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David S. Xu and Francisco A. Ponce

OBJECTIVE

The aim of this article is to review the authors’ and published experience with deep brain stimulation (DBS) therapy for the treatment of patients with Alzheimer’s disease (AD) and Parkinson’s disease dementia (PDD).

METHODS

Two targets are current topics of investigation in the treatment of AD and PDD, the fornix and the nucleus basalis of Meynert. The authors reviewed the current published clinical experience with attention to patient selection, biological rationale of therapy, anatomical targeting, and clinical results and adverse events.

RESULTS

A total of 7 clinical studies treating 57 AD patients and 7 PDD patients have been reported. Serious adverse events were reported in 6 (9%) patients; none resulted in death or disability. Most studies were case reports or Phase 1/2 investigations and were not designed to assess treatment efficacy. Isolated patient experiences demonstrating improved clinical response after DBS have been reported, but no significant or consistent cognitive benefits associated with DBS treatment could be identified across larger patient populations.

CONCLUSIONS

PDD and AD are complex clinical entities, with investigation of DBS intervention still in an early phase. Recently published studies demonstrate acceptable surgical safety. For future studies to have adequate power to detect meaningful clinical changes, further refinement is needed in patient selection, metrics of clinical response, and optimal stimulation parameters.

Free access

David S. Xu, Konrad Bach, and Juan S. Uribe

OBJECTIVE

Minimally invasive anterior and lateral approaches to the lumbar spine are increasingly used to treat and reduce grade I spondylolisthesis, but concerns still exist for their usage in the management of higher-grade lesions. The authors report their experience with this strategy for grade II spondylolisthesis in a single-surgeon case series and provide early clinical and radiographic outcomes.

METHODS

A retrospective review of a single surgeon’s cases between 2012 and 2016 identified all patients with a Meyerding grade II lumbar spondylolisthesis who underwent minimally invasive lateral lumbar interbody fusion (LLIF) or anterior lumbar interbody fusion (ALIF) targeting the slipped level. Demographic, clinical, and radiographic data were collected and analyzed. Changes in radiographic measurements, Oswestry Disability Index (ODI), and visual analog scale (VAS) scores were compared using the paired t-test and Wilcoxon signed rank test for continuous and ordinal variables, respectively.

RESULTS

The average operative time was 199.1 minutes (with 60.6 ml of estimated blood loss) for LLIFs and 282.1 minutes (with 106.3 ml of estimated blood loss), for ALIFs. Three LLIF patients had transient unilateral anterior thigh numbness during the 1st week after surgery, and 1 ALIF patient had transient dorsiflexion weakness, which was resolved at postoperative week 1. The mean follow-up time was 17.6 months (SD 12.5 months) for LLIF patients and 10 months (SD 3.1 months) for ALIF patients. Complete reduction of the spondylolisthesis was achieved in 12 LLIF patients (75.0%) and 7 ALIF patients (87.5%). Across both procedures, there was an increase in both the segmental lordosis (LLIF 5.6°, p = 0.002; ALIF 15.0°, p = 0.002) and overall lumbar lordosis (LLIF 2.9°, p = 0.151; ALIF 5.1°, p = 0.006) after surgery. Statistically significant decreases in the mean VAS and the mean ODI measurements were seen in both treatment groups. The VAS and ODI scores fell by a mean value of 3.9 (p = 0.002) and 19.8 (p = 0.001), respectively, for LLIF patients and 3.8 (p = 0.02) and 21.0 (p = 0.03), respectively, for ALIF patients at last follow-up.

CONCLUSIONS

Early clinical and radiographic results from using minimally invasive LLIF and ALIF approaches to treat grade II spondylolisthesis appear to be good, with low operative blood loss and no neurological deficits. Complete reduction of the spondylolisthesis is frequently possible with a statistically significant reduction in pain scores.

Free access

Isaac Josh Abecassis, David S. Xu, H. Hunt Batjer, and Bernard R. Bendok

Object

The authors aimed to systematically review the literature to clarify the natural history of brain arteriovenous malformations (BAVMs).

Methods

The authors searched PubMed for one or more of the following terms: natural history, brain arteriovenous malformations, cerebral arteriovenous malformations, and risk of rupture. They included studies that reported annual rates of hemorrhage and that included either 100 patients or 5 years of treatment-free follow-up.

Results

The incidence of BAVMs is 1.12–1.42 cases per 100,000 person-years; 38%–68% of new cases are first-ever hemorrhage. The overall annual rates of hemorrhage for patients with untreated BAVMs range from 2.10% to 4.12%. Consistently implicated in subsequent hemorrhage are initial hemorrhagic presentation, exclusively deep venous drainage, and deep and infrantentorial brain location. The risk for rupture seems to be increased by large nidus size and concurrent arterial aneurysms, although these factors have not been studied as thoroughly. Venous stenosis has not been implicated in increased risk for rupture.

Conclusions

For patients with BAVMs, although the overall risk for hemorrhage seems to be 2.10%–4.12% per year, calculating an accurate risk profile for decision making involves clinical attention and accounting for specific features of the malformation.

Restricted access

David J. Salvetti, Tara G. Nagaraja, Ian T. McNeill, Zhiyuan Xu, and Jason Sheehan

Object

It has been generally accepted that Gamma Knife surgery (GKS) is an effective primary or adjunct treatment for patients with 1–4 metastases to the brain. The number of studies detailing the use of GKS for 5 or more brain metastases, however, remains minimal. The aim of the current retrospective study was to elucidate the utility of GKS in patients with 5–15 brain metastases.

Methods

Patients were chosen for GKS based on prior MRI of these metastatic lesions and a known primary cancer diagnosis. Magnetic resonance imaging was used post-GKS to assess tumor control; patients were also followed up clinically. Overall survival (OS) from the date of GKS was used as the primary end point. Statistical analysis was performed to identify prognostic factors related to OS.

Results

Between 2003 and 2012, 96 patients were treated for a total of 704 metastatic brain lesions. The histology of these lesions varied among non–small cell lung cancer (NSCLC), breast cancer, melanoma, renal cancer, and other more rare carcinomas. At the initial treatment, 18 of the patients (18.8%) were categorized in Recursive Partitioning Analysis (RPA) Class 1 and 77 (80.2%) in RPA Class 2; none were in RPA Class 3. The median number of treated lesions was 7 (mean 7.13), and the median planned treatment volume was 6.12 cm3 (range 0.42–57.83 cm3) per patient. The median clinical follow-up was 4.1 months (range 0.1–40.70 months). Actuarial tumor control was calculated to be 92.4% at 6 months, 84.8% at 12 months, and 74.9% at 24 months post-GKS. The median OS was found to be 4.73 months (range 0.4–41.8 months). Multivariate analysis demonstrated that RPA class was a significant predictor of death (HR = 2.263, p = 0.038). Number of lesions, tumor histology, Graded Prognostic Assessment score, prior whole-brain radiation therapy, prior resection, prior chemotherapy, patient age, patient sex, controlled primary tumor, extracranial metastases, and planned treatment volume were not significant predictors of OS.

Conclusions

In patients with 5–15 brain metastases at presentation, the number of lesions did not predict survival after GKS; however, the RPA class was predictive of OS in this group of patients. Gamma Knife surgery for such patients offers an excellent rate of local tumor control.

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Jason P. Sheehan, Zhiyuan Xu, Britney Popp, Leigh Kowalski, and David Schlesinger

Object

The survival of patients with high-grade gliomas remains unfavorable. Mibefradil, a T-type calcium channel inhibitor capable of synchronizing dividing cells at the G1 phase, has demonstrated potential benefit in conjunction with chemotherapeutic agents for gliomas in in vitro studies. In vivo study of mibefradil and radiosurgery is lacking. The authors used an intracranial C6 glioma model in rats to study tumor response to mibefradil and radiosurgery.

Methods

Two weeks after implantation of C6 cells into the animals, each rat underwent MRI every 2 weeks thereafter for 8 weeks. After tumor was confirmed on MRI, the rats were randomly assigned to one of the experimental groups. Tumor volumes were measured on MR images. Experimental Group 1 received 30 mg/kg of mibefradil intraperitoneally 3 times a day for 1 week starting on postoperative day (POD) 15; Group 2 received 8 Gy of cranial radiation via radiosurgery delivered on POD 15; Group 3 underwent radiosurgery on POD 15, followed by 1 week of mibefradil; and Group 4 received mibefradil on POD 15 for 1 week, followed by radiosurgery sometime from POD 15 to POD 22. Twenty-seven glioma-bearing rats were analyzed. Survival was compared between groups using Kaplan-Meier methodology.

Results

Median survival in Groups 1, 2, 3, and 4 was 35, 31, 43, and 52 days, respectively (p = 0.036, log-rank test). Two animals in Group 4 survived to POD 60, which is twice the expected survival of untreated animals in this model. Analysis of variance and a post hoc test indicated no tumor volume differences on PODs 15 and 29. However, significant volume differences were found on POD 43; mean tumor volumes for Groups 1, 2, 3, and 4 were 250, 266, 167, and 34 mm3, respectively (p = 0.046, ANOVA). A Cox proportional hazards regression test showed survival was associated with tumor volume on POD 29 (p = 0.001) rather than on POD 15 (p = 0.162). In vitro assays demonstrated an appreciable and dose-dependent increase in apoptosis between 2- and 7-μM concentrations of mibefradil.

Conclusions

Mibefradil response is schedule dependent and enhances survival and reduces glioblastoma when combined with ionizing radiation.

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David J. Salvetti, Tara G. Nagaraja, Carl Levy, Zhiyaun Xu, and Jason Sheehan

Object

Increasingly, meningiomas are detected incidentally, prior to symptom development. While these lesions are traditionally managed conservatively until symptoms develop or lesion growth occurs, it is conceivable that patients at high risk for symptom development may benefit from earlier intervention prior to the appearance of symptoms. However, little research has been performed to determine whether Gamma Knife surgery (GKS) can alter the rate of symptom development in such patients.

Methods

A retrospective case study was performed by screening the University of Virginia GKS database for patients treated for asymptomatic meningiomas. From the patient's medical records, pertinent demographic and treatment information was obtained. Yearly follow-up MRI had been performed to assess tumor control and detect signs of radiation-induced injury. Clinical follow-up via neurological examination had been performed to assess symptom development.

Results

Forty-two patients, 33 females (78.6%) and 9 males (21.4%), with 42 asymptomatic meningiomas were included in the analysis. The median age at GKS was 53 years. The most common lesion location was the cerebral convexities (10 lesions [23.8%]), and the median lesion size was 4.0 ml. The median duration of imaging and clinical follow-ups was 59 and 76 months, respectively. During the follow-up period, 1 tumor (2.4%) increased in size, 2 patients (4.8%) demonstrated symptoms, and 1 patient (2.4%) exhibited possible signs of radiation-induced injury. Thus, actuarial tumor control rates were 100%, 95.7%, and 95.7% for 2, 5, and 10 years, respectively. Actuarial symptom control at 5 and 10 years was 97% and 93.1%, respectively. Overall progression-free survival was 91.1% and 77.8% at 5 and 10 years, respectively.

Conclusions

Compared with published rates of symptom development in patients with untreated meningiomas, results in this study indicated that patients with asymptomatic lesions may benefit from prophylactic radiosurgery prior to the appearance of symptoms. Additionally, GKS is a treatment option that offers low morbidity.

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Jason P. Sheehan, Gregory Patterson, David Schlesinger, and Zhiyuan Xu

Object

Obsessive-compulsive disorder (OCD) is a challenging psychiatric condition associated with anxiety and ritualistic behaviors. Although medical management and psychiatric therapy are effective for many patients, severe and extreme cases may prove refractory to these approaches. The authors evaluated their experience with Gamma Knife (GK) capsulotomy in treating patients with severe OCD.

Methods

A retrospective review of an institutional review board–approved prospective clinical GK database was conducted for patients treated for severe OCD. All patients were evaluated preoperatively by at least one psychiatrist, and their condition was deemed refractory to pharmacological and psychiatric therapy.

Results

Five patients were identified. Gamma Knife surgery with the GK Perfexion unit was used to target the anterior limb of the internal capsule bilaterally. A single 4-mm isocenter was used; maximum radiation doses of 140–160 Gy were delivered. All 5 patients were preoperatively and postoperatively assessed for clinical response by using both subjective and objective metrics, including the Yale-Brown Obsessive Compulsive Scale (YBOCS); 4 of the 5 patients had postoperative radiological follow-up. The median clinical follow-up was 24 months (range 6–33 months). At the time of radiosurgery, all patients had YBOCS scores in the severe or extreme range (median 32, range 31–34). At the last follow-up, 4 (80%) of the 5 patients showed marked clinical improvement; in the remaining patient (20%), mild improvement was seen. The median YBOCS score was 13 (range 12–31) at the last follow-up. Neuroimaging studies at 6 months after GK treatment demonstrated a small area of enhancement corresponding to the site of the isocenter and some mild T2 signal changes in the internal capsule. No adverse clinical effects were noted from the radiosurgery.

Conclusions

For patients with severe OCD refractory to medications and psychiatric therapy, GK capsulotomy afforded clinical improvement. Further study of this approach seems warranted.

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Douglas Kondziolka

Open access

Peyton L. Nisson, Robert T. Wicks, Xiaochun Zhao, Whitney S. James, David Xu, and Peter Nakaji

Cavernous malformations of the brain are low-flow vascular lesions that have a propensity to hemorrhage. Extensive surgical approaches are often required for operative cure of deep-seated lesions. A 23-year-old female presented with a cavernous malformation of the left posterior insula with surrounding hematoma measuring up to 3 cm. A minimally invasive (mini-)pterional craniotomy with a transsylvian approach was selected. Endoscopic assistance was utilized to confirm complete resection of the lesion. The minipterional craniotomy is a minimally invasive approach that provides optimal exposure for sylvian fissure dissection and resection of many temporal and insular lesions.

The video can be found here: https://youtu.be/9z6_EhU6lxs.

Restricted access

Corey T. Walker, S. Harrison Farber, Tyler S. Cole, David S. Xu, Jakub Godzik, Alexander C. Whiting, Cory Hartman, Randall W. Porter, Jay D. Turner, and Juan Uribe

OBJECTIVE

Minimally invasive anterolateral retroperitoneal approaches for lumbar interbody arthrodesis have distinct advantages attractive to spine surgeons. Prepsoas or transpsoas trajectories can be employed with differing complication profiles because of the inherent anatomical differences encountered in each approach. The evidence comparing them remains limited because of poor quality data. Here, the authors sought to systematically review the available literature and perform a meta-analysis comparing the two techniques.

METHODS

A systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A database search was used to identify eligible studies. Prepsoas and transpsoas studies were compiled, and each study was assessed for inclusion criteria. Complication rates were recorded and compared between approach groups. Studies incorporating an analysis of postoperative subsidence and pseudarthrosis rates were also assessed and compared.

RESULTS

For the prepsoas studies, 20 studies for the complications analysis and 8 studies for the pseudarthrosis outcomes analysis were included. For the transpsoas studies, 39 studies for the complications analysis and 19 studies for the pseudarthrosis outcomes analysis were included. For the complications analysis, 1874 patients treated via the prepsoas approach and 4607 treated with the transpsoas approach were included. In the transpsoas group, there was a higher rate of transient sensory symptoms (21.7% vs 8.7%, p = 0.002), transient hip flexor weakness (19.7% vs 5.7%, p < 0.001), and permanent neurological weakness (2.8% vs 1.0%, p = 0.005). A higher rate of sympathetic nerve injury was seen in the prepsoas group (5.4% vs 0.0%, p = 0.03). Of the nonneurological complications, major vascular injury was significantly higher in the prepsoas approach (1.8% vs 0.4%, p = 0.01). There was no difference in urological or peritoneal/bowel injury, postoperative ileus, or hematomas (all p > 0.05). A higher infection rate was noted for the transpsoas group (3.1% vs 1.1%, p = 0.01). With regard to postoperative fusion outcomes, similar rates of subsidence (12.2% prepsoas vs 13.8% transpsoas, p = 0.78) and pseudarthrosis (9.9% vs 7.5%, respectively, p = 0.57) were seen between the groups at the last follow-up.

CONCLUSIONS

Complication rates vary for the prepsoas and transpsoas approaches owing to the variable retroperitoneal anatomy encountered during surgical dissection. While the risks of a lasting motor deficit and transient sensory disturbances are higher for the transpsoas approach, there is a reciprocal reduction in the risks of major vascular injury and sympathetic nerve injury. These results can facilitate informed decision-making and tailored surgical planning regarding the choice of minimally invasive anterolateral access to the spine.