Amr Morsi

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.

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.

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.

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.

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.

Development and characterization of a clinically relevant mouse model of melanoma brain metastasis

Melanoma has a high predilection for neuronal dissemination, with 44% to 64% of patients developing brain metastases (B-Mets) during the course of metastatic progression which represents the leading cause of death in most of these cases (Davies et al., 2011; Johnson et al., 1996; Sampson et al., 1998). Current treatments for melanoma B-Mets aim to slow disease progression and are determined by their number and location (Eichler et al., 2007; Elliott et al., 2011; Rush et al., 2011). Preclinical models of melanoma B-Mets are fundamental for studying the biology behind the dissemination of melanoma cells to the brain and evaluating new therapeutic regimens’ efficacy. Over the years, several groups have reported the development of either experimental or spontaneous models of melanoma B-Mets with the majority using the highly invasive intra-carotid (IC) surgery as a standard technique for tumor induction (Fujimaki et al., 1996; Huang et al., 2008; Xie et al., 2006; Yano et al., 2000; Zhang et al., 2009, Cruz-Munoz et al., 2008). The scarcity of clinically relevant, well characterized models has hindered our understanding of the mechanism of melanoma brain tropism and response to therapies. The need to effectively examine different aspects of metastatic dissemination in vivo has motivated investigators to develop imaging strategies in which MRI is best positioned for intracranial imaging. MRI was used recently in B-Mets murine studies for monitoring the temporal and spatial development of breast lesions (Perera, Ribot et al. 2012). In melanoma preclinical studies, the use of in vivo MRI was limited to the detection of B-Mets (Izraely et al., 2012). Hence, there is still a need to establish the tumor growth profile and pattern of melanoma B-Mets using a 3D quantitative imaging analysis. Here, we aimed to establish an experimental melanoma B-Mets mouse model using the B16F10 murine and the 5B1 human cell lines by means of minimally invasive ultrasound-guided intra-cardiac injection (UGICI). Our goals were to characterize and compare the growth pattern of the developing B-Mets in both models using MRI with micrometric resolution termed micro-MRI (μ-MRI). By utilizing large cohorts of mice (n=80), we intended to overcome the following limitations imposed by in vivo MRI: the slow throughput, the prohibitive cost per scan, as well as limited access to scan time. We opted to use an ex vivo setup devised in our laboratory which enabled simultaneous imaging of multiple whole mouse heads placed in a larger MRI probe. Four heads could be scanned simultaneously during one unattended overnight session (Data S1). Our approach capitalized on the paramagnetic nature of melanin present in both tumor cell lines; the B16F10 murine and to a lesser extent the 5B1 human cell line. The signal brightening endogenous effect of melanoma in tracer-free T1-weighted MRI datasets correlates with the percentage of melanin-containing cells. This feature combined with the signal darkening effect of a T2*-weighted sequence used in our protocol is specific for melanotic tumors but not in amelanotic tumors. Conversely, the latter exhibit T1-weighted hypointense or isointense signal and T2-weighted hyperintense or isointense contrast (Isiklar et al.1995) (Data S2). Our first goal was to establish a safer and physiologically relevant tumor induction route. For that, we used (1×105cells/100μl/mouse) B16F10 cells and C57Bl6 mouse strain (n=18) in each group to compare the safety and efficacy of our proposed UGICI route to the standard IC injection. The UGICI closely simulate the spread of melanoma cells from the blood stream to the brain tissue. Melanoma cells are introduced through the left ventricle allowing them to circulate freely throughout the entire intact vascular system. This provides the cells with an equal opportunity to colonize different organs and thereby objectively reflects inherent tissue tropism. The use of ultrasound to visualize the advancing needle into the left ventricle of the heart in real time reduced the number of puncture attempts and allowed us to monitor and confirm the proper and uniform transmission of cells into each mouse (Data S3). Comparing this novel minimally invasive technique of tumor induction to the traditional IC injection, we noticed a distinct difference in mortality rate ranging from 20% to 25% for the IC to ~1% with the UGICI. Moreover, we recorded a marked decrease in surgery-related morbidity, evident by stable mouse weight reflecting a better ability of mice to mobilize and feed following UGICI (Data S4). Additionally, the time required to induce the animals was significantly shorter using the UGICI (10–12 minutes) compared to the IC (35–60 minutes) allowing for large scale experiments to be conducted, which is essential for achieving meaningful, statistically-sound data. Taking advantage of the safer and more efficient UGICI route for tumor induction, we compared the growth pattern and distribution of two experimental melanoma models based on the B16F10 murine and the 5B1 human cell lines. While the B16F10 has no reported predilection for a particular site of metastasis, the 5B1, an in vivo selected subpopulation of the WM239A cell line, was previously reported to show enhanced brain tropism (Cruz-Munoz et al., 2008). In this system, B16F10 cells showed relatively low brain tropism with 27.5% brain penetrance and high affinity to extra-cranial sites while the 5B1 cells had a high predilection for brain tissue with a penetrance rate of 70% and less extra-cranial organ involvement (Data S5). In addition, the extra-cranial metastatic lesions in the 5B1 model were less aggressive and often unilateral (Data S6). The ex vivo MRI protocol implemented was able to recapitulate the characteristic in vivo clinical radiological findings of melanoma B-Mets in both models: bright enhancing areas on a T1-weighted sequence and susceptibility-induced signal darkening on T2*-weighted imaging (Data S7). These findings are used radiologically to distinguish melanoma B-Mets from other types of B-Mets for which the systemic injection of a contrast agent is usually required in the clinical setting (Gaviani et al., 2006). Although T2*-based imaging did not demonstrate systematic tumor detection via signal darkening, the blooming effect associated with this sequence proved useful in combination with T1-hyperintensity in presence of poor contrast and for identifying small lesions. Hence, the evaluation of the tumor volumes in this study relied principally on T1-weighted imaging in which T2*-darkening was complementary when needed. Ex vivo data acquired from the B16F10 model (n=40) revealed exclusive ventricular and leptomeningeal spread (Data S8a-c), while 5B1 injected mice (n=40) showed generally parenchymal lesions, reflecting the phenotype mostly seen in the clinic (Chen et al., 2012) (Data S8d-f). In addition, MRI allowed for the exploration of the multicentric nature of the two melanoma cell lines used, where 67.9% of the 5B1 injected mice with brain tumors (n=28) showed multiple lesions (range 1 - 16, median: 3) compared to 18% in the B16 mouse model (n=11) (range 1 - 3, median: 1) (Data S9b, c). The 5B1 cells were injected in immune deficient athymic/nude (nu/nu) mice which may account for the higher number of B-Mets developing in the 5B1 model. However, the relatively lower number of extra-cranial metastasis compared to the B16F10 immune competent model suggests that an intrinsically higher brain tropism of the 5B1 cell line, rather than a more permissive host immune system, allows more cells to actively seed and adapt to brain tissue microenvironment. Tumor segmentation, 3D reconstruction and quantitative volumetric analysis at different time points, post-tumor induction (Data S10a for 5B1 model and S10b for B16F10 model) revealed differences in growth pattern of tumors in both models; B16F10 B-Mets were detected on day 15 post-tumor induction at a volume of 0.65 mm3 and exhibited a rapid pattern of growth over a short time frame of 8 days with some lesions detected at a volume of 44.7mm3 on day 23 post-tumor induction (range: 0.14 mm3 - 44.7 mm3, median: 2.01 mm3). The 5B1 metastatic lesions had a delayed onset of tumor detection on day 27 post-injection at a starting volume of 0.03mm3. In addition, the 5B1 lesions were less aggressive and showed a slower growth rate, acquiring a maximum detected volume of 34.01mm3 (range 0.02 mm3 - 34.01 mm3, median: 0.37 mm3) on day 56 post-tumor induction (Data S9a). Using 5B1 melanoma human cell line and UGICI for tumor induction together with our novel ex vivo MRI technique we provide the field with a clinically relevant B-Mets experimental model and a faithful tool to assess changes in tumor behavior in preclinical therapeutic studies.

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.

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

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.

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.