraspinal synovial cyst. CONCLUSIONS: The diagnosis of synovial cysts are increasing in frequency due to their ease of identification with computed tomography and MRI. For cases of refractory pain and/or neurologic deficits, surgical decompression is usually necessary. In rare instances, synovial cysts may spontaneously regress or resolve secondary to other events. This is the first description of resolution after a traumatic fall. Due to limited data on this topic, this report may provide additional insight into the pathophysiology of synovial cyst formation and resolution.

Adjacent-segment disease following two-level axial lumbar interbody fusion.

OBJECTIVEWhile long-term studies have evaluated adjacent-segment disease (ASD) following posterior lumbar spine arthrodesis, no such studies have assessed the incidence and prevalence of ASD following axial lumbar interbody fusion (AxiaLIF). The aim of this study was to estimate the incidence of ASD following AxiaLIF.METHODSThe authors retrospectively reviewed the medical records of 149 patients who underwent two-level index AxiaLIF and had at least 2 years of radiographic and clinical follow-up. ASD and pre- and postoperative lumbar lordosis were evaluated in each patient. ASD was defined as both radiographic and clinically significant disease at a level adjacent to a previous fusion requiring surgical intervention. The mean duration of follow-up was 6.01 years.RESULTSTwenty (13.4%) of the 149 patients developed ASD during the data collection period. Kaplan-Meier analysis predicted a disease-free ASD survival rate of 95.3% (95% CI 90.4%-97.7%) at 2 years and 89.1% (95% CI 82.8%-93.2%) at 5 years for two-level fusion. A laminectomy adjacent to a fusion site was associated with 5.1 times the relative risk of developing ASD. Furthermore, the ASD group had significantly greater loss of lordosis than the no-ASD group (p = 0.033).CONCLUSIONSFollowing two-level AxiaLIF, the rate of symptomatic ASD warranting either decompression or arthrodesis was found to be 4.7% at 2 years and 10.9% at 5 years. Adjacent-segment decompression and postoperative loss of lumbar lordosis predicted future development of ASD. To the authors' knowledge, this is the largest reported cohort of patients to undergo two-level AxiaLIF in the United States.

Effects of 5-ALA dose on resection of glioblastoma.

PURPOSE: Fluorescence-guided surgery (FGS) with the use of 5-aminolevulinic acid (5-ALA) leads to more extensive resection of high-grade glioma (HGG) and longer overall survival (OS) of patients compared to conventional resection. The purpose of this study is to investigate the effect of 5-ALA dosages on residual tumor volume (RTV) and OS in patients with glioblastoma. METHODS: A retrospective cohort study for patients who participated in a phase I and II dose-escalation clinical trial on 5-ALA for resection of HGG. A total of 25 patients were found to have newly diagnosed glioblastoma on histology and enrolled in our study. Patients receiving low doses of 5-ALA (10-30 mg/kg) (n = 6) were compared to those receiving high doses (40-50 mg/kg) (n = 19). Pre- and post-operative contrast enhanced T1W MRI were evaluated with volumetric analysis. RESULTS: Median RTV was 0.69 cm3 and 0.00 cm3 in the low and high dose groups respectively (p = 0.975). A gross total resection (GTR) was more likely in the high dose group, though this was not statistically significant. No significant difference was found in median OS between the high and low dose groups (p = 0.6787). CONCLUSIONS: High doses of 5-ALA FGS are associated with less RTV and greater probability of GTR. 5-ALA dose was not associated with OS. Further studies with a larger patient cohort are warranted.

A Phase 1 Dose-Escalation Study of Oral 5-Aminolevulinic Acid in Adult Patients Undergoing Resection of a Newly Diagnosed or Recurrent High-Grade Glioma.

BACKGROUND: The utility of oral 5-aminolevulinic acid (5-ALA)/protoporphyrin fluorescence for the resection of high-grade gliomas is well documented. This drug has received regulatory approval in Europe but awaits approval in the United States. OBJECTIVE: To identify the appropriate dose and toxicity or harms of 5-ALA used for enhanced intraoperative visualization of malignant brain tumors, reported from a single medical center in the United States. METHODS: Prior to craniotomy for resection of a presumed high-grade glioma, individuals were given oral 5-ALA as part of a rapid dose-escalation scheme. At least 3 patients were selected for each dose level from 10 to 50 mg/kg in 10 mg/kg increments. Adverse events, intensity of tumor fluorescence, and results of biopsies in areas of tumor and the tumor bed under white light and deep blue light were recorded. RESULTS: A total of 19 patients were studied in this phase 1 study. Serious adverse events were unrelated to the ingestion of 5-ALA. At the highest dose level studied (50 mg/kg), 2 out of 6 patients were observed to have transient dermatologic redness and peeling. These were grade 1 adverse events, which were not serious enough to be dose limiting. Patients at higher dose levels (>40 mg/kg) were more likely to have strong tumor fluorescence. There were no instances of false positive fluorescence. CONCLUSION: The use of 5-ALA for brain tumor fluorescence is safe and effective to a dose of 50 mg/kg. Dose-limiting toxicity was not reached in this study.

Paradoxical Herniation following Decompressive Craniectomy in the Subacute Setting.

Decompressive craniectomy is reserved for extreme cases of intracranial hypertension. An uncommon complication known as paradoxical herniation has been documented within weeks to months following surgery. Here we present a unique case within days of surgery. Since standard medical treatment for intracranial hypertension will exacerbate paradoxical herniation, any abrupt neurological changes following decompressive craniectomy should be carefully investigated. Immediate treatment for paradoxical herniation is placement of the patient in the supine position with adequate hydration. Cranioplasty is the ultimate treatment option.

Evaluation of Cortical Thickness after Traumatic Brain Injury in Military Veterans.

Military service members frequently sustain traumatic brain injuries (TBI) while on active duty, a majority of which are related to explosive blasts and are mild in severity. Studies evaluating the cortical gray matter in persons with injuries of this nature remain scarce. The purpose of this study was to assess cortical thickness in a sample of military veterans with chronic blast-related TBI. Thirty-eight veterans with mild TBI and 17 veterans with moderate TBI were compared with 58 demographically matched healthy civilians. All veterans with TBI sustained injuries related to a blast and were between 5 and 120 months post-injury (M = 62.08). Measures of post-traumatic stress disorder (PTSD) and depression were administered, along with a battery of neuropsychological tests to assess cognition. The Freesurfer software package was used to calculate cortical thickness of the participants. Results demonstrated significant clusters of cortical thinning in the right hemispheric insula and inferior portions of the temporal and frontal lobe in both mild and moderate TBI participants. The TBI sample from this study demonstrated a high incidence of comorbid PTSD and depression symptoms, which is consistent with the previous literature. Cortical thickness values correlated with measures of PTSD, depression, and post-concussive symptoms. This study provides evidence of cortical thinning in the context of chronic blast-related mild and moderate TBI in military veterans who have comorbid psychiatric symptoms. Our findings provide important insight into the natural progression of long-term cortical change in this population and may have implications for future clinical evaluation and treatment.

Spaceflight-Induced Intracranial Hypertension.

INTRODUCTION: Although once a widely speculated about and largely theoretical topic, spaceflight-induced intracranial hypertension has gained acceptance as a distinct clinical phenomenon, yet the underlying physiological mechanisms are still poorly understood. In the past, many terms were used to describe the symptoms of malaise, nausea, vomiting, and vertigo, though longer duration spaceflights have increased the prevalence of overlapping symptoms of headache and visual disturbance. Spaceflight-induced visual pathology is thought to be a manifestation of increased intracranial pressure (ICP) because of its similar presentation to cases of known intracranial hypertension on Earth as well as the documentation of increased ICP by lumbar puncture in symptomatic astronauts upon return to gravity. The most likely mechanisms of spaceflight-induced increased ICP include a cephalad shift of body fluids, venous outflow obstruction, blood-brain barrier breakdown, and disruption to CSF flow. The relative contribution of increased ICP to the symptoms experienced during spaceflight is currently unknown, though other factors recently posited to contribute include local effects on ocular structures, individual differences in metabolism, and the vasodilator effects of carbon dioxide. This review article attempts to consolidate the literature regarding spaceflight-induced intracranial hypertension and distinguish it from other pathologies with similar symptomatology. It discusses the proposed physiological causes and the pathological manifestations of increased ICP in the spaceflight environment and provides considerations for future long-term space travel. In the future, it will be critical to develop countermeasures so that astronauts can participate at their peak potential and return safely to Earth.