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Somatic gain-of-function (GOF) mutations in phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), the catalytic subunit of phosphoinositide 3-kinase (PI3K), have been recently discovered in cerebral cavernous malformations (CCMs), raising the possibility that the activation of PI3K pathways is a possible universal regulator of vascular morphogenesis. However, there have been contradicting data presented among various groups and studies. To enhance the current understanding of vascular anomalies, it is essential to explore this possible relationship between altered PI3K signalling pathways and its influence on the pathogenesis of CCMs. GOFPIK3CA-mutants have been linked to overgrowth syndromes, allowing this group of disorders, resulting from somatic activating mutations inPIK3CA,to be collectively named asPIK3CA-related overgrowth spectrum disorders. This paper reviews and attempts to conceptualise the relationships and differences among clinical presentations, genotypic and phenotypic correlations and possible coexistence ofPIK3CAandCCMmutations/phenotypes in CCM lesions. Finally, we present a model reflecting our hypothetical understanding of CCM pathogenesis based on a systematic review and conceptualisation of data obtained from other studies.

OBJECTIVE International research fellows have been historically involved in academic neurosurgery in the United States (US). To date, the contribution of international research fellows has been underreported. Herein, the authors aimed to quantify the academic output of international research fellows in the Department of Neurosurgery at The Johns Hopkins University School of Medicine. METHODS Research fellows with Doctor of Medicine (MD), Doctor of Philosophy (PhD), or MD/PhD degrees from a non-US institution who worked in the Hopkins Department of Neurosurgery for at least 6 months over the past decade (2010–2020) were included in this study. Publications produced during fellowship, number of citations, and journal impact factors (IFs) were analyzed using ANOVA. A survey was sent to collect information on personal background, demographics, and academic activities. RESULTS Sixty-four international research fellows were included, with 42 (65.6%) having MD degrees, 17 (26.6%) having PhD degrees, and 5 (7.8%) having MD/PhD degrees. During an average 27.9 months of fellowship, 460 publications were produced in 136 unique journals, with 8628 citations and a cumulative journal IF of 1665.73. There was no significant difference in total number of publications, first-author publications, and total citations per person among the different degree holders. Persons holding MD/PhDs had a higher number of citations per publication per person (p = 0.027), whereas those with MDs had higher total IFs per person (p = 0.048). Among the 43 (67.2%) survey responders, 34 (79.1%) had nonimmigrant visas at the start of the fellowship, 16 (37.2%) were self-paid or funded by their country of origin, and 35 (81.4%) had mentored at least one US medical student, nonmedical graduate student, or undergraduate student. CONCLUSIONS International research fellows at the authors’ institution have contributed significantly to academic neurosurgery. Although they have faced major challenges like maintaining nonimmigrant visas, negotiating cultural/language differences, and managing self-sustainability, their scientific productivity has been substantial. Additionally, the majority of fellows have provided reciprocal mentorship to US students.

BACKGROUND AND PURPOSE: Imaging evaluation of ventriculostomy tubes, despite the frequency of malfunction, has remained inadequate due to the absence of a systematic way of assessing the catheter itself. In this retrospective review, we assessed the utility of high-resolution 3D MR imaging techniques, including CISS and volumetric interpolated breath-hold examination sequences, in the evaluation of ventriculostomy catheters. MATERIALS AND METHODS: We performed a retrospective review of 23 clinical MR imaging cases of shunted hydrocephalus spanning a 3-year period, all depicting ventriculostomy catheters. The MR imaging examinations included isotropic CISS and volumetric interpolated breath-hold examination sequences performed with and without contrast. These were independently evaluated by 2 neuroradiologists with respect to the catheter course, side hole position, relationship of the side holes to the ventricles, patency, and the presence or absence of intraluminal debris. RESULTS: The catheter tip was best seen on isotropic CISS sequences reformatted in an oblique plane, and side holes were visualized as CSF signal defects along the catheter wall in 10/23 (43%) cases. The relationship of the catheter side holes to the ventricles was seen in 47% of cases and was best visualized on the coronal CISS sequences. Catheter patency was confirmed in 12/23 (52%) cases, while the other 48% were notable for T2 hypointense filling defects compatible with luminal obstruction. Enhancement of some of these filling defects on imaging is suggestive of choroid plexus ingrowth rather than debris. CONCLUSIONS: High-resolution 3D MR imaging using isotropic CISS sequences allows systematic evaluation of catheter positioning, patency, and potential etiologic differentiation of filling defects when shunt dysfunction is suspected.

Surgical indications for cerebral cavernous malformations (CCMs) remain significantly center- and surgeon-dependent; available grading systems are potentially limited, as they do not include epileptologic and radiologic data. Several experienced authors proposed a new grading system for CCM and the first group of patients capable of providing its statistical validation was analyzed.A retrospective series of 289 CCMs diagnosed between 2008 and 2021 was collected in a shared anonymous database among 9 centers. The new grading system ranges from -1 to 10. For each patient with cortical and cerebellar cavernous malformations the grading system was applied, and a retrospective outcome analysis was performed. We proposed a score of 4 as a cutoff for surgical indication.Operated patients with a score ≥4 were grouped with non-operated patients with a score4, as they constituted the group that received correct treatment according to the new grading system. Patients with a score ≥4, who underwent surgery and had an improved outcome, were compared to patients with a score ≥4 who were not operated (P = 0.04), and to patients with a score4 who underwent surgery (P0.001).This preliminary statistical analysis demonstrated that this new grading would be applicable in surgical reality. The cutoff score of 4 correctly separated the patients who could benefit from surgical intervention from those who would not. The outcome analysis showed that the treated patients in whom the grading system has been correctly applied have a better outcome than those in whom the grading system has not been applied.

BACKGROUNDCerebral cavernous malformations (CCMs) are microvascular CNS lesions prone to hemorrhage leading to neurological sequela such as stroke and seizure. A subset of CCM patients have aggressive disease leading to multiple bleeding events, likely resulting multiple hospitalizations. Hospital admission rates are an important metric that has direct financial impact on hospitals and an indicator of overall disease burden. Furthermore, analysis of hospital readmissions can lead to early identification of high-risk patients and provides insight into the pathogenesis of CCM lesions. The purpose of this study is to identify high risk CCM patients with increased all cause readmission and comorbidities associated with increased readmissions.METHODSAll US hospital admissions due to CCMs were searched using the 2017 National Readmission Database (NRD). Patients with readmissions within 30 days of discharge from index hospitalization were identified and analyzed, relative to the remaining population.RESULTSAmong all patients hospitalized for CCM, 14.9% (13.7-16.2%) required all cause readmission within 30 days. Multivariate logistical regression analysis showed that substance abuse (p=0.003), diabetes (p=0.018), gastrointestinal bleed (p=0.002), renal failure (p=0.027), and coronary artery disease (p=0.010) were predictive of all cause readmissions, while age group 65-74 (p=0.042), private insurance (pCONCLUSIONSAll identified comorbidities associated with increased risks of readmission contribute to vascular stress, suggesting its role in lesion pathogenesis. This is the first and only study to analyze readmission metrics for CCMs in order to identify high risk patient factors to date.

Because of his exceptional and pioneering contributions to the understanding and treatment of neurosurgical conditions, Walter Dandy is considered to be one of the founders of both neurosurgery and neuroradiology. In the field of hydrocephalus, Dandy developed revolutionary research models, imaging modalities, and operative procedures. His laboratory and clinical experiences at the Johns Hopkins Hospital, including the surgical treatment of hydrocephalus, are well illustrated in the publications he authored. Archival materials housed at the Johns Hopkins University School of Medicine provide a window into Dandy’s clinical experience and supplement the work published during his lifetime. His operative experience with hydrocephalus spanned 1915–1946 and comprised 381 surgeries. From this clinical experience, Dandy created much of the framework for modern diagnostic imaging and treatment of hydrocephalus.

In 2000, "To Err Is Human" brought to light the fact that the estimated number of people dying from medical errors occurring in hospitals exceeded those that die from motor vehicle accidents (MVAs), breast cancer, or acquired immunodeficiency syndrome (AIDS) - three causes receiving far more public attention. The report prompted the gradual adoption of safety processes developed in the nuclear and aviation industries. However, sophisticated engineering solutions to operations are not enough. High and low mortality hospitals have similar processes and procedures, but low-mortality hospitals are more proficient at recognizing and managing serious complications as they unfold. This ability to rescue a deteriorating situation (resilience) reflects a healthier safety culture. Organizations move within the safety space in the direction of either more or less resilience depending on the fluctuation of their safety culture. Improving resilience requires transforming learned safety practices into a "habit" in conjunction with accepting accountability. Personal accountability means commitment to safe practices along with effective and transparent reporting of near misses/close calls and adverse events (AEs). Institutional accountability means putting safety first by ensuring the availability of appropriate resources, role leadership modeling, and effective management of sentinel events (SEs) to reduce harm occurrence and re-occurrence. This requires a more robust root cause analysis (RCA) process to guarantee that action plans produce strong and effective corrective measures. Synergistic coaching interventions include instilling the awareness that failure can and will happen, mapping team talents, and assessing gaps. These interventions will optimize group expertise, reaffirming the concept of institutional and personal accountability. The unending performance of drills will sustain the group resilience under both expected and unexpected conditions. Given the strong correlation between practice environment and outcomes, sustained improvement of the safety climate will produce more robust safety behaviors and ultimately better outcomes.

Following the emergence of the coronavirus disease 19 (COVID-19) pandemic, healthcare organizations began concentrating on the preparation for and management of the surge of COVID-19 cases while trying to protect the healthcare workers and other patients from getting COVID-19. Changing the way people work requires innovative approaches and questioning some long-held medical practices. There are multiple factors contributing to the apparent reduced utilization of healthcare services to non-COVID-19 patients. The current world crisis is highlighting the need of re-engineering the way we deliver inpatient and outpatient health care, including bolstering social support, in order to be prepared when the next calamity will present itself.

Introduction The pathophysiology of normal-pressure hydrocephalus and the correlation with its symptomatology is not well understood. Objective To monitor and evaluate the enlargement patterns of the ventricular system for each ventricle and its correlation with the presenting symptoms. Methods Bilateral kaolin injection into the subarachnoid space overlying the cranial convexities was done in 18 adult rats. Magnetic resonance imaging was performed on an 11.7-T scanner 15, 60, 90, and 120 days after injection. Volumes of the ventricular system were measured for each ventricle and correlated with biweekly behavioral findings. Results There was a progressive increase in the ventricular volume for the lateral ventricles since day 15 in the kaolin-injected animals. There was a nonsignificant trend in volume growth for the third ventricle, but its enlargement was synchronous with the lateral ventricles. No significant change for the fourth ventricle. No symptoms were detected in the first 60 days. Association was found between the ventricular volume and locomotor changes. In addition, the odds of locomotor symptoms increased by 3% for every additional cubic millimeter of volume in the left (P < 0.001) and right (P = 0.023) ventricles, and for the total magnetic resonance imaging volume by 1% (P = 0.013). Conclusions Expansion of the lateral ventricles maintained similar proportions over time, accompanied by a synchronous third ventricular expansion with less proportion and a nonsignificant fourth enlargement. Lateral ventricles enlarged most in those animals that were to develop late locomotor deterioration. Further research using this animal model combined with different radiologic imaging techniques, such as diffusion tensor imaging and perfusion studies, is recommended.

BACKGROUND AND PURPOSE: Endoscopic third ventriculostomy is a well-accepted treatment choice for hydrocephalus and is used most frequently with a known impediment to CSF flow between the third ventricle and basal cisterns. However, there are scarce data on the imaging evolution of the defect in the floor of the third ventricle and how this affects patency rates and clinical outcomes. The purpose of this study was to assess whether, and how, the endoscopic third ventriculostomy defect changes in size with time. MATERIALS AND METHODS: All high-resolution endoscopic third ventriculostomy protocol MRIs performed between 2009 through 2014 were retrospectively identified. Two fellowship-trained neuroradiologists, blinded to clinical information, independently reviewed all retrospective cases. RESULTS: A total of 98 imaging studies were included from 34 patients. The average change in the area throughout the studied period was 0.02 mm(2)/day (7.5 mm(2)/year), with a higher increase in size noted in the first 3 postsurgical months, with a gradual decrease in the degree of defect-size change. Use of the NICO Myriad device was correlated with the area of the endoscopic third ventriculostomy defect on the last follow-up, demonstrating a larger final defect size in patients in whom the surgical technique included debridement of the endoscopic third ventriculostomy defect walls with the NICO Myriad device (28.21 versus 11.25 mm, P < .05). CONCLUSIONS: High-resolution MR imaging with sagittal CISS images is useful in the postoperative evaluation of endoscopic third ventriculostomies. Such findings may prove useful in determining the optimal duration of follow-up with MR imaging of patients who have undergone endoscopic third ventriculostomy.

We evaluated the toxicity associated with stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT) in elderly and very elderly patients with brain metastases, as the role of SRS in geriatric patients who would traditionally receive WBRT is unclear.We conducted a retrospective review of elderly patients (aged 70-79 years) and very elderly patients (aged ≥80 years) with brain metastases who underwent RT from 2010 to 2015 at Johns Hopkins Hospital. Patients received either upfront WBRT or SRS for metastatic solid malignancies, excluding small cell lung cancer. Acute central nervous system toxicity within 3 months of RT was graded using the Radiation Therapy Oncology Group acute radiation central nervous system morbidity scale. The toxicity data between age groups and treatment modalities were analyzed using Fisher's exact test and multivariate logistic regression analysis. Kaplan-Meier curves were used to estimate the median overall survival, and the Cox proportion hazard model was used for multivariate analysis.A total of 811 brain metastases received RT in 119 geriatric patients. The median overall survival from the diagnosis of brain metastases was 4.3 months for the patients undergoing WBRT and 14.4 months for the patients undergoing SRS. On multivariate analysis, WBRT was associated with worse overall survival in this cohort of geriatric patients (odds ratio [OR] 3.7, 95% confidence interval [CI] 1.9-7.0, P.0001) and age ≥80 years was not. WBRT was associated with significantly greater rates of any grade 1 to 4 toxicity (OR 7.5, 95% CI 1.6-33.3, P=.009) and grade 2 to 4 toxicity (OR 2.8, 95% CI 1.0-8.1, P=.047) on multivariate analysis. Elderly and very elderly patients did not have significantly different statistically acute toxicity rates when stratified by age.WBRT was associated with increased toxicity compared with SRS in elderly and very elderly patients with brain metastases. SRS, rather than WBRT, should be prospectively evaluated in geriatric patients with the goal of minimizing treatment-related toxicity.

Pseudotumour cerebri syndrome, previously known as benign intracranial hypertension and more recently termed idiopathic intracranial hypertension, is characterized by headaches, raised intracranial pressure, and the risk of sudden irreversible visual loss. The pathophysiology of the condition is not fully understood but reduced cerebrospinal fluid absorption secondary to venous outflow obstruction seems to be an important factor. Treatment of patients with this condition is generally with lumbar punctures, weight loss, and lumboperitoneal shunts but ventriculoperitoneal shunts, subtemporal decompression, venous sinus stenting, and acetazolamide may also be used. Prognosis in pseudotumour cerebri syndrome is variable—some patients stabilize after a single lumbar puncture, while others have persistent symptoms for many years. A patient’s symptoms may improve and then recur years later, especially if weight has been lost and then regained again.

Digital, Background Idiopathic normal pressure hydrocephalus (iNPH) is a cause of dementia that can be reversed when treated timely with cerebrospinal fluid (CSF) diversion. Understanding CSF dynamics throughout the development of hydrocephalus is crucial to identify prognostic markers to estimate benefit/risk to shunts. Objective To explore the cerebral aqueduct CSF flow dynamics with phase-contrast magnetic resonance imaging (MRI) in a novel rodent model of adult chronic communicating hydrocephalus. Methods Kaolin was injected into the subarachnoid space at the convexities in Sprague-Dawley adult rats. 11.7-T Bruker MRI was used to acquire T2-weighted images for anatomic identification and phase-contrast MRI at the cerebral aqueduct. Aqueductal stroke volume (ASV) results were compared with the ventricular volume (VV) at 15, 60, 90, and 120 days. Results Significant ventricular enlargement was found in kaolin-injected animals at all times (P < 0.001). ASV differed between cases and controls/shams at every time point (P = 0.004, 0.001, 0.001, and, Ciencias Médicas y de la Salud

Normal pressure hydrocephalus (NPH) is an underdiagnosed and undertreated condition affecting the elderly population and with costs associated with its surgical management reported to be less than those associated with conservative management.To determine if the rate of diagnosis of NPH has improved over the last decade, the rate of treatment has increased, and if surgical treatment costs and socioeconomic factors related to receipt of treatment have changed over time compared with conservative therapy.A retrospective study based on data from a nationally representative random sample of 2,378,637 Medicare beneficiaries (2006-2010) was performed. Shunt surgery, shunt revision, replacement, and removal were analyzed as independent variables.A total of 2321 patients with NPH were included, with 580 (24.99%) receiving a first shunt procedure. The adjusted effect of the procedure is that total 5-year expenditures are $11,676 more per patient (P0.001) than expenditures associated with nonsurgical management. Shunt revision ($22,715, P0.01) and/or replacement ($46,607, P0.001) add significantly to 5-year expenditures. Socioeconomic factors including African American race (P = 0.006); age 75-79 years (P = 0.024), 80-84 years (P 0.001), and ≥85 years (P0.001); and Medicaid (P 0.001) have significant negative associations with shunt surgery.There was a 1.66-fold increase in the rate of diagnosis of NPH, from 0.12% in 1999 to 0.2% in 2008. The total costs per surgical patient rose by approximately 145% to 160% comparing 2001 and 2010. This increase was mainly due to hospital (by 167% to 168%) and home health costs (by 118% to 148%). Providing appropriate care across the socioeconomic spectrum warrants further study and requires identifying the factors that limit access to care.

Background: To describe the outcome for a cohort of patients with non-functioning pituitary macroadenomas (NFPMA), managed by debulking surgery with radiation therapy delayed until progression.Methods: Two hundred and sixty-seven patients were treated surgically for pituitary tumors at our institution between 1997 and 2005. One hundred and twenty-six patients met the inclusion criteria of NFPMA. They were followed for at least 2 years.Results: At presentation, 58% of patients had objectively decreased visual function, 66% had endocrine abnormalities, and 46% had headaches. Of the entire cohort, 75% of tumors abutted the optic chiasm and 87% had suprasellar extension. Over a median follow up of 112 months from surgery, 52% of patients had evidence of radiographic tumor progression, and 39% required additional treatment. There was a significant difference freedom from progression and in the number of patients receiving additional treatment with preoperative adenoma size of < 2 vs. ≥2 cm (p < 0.05).Conclusion: Close observation with radiation therapy delayed until the time of progression is an appropriate option for patients presenting with initial adenoma size < 2 cm, and can be considered for those with initial sizes up to 4 cm, as the majority of patients do not require further intervention for 10 or more years, thereby meaningfully postponing the risks of radiotherapy.

As is the case in many areas of medicine and science in general, there has been a dramatic acceleration in the acquisition of understanding during the last few decades. This is also the case for cerebral cavernous malformations (CCMs). We like to artificially divide the progress that we have personally witnessed into three phases: pre-magnetic resonance imaging (MRI), post-MRI, and molecular. We highlight the major leaps forward linked to the specific discovery.

Background The pathogenesis of adult chronic hydrocephalus is not fully understood, and the temporal relationship between development of the radiological changes and neurological deterioration is unknown. Objective To clarify the progression of radiological-histological changes and subsequent clinical manifestations of adult chronic hydrocephalus. Methods Kaolin was injected bilaterally into the subarachnoid space overlying the cranial convexities in 20 adult rats. Magnetic resonance imaging (MRI) was obtained by using an 11.7 T scanner at 14, 60, 90, and 120 days after kaolin injection. Locomotor, gait, and cognitive evaluations were performed independently. Kaolin distribution and the associated inflammatory and fibrotic responses were histologically analyzed. Results Evans index of ventriculomegaly showed significant progressive growth in ventricular size over all time points examined. The greatest enlargement occurred within the first 2 months. Evans index also correlated with the extent of kaolin distribution by MRI and by pathological examination at all time points. First gait changes occurred at 69 days, anxiety at 80, cognitive impairment at 81, and locomotor difficulties after 120 days. Only locomotor deterioration was associated with Evans index or the radiological evaluation of kaolin extension. Inflammatory/fibrotic response was histologically confirmed over the cranial convexities in all rats, and its extension was associated with ventricular size and with the rate of ventricular enlargement. Conclusion Kaolin injected into the subarachnoid space over the cerebral hemispheres of adult rats produces an inflammatory/fibrotic response leading in a slow-onset communicating hydrocephalus that is initially asymptomatic. Increased ventricular size eventually leads to gait, memory, and locomotor impairment closely resembling the course of human adult chronic hydrocephalus. Abbreviation NPH, normal pressure hydrocephalus.

Placement of a ventriculoperitoneal (VP) shunt is the treatment of choice for communicating hydrocephalus; however, the extent to which VP shunting is able to relieve symptoms in patients who had previously been treated with cerebrospinal fluid diverting therapy at an outside institution remains unclear. A retrospective review of patients with idiopathic normal pressure hydrocephalus treated with VP shunts at a single institution between 1993 and 2013 was conducted. Patients were classified as having received a primary VP shunt if they had not been previously treated with a VP shunt, ventriculoatrial shunt, lumboperitoneal shunt, or endoscopic third ventriculostomy. Patients were classified as having received a salvage VP shunt if they had been previously treated by one of these four modalities at an outside institution prior to their presentation to our institution. There were 357 patients who received a primary shunt and 33 patients who received a salvage shunt. Patients who had a salvage shunt placed had significantly higher odds of requiring a future revision (54% versus 41%; odds ratio=2.85; 95% confidence interval [CI]: 1.24-6.57; p=0.014). Patients who received a salvage shunt had statistically significantly lower rates of gait improvement at 6months in comparison to patients who received a primary shunt (relative risk=0.35; 95% CI: 0.14-0.87; p=0.025). Despite these findings, there was no significant difference at last follow-up in improvement in gait, continence, and cognition, indicating that outcomes for patients requiring a salvage shunt were comparable to patients receiving a primary shunt.

To evaluate the prevalence, outcomes, and toxicities of concurrent delivery of systemic therapy with stereotactic radiosurgery (SRS) for treatment of brain metastases.We conducted a retrospective review of 193 patients treated at our institution with SRS without prior whole-brain radiation therapy (WBRT) for brain metastases between 2009 and 2014. Outcome metrics included administration of concurrent systemic therapy, myelosuppression, neurotoxicity, and survival.One hundred ninety-three patients with a median age of 61 years underwent a total of 291 SRS treatments. Thirty-seven percent of SRS treatments were delivered concurrently with systemic therapy, of which 46% were with conventional myelosuppressive chemotherapy, and 54% with targeted and immune therapy agents. Myelosuppression was minimal after treatment with both systemic therapy and SRS, with 14% grade 3-4 toxicity for lymphopenia and 4-9% for leukopenia, neutropenia, anemia, and thrombocytopenia. Neurotoxicity was also minimal after combined therapy, with no grade 4 and 5% grade 3 toxicity, 34% dexamethasone requirement, and 4% radiation necrosis, all similar to treatments with SRS alone. Median overall survival was similar after SRS alone (14.4 months) versus SRS with systemic therapy (12.9 months). In patients with a new diagnosis of primary cancer with brain metastasis, early treatment with concurrent systemic therapy and SRS correlated with improved survival versus SRS alone (41.6 vs 21.5 months, P.05).Systemic therapy can be safely given concurrently with SRS for brain metastases: our results suggest minimal myelosuppression and neurotoxicity. Concurrent therapy is an attractive option for patients who have both intracranial and extracranial metastatic disease and may be particularly beneficial in patients with a new diagnosis of primary cancer with brain metastasis.

Few studies have focused on predictive factors of ventriculoperitoneal (VP) shunt revision in patients with idiopathic normal pressure hydrocephalus (iNPH). This study aims to determine whether comorbidities and baseline symptoms are associated with the need for shunt revision.A retrospective review of patients with iNPH treated with VP shunts by the senior author from 1993 to 2013 was conducted. Demographics and baseline symptoms were compared between patients with and without shunt revision. The need for revision, total number of revisions, and time to first revision were examined. Statistical analysis was performed using simple logistic, linear, and Poisson regression, and a multivariate analysis was performed.A total of 347 patients with iNPH who received VP shunts were included. One hundred patients (28.8%) required shunt revision, with an average of 1.38 ± 0.76 revisions per patient. Mean time to revision was 19.2 ± 31.7 months. Gait and cognitive symptoms were associated with fewer revisions (incidence rate ratio, 0.45 and 0.67; P = 0.03 and 0.004, respectively). Headaches and urinary incontinence showed a greater time to revision (32.0 and 12.0 months; P = 0.014 and0.0005, respectively). Gait instability demonstrated decreased time to revision (P0.0005).Preoperative symptoms, such as headaches, gait instability, cognitive decline, and urinary incontinence, were significantly correlated with number of revisions and time to first revision. These factors should be considered during the initial counseling of prognosis for patients with iNPH receiving VP shunts.

OBJECT Endoscopic third ventriculostomy (ETV) is the treatment of choice for obstructive hydrocephalus; however, the success of ETV in patients who have previously undergone shunt placement remains unclear. The present study analyzed 103 adult patients with aqueductal stenosis who underwent ETV for obstructive hydrocephalus and evaluated the effect of previous shunt placement on post-ETV outcomes. METHODS This study was a retrospective review of 151 consecutive patients who were treated between 2007 and 2013 with ETV for hydrocephalus. One hundred three (68.2%) patients with aqueductal stenosis causing obstructive hydrocephalus were included in the analysis. Postoperative ETV patency and aqueductal and cisternal flow were assessed by high-resolution, gradient-echo MRI. Post-ETV Mini-Mental State Examination, Timed Up and Go, and Tinetti scores were compared with preoperative values. Univariate and multivariate analyses were performed comparing the post-ETV outcomes in patients who underwent a primary (no previous shunt) ETV (n = 64) versus secondary (previous shunt) ETV (n = 39). RESULTS The majority of patients showed significant improvement in symptoms after ETV; however, no significant differences were seen in any of the quantitative tests performed during follow-up. Symptom recurrence occurred in 29 (28.2%) patients after ETV, after a median of 3.0 (interquartile range 0.8–8.0) months post-ETV failure. Twenty-seven (26.2%) patients required surgical revision after their initial ETV. Patients who received a secondary ETV had higher rates of symptom recurrence (p = 0.003) and surgical revision (p = 0.003), particularly in regard to additional shunt placement/revision post-ETV (p = 0.005). These differences remained significant after multivariate analysis for both symptom recurrence (p = 0.030) and surgical revision (p = 0.043). CONCLUSIONS Patients with obstructive hydrocephalus due to aqueductal stenosis exhibit symptomatic improvement after ETV, with a relatively low failure rate. Patients with a primary history of shunt placement who undergo ETV as a secondary intervention are at increased risk of symptom recurrence and need for surgical revision post-ETV.

Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder that classically presents with a triad of progressive gait impairment, urinary incontinence, and cognitive deterioration. Treatment predominantly involves ventriculoperitoneal (VP) shunting, but one alternative is ventriculoatrial (VA) shunting. This study sought to describe and evaluate the clinical outcomes of patients with iNPH primarily treated with VA shunting.A retrospective review of patients with iNPH who were treated with VA shunting at a single institution, from 2003 to 2013, was performed.58 patients with iNPH underwent primary VA shunting at a median age of 74 (IQR: 70-80) years. The most common comorbidities included hypertension (n=39, 67%) and diabetes mellitus (n=11, 19%). Median duration of symptoms prior to VA shunting was 24 (IQR: 12-36) months. All patients had gait impairment, 52 (90%) had cognitive decline, and 43 (74%) had urinary incontinence. Forty-three (74%) patients had all three symptoms. At a median last follow-up of 16 (IQR: 7-26) months, median iNPH score improved from 6 to 3 (p0.0001), mini mental status exam (MMSE) tended to increase from 26 to 29 (p=0.082), timed up-and-go (TUG) improved from 18 to 13s (p0.0001), and Tinetti score improved from 19 to 25 (p0.0001) after VA shunting. 78% of patients had improvement in at least one of their symptoms with 66% of patients having improvement in gait, 53% having improvement in their cognition, and 52% having improved urinary incontinence. A total of 21 patients (36%) had improvement in all 3 symptoms.There were significant improvements in functional outcomes as evaluated via the iNPH score, TUG, and Tinetti score, while improvement in MMSE trended toward significance. Patients also had improvement of clinical symptoms related to gait, urinary function and cognition. These results suggest that VA shunting can be an effective primary treatment alternative to VP shunting for iNPH.

BACKGROUND AND PURPOSE: The DESH (disproportionately enlarged subarachnoid-space hydrocephalus) pattern of “tight high-convexity and medial subarachnoid spaces, and enlarged Sylvian fissures with ventriculomegaly” is used to determine which patients undergo an operation for adult hydrocephalus at many centers. Our aim was to review adult hydrocephalus cases when DESH has not been a criterion for an operation to determine the prevalence of DESH among the cohort and compare the surgical outcomes in the presence or absence of DESH. MATERIALS AND METHODS: A retrospective cohort study was conducted at a single institution (Johns Hopkins Hospital) to include patients surgically treated for adult hydrocephalus between 2003 and 2014 drawn from a data base of patients who had undergone standardized hydrocephalus protocol MR imaging. Preoperative imaging was reviewed by 2 blinded neuroradiologists to characterize the presence of DESH. Preoperative and postoperative clinical symptomatology was recorded. Frequencies were compared using the Fisher exact test, and nonparametric means were compared using the Mann-Whitney U Test. RESULTS: One hundred thirty-three subjects were identified and included (96 DESH absent, 37 DESH present). Shunting led to significant improvement in gait and urinary and cognitive symptoms for the overall cohort and for patients with and without DESH (P < .05). The Fisher exact test did not demonstrate any significant differences in either gait or urinary or cognitive symptom improvement between patients with or without DESH (P > .05). CONCLUSIONS: The current study demonstrated symptom improvement in patients with adult hydrocephalus following shunting, with no significant differences between subjects with and without DESH. Thus, shunt insertion for patients with adult hydrocephalus should not rely solely on the presence of preoperative DESH findings.

BACKGROUND AND PURPOSE: Radiologic imaging plays a key role in diagnosing chronic adult hydrocephalus, but its role in predicting prognosis is still controversial. We sought to evaluate the effectiveness of cardiac-gated phase-contrast MR imaging through the cerebral aqueduct in predicting the clinical response to diagnostic lumbar puncture/lumbar drainage and shunt surgery in suspected adult hydrocephalus. MATERIALS AND METHODS: In this retrospective study, the phase-contrast MR imaging of 185 patients with suspected chronic adult hydrocephalus was evaluated using the CSF Flow software package. Decision-making for shunt placement was performed in this cohort on the basis of clinical assessment alone without the availability of quantitative phase-contrast MR imaging results. We recorded the response to lumbar puncture or lumbar drainage and shunt surgery using quantitative tests such as the Tinetti Test, the Timed Up and Go, and the Mini-Mental State Examination and qualitative measures of gait, urinary, and cognitive symptom improvement before and after lumbar puncture/lumbar drainage and shunt surgery. Quantitative analysis of phase-contrast MR imaging was compared with clinical outcome measures. RESULTS: Both CSF stroke volume and flow rate overlapped between lumbar puncture/lumbar drainage responders and nonresponders. There was also a significant overlap between shunt responders and nonresponders. Aqueductal stroke volume or flow rate alone was a poor predictor of lumbar puncture/lumbar drainage and shunt surgery response. Quantitative clinical measures after lumbar puncture/lumbar drainage were better predictors of shunt response. CONCLUSIONS: This study suggests that the results of phase-contrast MR imaging through the cerebral aqueduct alone should not be used to select patients for diagnostic or therapeutic CSF diversion.

We evaluated if patients with idiopathic normal pressure hydrocephalus (iNPH) showed functional improvement after primary endoscopic third ventriculostomy (ETV). The efficacy of ETV for iNPH remains controversial. We retrospectively reviewed 10 consecutive patients treated between 2009 and 2011 with ETV for iNPH. Seven patients with a median age of 73 years (range: 60-80) who underwent a primary ETV for iNPH were included for analysis. Median follow-up was 39 months (range: 26-46). Post-ETV stoma and aqueductal and cisternal flows were confirmed via high resolution, gradient echo and phase contrast MRI. Post-ETV timed up and go (TUG) and Tinetti performance oriented mobility assessment scores were compared to pre- and post-lumbar puncture (LP) values. A second LP was performed if ETV failed to sustain the observed improvement after initial LP. Patients who demonstrated ETV failure were subsequently shunted. Compared to pre-LP TUG and Tinetti values of 14.00 seconds (range: 12.00-23.00) and 22 (range: 16-24), post-LP scores improved to 11.00 seconds (range: 8.64-15.00; p=0.06) and 25 (range: 24-28; p=0.02), respectively. ETV failed to sustain this improvement with slight worsening between pre-LP and post-ETV TUG and Tinetti scores. Improvement from pre-LP assessment was regained after shunting and at last follow-up with TUG and Tinetti scores of 12.97 seconds (range: 9.00-18.00; p=0.250) and 25 (range: 18-27; p=0.07), and 11.87 seconds (range: 8.27-18.50; p=0.152) and 23 (range: 18-26; p=0.382), respectively. Despite stoma patency, ETV failed to sustain functional improvement seen after LP, however, improvement was regained after subsequent shunting suggesting that shunt placement remains the preferred treatment for iNPH.

Cell-free DNA shed by cancer cells has been shown to be a rich source of putative tumor-specific biomarkers. Because cell-free DNA from brain and spinal cord tumors cannot usually be detected in the blood, we studied whether the cerebrospinal fluid (CSF) that bathes the CNS is enriched for tumor DNA, here termed CSF-tDNA. We analyzed 35 primary CNS malignancies and found at least one mutation in each tumor using targeted or genome-wide sequencing. Using these patient-specific mutations as biomarkers, we identified detectable levels of CSF-tDNA in 74% [95% confidence interval (95% CI) = 57-88%] of cases. All medulloblastomas, ependymomas, and high-grade gliomas that abutted a CSF space were detectable (100% of 21 cases; 95% CI = 88-100%), whereas no CSF-tDNA was detected in patients whose tumors were not directly adjacent to a CSF reservoir (P0.0001, Fisher's exact test). These results suggest that CSF-tDNA could be useful for the management of patients with primary tumors of the brain or spinal cord.

To determine clinical outcome of patients with vestibular schwannoma (VS) after treatment with fractionated stereotactic radiotherapy (FSRT) and single-session stereotactic radiosurgery (SRS) by using 3D quantitative response assessment on MRI.This retrospective analysis included 162 patients who underwent radiation therapy for sporadic VS. Measurements on T1-weighted contrast-enhanced MRI (in 2-year post-therapy intervals: 0-2, 2-4, 4-6, 6-8, 8-10, 10-12 years) were taken for total tumour volume (TTV) and enhancing tumour volume (ETV) based on a semi-automated technique. Patients were considered non-responders (NRs) if they required subsequent microsurgical resection or developed radiological progression and tumour-related symptoms.Median follow-up was 4.1 years (range: 0.4-12.0). TTV and ETV decreased for both the FSRT and SRS groups. However, only the FSRT group achieved significant tumour shrinkage (p 0.015 for TTV, p 0.005 for ETV over time). The 11 NRs showed proportionally greater TTV (median TTV pre-treatment: 0.61 cm(3), 8-10 years after: 1.77 cm(3)) and ETV despite radiation therapy compared to responders (median TTV pre-treatment: 1.06 cm(3); 10-12 years after: 0.81 cm(3); p = 0.001).3D quantification of VS showed a significant decrease in TTV and ETV on FSRT-treated patients only. NR had significantly greater TTV and ETV over time.Only FSRT not GK-treated patients showed significant tumour shrinkage over time. Clinical non-responders showed significantly less tumour shrinkage when compared to responders. 3D volumetric assessment of vestibular schwannoma shows advantages over unidimensional techniques.

Posterior fossa arteriovenous malformations (AVM) present particular therapeutic challenges. Studies aimed at clarifying risk of hemorrhage focus on obliteration rates, but few have addressed functional outcomes in these patients. In this study, we aim to explore the predictors of good functional outcome for posterior fossa AVM after treatment. A retrospective review of patients diagnosed with posterior fossa AVM at our institution from 1990 to 2013 was performed, and 61 patients met the inclusion criteria. Functional outcomes were assessed using the modified Rankin Scale (mRS), and mRS ⩽ 1 was defined as good outcome. Within our cohort, 39 patients presented with hemorrhage (64.0%). Spetzler-Martin grades were I (n = 9, 14.8%), II (n = 20, 32.8%), III (n = 22, 36.1%), IV (n = 8, 13.1%), and V (n = 2, 3.3%). Patients were treated with surgery (n = 8), radiosurgery (n = 34), embolization (n = 2) or multimodal therapies (n = 8). Nine patients did not undergo treatment. Average follow-up was 41.9 months. Obliteration of AVM was confirmed in 44.3% of patients (n = 27). Forty-three patients (70.5%) achieved good functional outcomes (mRS ⩽ 1). The absence of pre-treatment symptoms (p < 0.01) and AVM obliteration (p = 0.04) were predictive of good functional outcomes. In contrast, non-hemorrhagic presentation was not a significant predictor (p = 0.60). Asymptomatic presentation and AVM obliteration are associated with good functional outcomes in patients with posterior fossa AVM. Non-hemorrhagic presentation does not necessarily predict good functional outcome. Therefore treatment should not be considered only for those who present with hemorrhage. Posterior fossa AVM should be considered for definitive treatment in order to prevent future hemorrhages and subsequent poor functional outcomes.

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Purpose The aim of this study is to evaluate long-term treatment outcome and toxicities among vestibular schwannoma (VS) patients treated with hypofractionated stereotactic radiotherapy (HSRT). Methods 383 patients with unilateral VS treated with HSRT (25 Gy, five fractions) between 1995 and 2007 were retrospectively reviewed. Treatment failure was defined as requiring salvage microsurgery. Posttreatment new/progressive clinical symptoms or increases in baseline tumor volume (BTV) due to treatment effect or progression were noted. Symptom outcomes were reported as baseline and posttreatment ± improvement, respectively. Symptoms were grouped by cranial nerve (CN) VII or CNVIII. Audiometry was assessed baseline and posttreatment hearing. Patients were grouped as having greater than serviceable hearing [Gardner Robertson (GR) score 1–2] or less than non-serviceable hearing (GR score 3–5) by audiometry. Results Median follow-up was 72.0 months. Nine (2.3%) experienced treatment failure. At last follow-up, 74 (19.3%) had new/progressive symptoms and were categorized as radiologic non-responders, whereas 300 (78.3%) had no tumor progression and were grouped as radiologic responders. Average pretreatment BTV for treatment failures, radiologic non-responders, and radiologic responders was 2.11, 0.44, and 1.87 cm3, respectively. Pretreatment CNVII and CNVIII symptoms were present in 9.4 and 93.4% of patients, respectively. Eight (24%) with pre-HSRT CNVII and 37 (10%) with pre-HSRT CNVIII symptoms recovered CN function post-HSRT. Thirty-five (9%) and 36 (9.4%) experienced new CNVII and CNVIII deficit, respectively, after HSRT. Of these, 20 (57%) and 18 (50%) recovered CNVII and CNVIII function, respectively, after HSRT. Evaluable audiograms were available in 199 patients. At baseline and at last follow-up, 65.8 and 36.2% had serviceable hearing, respectively. Fifty-one percent had preservation of serviceable hearing at last follow-up. Conclusion Treatment of VS with HSRT is effective with treatment success in 97.7% and an acceptable toxicity profile. Less than one-third of patients experience any new CNVII or CNVIII deficit posttreatment. Greater than 50% of patients with serviceable hearing at baseline maintained hearing function. Improved methods to differentiate treatment effect and tumor progression are needed.

Shunts that are used for the treatment of hydrocephalus have a propensity towards malfunction, however, diagnosing a shunt malfunction can sometimes be a challenge. The purpose of this study was to investigate whether ultrasound technology can be safely and effectively used to assess for distal shunt malfunction. This was a prospective cohort study at a single institution. Eighteen adult patients that received a radionuclide shunt patency study also underwent an ultrasound shunt patency study. Ultrasound with Doppler technology was used to visualize flow through the shunt tubing following manual compression of the shunt reservoir. A peak flow speed was recorded and the results were compared to the results of the radionuclide shunt patency study. A Receiver Operating Characteristic (ROC) curve comparing the ultrasound to the radionuclide shunt patency study was generated, revealing an Area Under the Curve (AUC) of 0.95 (95% CI: 0.84-1.00). The ultrasound test performed maximally with a cutoff speed of ≤10cm/s as the criteria for malfunction, with a sensitivity of 100.00%, specificity of 90.91%, accuracy of 94.44%, positive likelihood ratio of 11.000 and negative likelihood ratio of 0.000 using the radionuclide study results as criteria for comparison. Overall, ultrasound has the potential to be a safe, quick, available and cost-effective screening test for patients with suspected distal shunt malfunction. The high sensitivity of the test makes it an attractive option for use as a screening method that could potentially reduce the number of cases requiring radionuclide shunt patency study.

BackgroundDespite many publications about cerebral cavernous malformations (CCMs), controversy remains regarding diagnostic and management strategies.ObjectiveTo develop guidelines for CCM management.MethodsThe Angioma Alliance ( www.angioma.org ), the patient support group in the United States advocating on behalf of patients and research in CCM, convened a multidisciplinary writing group comprising expert CCM clinicians to help summarize the existing literature related to the clinical care of CCM, focusing on 5 topics: (1) epidemiology and natural history, (2) genetic testing and counseling, (3) diagnostic criteria and radiology standards, (4) neurosurgical considerations, and (5) neurological considerations. The group reviewed literature, rated evidence, developed recommendations, and established consensus, controversies, and knowledge gaps according to a prespecified protocol.ResultsOf 1270 publications published between January 1, 1983 and September 31, 2014, we selected 98 based on methodological criteria, and identified 38 additional recent or relevant publications. Topic authors used these publications to summarize current knowledge and arrive at 23 consensus management recommendations, which we rated by class (size of effect) and level (estimate of certainty) according to the American Heart Association/American Stroke Association criteria. No recommendation was levelA (because of the absence of randomized controlled trials), 11 (48%) were levelB, and 12 (52%) were levelC. Recommendations were classI in 8 (35%), classII in 10 (43%), and classIII in 5 (22%).ConclusionCurrent evidence supports recommendations for the management of CCM, but their generally low levels and classes mandate further research to better inform clinical practice and update these recommendations. The complete recommendations document, including the criteria for selecting reference citations, a more detailed justification of the respective recommendations, and a summary of controversies and knowledge gaps, was similarly peer reviewed and is available on line www.angioma.org/CCMGuidelines .

Idiopathic normal pressure hydrocephalus (iNPH) is a devastating condition that affects the elderly population. Although ventriculoatrial (VA) shunts can be used to manage iNPH, concerns for associated cardiopulmonary and renal complications have decreased their use. However, the rate of these complications is not well understood within this population of patients.A retrospective review of the electronic medical records of patients diagnosed with iNPH by the senior author between 1993 and 2015 was performed. Demographic information and baseline symptoms were assessed. Complications including infection, shunt obstruction, overdrainage, cardiopulmonary events, renal dysfunction, and shunt revision were recorded. Complication rates were compared between VA and VP shunted patients. Statistical analysis using Chi-square test, Fisher's exact test, logistic regression, Wald t-test, Poisson regression, ANOVA, and ANCOVA was performed.496 Patients, including 150 receiving VA shunts and 346 receiving VP shunts, were included in the study. The median age was 74 and 73 for VA and VP shunted patients, respectively, with slight male predominance in both (58.0% and 58.4% for VA and VP groups, respectively). A total of 36.0% of VA shunted patients and 42.5% of VP shunted patients experienced at least one post-operative complication. Overdrainage was the most commonly experienced complication in both VA (27.4%) and VP patients (19.9%). Infection occurred in only 2.0% of patients, and renal complications occurred in 1.3%. No patients had cardiopulmonary complications. VA shunted patients were significantly less likely to experience shunt obstruction and require shunt revision compared to VP shunted patients (p=0.008 and0.001, respectively). Only dizziness and gait disturbance at baseline were correlated with a shorter time to revision in VA shunted patients (p=0.002 for both).Although cardiopulmonary and renal complications are serious concerns associated with VA shunt placement, they were uncommon in patients with iNPH. VA shunted patients were less likely to experience shunt obstruction and require shunt revision compared to VP shunted patients. Therefore, VA shunts should be considered as an alternative primary treatment option in the iNPH population.

Hydrocephalus can develop secondarily to a disturbance in production, flow and/or absorption of cerebrospinal fluid. Experimental models of hydrocephalus, especially subacute and chronic hydrocephalus, are few and limited, and the effects of hydrocephalus on the subventricular zone are unclear. The aim of this study was to analyze the effects of long-term obstructive hydrocephalus on the subventricular zone, which is the neurogenic niche lining the lateral ventricles. We developed a new method to induce hydrocephalus by obstructing the aqueduct of Sylvius in the mouse brain, thus simulating aqueductal stenosis in humans. In 120-day-old rodents (n = 18 per group), the degree of ventricular dilatation and cellular composition of the subventricular zone were studied by immunofluorescence and transmission electron microscopy. In adult patients (age > 18 years), the sizes of the subventricular zone, corpus callosum, and internal capsule were analyzed by magnetic resonance images obtained from patients with and without aqueductal stenosis (n=25 per group). Mice with 60-day hydrocephalus had a reduced number of Ki67+ and doublecortin+ cells on immunofluorescence, as well as decreased number of neural progenitors and neuroblasts in the subventricular zone on electron microscopy analysis as compared to non-hydrocephalic mice. Remarkably, a number of extracellular matrix structures (fractones) contacting the ventricular lumen and blood vessels were also observed around the subventricular zone in mice with hydrocephalus. In humans, the widths of the subventricular zone, corpus callosum, and internal capsule in patients with aqueductal stenosis were significantly smaller than age and gender-matched patients without aqueductal stenosis. In summary, supratentorial hydrocephalus reduces the proliferation rate of neural progenitors and modifies the cytoarchitecture and extracellular matrix compounds of the subventricular zone. In humans, this similar process reduces the subventricular niche as well as the width of corpus callosum and internal capsule.

Objective The management of patients with brain metastases is typically dependent on their prognosis. Recursive partitioning analysis (RPA) is the most commonly used method for prognosticating survival, but has limitations for patients in the intermediate class. The aims of this study were to ascertain preoperative risk factors associated with survival, develop a preoperative prognostic grading system, and evaluate the utility of this system in predicting survival for RPA class 2 patients. Methods Adult patient who underwent intracranial metastatic tumor surgery at an academic tertiary care institution from 1997 to 2011 were retrospectively reviewed. Multivariate proportional hazards regression analysis was used to identify preoperative factors associated with survival. The identified associations were then used to develop a grading system. Survival as a function of time was plotted using the Kaplan-Meier method, and survival rates were compared using log-rank analyses. Results A total of 421 (59%) of 708 patients were RPA class 2. The preoperative factors found to be associated with poorer survival were: male gender ( P P = 0.0007), cognitive deficit ( P = 0.0004), nonsolitary metastases ( P = 0.002), and tumor size >2 cm ( P = 0.003). Patients having 0–1, 2, and 3–5 of these variables were assigned a preoperative grade of A, B, and C, respectively. Patients with a preoperative grade of A, B, and C had a median survival of 17.0, 10.3, and 7.3 months, respectively. These grades had distinct survival times ( P Conclusions The present study devised a preoperative grading system that may provide prognostic information for RPA class 2 patients, which may also guide medical and surgical therapies before any intervention is pursued.

ABSTRACT: A familiar challenge for neuroradiologists and neuro-oncologists is differentiating between radiation treatment effect and disease progression in the CNS. Both entities are characterized by an increase in contrast enhancement on MRI and present with similar clinical signs and symptoms that may occur either in close temporal proximity to the treatment or later in the disease course. When radiation-related imaging changes or clinical deterioration are mistaken for disease progression, patients may be subject to unnecessary surgery and/or a change from otherwise effective therapy. Similarly, when disease progression is mistaken for treatment effect, a potentially ineffective therapy may be continued in the face of progressive disease. Here we describe the three types of radiation injury to the brain based on the time to development of signs and symptoms – acute, subacute and late – and then review specific imaging changes after intensity-modulated radiation therapy, stereotactic radiosurgery and brachytherapy. We provide an overview of these phenomena in the treatment of a wide range of malignant and benign CNS illnesses. Finally, we review the published data regarding imaging techniques under investigation to address this well-known problem.

Stereotactic radiosurgery has become standard adjuvant treatment for patients with metastatic intracranial lesions. There has been a growing appreciation for benign imaging changes following radiation that are difficult to distinguish from true tumor progression. These imaging changes, termed pseudoprogression, carry significant implications for patient management. In this review, we discuss the current understanding of pseudoprogression in metastatic brain lesions, research to differentiate pseudoprogression from true progression, and clinical implications of pseudoprogression on treatment decisions.