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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.

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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.

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Mohamed Elsharkawy, Zhiyuan Xu, David Schlesinger and Jason P. Sheehan

Object

Most intracranial schwannomas arise from cranial nerve (CN) VIII. Stereotactic radiosurgery is a mainstay of treatment for vestibular schwannomas. Intracranial schwannomas arising from other CNs are much less common. We evaluate the efficacy of Gamma Knife surgery on nonvestibular schwannomas including trigeminal, hypoglossal, abducent, facial, trochlear, oculomotor, glossopharyngeal, and jugular foramen tumors.

Methods

Thirty-six patients with nonvestibular schwannomas were treated at the University of Virginia Gamma Knife center from 1989 to 2008. The median patient age was 48 years (mean 45.6 years, range 10–72 years). Schwannomas arose from the following CNs: CN III (in 1 patient), CN IV (in 1), CN V (in 25), CN VI (in 2), CN VII (in 1), CN IX (in 1), and CN XII (in 3). In 2 patients, tumors arose from the jugular foramen. The median tumor volume was 2.9 cm3 (mean 3.3 cm3, range 0.07–8.8 cm3). The median margin dose was 13.5 Gy (range 9.3–20 Gy); the median maximum dose was 30 Gy (range 21.7–50.0 Gy).

Results

The mean and median follow-up times of 36 patients were 54 and 37 months, respectively (range 2–180 months). At the last radiological follow-up, the tumor size had decreased in 20 patients, remained stable in 9 patients, and increased in 7 patients. The 2-year actuarial progression-free survival was 91%. Higher maximum dose was statistically related to tumor control (p = 0.027).

Thirty-three patients had adequate clinical follow-up. Among them, 21 patients had improvement in their presenting symptoms, 8 patients were stable after treatment with no worsening of their presenting symptoms, 2 patients developed new symptoms, and 1 patient experienced symptom deterioration. Notably, 1 patient with neurofibromatosis Type 2 developed new symptoms that were unrelated to the tumor treated with Gamma Knife surgery.

Conclusions

Gamma Knife surgery is a reasonably effective treatment option for patients with nonvestibular schwannomas. Patients require careful follow-up for tumor progression and signs of neurological deterioration.

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Mohamed Samy Elhammady and Roberto C. Heros

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Cheng-Chia Lee, Chun-Po Yen, Zhiyuan Xu, David Schlesinger and Jason Sheehan

Object

The use of radiosurgery has been well accepted for treating small to medium-size metastatic brain tumors (MBTs). However, its utility in treating large MBTs remains uncertain due to potentially unfavorable effects such as progressive perifocal brain edema and neurological deterioration. In this retrospective study the authors evaluated the local tumor control rate and analyzed possible factors affecting tumor and brain edema response.

Methods

The authors defined a large brain metastasis as one with a measurement of 3 cm or more in at least one of the 3 cardinal planes (coronal, axial, or sagittal). A consecutive series of 109 patients with 119 large intracranial metastatic lesions were treated with Gamma Knife surgery (GKS) between October 2000 and December 2012; the median tumor volume was 16.8 cm3 (range 6.0–74.8 cm3). The pre-GKS Karnofsky Performance Status (KPS) score for these patients ranged from 70 to 100. The most common tumors of origin were non–small cell lung cancers (29.4% of cases in this series). Thirty-six patients (33.0%) had previously undergone a craniotomy (1–3 times) for tumor resection. Forty-three patients (39.4%) underwent whole-brain radiotherapy (WBRT) before GKS. Patients were treated with GKS and followed clinically and radiographically at 2- to 3-month intervals thereafter.

Results

The median duration of imaging follow-up after GKS for patients with large MBTs in this series was 6.3 months. In the first follow-up MRI studies (performed within 3 months after GKS), 77 lesions (64.7%) had regressed, 24 (20.2%) were stable, and 18 (15.1%) were found to have grown. Peritumoral brain edema as defined on T2-weighted MRI sequences had decreased in 79 lesions (66.4%), was stable in 21 (17.6%), but had progressed in 19 (16.0%). In the group of patients who survived longer than 6 months (76 patients with 77 MBTs), 88.3% of the MBTs (68 of 77 lesions) had regressed or remained stable at the most recent imaging follow-up, and 89.6% (69 of 77 lesions) showed regression of perifocal brain edema volume or stable condition. The median duration of survival after GKS was 8.3 months for patients with large MBTs. Patients with small cell lung cancer and no previous WBRT had a significantly higher tumor control rate as well as better brain edema relief. Patients with a single metastasis, better KPS scores, and no previous radiosurgery or WBRT were more likely to decrease corticosteroid use after GKS. On the other hand, higher pre-GKS KPS score was the only factor that showed a statistically significant association with longer survival.

Conclusions

Treating large MBTs using either microsurgery or radiosurgery is a challenge for neurosurgeons. In selected patients with large brain metastases, radiosurgery offered a reasonable local tumor control rate and favorable functional preservation. Exacerbation of underlying edema was rare in this case series. Far more commonly, edema and steroid use were lessened after radiosurgery. Radiosurgery appears to be a reasonable option for some patients with large MBTs.

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Or Cohen-Inbar, Cheng-Chia Lee, Zhiyuan Xu, David Schlesinger and Jason P. Sheehan

OBJECT

The authors review outcomes following Gamma Knife radiosurgery (GKRS) of cerebral arteriovenous malformations (AVMs) and their correlation to postradiosurgery adverse radiation effects (AREs).

METHODS

From a prospective institutional review board–approved database, the authors identified patients with a minimum of 2 years of follow-up and thin-slice T2-weighted MRI sequences for volumetric analysis. A total of 105 AVM patients were included. The authors analyzed the incidence and quantitative changes in AREs as a function of time after GKRS. Statistical analysis was performed to identify factors related to ARE development and changes in the ARE index.

RESULTS

The median clinical follow-up was 53.8 months (range 24–212.4 months), and the median MRI follow-up was 36.8 months (range 24–212.4 months). 47.6% of patients had an AVM with a Spetzler-Martin grade ≥ III. The median administered margin and maximum doses were 22 and 40 Gy, respectively. The overall obliteration rate was 70.5%. Of patients who showed complete obliteration, 74.4% developed AREs within 4–6 months after GKRS. Late-onset AREs (i.e., > 12 months) correlated to a failure to obliterate the nidus. 58.1% of patients who developed appreciable AREs (defined as ARE index > 8) proceeded to have a complete nidus obliteration. Appreciable AREs were found to be influenced by AVM nidus volume > 3 ml, lobar location, number of draining veins and feeding arteries, prior embolization, and higher margin dose. On the other hand, a minimum ARE index > 8 predicted obliteration (p = 0.043).

CONCLUSIONS

ARE development after radiosurgery follows a temporal pattern peaking at 7–12 months after stereotactic radiosurgery. The ARE index serves as an important adjunct tool in patient follow-up and outcome prediction.

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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

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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.