Global Neurosurgery Advances From Trenches to Bedside: Lessons From Neurosurgical Care in War, Humanitarian Assistance, and Disaster Response.

INTRODUCTION: War has influenced the evolution of global neurosurgery throughout the past century. Armed conflict and mass casualty disasters (MCDs), including Humanitarian Assistance Disaster Relief missions, require military surgeons to innovate to meet extreme demands. However, the military medical apparatus is seldom integrated into the civilian health care sector. Neurosurgeons serving in the military have provided a pragmatic template for global neurosurgeons to emulate in humanitarian disaster responses. In this paper, we explore how wars and MCD have influenced innovations of growing interest in the resource-limited settings of global neurosurgery. METHODS: We performed a narrative review of the literature examining the influence of wars and MCD on contemporary global neurosurgery practices. RESULTS: Wartime innovations that influenced global neurosurgery include the development of triage systems and modernization with airlifts, the implementation of ambulance corps, early operation on cranial injuries in hospital camps near the battlefield, the use of combat body armor, and the rise of damage control neurosurgery. In addition to promoting task-shifting and task-sharing, workforce shortages during wars and disasters contributed to the establishment of the physician assistant/physician associate profession in the USA. Low- and middle-income countries (LMICs) face similar challenges in developing trauma systems and obtaining advanced technology, including neurosurgical equipment like battery-powered computed tomography scanners. These challenges-ubiquitous in low-resource settings-have underpinned innovations in triage and wound care, rapid evacuation to tertiary care centers, and minimizing infection risk. CONCLUSION: War and MCDs have catalyzed significant advancements in neurosurgical care both in the pre-hospital and inpatient settings. Most of these innovations originated in the military and subsequently spread to the civilian sector as military neurosurgeons and reservist civilian neurosurgeons returned from the battlefront or other low-resource locations. Military neurosurgeons have utilized their experience in low-resource settings to make volunteer global neurosurgery efforts in LMICs successful. LMICs have, by necessity, responded to challenges arising from resource shortages by developing innovative, context-specific care paradigms and technologies.

Distinctive Characteristics of Thoracolumbar Junction Region Stenosis.

STUDY DESIGN: Retrospective case series and systemic literature meta-analysis. BACKGROUND: Thoracolumbar junction region stenosis produces spinal cord compression just above the conus and may manifest with symptoms that are not typical of either thoracic myelopathy or neurogenic claudication from lumbar stenosis. OBJECTIVE: As few studies describe its specific pattern of presenting symptoms and neurological deficits, this investigation was designed to improve understanding of this pathology. METHODS: A retrospective review assessed surgically treated cases of T10-L1 degenerative stenosis. Clinical outcomes were evaluated with the thoracic Japanese Orthopedic Association score. In addition, a systematic review and meta-analysis was performed in accordance with guidelines provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS: Of 1069 patients undergoing laminectomy at 1477 levels, 31 patients (16M/15F) were treated at T10-L1 a mean age 64.4 (SD=11.8). Patients complained of lower extremity numbness in 29/31 (94%), urinary dysfunction 11/31 (35%), and back pain 11/31 (35%). All complained about gait difficulty and objective motor deficits were detected in 24 of 31 (77%). Weakness was most often seen in foot dorsiflexion 22/31 (71%). Deep tendon reflexes were increased in 10 (32%), decreased in 11 (35%), and normal 10 (32%); the Babinski sign was present 8/31 (26%). Mean thoracic Japanese Orthopedic Association scores improved from 6.4 (SD=1.8) to 8.4 (SD=1.8) ( P <0.00001). Gait subjectively improved in 27/31 (87%) numbness improved in 26/30 (87%); but urinary function improved in only 4/11 (45%). CONCLUSIONS: Thoracolumbar junction stenosis produces distinctive neurological findings characterized by lower extremity numbness, weakness particularly in foot dorsiflexion, urinary dysfunction, and inconsistent reflex changes, a neurological pattern stemming from epiconus level compression and the myelomeres for the L5 roots. Surgery results in significant clinical improvement, with numbness and gait improving more than urinary dysfunction. Many patients with thoracolumbar junction stenosis are initially misdiagnosed as being symptomatic from lumbar stenosis, thus delaying definitive surgery.

Troubleshooting the bypass: intraoperative management of initially failed anastomosis in direct cerebral revascularization surgery.

OBJECTIVE: Direct cerebral revascularization is considered as one of the most technically challenging operations in neurosurgery. Technical errors are often not identified during the case, but only after the recirculation stage, making management crucial at that time of the procedure. In this study, the authors sought to describe troubleshooting of the technical errors encountered in initially failed bypass cases. METHODS: A retrospective analysis describing a single-surgeon, single-institution experience between 2014 and 2021 was performed, based on operative reports and videos, including a 30-day follow-up period. Initially failed bypass was defined if the bypass was not patent or had a significant leak after recirculation, irrespective of the final result. RESULTS: One hundred thirty-eight bypass cases were reviewed for complex aneurysms (n = 49), moyamoya disease (n = 59), and atherosclerosis (n = 30). Fifty-one initially failed anastomoses were identified; 43 of these were the result of a technical error. Etiologies of these failed anastomoses included a clot (n = 14), vessel kinking (n = 4), spasm (n = 5), suture-related cause (n = 5), inappropriate donor or recipient (n = 3), or lack of demand (n = 8). A major leak was attributed to an uncoagulated side branch (n = 4), vessel injury due to suture/clip placement (n = 1), or inadequate suture line coverage (n = 7). Thirty-seven (86%) of 43 cases were troubleshot successfully, as salvage maneuvers included papaverine vessel massage, donor repositioning, re-anastomosis for occlusion in select cases, local hemostatic agents, and suturing or coagulating side branches in a leak. Thirty-day follow-up revealed similar rates of patency between successfully troubleshot patients (35/37) and the rest of the cases (80/87, p = 0.6). CONCLUSIONS: Three major patterns of a noncompatible bypass were found: a major leak, an acute occlusion, or a delayed occlusion. Based on the authors' experience, salvage strategies proved successful, showing an eventual high patency rate. The authors suggest a gradual, structured algorithm to address this stage in surgery that may contribute specifically to cerebrovascular neurosurgeons at the beginning of their careers.

Thecal sac ligation in the setting of thoracic spondyloptosis with complete cord transection.

Background: Traumatic spondyloptosis (TS) with complete spinal cord transection and unrepairable durotomy is particularly rare and can lead to a difficult-to-manage cerebrospinal fluid (CSF) leak. Methods: We performed a systematic review of the literature on TS and discuss the management strategies and outcomes of TS with cord transection and significant dural tear. We also report a novel case of a 26-year-old female who presented with thoracic TS with complete spinal cord transection and unrepairable durotomy with high-flow CSF leak. Results: Of 93 articles that resulted in the search query, 13 described cases of TS with complete cord transection. The approach to dural repair was only described in 8 (n = 20) of the 13 articles. The dura was not repaired in two (20%) of the cases. Ligation of the proximal end of the dural defect was done in 15 (75%) of the cases, all at the same institution. One (5%) case report describes ligation of the distal end; one (5%) case describes the repair of the dura with duraplasty; and another (5%) case describes repair using muscle graft to partially reconstruct the defect. Conclusion: Suture ligation of the thecal sac in the setting of traumatic complete spinal cord transection with significant dural disruption has been described in the international literature and is a safe and successful technique to prevent complications associated with persisting high-flow CSF leakage. To the best of our knowledge, this is the first report of thecal sac ligation of the proximal end of the defect from the United States.

Adjustable, Dynamic Subcortical Stimulation Technique for Brain Tumor Resection: A Case-Series.

BACKGROUND AND OBJECTIVES: Subcortical stimulation (SCS) is the gold standard neuromonitoring technique for intraoperative identification of descending white matter tracts. Dynamic SCS confers several advantages over more commonly used static devices; however, current commercially available devices for dynamic SCS have not been widely adopted. METHODS: We fashioned a dynamic SCS device using a stainless-steel suction and commonly available materials and assessed its efficacy in a series of 14 patients with brain tumors. The device was used to provide continuous SCS during tumor resection. Preoperative and postoperative motor function were characterized, and preoperative and postoperative imaging were analyzed to determine extent of tumor resection and proximity to motor-eloquent structures. Inferential statistics were used to correlate study parameters. RESULTS: Fourteen patients (12 male and 2 female, median age 52.5 years) were analyzed. The lowest intraoperative SCS intensities were 10 to 15 mA (3 surgeries), 5 to 10 mA (4 surgeries), and <5 mA (2 surgeries). SCS with this device did not elicit motor evoked potentials in 5 surgeries because of distance from the corticospinal tract (CST) and served as negative controls. Three patients (21.4%) experienced new postoperative motor deficits immediately after surgery that resolved by discharge. We observed no instances of mechanical CST injury resulting in permanent postoperative motor deficits using this technique and no correlation between lower SCS intensity and the presence of new motor impairments after surgery. No patient experienced an intraoperative seizure. CONCLUSION: The novel dynamic SCS device is easily adoptable and allows accurate intraoperative identification of the CST, facilitating safe resection of tumors near motor-eloquent structures.

Disparities in anterior cervical discectomy and fusion provision and outcomes for cervical stenosis.

Background: Disparities in neurosurgical care have emerged as an area of interest when considering the impact of social determinants on access to health care. Decompression via anterior cervical discectomy and fusion (ACDF) for cervical stenosis (CS) may prevent progression towards debilitating complications that may severely compromise one's quality of life. This retrospective database analysis aims to elucidate demographic and socioeconomic trends in ACDF provision and outcomes of CS-related pathologies. Methods: The Healthcare Cost and Utilization Project National Inpatient Sample database was queried between 2016 and 2019 using International Classification of Diseases 10th edition codes for patients undergoing ACDF as a treatment for spinal cord and nerve root compression. Baseline demographics and inpatient stay measures were analyzed. Results: Patients of White race were significantly less likely to present with manifestations of CS such as myelopathy, plegia, and bowel-bladder dysfunction. Meanwhile, Black patients and Hispanic patients were significantly more likely to experience these impairments representative of the more severe stages of the degenerative spine disease process. White race conferred a lesser risk of complications such as tracheostomy, pneumonia, and acute kidney injury in comparison to non-white race. Insurance by Medicaid and Medicare conferred significant risks in terms of more advanced disease prior to intervention and negative inpatient. Patients in the highest quartile of median income consistently fared better than patients in the lowest quartile across almost every aspect ranging from degree of progression at initial presentation to incidence of complications to healthcare resource utilization. All outcomes for patients age > 65 were worse than patients who were younger at the time of the intervention. Conclusions: Significant disparities exist in the trajectory of CS and the risks associated with ACDF amongst various demographic cohorts. The differences between patient populations may be reflective of a larger additive burden for certain populations, especially when considering patients' intersectionality.

Frailty as a Superior Predictor of Dysphagia and Surgically Placed Feeding Tube Requirement After Anterior Cervical Discectomy and Fusion Relative to Age.

Frailty is a measure of physiological reserve that has been demonstrated to be a discriminative predictor of worse outcomes across multiple surgical subspecialties. Anterior cervical discectomy and fusion (ACDF) is one of the most common neurosurgical procedures in the United States and has a high incidence of postoperative dysphagia. To determine the association between frailty and dysphagia after ACDF and compare the predictive value of frailty and age. 155,300 patients with cervical stenosis (CS) who received ACDF were selected from the 2016-2019 National Inpatient Sample (NIS) utilizing International Classification of Disease, tenth edition (ICD-10) codes. The 11-point modified frailty index (mFI-11) was used to stratify patients based on frailty: mFI-11 = 0 was robust, mFI-11 = 1 was prefrail, mFI-11 = 2 was frail, and mFI-11 = 3 + was characterized as severely frail. Demographics, complications, and outcomes were compared between frailty groups. A total of 155,300 patients undergoing ACDF for CS were identified, 33,475 (21.6%) of whom were frail. Dysphagia occurred in 11,065 (7.1%) of all patients, and its incidence was significantly higher for frail patients (OR 1.569, p < 0.001). Frailty was a risk factor for postoperative complications (OR 1.681, p < 0.001). Increasing frailty and undergoing multilevel ACDF were significant independent predictors of negative postoperative outcomes, including dysphagia, surgically placed feeding tube (SPFT), prolonged LOS, non-home discharge, inpatient death, and increased total charges (p < 0.001 for all). Increasing mFI-11 score has better prognostic value than patient age in predicting postoperative dysphagia and SPFT after ACDF.

Comparison of Characteristics, Inpatient Outcomes, and Trends in Percutaneous Versus Open Placement of Spinal Cord Stimulators.

OBJECTIVES: Spinal cord stimulation (SCS) is an effective treatment modality for chronic pain conditions for which other treatment modalities have failed to provide relief. Ample prospective studies exist supporting its indications for use and overall efficacy. However, less is known about how SCS is used at the population level. Our objective is to understand the demographics, clinical characteristics, and utilization patterns of open and percutaneous SCS procedures. MATERIALS AND METHODS: The Nationwide Inpatient Sample data base of 2016-2019 was queried for cases of percutaneous or open placement (through laminotomy/laminectomy) of SCS (excluding SCS trials) using International Classification of Disease (ICD), 10th revision, procedure coding system. Baseline demographic characteristics, complications, ICD-Clinical Modification, Diagnosis Related Group, length of stay (LOS), and yearly implementation data were collected. Complications and outcomes were evaluated in total and between the open and percutaneous SCS groups. RESULTS: A total of 2455 inpatients had an SCS placed, of whom 1970 (80.2%) received SCS through open placement. Placement of open SCS was associated with Caucasian race (odds ratio [OR] = 1.671, p < 0.001), private insurance (OR = 1.332, p = 0.02), and age more than 65 years (OR = 1.25, p = 0.034). The most common diagnosis was failed back surgery syndrome (23.8%). Patients with percutaneous SCS were more likely to have a hospital stay of < 1 day (OR = 2.318; 95% CI, 1.586-3.387; p < 0.001). Implant complications during the inpatient stay were positively associated with open SCS placement and reported in 9.4% of these cases (OR = 3.247, p < 0.001). CONCLUSIONS: Patients who underwent open SCS placement were more likely to be older, Caucasian, and privately insured. Open SCS placement showed greater LOS and implant-related complications during their hospital stay. These findings highlight both potential socioeconomic disparities in health care access for chronic pain relief and the importance of increasing age and medical comorbidities as important factors that can influence SCS implants in the inpatient setting.

International Survey of Antiseizure Medication Use in Patients with Complicated Mild Traumatic Brain Injury: A New York Neurotrauma Consortium Study.

BACKGROUND: Seizures and epilepsy after traumatic brain injury (TBI) negatively affect quality of life and longevity. Antiseizure medication (ASM) prophylaxis after severe TBI is associated with improved outcomes; these medications are rarely used in mild TBI. However, a paucity of research is available to inform ASM use in complicated mild TBI (cmTBI) and no empirically based clinical care guidelines for ASM use in cmTBI exist. We aim to identify seizure prevention and management strategies used by clinicians experienced in treating patients with cmTBI to characterize standard care and inform a systematic approach to clinical decision making regarding ASM prophylaxis. METHODS: We recruited a multidisciplinary international cohort through professional organizational listservs and social media platforms. Our questionnaire assessed factors influencing ASM prophylaxis after cmTBI at the individual, institutional, and health system-wide levels. RESULTS: Ninety-two providers with experience managing cmTBI completed the survey. We found a striking diversity of ASM use in cmTBI, with 30% of respondents reporting no/infrequent use and 42% reporting frequent use; these tendencies did not differ by provider or institutional characteristics. Certain conditions universally increased or decreased the likelihood of ASM use and represent consensus. Based on survey results, ASMs are commonly used in patients with cmTBI who experience acute secondary seizure or select positive neuroimaging findings; we advise caution in elderly patients and those with concomitant neuropsychiatric illness. CONCLUSIONS: This study is the first to characterize factors influencing clinical decision making in ASM prophylaxis after cmTBI based on multidisciplinary multicenter provider practices. Prospective controlled studies are necessary to inform standardized guideline development.

Tranexamic Acid Dosing in Craniosynostosis Surgery: A Systematic Review with Meta-analysis.

This study aimed to compare operative time, blood loss, and transfusion requirement in patients receiving a high tranexamic acid (TXA) dose of greater than 10 mg/kg versus those receiving a low dose of 10 mg/kg or less. Methods: PubMed, Cochrane Central, and Embase were queried to perform a systematic review with meta-analysis. Studies reporting outcomes of TXA use in craniosynostosis surgery were included. TXA dosing, operative time, blood loss, and transfusion requirement were the primary outcomes studied. Other variables studied included age and types of craniosynostosis. Results: In total, 398 individuals in the included articles received TXA for craniosynostosis surgery. TXA loading doses ranged from 10 mg/kg to 50 mg/kg. Overall, administration of TXA was not associated with changes in operative time, but was associated with decreased blood loss and transfusion requirement on meta-analysis. Comparison of high dose TXA (>10 mg/kg) versus low dose (10 mg/kg or less) showed no statistical differences in changes in operative time, blood loss, or transfusion requirement. Conclusions: Overall, TXA reduced blood loss and transfusion requirement in patients undergoing surgery for craniosynostosis. There was no difference in outcomes between high dose and low dose regimens amongst those receiving TXA. Low dose TXA appears adequate to achieve clinical efficacy with a low adverse event rate.

A Cost-Effective, Adjustable, Dynamic Subcortical Stimulation Device - Technical Note.

Brain mapping and neuromonitoring remain the gold standard for identifying and preserving functional neuroanatomic regions during safe, maximal brain tumor resection. Subcortical stimulation (SCS) can identify white matter tracts and approximate their distance from the leading edge of an advancing resection cavity. Dynamic (continuous) devices permitting simultaneous suction and stimulation have recently emerged as time-efficient alternatives to traditional static (discontinuous) techniques. However, the high cost, fixed cap size, and fixed tube diameter of commercially available suction devices preclude universal adoption. Our objective is to modify available suction devices into monopolar probes for subcortical stimulation mapping. We describe our technique using a novel, cost-effective, dynamic SCS technique as part of our established neuromonitoring protocol. We electrified and insulated a conventional variable suction device using an alligator clip and red rubber catheter, respectively. We adjusted the catheter's length to expose metal on both sides, effectively converting the suction device into a monopolar stimulation probe capable of cortical and subcortical monopolar stimulation that does not differ from commercially available discontinuous or continuous devices. We fashioned a dynamic SCS suction probe using inexpensive materials compatible with all suction styles and sizes. Qualitative and quantitative analysis in future prospective case series is needed to assess efficacy and utility.

Enhanced Recovery After Surgery (ERAS) for Cranial Tumor Resection: A Review.

Enhanced Recovery After Surgery (ERAS) protocols describe a standardized method of preoperative, perioperative, and postoperative care to enhance outcomes and minimize complication risks surrounding elective surgical intervention. A growing body of evidence is being generated as we learn to apply principles of ERAS standardization to neurosurgical patients. First applied in spinal surgery, ERAS protocols have been extended to cranial neuro-oncologic procedures. This review synthesizes recent findings to generate evidence-based guidelines to manage neurosurgical oncology patients with standardized systems and assess ability of these systems to coordinate multidisciplinary, patient-centric care efforts. Furthermore, we highlight the potential usefulness of multimedia, app-based communication platforms to facilitate patient education, autonomy, and team communication within each of the 3 settings.

Subcortical Stimulation in Brain Tumor Surgery: A Closer Look Beneath the Surface.

BACKGROUND: Maximizing the patient's onco-functional balance is the central tenet of brain tumor surgery. Consequently, numerous surgical adjuncts have been developed to facilitate identification of the tumor-brain interface and preservation of functional anatomy. Among these, intraoperative neurophysiologic monitoring (IONM) with direct cortical stimulation (DCS) and subcortical stimulation (SCS) remains the gold standard for real-time, functional mapping of motor and language activity. Stimulation techniques are not standardized and vary significantly across institutions, however. This is particularly true with SCS for mapping motor function. METHODS: We reviewed the state of subcortical IONM and mapping techniques, including historical and predicate literature as well as new and emerging techniques. Here we discuss their evolution, clinical utility, and limitations to direct future research and application. RESULTS: Our evaluation of the background and current clinical use of DCS and SCS techniques and protocols and identification of current trends and limitations focuses specifically on methods of SCS, given the heterogeneity in the published literature. We suggest directions to optimize the clinical utility of these tools. CONCLUSIONS: Despite significant heterogeneity in published techniques, trends support use of the Taniguchi method for SCS. Novel dynamic stimulation techniques may improve accuracy. Prospective studies to define standardized guidelines are needed.

Incidence of Neo-Intimal Hyperplasia in Anterior Circulation Aneurysms Following Pipeline Flow Diversion.

INTRODUCTION: Flow diversion of the distal anterior circulation cerebral vasculature may be used for management of wide necked aneurysms not amenable to other endovascular approaches. Follow-up angiography sometimes demonstrates neo-intimal hyperplasia within or adjacent to the stent, however there is limited evidence in the literature examining the incidence in MCA and ACA aneurysms. We present our experience with flow diversion of the distal vasculature and evaluate the incidence of neo-intimal hyperplasia. MATERIALS AND METHODS: Retrospective review of patients who underwent Pipeline embolization device (PED) treatment for ruptured and unruptured anterior circulation aneurysms. RESULTS: A total of 251 anterior circulation aneurysms were treated by pipeline flow diversion, of which 175 were ICA aneurysms, 14 were ACA aneurysms and 18 were MCA aneurysms. 6-month follow-up angiography was available in 207 patients. The incidence of neo-intimal hyperplasia was 15.9%, 21.4%, and 61.1% in ICA, ACA, and MCA aneurysms, respectively. MCA-territory aneurysms developed neo-intimal hyperplasia at a significantly higher rate than aneurysms in other vessel territories. Rates of aneurysmal occlusion did not significantly differ from those patients who did not exhibit intimal hyperplasia on follow-up angiography. CONCLUSION: In our experience, flow diversion of distal wide-necked MCA and ACA aneurysms is a safe and effective treatment strategy. The presence of neo-intimal hyperplasia at 6-month angiography is typically clinically asymptomatic. Given the statistically higher rate of neo-intimal hyperplasia in MCA aneurysms at 6-month angiography, we propose delaying initial follow-up angiography to 12-months and maintaining dual antiplatelet therapy during that time.

Flow diversion in anterior cerebral artery aneurysms.

INTRODUCTION: Anterior cerebral artery (ACA) aneurysms are commonly encountered in clinical practice but can be challenging to treat. Flow diversion is a viable treatment in this population. METHODS: We retrospectively evaluated patients treated at our center from May 2017 to December 2020 who underwent flow diversion for an ACA aneurysm at or distal to the anterior communicating artery (ACOM). We defined ACA aneurysms as any aneurysm involving the ACOM itself, at the junction of the ACA with the ACOM (A1/A2), or in distal A2/A3 branches; both ruptured and unruptured aneurysms were included. Baseline and follow-up clinical and angiographic data were collected; the primary measure was elimination of the aneurysm on follow-up angiogram. Patients underwent flow diversion with a Pipeline stent. A single flow diverting stent was placed in the dominant ACA spanning from the A2 segment extending into the A1 segment; two patients required H-pipe technique. Distal aneurysms were treated with a single Pipeline device deployed across the parent vessel, covering the aneurysm. RESULTS: Two-seven patients underwent a total of 28 flow diversion procedures; median age was 57 and 16 (59.3%) were male. Thirteen (48.2%) patients presented with subarachnoid hemorrhage; of these, four were treated within 6 weeks of the index hemorrhage. Most patients (22; 81.5%) had significant ACA asymmetry. There was one postoperative intracerebral hemorrhage and one groin complication. Follow-up data were available for 19 patients, 15 (78.9%) of which showed no residual aneurysm and 17 (89.5%) had protection of the dome. CONCLUSION: Flow diversion of ACA aneurysms can be a primary treatment modality in an unruptured aneurysm or a complement to initial coil protection of a ruptured aneurysm. Further studies are needed to confirm these results.

Migraine Progression: A Systematic Review.

BACKGROUND: Migraine is a common and often debilitating neurological disease. It can be divided into episodic and chronic subforms based on the number of monthly headache days. Because only a subset of individuals with episodic migraine (EM) progress to chronic migraine (CM) over any given time period, understanding the factors that predict the new onset of CM or "migraine progression" may provide insights into the mechanisms, pathophysiology, prevention, and treatment of CM. In this review, we identify and summarize studies that report risk factors associated with the new onset of CM or related chronic headache diagnoses, group these risk factors and report the strength of evidence for the identified risk factors. OBJECTIVE: To conduct a systematic review of studies that identify risk factors for the new onset of CM or related chronic headache diagnoses such as transformed migraine (TM) and chronic daily headache (CDH). METHODS: Herein we summarize the findings of studies of risk factors associated with the new onset of CM/TM, CDH, or related diagnoses from the English language literature published before March 2018. The PubMed database was searched for relevant studies. Longitudinal studies with follow-up data and case-control studies were included in this qualitative synthesis. We report methodology, analytic criteria, and results for each manuscript and for the parent study. Next, we review the strength of evidence for each of the identified risk factors using a modified version of AB Hill's criteria for causation and rank evidence as fair, moderate, or strong. We categorized risk factors as nonmodifiable, modifiable and based on putative mechanisms. We further categorized risk factors into sociodemographics, lifestyle factors and habits, headache features, comorbid and concomitant diseases and conditions and pharmacologic treatment-related. Finally, we review theories of the pathophysiology underlying the development of new onset chronic migraine or increasing attack frequency. RESULTS: The PubMed search yielded 1870 records after duplicates were removed. Nine additional records were identified through expert consultation and other methods (eg, citations found as references in manuscripts identified in the literature review and through communication with the authors of manuscripts included in the review). The 1879 manuscripts were screened against the inclusion and exclusion criteria and 109 were found to be potentially eligible. Of 109 full-text articles, 17 studies were identified as meeting the prespecified criteria based on the consensus of all authors. Of the 17 full texts, 13 were longitudinal cohort studies and 4 were case-controlled studies. We found strength of evidence ranging from fair to strong for the identified risk factors. The strongest data were found for increased headache day frequency, depression, and medication overuse/high-frequency use. Risk factors for new onset CM and CDH in children and adolescents were similar to those identified in adults. CONCLUSIONS: A range of risk factors for the new onset of CM/TM, CDH, or related chronic headache diseases were identified with the strongest data supporting increased headache day frequency, acute medication overuse/high-frequency use and depression, which are potentially modifiable risk factors. Modifiable risk factors may provide targets for intervention. The lack of strong evidence or any evidence does not imply that there is not a relationship between a particular risk factor and new onset CM or related disease; but may indicate little or no research or that research did not have sufficient methodological rigor. In addition, it is likely that additional risk factors exist which have not yet been identified. Putative factors include pro-inflammatory states and pro-thrombotic states. Development of central sensitization and increased activation of the trigeminal nociceptive pathways may be drivers of the new onset of CM or CDH. Future research may include the systematic testing of interventions targeting modifiable risk factors to determine if progression can be prevented as well as continued exploration of the benefits of treating these risk factors among people with CM in an effort to increase rates of remission. Future work should also consider the natural fluctuations in headache day frequency and examine progression in terms of continuous definitions rather than or in addition to a dichotomous boundary.