Ultrasound Opens the Brain to Promising Drugs


The protective sheath surrounding the brain’s blood supply—known as the blood-brain barrier—is a safeguard against nasty germs and toxins. But it also prevents existing drugs that could potentially be used to treat brain cancer or Alzheimer’s disease from reaching the brain. That’s why scientists want to unchain the gates of this barrier. Now a new study shows it’s been done in cancer patients.

The procedure works by first injecting microbubbles into the bloodstream and then using a device implanted near patients’ tumors to send ultrasonic soundwaves into the brain, exciting the bubbles. The physical pressure of the bubbles pushing on the cells temporarily opens the blood-brain barrier, letting an injected drug cross into the brain.

Alexandre Carpentier holds the SonoCloud device, which he has implanted in 15 brain cancer patients.

“People for years have been trying to open the blood-brain barrier,” said Neal Kassell, founder of theFocused Ultrasound Foundation. The device, called SonoCloud, was implanted and used on 15 patients during monthly chemotherapy with no ill effects after six months.

Although this is the first published study using ultrasound to open the blood-brain barrier in humans, it is not the first study to hit the news. In November, a team at the Sunnybrook Health Sciences Centre in Toronto announced the start of a clinical trial to open the blood-brain barrier using ultrasound in a single brain cancer patient. Carpentier’s trial, on the other hand, began in July 2014, and Kassell said the French study “is the first time they’ve shown the safety of repetitively opening the blood-brain barrier in humans.” Both clinical trials are ongoing.

The Sunnybrook trial used a focused ultrasound device, which is good for pinpointing localized cancers. In contrast, SonoCloud emits ultrasound more diffusely, which is useful for glioblastomas that blend into surrounding brain tissue. “It seems a little more aggressive to implant something,” Carpentier said, but the wider-ranging ultrasound opens a larger swath of the blood-brain barrier. This enables chemotherapy drugs to reach cancer cells around the periphery of the main tumor, hopefully reducing the chance that the cancer will grow back.

Magnetic resonance brain scans from one patient indicate that opening the blood-brain barrier with SonoCloud resulted in no further tumor progression.

Carpentier, who invented SonoCloud and founded its parent company, CarThera, says the most surprising part was the patients’ response to the implant. “The patients don’t feel anything when we emit ultrasound,” he says. “And they actually don’t complain about it. It was set up in the protocol to remove it after six months, but patients don’t want to remove it.”

He is now designing the next phase of the clinical trial to determine how much more effective the chemotherapy is with an opened blood-brain barrier. Carpentier says the technology is a “huge opportunity” to improve treatment of many diseases. He is also beginning work on a trial with Alzheimer’s patients, since studies in mice have showed that merely opening the blood-brain barrier with ultrasound helps remove the amyloid-β protein thought to be responsible for Alzheimer’s without using any drugs.

The ultimate goal of ultrasound therapy is “to be able to repetitively and reversibly open the blood-brain barrier in a non-invasive, targeted, and focused manner,” Kassell says. “This is one more step toward that goal.”

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Novel embalming solution for neurosurgical simulation in cadavers Laboratory investigation.


Surgical simulation using postmortem human heads is one of the most valid strategies for neurosurgical research and training. The authors customized an embalming formula that provides an optimal retraction profile and lifelike physical properties while preventing microorganism growth and brain decay for neurosurgical simulations in cadavers. They studied the properties of the customized formula and compared its use with the standard postmortem processing techniques: cryopreservation and formaldehyde-based embalming.

METHODS

Eighteen specimens were prepared for neurosurgical simulation: 6 formaldehyde embalmed, 6 cryopreserved, and 6 custom embalmed. The customized formula is a mixture of ethanol 62.4%, glycerol 17%, phenol 10.2%, formaldehyde 2.3%, and water 8.1%. After a standard pterional craniotomy, retraction profiles and brain stiffness were studied using an intracranial pressure transducer and monitor. Preservation time—that is, time that tissue remained in optimal condition—between specimen groups was also compared through periodical reports during a 48-hour simulation.

RESULTS

The mean (± standard deviation) retraction pressures were highest in the formaldehyde group and lowest in the cryopreserved group. The customized formula provided a mean retraction pressure almost 3 times lower than formaldehyde (36 ± 3 vs 103 ± 14 mm Hg, p < 0.01) and very similar to cryopreservation (24 ± 6 mm Hg, p < 0.01). For research purposes, preservation time in the cryopreserved group was limited to 4 hours and was unlimited for the customized and formaldehyde groups for the duration of the experiment.

CONCLUSIONS

The customized embalming solution described herein is optimal for allowing retraction and surgical maneuverability while preventing decay. The authors were able to significantly lower the formaldehyde content as compared with that in standard formulas. The custom embalming solution has the benefits from both cryopreservation (for example, biological brain tissue properties) and formaldehyde embalming (for example, preservation time and microorganism growth prevention) and minimizes their drawbacks, that is, rapid decay in the former and stiffness in the latter. The presented embalming formula provides an important advance for neurosurgical simulations in research and teaching.

A novel device to simplify intraoperative radiographic visualization of the cervical spine by producing transient caudal shoulder displacement


Abstract

OBJECT

Intraoperative radiographic localization within the cervical spine can be a challenge because of the anatomical relation of the musculoskeletal structures of the pectoral girdle. On standard cross-table lateral radiographs, these structures can produce shadowing that obscure the anatomical features of the cervical vertebrae, particularly at the caudal levels. Surgical guidelines recommend accurate intraoperative localization as a means to reduce wrong-level spine surgery, and unobstructed visualization is needed for fluoroscopy-guided placement of spinal instrumentation. In this article, the authors describe and evaluate a novel device designed to provide transient intraoperative caudal displacement of the shoulders to improve and simplify radiographic visualization of the cervical spine.

METHODS

A 2-center prospective study was conducted to evaluate the device. The study included a total of 80 patients undergoing cervical spine surgery. The device was evaluated in a cohort of 50 patients undergoing elective single-level anterior discectomy and fusion and also in a second cohort of 30 patients at an independent institution. The patients in this second cohort were undergoing a variety of cervical spine procedures for multiple indications and were included in the study to allow the authors to assess the effectiveness of the device in a general neurosurgical practice. After the patients were anesthetized and positioned, consecutive standard cross-table lateral radiographs or intraoperative fluoroscopic were obtained before and after use of the device. The images were compared in order to determine the difference in lowest vertebral level visible.

RESULTS

There was an average difference in cervical spine visualization of +2.8 ± 0.9 vertebral levels in the first cohort, while in the second the improvement was +1.2 ± 0.7 levels (p < 0.0001 between cohorts, unpaired t-test). There was one complication, a minor shoulder abrasion, which required no specific management.

CONCLUSIONS

This device is safe and effective for increasing the radiographic visualization of the cervical spine for intraoperative localization.

Source: JNS.

William P. Van Wagenen (1897–1961): pupil, mentor, and neurosurgical pioneer.


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William Perrine (“Van”) Van Wagenen (1897–1961) was the first Chief of Neurosurgery at the University of Rochester Medical Center (URMC), serving from 1928 to 1954, and was a leading figure in 20th-century neurosurgery. He was a devoted pupil of Dr. Harvey Cushing and helped to found the Harvey Cushing Society (now the AANS) in honor of his mentor and was elected as its first President in 1932. He served as the 27th President of the Society of Neurological Surgeons in 1952. Upon his death in 1961 he bequeathed an endowment for the Van Wagenen Fellowship, which has advanced the education of many leaders in American neurosurgery. His legacy of operative skill, his commitment to resident education and research in neurological disease, his inspiration for the foundation of the Cushing Brain Tumor registry, and his contributions to organized neurosurgery form the foundation of the legacy of neurosurgery at URMC.

Source: JNS

 

Early and long-term excess mortality in 227 patients with intracranial dural arteriovenous fistulas.


Abstract

OBJECT

The aim of this study was to assess the early and long-term excess mortality in patients with intracranial dural arteriovenous fistula (DAVF) compared with a matched general Finnish population in an unselected, population-based series.

METHODS

The authors identified 227 patients with DAVFs admitted to 2 of the 5 Departments of Neurosurgery in FinlandHelsinki and Kuopio University Hospitals—between 1944 and 2006. All patients were followed until death or the end of 2009. Long-term excess mortality was estimated using the relative survival ratio compared with the general Finnish population matched by age, sex, and calendar year.

RESULTS

The median follow-up period was 10 years (range 0–44 years). Two-thirds (67%) of the DAVFs were located in the region of transverse and sigmoid sinuses. Cortical venous drainage (CVD) was present in 28% of the DAVFs (18% transverse and sigmoid sinus, 42% others). Of the 61 deaths counted, 11 (18%) were during the first 12 months and were mainly caused by treatment complications (5 of 11, 45%). The 1-year survivors presenting with hemorrhage experienced excess mortality until 7 years from admission. However, DAVFs with CVD were associated with significant, continuous excess mortality. There were more cerebrovascular and cardiovascular deaths in this group of patients than expected in the general Finnish population. Location other than transverse and sigmoid sinuses was also associated with excess mortality.

CONCLUSIONS

In the patients with DAVF there was excess mortality during the first 12 months, mainly due to treatment complications. Thereafter, their overall long-term survival became similar to that of the matched general population. However, DAVFs with CVD and those located in regions other than transverse and sigmoid sinuses were associated with marked long-term excess mortality after the first 12 months.

Source: JNS

 

Response to acute concussive injury in soccer players: is gender a modifying factor?


Several studies have suggested a gender difference in response to sports-related concussion (SRC). The Concussion in Sport group did not include gender as a modifying factor in SRC, concluding that the evidence at that point was equivocal. In the present study the authors endeavored to assess acute neurocognitive and symptom responses to an SRC in equivalent cohorts of male and female soccer players. The authors hypothesized that female athletes would experience greater levels of acute symptoms and neurocognitive impairment than males.

Methods

Baseline symptom and neurocognitive scores were determined in 40 male and 40 female soccer players by using the Immediate Postconcussion Assessment and Cognitive Testing (ImPACT) scale prior to any SRC. After sustaining an SRC, each athlete completed postconcussion ImPACT tests and was carefully matched on a wide array of biopsychosocial variables. Baseline symptom and neurocognitive test scores were compared, and their acute symptoms and neurocognitive responses to concussive injury were assessed.

Results

Specific a priori hypotheses about differences between males and females at baseline and at postconcussion measurements of verbal and visual memory ImPACT scores were evaluated according to simple main effects of the gender variable and according to baseline-to-postconcussion main effect and interaction of 2 × 2 split-plot ANOVA. Neither the interaction nor the main effects nor the simple main effects for either ImPACT variable were found to be statistically significant. Exploratory ANOVAs applied to the remaining ImPACT variables of visualmotor speed, reaction time, impulse control, and symptom total scores revealed only a single statistically significant baseline-to-postconcussion main effect for the symptom total.

Conclusions

The results failed to replicate prior findings of gender-specific baseline neurocognitive differences in verbal and visual memory. The findings also indicated no differential gender-based acute response to concussion (symptoms or neurocognitive scores) among high school soccer players. The implications of these findings for the inclusion of gender as a modifying factor in this tightly matched cohort are addressed. Potential explanations for the null findings are discussed.

Source: Journal of Neurosurgery

Incidence and causes of perioperative mortality after primary surgery for intracranial tumors.


Surgical mortality is a frequent outcome measure in studies of volume-outcome relationships, and the Agency for Healthcare Research and Quality has endorsed surgical mortality after craniotomies as an Inpatient Quality Indicator. Still, the frequency and causes of 30-day mortality after neurosurgical procedures have not been much explored. The authors sought to study the frequency and possible causes of death following primary intracranial tumor operations. They also sought to explore a possible predictive value of perioperative mortality rates from neurosurgical centers in relation to long-term survival.

Methods

Using population-based data from the Norwegian cancer registry, the authors identified 15,918 primary operations for primary CNS tumors treated in Norway in the period from August 1955 through December 2008. Patients were followed up until death, emigration, or September 2009. Causes of mortality as indicated on death certificates were studied. Factors associated with an increased risk of perioperative death were identified.

Results

The overall risk of perioperative death after first-time surgery for primary intracranial tumors is currently 2.2% and has decreased over the last decades. An age ≥ 70 years and histopathological entities with poor long-term prognoses are risk factors. Overlapping lesions are also associated with excess risk, indicating that lesion size or multifocality may matter. The overall risk of perioperative death is also higher in biopsy cases than in resection cases. Perioperative mortality rates of the 4 Norwegian neurosurgical centers were not predictive of their respective long-term survival rates.

Conclusions

Although considered surgically related if they occur within the first 30 days of surgery, most early postoperative deaths can happen independent of the handiwork of the operating surgeon or anesthesiologist. Overall prognosis of the disease seems to be a strong predictor of perioperative death—perhaps not surprisingly since the 30-day mortality rate is merely the intonation of the Kaplan-Meier curve. Both referral and treatment policies at a neurosurgical center will therefore markedly affect such early outcomes, but early deaths may not necessarily reflect overall quality of care or long-term results. The low incidence of perioperative death in intracranial tumor surgery also greatly limits the statistical power in comparative analyses, such as between published patient series or between centers and certainly between surgeons. Therefore the authors question the value of perioperative mortality rates as a quality indicator in modern neurosurgery for tumors.

Source: Journal of Neurosurgery