Review of Cerebrospinal Fluid Physiology and Dynamics: A Call for Medical Education Reform

Neurosurgery 91:1–7, 2022

The flow of cerebrospinal fluid (CSF) has been described as a unidirectional system with the choroid plexus serving as the primary secretor of CSF and the arachnoid granulations as primary reabsorption site. This theory of neurosurgical forefathers has been universally adopted and taught as dogma. Many neuroscientists have found difficulty reconciling this theory with common pathologies, and recent studies have found that this “classic” hypothesis may not represent the full picture.

OBJECTIVE: To review modern CSF dynamic theories and to call formedical education reform.

METHODS: We reviewed the literature from January 1990 to December 2020. We searched the PubMed database using key terms “cerebrospinal fluid circulation,” “cerebrospinal fluid dynamics,” “cerebrospinal fluid physiology,” “glymphatic system,” and “glymphatic pathway.” We selected articles with a primary aim to discuss either CSF dynamics and/or the glymphatic system.

RESULTS: The Bulat–Klarica–Oreˇskovi´c hypothesis purports that CSF is secreted and reabsorbed throughout the craniospinal axis. CSF demonstrates similar physiology to that of water elsewhere in the body. CSF “circulates” throughout the subarachnoid space in a pulsatile to-and-fro fashion. Osmolarity plays a critical role in CSF dynamics. Aquaporin-4 and the glymphatic system contribute to CSF volume and flow by establishing osmolarity gradients and facilitating CSF movement. Multiple studies demonstrate that the choroid plexus does not play any significant role in CSF circulation.

CONCLUSION: We have highlighted major studies to illustrate modern principles of CSF dynamics. Despite these, the medical education system has been slow to reform curricula and update learning resources.

Contemporary concepts of pain surgery

J Neurosurg 130:1039–1049, 2019

Pain surgery is one of the historic foundations of neurological surgery. The authors present a review of contemporary concepts in surgical pain management, with reference to past successes and failures, what has been learned as a subspecialty over the past 50 years, as well as a vision for current and future practice.

This subspecialty confronts problems of cancer pain, nociceptive pain, and neuropathic pain. For noncancer pain, ablative procedures such as dorsal root entry zone lesions and rhizolysis for trigeminal neuralgia (TN) should continue to be practiced. Other procedures, such as medial thalamotomy, have not been proven effective and require continued study. Dorsal rhizotomy, dorsal root ganglionectomy, and neurotomy should probably be abandoned.

For cancer pain, cordotomy is an important and underutilized method for pain control. Intrathecal opiate administration via an implantable system remains an important option for cancer pain management.

While there are encouraging results in small case series, cingulotomy, hypophysectomy, and mesencephalotomy deserve further detailed analysis.

Electrical neuromodulation is a rapidly changing discipline, and new methods such as high-frequency spinal cord stimulation (SCS), burst SCS, and dorsal root ganglion stimulation may or may not prove to be more effective than conventional SCS. Despite a history of failure, deep brain stimulation for pain may yet prove to be an effective therapy for specific pain conditions. Peripheral nerve stimulation for conditions such as occipital neuralgia and trigeminal neuropathic pain remains an option, although the quality of outcomes data is a challenge to these applications. Based on the evidence, motor cortex stimulation should be abandoned. TN is a mainstay of the surgical treatment of pain, particularly as new evidence and insights into TN emerge.

Pain surgery will continue to build on this heritage, and restorative procedures will likely find a role in the armamentarium. The challenge for the future will be to acquire higher-level evidence to support the practice of surgical pain management.



The microneurosurgical anatomy legacy of Albert L. Rhoton Jr., MD: an analysis of transition and evolution over 50 years

J Neurosurg 129:1331–1341, 2018

Dr. Albert L. Rhoton Jr. was a pioneer of the study of microneurosurgical anatomy. Championing this field over the past half century, he produced more than 500 publications.

In this paper, the authors review his body of work, focusing on approximately 160 original articles authored by Rhoton and his microneuroanatomy fellows.

The articles are categorized chronologically into 5 stages: 1) dawn of microneurosurgical anatomy, 2) study of basic anatomy for general neurosurgery, 3) study for skull base surgery, 4) study of the internal structures of the brain by fiber dissection, and 5) surgical anatomy dealing with new advanced surgical approaches.

Rhoton introduced many new research ideas and surgical techniques and approaches, along with better microsurgery instruments, through studying and teaching microsurgical anatomy, especially during the first stage. The characteristic features of each stage are explained and the transition phases of his projects are reviewed.


International differences in the management of intracranial aneurysms: implications for the education of the next generation of neurosurgeons

MCA aneurysm

Acta Neurochir 2015, 157,(9):1467-1475

The publication of the International Subarachnoid Aneurysm Trial rapidly changed the management of patients with subarachnoid hemorrhage. The present and perceived future trends of aneurysm management have significant implications for patients and how we educate future cerebrovascular specialists.


To determine present perceived competencies of final-year neurosurgical residents who have just finished their residencies and to relate those to what practitioners from a variety of continents expect of these persons. The goal is to provide a basis for further discussion regarding the design of further educational programs in neurosurgery.


A 55-item questionnaire with 33 questions related to competencies and expectations of competency from final-year residents who have just finished residency was completed by 229 neurosurgeons and neuro-radiologists (81 % response rate) of mixed seniority from 45 countries. We used bivariate and descriptive analyses to determine future trends and geographic differences in cerebral aneurysm management as well as the educational implications on the future.


More North Americans than those from the rest of the world are of the opinion that graduating residents are presently competent to perform basic cerebrovascular procedures like evacuation of a hematoma and clipping a simple 7-mm middle cerebral artery aneurysm. Extremely few graduating neurosurgical residents anywhere are presently capable of performing endovascular techniques for even the most basic of aneurysms. Most of those surveyed also believe that endovascular and open surgical management of aneurysms should be a part of residency training for all residents (70.4 and 88.7 %, respectively).


Our findings have implications for the design of neurosurgical curricula for residents as well as for certification examinations and procedures. Specialty and educational organizations and those responsible for the education of future clinicians who will care for patients with cerebrovascular problems should adjust educational objectives and implement curricula and learning experiences that will ensure that cerebrovascular specialists are capable of providing the best care possible to the patient with an aneurysm, whether that be open surgery or endovascular management. These findings mean that organizations around the world will need to make these adjustments to the education of future specialists.

Attrition rates in neurosurgery residency


J Neurosurg 122:240–249, 2015

The objective of this study is to determine neurosurgery residency attrition rates by sex of matched applicant and by type and rank of medical school attended.

Methods The study follows a cohort of 1361 individuals who matched into a neurosurgery residency program through the SF Match Fellowship and Residency Matching Service from 1990 to 1999. The main outcome measure was achievement of board certification as documented in the American Board of Neurological Surgery Directory of Diplomats. A secondary outcome measure was documentation of practicing medicine as verified by the American Medical Association DoctorFinder and National Provider Identifier websites. Overall, 10.7% (n = 146) of these individuals were women. Twenty percent (n = 266) graduated from a top 10 medical school (24% of women [35/146] and 19% of men [232/1215], p = 0.19). Forty-five percent (n = 618) were graduates of a public medical school, 50% (n = 680) of a private medical school, and 5% (n = 63) of an international medical school. At the end of the study, 0.2% of subjects (n = 3) were deceased and 0.3% (n = 4) were lost to follow-up.

Results The total residency completion rate was 86.0% (n = 1171) overall, with 76.0% (n = 111/146) of women and 87.2% (n = 1059/1215) of men completing residency. Board certification was obtained by 79.4% (n = 1081) of all individuals matching into residency between 1990 and 1999. Overall, 63.0% (92/146) of women and 81.3% (989/1215) of men were board certified. Women were found to be significantly more at risk (p < 0.005) of not completing residency or becoming board certified than men. Public medical school alumni had significantly higher board certification rates than private and international alumni (82.2% for public [508/618]; 77.1% for private [524/680]; 77.8% for international [49/63]; p < 0.05). There was no significant difference in attrition for graduates of top 10–ranked institutions versus other institutions. There was no difference in number of years to achieve neurosurgical board certification for men versus women.

Conclusions Overall, neurosurgery training attrition rates are low. Women have had greater attrition than men during and after neurosurgery residency training. International and private medical school alumni had higher attrition than public medical school alumni.

Case-control studies in neurosurgery


J Neurosurg 121:285–296, 2014

Observational studies, such as cohort and case-control studies, are valuable instruments in evidencebased medicine. Case-control studies, in particular, are becoming increasingly popular in the neurosurgical literature due to their low cost and relative ease of execution; however, no one has yet systematically assessed these types of studies for quality in methodology and reporting.

Methods. The authors performed a literature search using PubMed/MEDLINE to identify all studies that explicitly identified themselves as “case-control” and were published in the JNS Publishing Group journals (Journal of Neurosurgery, Journal of Neurosurgery: Pediatrics, Journal of Neurosurgery: Spine, and Neurosurgical Focus) or Neurosurgery. Each paper was evaluated for 22 descriptive variables and then categorized as having either met or missed the basic definition of a case-control study. All studies that evaluated risk factors for a well-defined outcome were considered true case-control studies. The authors sought to identify key features or phrases that were or were not predictive of a true case-control study. Those papers that satisfied the definition were further evaluated using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist.

Results. The search detected 67 papers that met the inclusion criteria, of which 32 (48%) represented true case-control studies. The frequency of true case-control studies has not changed with time. Use of odds ratios (ORs) and logistic regression (LR) analysis were strong positive predictors of true case-control studies (for odds ratios, OR 15.33 and 95% CI 4.52–51.97; for logistic regression analysis, OR 8.77 and 95% CI 2.69–28.56). Conversely, negative predictors included focus on a procedure/intervention (OR 0.35, 95% CI 0.13–0.998) and use of the word “outcome” in the Results section (OR 0.23, 95% CI 0.082–0.65). After exclusion of nested case-control studies, the negative correlation between focus on a procedure/intervention and true case-control studies was strengthened (OR 0.053, 95% CI 0.0064–0.44). There was a trend toward a negative association between the use of survival analysis or Kaplan-Meier curves and true case-control studies (OR 0.13, 95% CI 0.015–1.12). True case-control studies were no more likely than their counterparts to use a potential study design “expert” (OR 1.50, 95% CI 0.57–3.95). The overall average STROBE score was 72% (range 50–86%). Examples of reporting deficiencies were reporting of bias (28%), missing data (55%), and funding (44%).

Conclusions. The results of this analysis show that the majority of studies in the neurosurgical literature that identify themselves as “case-control” studies are, in fact, labeled incorrectly. Positive and negative predictors were identified. The authors provide several recommendations that may reverse the incorrect and inappropriate use of the term “case-control” and improve the quality of design and reporting of true case-control studies in neurosurgery.

Are readmission rates on a neurosurgical service indicators of quality of care?


J Neurosurg 119:1043–1049, 2013

The goal of this study was to examine the reasons for early readmissions within 30 days of discharge to a major academic neurosurgical service.

Methods. A database of readmissions within 30 days of discharge between April 2009 and September 2010 was retrospectively reviewed. Clinical and administrative variables associated with readmission were examined, including age, sex, race, days between discharge and readmission, and insurance type. The readmissions were then assigned independently by 2 neurosurgeons into 1 of 3 categories: scheduled, adverse event, and unrelated. The adverse event readmissions were further subcategorized into patients readmitted although best practices were followed, those readmitted due to progression of their underlying disease, and those readmitted for preventable causes. These variables were compared descriptively.

Results. A total of 348 patients with 407 readmissions were identified, comprising 11.5% of the total 3552 admissions. The median age of readmitted patients was 55 years (range 16–96 years) and patients older than 65 years totaled 31%. There were 216 readmissions (53% of 407) for management of an adverse event that was classified as either preventable (149 patients; 37%) or unpreventable (67 patients; 16%). There were 113 patients (28%) who met readmission criteria but who were having an electively scheduled neurosurgical procedure. Progression of disease (48 patients; 12%) and treatment unrelated to primary admission (30 patients; 7%) were additional causes for readmission. There was no significant difference in the proportion of early readmissions by payer status when comparing privately insured patients and those with public or no insurance (p = 0.09).

Conclusions. The majority of early readmissions within 30 days of discharge to the neurosurgical service were not preventable. Many of these readmissions were for adverse events that occurred even though best practices were followed, or for progression of the natural history of the neurosurgical disease requiring expected but unpredictably timed subsequent treatment. Judicious care often requires readmission to prevent further morbidity or death in neurosurgical patients, and penalties for readmission will not change these patient care obligations.

Cancer Immunoediting in Malignant Glioma

Neurosurgery 71:201–223, 2012

Significant work from many laboratories over the last decade in the study of cancer immunology has resulted in the development of the cancer immunoediting hypothesis. This contemporary framework of the naturally arising immune system–tumor interaction is thought to comprise 3 phases: elimination, wherein immunity subserves an extrinsic tumor suppressor function and destroys nascent tumor cells; equilibrium, wherein tumor cells are constrained in a period of latency under immune control; and escape, wherein tumor cells outpace immunity and progress clinically.

In this review, we address in detail the relevance of the cancer immunoediting concept to neurosurgeons and neuro-oncologists treating and studying malignant glioma by exploring the de novo immune response to these tumors, how these tumors may persist in vivo, the mechanisms by which these cells may escape/attenuate immunity, and ultimately how this concept may influence our immunotherapeutic approaches.

Role of Cancer Stem Cells in Spine Tumors

Neurosurgery 71:117–125, 2012 DOI: 10.1227/NEU.0b013e3182532e71

The management of spinal column tumors continues to be a challenge for clinicians. The mechanisms of tumor recurrence after surgical intervention as well as resistance to radiation and chemotherapy continue to be elucidated. Furthermore, the pathophysiology of metastatic spread remains an area of active investigation.

There is a growing body of evidence pointing to the existence of a subset of tumor cells with high tumorigenic potential in many spine cancers that exhibit characteristics similar to those of stem cells. The ability to self-renew and differentiate into multiple lineages is the hallmark of stem cells, and tumor cells that exhibit these characteristics have been described as cancer stem cells (CSCs).

The mechanisms that allow nonmalignant stem cells to promote normal developmental programming by way of enhanced proliferation, promotion of angiogenesis, and increased motility may be used by CSCs to fuel carcinogenesis.

The purpose of this review is to discuss what is known about the role of CSCs in tumors of the osseous spine. First, this article reviews the fundamental concepts critical to understanding the role of CSCs with respect to chemoresistance, radioresistance, and metastatic disease. This discussion is followed by a review of what is known about the role of CSCs in the most common primary tumors of the osseous spine.

Cell Surface Receptors in Malignant Glioma

Neurosurgery 69:980–994, 2011 DOI: 10.1227/NEU.0b013e318220a672

Despite advances in surgery, radiation, and chemotherapy, malignant gliomas are still highly lethal tumors. Traditional treatments that rely on nonspecific, cytotoxic approaches have a marginal impact on patient survival.

However, recent advances in the molecular cancer biology underlying glioma pathogenesis have revealed that abnormalities in common cell surface receptors, including receptor tyrosine kinase and other cytokines, mediate the abnormal cellular signal pathways and aggressive biological behavior among the majority of these tumors.

Some cell surface receptors have been targeted by novel agents in preclinical and clinical development. Such cancer-specific targeted agents might offer the promise of improved cancer control without substantial toxicity.

Here, we review these common cell surface receptors with clinical significance for malignant glioma and discuss the molecular characteristics, pathological significance, and potential therapeutic application of these cell surface receptors.

We also summarize the clinical trials of drugs targeting these cell surface receptors in malignant glioma patients.

Highly cited works in neurosurgery. Part II: the citation classics

J Neurosurg 112:233–246, 2010. (DOI: 10.3171/2009.12.JNS091600)

Object. The term “citation classic” has been used in reference to an article that has been cited more than 400 times. The purpose of this study is to identify such articles that pertain to clinical neurosurgery.

Methods. A list of search phrases relating to neurosurgery was compiled. A topic search was performed using the Institute for Scientific Information Web of Science for phrases. Articles with more than 400 citations were identified, and nonclinical articles were omitted. The journals, year of publication, topics, and study types were analyzed.

Results. There were 106 articles with more than 400 citations relating to clinical neurosurgery. These articles appeared in 28 different journals, with more than half appearing in the Journal of Neurosurgery or the New England Journal of Medicine. Fifty-three articles were published since 1990. There were 38 articles on cerebrovascular disease, 21 on stereotactic and functional neurosurgery, 21 on neurooncology, 19 on trauma, 4 on nontraumatic spine, 2 on CSF pathologies, and 1 on infection. There were 29 randomized trials, of which 86% appeared in the New England Journal of Medicine, Lancet, or the Journal of the American Medical Association, and half concerned the prevention or treatment of stroke. In addition, there were 16 prospective studies, 15 classification or grading systems, and 7 reviews. The remaining 39 articles were case series, case reports, or technical notes.

Conclusions. More than half of the citation classics identified in this study have been published in the past 20 years. Case series, classifications, and reviews appeared more frequently in neurosurgical journals, while randomized controlled trials tended to be published in general medical journals.

Highly cited works in neurosurgery. Part I: the 100 top-cited papers in neurosurgical journals

J Neurosurg 112:223–232, 2010.(DOI: 10.3171/2009.12.JNS091599)

Object. The number of citations a published article receives is a measure of its impact in the scientific community. This study identifies and characterizes the current 100 top-cited articles in journals specifically dedicated to neurosurgery.

Methods. Neurosurgical journals were identified using the Institute for Scientific Information Journal Citation Reports. A search was performed using Institute for Scientific Information Web of Science for articles appearing in each of these journals. The 100 top-cited articles were selected and analyzed.

Results. The 100 most cited manuscripts in neurosurgical journals appeared in 3 of 13 journals dedicated to neurosurgery. These included 79 in the Journal of Neurosurgery, 11 in the Journal of Neurology, Neurosurgery and Psychiatry, and 10 in Neurosurgery. The individual citation counts for these articles ranged from 287 to 1515. Seventy- seven percent of articles were published between 1976 and 1995. Representation varied widely across neurosurgical disciplines, with cerebrovascular diseases leading (43 articles), followed by trauma (27 articles), stereotactic and functional neurosurgery (13 articles), and neurooncology (12 articles). The study types included 5 randomized trials, 5 cooperative studies, 1 observational cohort study, 69 case series, 8 review articles, and 12 animal studies. Thirty articles dealt with surgical management and 12 with nonsurgical management. There were 15 studies of natural history of disease or outcomes after trauma, 11 classification or grading scales, and 10 studies of human pathophysiology.

Conclusions. The most cited articles in neurosurgical journals are trials evaluating surgical or medical therapies, descriptions of novel techniques, or systems for classifying or grading disease. The time of publication, field of study, nature of the work, and the journal in which the work appears are possible determinants of the likelihood of citation and impact.

Use of the h index in neurosurgery

Journal of Neurosurgery, Aug 2009, Vol. 111, No. 2, Pages 387-392

Assessing academic productivity through simple quantification may overlook key information, and the use of statistical enumeration of academic output is growing. The h index, which incorporates both the total number of publications and the citations of those publications, has been recently proposed as an objective measure of academic productivity. The authors used several tools to calculate the h index for academic neurosurgeons to provide a basis for evaluating publishing by physicians.

The h index of randomly selected academic neurosurgeons from a sample of one-third of the academic programs in the US was calculated using data from Google Scholar and from the Scopus database. The mean h index for each academic rank was determined. The h indices were also correlated with various other factors (such as time spent practicing neurosurgery, authorship position) to identify how these factors influenced the h index. The h indices were then compared with other citation statistics to evaluate the robustness of this metric. Finally, h indices were also calculated for a sampling of physicians in other medical specialties for comparison.

As expected, the h index increased with academic rank and there was a statistically significant difference between each rank. A weighting based on position of authorship did not affect h indices. The h index was positively correlated with time since American Board of Neurological Surgery certification, and it was also correlated with other citation metrics. A comparison among medical specialties supports the assertion that h index values may not be comparable between fields, even closely related specialties.

The h index appears to be a robust statistic for comparing academic output of neurosurgeons. Within the field of academic neurosurgery, clear differences of h indices between academic ranks exist. On average, an increase of the h index by 5 appears to correspond to the next highest academic rank, with the exception of chairperson. The h index can be used as a tool, along with other evaluations, to evaluate an individual’s productivity in the academic advancement process within the field of neurosurgery but should not be used for comparisons across medical specialties.