Human Substantia Nigra Neurons Encode Reward Expectations.

Dopamine (DA) signals originating from substantia nigra (SN) neurons are centrally involved in the regulation of motor and reward processing. DA signals behaviorally relevant events where reward outcomes differ from expectations (reward prediction errors, RPEs). RPEs play a crucial role in learning optimal courses of action and in determining response vigor when an agent expects rewards. Nevertheless, how reward expectations, crucial for RPE calculations, are conveyed to and represented in the dopaminergic system is not fully understood, especially in the human brain where the activity of DA neurons is difficult to study. One possibility, suggested by evidence from animal models, is that DA neurons explicitly encode reward expectations. Alternatively, they may receive RPE information directly from upstream brain regions. To address whether SN neuron activity directly reflects reward expectation information, we directly examined the encoding of reward expectation signals in human putative DA neurons by performing single-unit recordings from the SN of patients undergoing neurosurgery. Patients played a two-armed bandit decision-making task in which they attempted to maximize reward. We show that neuronal firing rates (FR) of putative DA neurons during the reward expectation period explicitly encode reward expectations. First, activity in these neurons was modulated by previous trial outcomes, such that FR were greater after positive outcomes than after neutral or negative outcome trials. Second, this increase in FR was associated with shorter reaction times, consistent with an invigorating effect of DA neuron activity during expectation. These results suggest that human DA neurons explicitly encode reward expectations, providing a neurophysiological substrate for a signal critical for reward learning.

Does Stereoelectroencephalography Add Value in Patients with Lesional Epilepsy?

OBJECTIVE: Stereoelectroencephalography (SEEG) has gained popularity as an invasive monitoring modality for epileptogenic zone (EZ) localization. The need and indications for SEEG in patients with evident brain lesions or associated abnormalities on imaging is debated. We report our experience with SEEG as a presurgical evaluation tool for patients with lesional epilepsy. METHODS: A retrospective cohort study was performed of 131 patients with lesional or magnetic resonance imaging abnormality-associated medically refractory focal epilepsy who underwent resections from 2010 to 2017. Seventy-one patients had SEEG followed by resection, and 60 had no invasive recordings. Volumetric analysis of resection cavities from 3T magnetic resonance imaging was performed. RESULTS: Mean lesion and resection volumes for SEEG and non-SEEG were 16.2 (standard deviation [SD] = 29) versus 23.7 cm3 (SD = 38.4) and 28.1 (SD = 23.2) versus 43.6 cm3 (SD = 43.5), respectively (P = 0.009). Comparing patients with seizure recurrence and patients who remained seizure free, significantly associated variables with seizure recurrence included mean number of failed antiseizure medications (6.86 [SD = 0.32] vs. 5.75 [SD = 0.32]; P = 0.01) and in SEEG patients the mean number of electrodes implanted (8.1 [SD = 0.8] vs. 5.0 [SD = 0.8]; P = 0.005). After multivariate analysis, only failed numbers of medication remained significantly associated with seizure recurrence. CONCLUSIONS: Seizure outcomes did not correlate with final resection volume after SEEG evaluation. SEEG evaluation presurgically can be used to maintain the efficacy of resection and decrease the volume and subsequent risk of extensive tissue removal. We believe that this technology allows resective surgery to proceed in a subpopulation of patients with lesional epilepsy who may otherwise not have been considered surgical candidates.

ResectVol: A tool to automatically segment and characterize lacunas in brain images.

OBJECTIVE: To assess and validate the performance of a new tool developed for segmenting and characterizing lacunas in postoperative MR images of epilepsy patients. METHODS: A MATLAB-based pipeline was implemented using SPM12 to produce the 3D mask of the surgical lacuna and estimate its volume. To validate its performance, we compared the manual and automatic lacuna segmentations obtained from 51 MRI scans of epilepsy patients who underwent temporal lobe resections. RESULTS: The code is consolidated as a tool named ResectVol, which can be run via a graphical user interface or command line. The automatic and manual segmentation comparison resulted in a median Dice similarity coefficient of 0.77 (interquartile range: 0.71-0.81). SIGNIFICANCE: Epilepsy surgery is the treatment of choice for pharmacoresistant focal epilepsies, and despite the extensive literature on the subject, we still cannot predict surgical outcomes accurately. As the volume and location of the resected tissue are fundamentally relevant to this prediction, researchers commonly perform a manual segmentation of the lacuna, which presents human bias and does not provide detailed information about the structures removed. In this study, we introduce ResectVol, a user-friendly, fully automatic tool to accomplish these tasks. This capability enables more advanced analytical techniques applied to surgical outcomes prediction, such as machine-learning algorithms, by facilitating coregistration of the resected area and preoperative findings with other imaging modalities such as PET, SPECT, and functional MRI ResectVol is freely available at https://www.lniunicamp.com/resectvol.

Vasospasm Following Hemispherectomy: A Case Report of a Novel Complication.

BACKGROUND: Hemispherectomy has been shown to be successful in treating medically intractable epilepsy, with favorable seizure-free outcomes. However, the procedure is technically challenging with high rates of in-hospital complications. We present a unique case of functional hemispherectomy complicated by diffuse cerebral vasospasm and subsequent death in a patient with COL4A1 gene mutation. CASE DESCRIPTION: A 17-year-old boy presented with right hemispheric epilepsy and a previously diagnosed autosomal dominant heterozygous COL4A1 gene mutation (c.4380T>G;p.Cys1460Trp). Functional hemispherectomy was performed without complications. On postoperative day 8, he developed an acute decline in neurologic status requiring urgent intubation for airway protection. Magnetic resonance imaging revealed areas of restricted diffusion throughout bilateral hemispheres that was explained by severe vasospasm and minimal cerebral blood flow seen on cerebral angiography. Intra-arterial calcium channel blocker infusion and balloon angioplasty were attempted without improvement in perfusion. With a worsening clinical picture, he was transitioned to comfort care and died. CONCLUSIONS: This is the first report in the literature describing global vasospasm and delayed cerebral ischemia following hemispherectomy in a patient carrying COL4A1 gene mutation. We postulate that his COL4A1 gene mutation might have resulted in this exaggerated vasospasm despite minimal residual postoperative subarachnoid hemorrhage burden. This hypothesis needs to be studied in animal models of this genetic disorder.

The Hypothalamic-Pituitary-Adrenal Axis and the Fetus.

Glucocorticoids (GCs), cortisol in humans, influence multiple essential maturational events during gestation. In the human fetus, fetal hypothalamic-pituitary-adrenal (HPA) axis function, fetal adrenal steroidogenesis, placental 11ß- hydroxysteroid dehydrogenase type 2 activity, maternal cortisol concentrations, and environmental factors impact fetal cortisol exposure. The beneficial effects of synthetic glucocorticoids (sGCs), such as dexamethasone and betamethasone, on fetal lung maturation have significantly shifted the management of preterm labor and threatened preterm birth. Accumulating evidence suggests that exposure to sGCs in utero at critical developmental stages can alter the function of organ systems and that these effects may have sequelae that extend into adult life. Maternal stress and environmental influences may also impact fetal GC exposure. This article explores the vulnerability of the fetal HPA axis to endogenous GCs and exogenous sGCs.

Long-term effect of intensive lifestyle intervention on cardiovascular risk factors in patients with diabetes in real-world clinical practice: a 5-year longitudinal study.

OBJECTIVE: We evaluated long-term impact of sustained weight loss versus weight regain on cardiovascular risk factors in real-world clinical practice. METHODS: We evaluated 129 obese patients with diabetes enrolled in Weight Achievement and Intensive Treatment (Why WAIT) program, a 12-week clinical model of intensive lifestyle intervention. After 1 year, we divided participants into group A, who maintained <7% weight loss (47.3%) and group B (52.7%), who maintained ≥7% weight loss. We continued to follow them for a total of 5 years. RESULTS: The total cohort lost 23.8 lbs (-9.7%) at 12 weeks and maintained -16.2 lbs (-6.4%) at 5 years (p<0.001). Group A maintained -8.4 lbs (-3.5%) and group B maintained -23.1 lbs (-9.0%) at 5 years. In group A, A1C decreased from 7.5±1.3% to 6.7±0.9% at 12 weeks but increased to 7.7±1.4% at 1 year and 8.0±1.9% at 5 years. In group B, A1C decreased from 7.4±1.2% to 6.4±0.9% at 12 weeks and rose to 6.8±1.2% at 1 year and 7.3±1.5% at 5 years. Despite weight regain, group A maintained improvement in low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol with worsening of serum triglycerides and no change in blood pressure (BP). Group B maintained improvement in lipid profile for 5 years and had significantly lower BP for 18 months. CONCLUSIONS: Weight reduction in patients with diabetes can be maintained for 5 years and is predicted by patients' ability to maintain ≥7% weight loss at 1 year. A1C and triglycerides deteriorate with weight regain, while other lipid improvements are maintained. Sustained weight loss is associated with significantly lower A1C for 5 years and lowers BP for 18 months. TRIAL REGISTRATION NUMBER: NCT01937845.

Outcome comparison of atlantoaxial fusion with transarticular screws and screw-rod constructs: meta-analysis and review of literature.

STUDY DESIGN: Literature review and meta-analysis. OBJECTIVE: To compare clinical and radiographic outcomes of patients treated with transarticular screws (TASs) and screw-rod constructs (SRCs) for posterior atlantoaxial fusion. BACKGROUND: Modern techniques for C1-C2 fusions include Magerl and Seeman's TAS and SRC using C1 lateral mass screws and C2 pars/pedicle screws as described by Goel and Laheri and later modified by Harms and Melcher. MATERIALS AND METHODS: Online databases were searched for English-language articles between 1986 and April 2011 describing posterior atlantoaxial instrumentation with C1-C2 TAS or SRC. Forty-five studies (2073 patients) treated with TAS and 24 studies (1073 patients) treated with SRC fulfilled inclusion criteria. Standard and formal meta-analysis techniques were used to compare the outcomes. RESULTS: All studies provided class III evidence. There were no differences in 30-day mortality (0.8% vs. 0.6%) or neurological injury (0.2% vs. 0%). There was a higher incidence of vertebral artery injury [4.1% (95% confidence interval (CI), 2.8%-5.4%) vs. 2.0% (95% CI, 1.1%-3.4%); P=0.02] and malpositioned screws [7.1% (95% CI, 5.7%-8.8%) vs. 2.4% (95% CI, 1.1%-4.1%); P<0.001] and a slightly lower rate of fusion with the TAS technique [97.5% (95% CI, 95.9%-98.5%) vs. 94.6% (95% CI, 92.6%-96.1%); P<0.001]. CONCLUSIONS: TAS and SRC are safe and effective treatment options for C1-C2 instability but require a thorough knowledge of atlantoaxial anatomy for successful insertion of screws. Slightly higher rates of fusion and less risk of injury to the vertebral artery during screw placement were observed with the SRC technique. However, differences in graft material and techniques were noted. Prospective, randomized studies with validated radiographic and clinical outcome metrics are necessary for proper comparison of these techniques.

Atlantoaxial fusion with screw-rod constructs: meta-analysis and review of literature.

OBJECTIVE: To review published series describing C1-2 posterior instrumented fusions and summarize clinical and radiographic outcomes of patients treated with screw-rod constructs (SRC). METHODS: Online databases were searched for English-language articles published between 1991 and April 2011 describing posterior atlantoaxial instrumentation with C1-2 SRC. There were 24 studies including 1073 patients treated with SRC that fulfilled inclusion criteria. Meta-analysis techniques were used to compare outcomes. RESULTS: All studies provided class III evidence. The 30-day perioperative mortality rate was 0.6%, and neurologic injury occurred in two patients with vertebral artery injury (VAI) from screw malpositions (0.2%). The incidence of clinically significant screw malpositions was 2.4% (confidence interval [CI], 1.1%-4.1%), the incidence of VAI was 2.0% (CI, 1.1%-3.4%), and the rate of fusion with the SRC technique was 97.5% (CI, 95.9%-98.5%). CONCLUSIONS: SRC is a safe and effective treatment option for C1-2 instability. The low but nonzero incidence of screw malposition and VAI emphasizes the necessity of having a thorough knowledge of atlantoaxial anatomy for successful insertion of screws.

Comparison of screw malposition and vertebral artery injury of C2 pedicle and transarticular screws: meta-analysis and review of the literature.

STUDY DESIGN: Literature review and meta-analysis. OBJECTIVES: To compare the incidence of screw malposition and vertebral artery injury (VAI) with transarticular screws (TAS) and C2 pedicle screws (C2PS) using meta-analysis techniques. SUMMARY OF BACKGROUND DATA: Posterior instrumentation for atlantoaxial fusions can be challenging and risky. Some centers report a higher incidence of VAI with the implantation of TAS compared with C2PS, whereas other data do not support this. METHODS: Online databases were searched for English language articles between 1994 and April 2011 describing the clinical and radiographic outcomes after insertion of C2PS or TAS. Forty-one studies reporting on 3627 TAS and 33 studies describing 2979 C2PS met inclusion criteria for VAI or clinically significant misplacements (VAI, neurological deficits, or misplacements requiring surgical revision), and 36 studies reporting on 3280 TAS and 28 studies describing 2532 C2PS met inclusion criteria for radiographic misplacement outcomes. RESULTS: All studies comprised class III evidence. VAI occurred in 26 of 3627 (0.72%) implanted TAS and in 10 of 2979 (0.34%) implanted C2PS (P=0.01). Clinically significant misplacements occurred in 67 TAS (1.84%) and in 10 C2PS (0.34%; P<0.0001). The point estimate of VAI for TAS was 1.68% [confidence interval (CI), 1.23%-2.29%] and was higher than C2PS (1.09%; CI, 0.73%-1.63%; P=0.01). The point estimate of clinically significant screw malposition for TAS was 2.33% (CI, 1.61%-3.37%) and was higher than that of C2PS (1.15%; CI, 0.77%-1.70%; P<0.001). CONCLUSIONS: With training, experience, and anatomic knowledge, both TAS and C2PS can be inserted accurately and safely. However, improper insertion and VAI can have catastrophic consequences. Our review identified a higher risk of VAI, neurological injury, and clinically significant malpositions with TAS compared with C2PS. These data provide preliminary support for the supposition that C2PS have a lower risk of morbidity.

Atlantoaxial fusion with transarticular screws: meta-analysis and review of the literature.

OBJECTIVE: To review published series describing C1-2 posterior instrumented fusions and summarize clinical and radiographic outcomes of patients treated with transarticular screw (TAS) fixation. METHODS: Online databases were searched for English-language articles published between 1986 and April 2011 describing posterior atlantoaxial instrumentation with C1-2 TAS fixation. There were 45 studies including 2073 patients treated with TAS that fulfilled inclusion criteria. Meta-analysis techniques were used to calculate outcomes. RESULTS: All studies provided class III evidence. The 30-day perioperative mortality rate was 0.8%, and the incidence of neurologic injury was 0.2%. The incidence of clinically significant malpositioned screws was 7.1% (confidence interval [CI], 5.7%-8.8%), the incidence of vertebral artery injury was 3.1% (CI, 2.3%-4.3%), and the rate of fusion with the TAS technique was 94.6% (CI, 92.6%-96.1%). CONCLUSIONS: TAS fixation is a safe and effective treatment option for C1-2 instability with high rates of fusion (approximately 95%). Screw malposition and vertebral artery injury occurred in approximately 5% of patients. The successful insertion of TAS requires a thorough knowledge of atlantoaxial anatomy.

Is external cervical orthotic bracing necessary after posterior atlantoaxial fusion with modern instrumentation: meta-analysis and review of literature.

BACKGROUND: No guidelines exist regarding external cervical orthoses (ECO) after atlantoaxial fusion. We reviewed published series describing C1-2 posterior instrumented fusions with screw-rod constructs (SRC) or transarticular screws (TAS) and compared rates of fusion with and without postoperative ECO. METHODS: Online databases were searched for English-language articles between 1986 and April 2011 describing ECO use after posterior atlantoaxial instrumentation with SRC or TAS. Eighteen studies describing 947 patients who had SRC (± ECO: 254 of 693 patients), and 33 studies describing 1424 patients with TAS (± ECO: 525 of 899 patients) met inclusion criteria. Meta-analysis techniques were applied to estimate rates of fusion with and without ECO use. RESULTS: All studies provided class III evidence, and no studies directly compared outcomes with or without ECO use. There was no significant difference in the proportion of patients who achieved successful fusion between patients treated with ECO and without ECO for SRC or TAS patients. Point estimates and 95% confidence intervals (CI) for rates of fusion ± ECO were 97.4% (CI: 95.2% to 98.6%) versus 97.9% (CI: 93.6% to 99.3%) for SRC and 93.6% (CI: 90.7% to 95.6%) versus 95.3% (CI: 90.8% to 97.7%) for TAS. There was no correlation between duration of ECO treatment and fusion (dose effect). CONCLUSIONS: After C1-2 fusion with modern instrumentation, ECO may be unnecessary (class III). Some centers recommend ECO use with patients with softer bone quality (class IV). Prospective, randomized studies with validated radiographic and clinical outcome metrics are necessary to determine the utility of ECO after C1-2 fusion and its impact on patient comfort and cost.

Is allograft sufficient for posterior atlantoaxial instrumented fusions with screw and rod constructs? A structured review of literature.

OBJECTIVE: Iliac crest autograft remains the gold standard for spinal fusion operations. Given risk of donor site morbidity, many centers utilize allograft. We reviewed published series of C1-2 posterolateral instrumented fusions with allograft and autograft. METHODS: Online databases were searched for English-language articles reporting quantifiable outcome data published between 1994 and 2011 of posterior atlantoaxial instrumented arthrodesis with C1 and C2 screws. Thirteen studies describing 652 patients having autograft and seven studies describing 60 patients having allograft serve as the basis of this report. RESULTS: All studies were retrospective case series (Class III evidence). There were no differences in complications or mortality between the groups. There were trends toward shorter operative times and less blood loss using allograft. A higher proportion of patients in the allograft group underwent sacrifice of the C2 nerve root and decortication and packing of the C1-2 joints (P<0.0001). There was no significant difference in the proportion of surviving patients who achieved solid fusion in the autograft (642 of 644 [99.7%]) and allograft patients (59 of 59 [100%]; P = 1.0). CONCLUSIONS: This review is limited by the retrospective data and inconsistent methodology of fusion determination used in most studies. Modern instrumentation and proper surgical techniques result in high rates of successful C1-2 arthrodesis. The use of allograft is a treatment option (Class III evidence) during posterior C1-2 instrumentation and fusion operations. Randomized, controlled trials using standardized radiographic assessments are needed across spinal arthrodesis studies to better determine the prevalence of radiographic fusion and establish technique superiority.

Vagus nerve stimulation for children with treatment-resistant epilepsy: a consecutive series of 141 cases.

OBJECT: The authors undertook this study to analyze the efficacy of vagus nerve stimulation (VNS) in a large consecutive series of children 18 years of age and younger with treatment-resistant epilepsy and compare the safety and efficacy in children under 12 years of age with the outcomes in older children. METHODS: The authors retrospectively reviewed 141 consecutive cases involving children (75 girls and 66 boys) with treatment-resistant epilepsy in whom primary VNS implantation was performed by the senior author between November 1997 and April 2008 and who had at least 1 year of follow-up since implantation. The patients' mean age at vagus nerve stimulator insertion was 11.1 years (range 1-18 years). Eighty-six children (61.0%) were younger than 12 years at time of VNS insertion (which constitutes off-label usage of this device). RESULTS: Follow-up was complete for 91.8% of patients and the mean duration of VNS therapy in these patients was 5.2 years (range 25 days-11.4 years). Seizure frequency significantly improved with VNS therapy (mean reduction 58.9%, p < 0.0001) without a significant reduction in antiepileptic medication burden (median number of antiepileptic drugs taken 3, unchanged). Reduction in seizure frequency of at least 50% occurred in 64.8% of patients and 41.4% of patients experienced at least a 75% reduction. Major (3) and minor (6) complications occurred in 9 patients (6.4%) and included 1 deep infection requiring device removal, 1 pneumothorax, 2 superficial infections treated with antibiotics, 1 seroma/hematoma treated with aspiration, persistent cough in 1 patient, severe but transient neck pain in 1 patient, and hoarseness in 2 patients. There was no difference in efficacy or complications between children 12 years of age and older (FDA-approved indication) and those younger than 12 years of age (off-label usage). Linear regression analyses did not identify any demographic and clinical variables that predicted response to VNS. CONCLUSIONS: Vagus nerve stimulation is a safe and effective treatment for treatment-resistant epilepsy in young adults and children. Over 50% of patients experienced at least 50% reduction in seizure burden. Children younger than 12 years had a response similar to that of older children with no increase in complications. Given the efficacy of this device and the devastating effects of persistent epilepsy during critical developmental epochs, randomized trials are needed to potentially expand the indications for VNS to include younger children.

Impact of failed intracranial epilepsy surgery on the effectiveness of subsequent vagus nerve stimulation.

BACKGROUND: Using the Cyberonics registry, Amar and colleagues reported poorer efficacy of vagus nerve stimulation (VNS) in patients who failed intracranial epilepsy surgery (IES). OBJECTIVE: To study the impact of failed IES and other surrogate marker of severe epilepsy on VNS effectiveness in a large cohort with treatment-resistant epilepsy (TRE). METHODS: We retrospectively reviewed 376 patients (188 female patients; 265 adults; mean age, 29.4 years at implantation) with TRE who underwent VNS implantation between 1997 and 2008 and had at least 1 year of follow-up. One hundred ten patients (29.3%) had failed ≥ 1 prior craniotomies for TRE, and 266 (70.7%) had no history of IES. RESULTS: The mean duration of VNS therapy was 5.1 years. Patients with prior IES were more commonly male and adult, had a greater number of seizure types, and more commonly had focal or multifocal vs generalized seizures (P < .05). There was no significant difference in the mean percentage seizure reduction between patients with and without a history of IES (59.1% vs 56.5%; P = .42). There was no correlation between type of failed IES (callosotomy vs resection) and seizure reduction with VNS therapy. CONCLUSION: Failed IES did not affect the response to VNS therapy. Unlike prior reports, patients with callosotomy did not respond better than those who had resective surgery. Nearly 50% of patients experienced at least 50% reduction in seizure frequency. For patients with TRE, including patients who failed cranial epilepsy surgeries, VNS should be considered a palliative treatment option.

Incidence, timing, and treatment of new brain metastases after Gamma Knife surgery for limited brain disease: the case for reducing the use of whole-brain radiation therapy.

OBJECT: In this paper, the authors' goal was to analyze the incidence, timing, and treatment of new metastases following initial treatment with 20-Gy Gamma Knife surgery (GKS) alone in patients with limited brain metastases without whole-brain radiation therapy (WBRT). METHODS: A retrospective analysis of 114 consecutive adults (75 women and 34 men; median age 61 years) with KPS scores of 60 or higher who received GKS for 1-3 brain metastases ≤ 2 cm was performed (median lesion volume 0.35 cm(3)). Five patients lacking follow-up data were excluded from analysis. After treatment, patients underwent MR imaging at 6 weeks and every 3 months thereafter. New metastases were preferentially treated with additional GKS. Indications for WBRT included development of numerous metastases, leptomeningeal disease, or diffuse surgical-site recurrence. RESULTS: The median overall survival from GKS was 13.8 months. Excluding the 3 patients who died before follow-up imaging, 12 patients (11.3%) experienced local failure at a median of 7.4 months. Fifty-three patients (50%) developed new metastases at a median of 5 months. Six (7%) of 86 instances of new lesions were symptomatic. Most patients (67%) with distant failures were successfully treated using salvage GKS alone. Whole-brain radiotherapy was indicated in 20 patients (18.3%). Thirteen patients (11.9%) died of neurological disease. CONCLUSIONS: For patients with limited brain metastases and functional independence, 20-Gy GKS provides excellent disease control and high-functioning survival with minimal morbidity. New metastases developed in almost 50% of patients, but additional GKS was extremely effective in controlling disease. Using our algorithm, fewer than 20% of patients required WBRT, and only 12% died of progressive intracranial disease.

Efficacy of vagus nerve stimulation over time: review of 65 consecutive patients with treatment-resistant epilepsy treated with VNS > 10 years.

OBJECTIVE: Studies have reported improved seizure control with increased duration of vagus nerve stimulation (VNS) but are prone to methodological biases. We analyzed the efficacy of VNS over time in patients with treatment-resistant epilepsy (TRE) who underwent VNS therapy 10 or more years. METHODS: We retrospectively reviewed 65 consecutive patients (29 females) who underwent VNS therapy ≥ 10 years. The mean age at VNS insertion was 30.0 years. Forty-four adults (≥ 18 years; 67.7%) and 21 children (32.3%) were included. Seizure frequency and antiepileptic drug (AED) regimens were recorded prior to VNS and, following VNS insertion, at 6 months, 1 year, 2 years, and every 2 years thereafter. RESULTS: The mean duration of VNS therapy for this group was 10.4 years, and the mean decrease in seizure frequency at last follow-up was 76.3%. The mean reduction in seizures at 6 months and years 1, 2, 4, 6, 8, and 10 years was 35.7, 52.1, 58.3, 60.4, 65.7, 75.5, and 75.5%, respectively. Seizure frequency was significantly reduced from baseline at each of the recorded intervals (P<0.001). There was a trend toward increased AED burden in the latter years of the follow-up period. CONCLUSION: Following a "ramp-up" and accommodation period throughout the initial 24 months after VNS implantation, seizure control improved slightly over the subsequent years of therapy and eventually stabilized. Variation in seizure frequency, however, was common, and frequent changes in AED regimens or stimulation parameters were likely an important and possibly synergistic component of seizure control.

Local control of newly diagnosed and distally recurrent, low-volume brain metastases with fixed-dose (20 gy) gamma knife radiosurgery.

BACKGROUND: Metastases to the brain occur in 20% to 30% of patients with cancer and have been identified on autopsy in as many as 50% of patients. OBJECTIVE: To analyze the efficacy of 20-Gy Gamma Knife radiosurgery (GKR) as initial treatment in patients with 1 to 3 brain metastases ≤ 2 cm in greatest diameter. METHODS: A retrospective analysis of 114 consecutive adults with Karnofsky performance status ≥ 60 who received GKR for 1 to 3 brain metastases ≤ 2 cm in size was performed. Five patients lacked detailed follow-up and were excluded, leaving 109 for outcome analysis (34 men and 75 women; median age, 61.2 years). All metastases received 20 Gy to the 50% isodose line. RESULTS: One hundred nine patients underwent treatment of 164 metastases at initial GKR. Twenty-six patients (23.9%) were alive at last follow-up (median time, 29.9 months; range, 6.6 months to 7.8 years). The median overall survival was 13.8 months (range, 1 day to 7.6 years). Among the 52 patients with distant failure, 33 patients received 20 Gy to 95 new lesions. A total of 259 metastases received 20 Gy, and 4 patients lacked imaging follow-up secondary to death before posttreatment imaging. Local failure occurred in 17 of 255 treated lesions (6.7%), yielding an overall local control rate of 93.3%. Actuarial local control at 6, 12, 24, and 36 months was 96%, 93%, 89%, and 88%, respectively. Permanent neurological complications occurred in 3 patients (2.8%). CONCLUSION: Among patients with 1 to 3 brain metastases ≤ 2 cm in size who have not received whole-brain radiation therapy, GKR with 20 Gy provides high rates of local control with low morbidity and excellent neurological symptom-free survival.

Vagus nerve stimulation in 436 consecutive patients with treatment-resistant epilepsy: long-term outcomes and predictors of response.

OBJECTIVE: The goal of this study was to assess the efficacy and safety of vagus nerve stimulation in a consecutive series of adults and children with treatment-resistant epilepsy (TRE). METHODS: In this retrospective review of a prospectively created database of 436 consecutive patients who underwent vagus nerve stimulator implantation for TRE between November 1997 and April 2008, there were 220 (50.5%) females and 216 (49.5%) males ranging in age from 1 to 76 years at the time of implantation (mean: 29.0 ± 16.5). Thirty-three patients (7.6%) in the primary implantation group had inadequate follow-up (<3 months from implantation) and three patients had early device removal because of infection and were excluded from seizure control outcome analyses. RESULTS: Duration of vagus nerve stimulation treatment varied from 10 days to 11 years (mean: 4.94 years). Mean seizure frequency significantly improved following implantation (mean reduction: 55.8%, P<0.0001). Seizure control ≥ 90% was achieved in 90 patients (22.5%), ≥ 75% seizure control in 162 patients (40.5%), ≥ 50% improvement in 255 patients (63.75%), and <50% improvement in 145 patients (36.25%). Permanent injury to the vagus nerve occurred in 2.8% of patients. CONCLUSION: Vagus nerve stimulation is a safe and effective palliative treatment option for focal and generalized TRE in adults and children. When used in conjunction with a multidisciplinary and multimodality treatment regimen including aggressive antiepileptic drug regimens and epilepsy surgery when appropriate, more than 60% of patients with TRE experienced at least a 50% reduction in seizure burden. Good results were seen in patients with non-U.S. Food and Drug Administration-approved indications. Prospective, randomized trials are needed for patients with generalized epilepsies and for younger children to potentially expand the number of patients who may benefit from this palliative treatment.

Neurological complications and symptom resolution following Gamma Knife surgery for brain metastases 2 cm or smaller in relation to eloquent cortices.

OBJECT: Reports on resection of tumors in or near eloquent cortices have noted neurological complications in up to 30% of patients. This paper contains an analysis of symptom resolution and neurological morbidity following 20-Gy Gamma Knife surgery (GKS) for supratentorial brain metastases < or = 2 cm in greatest diameter. METHODS: The authors performed a retrospective analysis of 98 consecutively treated adults (33 men and 65 women with a median age of 61.4 years at the time of GKS) with Karnofsky Performance Scale score > or = 60, who underwent GKS for supratentorial brain metastases < or = 2 cm in diameter. Lesion location was classified as noneloquent (Grade I), near eloquent (Grade II), or eloquent (Grade III), in accordance with the grading system developed by the group at M. D. Anderson Cancer Center. Following treatment, the patients underwent MR imaging and clinical examinations at 6 weeks and every 3 months thereafter. RESULTS: Ninety-eight patients underwent 20-Gy GKS for 131 metastases at initial presentation and 31 patients underwent salvage 20-Gy GKS for 76 new lesions, for a total of 207 lesions (mean lesion volume 0.44 cm3). Lesions were classified as follows: Grade I, 96 (46.4%); Grade II, 51 (24.6%); and Grade III, 60 (29%). Fifteen patients (2 with Grade II and 13 with Grade III lesions) presented with deficits referable to their lesions, yielding pre-GKS deficit rates of 7.2% per lesion and 15.3% per patient. The pre-GKS deficits improved or resolved in 10 patients (66.7%) at a median time of 2.8 months and remained stable in 3 patients (20%). Two patients (13.3%) experienced worsened neurological deficits. One patient who was neurologically intact prior to treatment developed a new hemiparesis (1 of 83 patients [1.2%]). The rates of permanent neurological deterioration following GKS for Grades I, II, and III lesions were 0% (0 of 96 tumors), 2% (1 of 51), and 3.3% (2 of 60), respectively. The pre-GKS neurological deficits and larger lesions were the most significant risk factors for post-GKS neurological deterioration. CONCLUSIONS: Gamma Knife surgery performed using a 20-Gy dose provides amelioration of neurological deficits from brain metastases that are < or = 2 cm in diameter and located in or near eloquent cortices in nearly two-thirds of patients with a low incidence of morbidity. Consistent with the surgical literature, higher rates of neurological complications were observed as proximity to eloquent regions and lesion size increased. There was no neurological deterioration in patients harboring metastases in noneloquent areas.