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Marie Roguski, Kyle Wu, Ron I. Riesenburger and Julian K. Wu

Object

A primary goal in the treatment of patients with warfarin-associated subdural hematoma (SDH) is reversal of coagulopathy with fresh-frozen plasma. Achieving the traditional target international normalized ratio (INR) of 1.3 is often difficult and may expose patients to risks of volume overload and of thromboembolic complications. This retrospective study evaluates the risk of mild elevations of INR from 1.31 to 1.69 at 24 hours after admission in patients presenting with warfarin-associated SDH.

Methods

Sixty-nine patients with warfarin-associated SDH and 197 patients with non–warfarin-associated SDH treated at a single institution between January 2005 and January 2012 were retrospectively identified. Charts were reviewed for patient age, history of trauma, associated injuries, neurological status at presentation, size and chronicity of SDH, associated midline shift, INR at admission and at hospital Day 1 (HD1), concomitant aspirin or Plavix use, platelet count, and medical comorbidities. Patients were stratified according to use of warfarin and by INR at HD1 (INR 0.8–1.3, 1.31–1.69, 1.7–1.99, and ≥ 2). The groups were evaluated for differences the in rate of radiographic expansion of SDH and in the rate of clinically significant SDH expansion resulting in death, unplanned procedure, and/or readmission.

Results

There was no difference in the rate of radiographic versus clinically significant expansion of SDH between patients not on warfarin and those on warfarin (no warfarin: 22.3% vs 20.3%, p = 0.866; warfarin: 10.7% vs 11.6%, p = 0.825), but the rate of medical complications was significantly higher in the warfarin subgroup (13.3% for patients who did not receive warfarin vs 26.1% for those who did; p = 0.023). For warfarin-associated SDH, there was no difference in the rate of radiographic versus clinically significant expansion between patients reversed to HD1 INRs of 0.8–1.3 and 1.31–1.69 (HD1 INR 0.8–1.3: 22.5% vs 20%, p = 1; HD1 INR 1.31–1.69: 15% vs 10%, p = 0.71).

Conclusions

Mild INR elevations of 1.31–1.69 in warfarin-associated SDH are not associated with a markedly increased risk of radiographic or clinically significant expansion of SDH. Larger prospective studies are needed to determine if subtherapeutic INR elevations at HD1 are associated with smaller increases in risk of SDH expansion.

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Carl B. Heilman, Eddie S. K. Kwan and Julian K. Wu

✓ Endovascular balloon occlusion is an alternative treatment for surgically unclippable cerebral aneurysms. The results of aneurysm occlusion with either a silicone or a latex balloon in a common carotid artery bifurcation aneurysm model are compared to determine which type of balloon was least likely to result in aneurysm recurrence. Five rabbits each underwent endovascular balloon occlusion with either a silicone or a latex balloon, with seven rabbits serving as controls. At 3 months postocclusion, nine of the 10 balloon-treated aneurysms had recurred. The recurrent aneurysm tended to be larger in animals treated with silicone than with latex balloons. A dense fibrotic response was present around the collar of the latex balloons, but no significant fibrotic response was found in the silicone balloon group. This study suggests that with currently available balloons, the initial complete angiographic obliteration of an aneurysm following balloon occlusion should not be interpreted as a cure and that periodic follow-up angiography should be performed.

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Jonathan A. Borden, Julian K. Wu and William A. Shucart

✓ A classification is proposed that unifies and organizes spinal and cranial dural arteriovenous fistulous malformations (AVFMs) into three types based upon their anatomical similarities. Type I dural AVFMs drain directly into dural venous sinuses or meningeal veins. Type II malformations drain into dural sinuses or meningeal veins but also have retrograde drainage into subarachnoid veins. Type III malformations drain into subarachnoid veins and do not have dural sinus or meningeal venous drainage. The arterial supply in each of these three types is derived from meningeal arteries.

The anatomical basis of the proposed classification is presented with several cases that illustrate the three types of dural AVFMs. A rationale for the treatment of spinal and cranial dural AVFMs according to their anatomical characteristics is discussed.

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Fotios D. Vrionis, Julian K. Wu, Peimin Qi, William G. Cano and Van Cherington

✓ A promising strategy in the treatment of neoplastic meningitis involves the use of herpes simplex virus—thymidine kinase (HSV-tk)—modified cells. In these experiments the authors used cells expressing HSV-tk to treat meningeal carcinomatosis in the rat Walker 256 model. Intrathecal injection of 2 × 105 Walker cells resulted in a median survival time of 15 days. Up to 80% of animals implanted with HSV-tk—modified Walker cells (Walker-tk+) and treated with ganciclovir showed long-term survival (120 days or more), whereas the remaining animals died from tumor growth between 37 and 44 days after implantation. Tumor cells from an animal in which the treatment failed were culturedin vitro and were shown to be still sensitive to ganciclovir. However, continuous ganciclovir administration for 6 weeks rather than 2 weeks did not improve survival. Histopathological studies confirmed leptomeningeal infiltration in the untreated Walker or Walker-tk+ animals. Walker-tk+ cells were mixed with Walker cells in 1:1, 10:1, or 50:1 ratios, respectively, and implanted intrathecally; the animals were treated with ganciclovir. All groups of treated animals had long-term survivors, with 40% of the rats in the 10:1 and 50:1 groups demonstrating long-term survival and absence of microscopic tumors in the brain or spinal cord. Similarly, murine fibroblast HSV-tk virus—producer cells improved survival. Walker-tk+ cells were better than fibroblast-producer cells in improving the survival of animals with Walker tumors at low (1:1) but not at high (10:1) effector-to-target cell ratios. Repeated intrathecal administration of Walker-tk+ cells resulted in inhibition of established Walker tumors. The authors conclude that Walker-tk+ cells are at least as effective as murine virus—producer cells and could be used in the treatment of meningeal neoplasia.

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Fotios D. Vrionis, Julian K. Wu, Peimin Qi, William Cano and Van Cherington

✓ Retrovirus-mediated herpes simplex virus—thymidine kinase (HSV-tk) gene therapy is a promising approach in the treatment of brain tumors. Previous in vitro and in vivo studies have demonstrated a bystander effect in which nonmodified tumor cells in proximity to HSV-tk—modified tumor cells are killed with the modified cells in the presence of ganciclovir. In the present study the authors assessed the contribution of infectious HSV-tk retrovirus made by producer cells to the bystander cytocidal effect in tissue culture using Walker 256 rat breast carcinosarcoma cells, which represent an established model for carcinomatous meningitis. The authors observed ganciclovir-dependent growth inhibition even when only one HSV-tk—positive Walker cell was mixed with 1000 HSV-tk—negative Walker cells and showed that the bystander cytocidal effect is not mediated by toxic cell lysis products. Walker cells engineered to produce HSV-tk retrovirus with titers ranging from 103 to 105 colony-forming units/ml exert no greater cytocidal effect than nonviral producer HSV-tk—positive Walker cells in vitro. Murine fibroblast—producer cells with viral titers ranging from 106 to 107 colony-forming units/ml exerted a stronger cytocidal effect than nonviral producer HSV-tk—positive murine fibroblasts. Despite the high viral titers of fibroblast producer cells, HSV-tk—modified Walker cells performed better than fibroblast producer cells in their cytotoxic effect on wild—type Walker tumor cells. Given that HSV-tk—modified tumor cells can become ganciclovir resistant, we tested γ-irradiation as a means to overcome resistance. Lethal γ-irradiation of the HSV-tk—positive Walker cells did not abolish their bystander effect on Walker HSV-tk—negative cells. One can infer from these results that HSV-tk—modified tumor cells, irradiated or not, may be a better alternative to murine fibroblast producer cells in the treatment of central nervous system neoplasia.

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Tomas Dvorak, Arkadiy Finn, Lori Lyn Price, John E. Mignano, Markus M. Fitzek, Julian K. Wu and Kevin C. Yao

Object

Trigeminal neuralgia (TN) is a disorder of the trigeminal nerve that results in intense episodic pain. Primary treatment with Gamma Knife surgery (GKS) is well established; however, a significant number of patients experience recurrence of TN over time. Repeat GKS can be performed, but the retreatment dose has not been well established. In this study, the authors present their institutional retreatment results and compare them with other series.

Methods

Between December 2003 and January 2006, 28 patients were treated at Tufts Medical Center with repeat GKS for recurrence of TN. All patients had been initially treated with GKS at this institution, and only those with significant pain improvement were offered retreatment. The maximum dose was prescribed using a single isocenter; the 4-mm collimator was used. The initial median GKS dose was 80 Gy, the median retreatment dose was 45 Gy, and the median cumulative dose was 125 Gy. The median time between GKS procedures was 18.1 months. Facial pain outcomes were defined using the Marseille scale. Excellent outcome was defined as no pain (with or without medications), and good outcome was defined as > 50% pain relief. Toxicity was categorized as none, mild, or bothersome. The median clinical follow-up after the second GKS was 19.7 months. Our clinical outcomes were compared with 8 previously reported retreatment series (including 1 abstract), both for rate of pain control and for rate of complications.

Results

Outcomes after the second GKS were excellent in 29% (8 patients), good in 32% (9), and poor in 39% (11). Four patients (14%) experienced no improvement after repeat GKS. Eight patients (29%) experienced new trigeminal nerve dysfunction, including numbness (11%), paresthesia (14%), dysesthesia (4%), taste alteration (11%), and bite weakness (4%). None of these were bothersome. No patient developed corneal numbness. Univariate analysis failed to reveal any significant predictors of pain control or complications.

Seven published peer-reviewed retreatment series and the authors' data (total 215 patients) were analyzed. There was a cumulative dose-response relationship for both pain control (p = 0.04) and new trigeminal dysfunction (p = 0.08). Successful pain control was strongly correlated with development of new dysfunction (p = 0.02). A cumulative dose > 130 Gy was more likely to result in successful (> 50%) pain control, but was also more likely (> 20%) to result in development of new dysfunction.

Conclusions

Successful retreatment of patients in whom the initial GKS treatment fails is feasible. Patients who respond initially may be at a higher risk of retreatment-related complications. There appears to be a dose-response relationship for both pain control and development of new side effects. It is important to counsel and treat patients individually based on this dose-response relationship.

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Pamela R. Sherwood, Thomas R. Hedges III, Carlos E. Mendoza-Santiesteban, Carl B. Heilman and Julian K. Wu

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Ron I. Riesenburger, Steven W. Hwang, Clemens M. Schirmer, Vasilios Zerris, Julian K. Wu, Kerry Mahn, Paul Klimo Jr., John Mignano, Clinton J. Thompson and Kevin C. Yao

Object

Gamma Knife surgery (GKS) has been shown to be effective in treating trigeminal neuralgia (TN). Existing studies have demonstrated success rates of 69.1–85% with median follow-up intervals of 19–60 months. However, series with uniform long-term follow-up data for all patients have been lacking. In the present study the authors examined outcomes in a series of patients with TN who underwent a single GKS treatment followed by a minimum follow-up of 36 months. They used a clinical scale that simplifies the reporting of outcome data for patients with TN.

Methods

Fifty-three consecutive patients with typical, intractable TN received a median maximum radiation dose of 80 Gy applied with a single 4-mm isocenter to the affected trigeminal nerve. Follow-up data were obtained by clinical examination and questionnaire. Outcome results were categorized into the following classes (in order of decreasing success): Class 1A, complete pain relief without medications; 1B, complete pain relief with either a decrease or no change in medications; 1C, ≥ 50% pain relief without medications; 1D, ≥ 50% pain relief with either a decrease or no change in medications; and Class 2, < 50% pain relief and/or increase in medications. Patients with Class 1A–1D outcome (equivalent to Barrow Neurological Institute Grades I–IIIb) were considered to have a good treatment outcome, whereas in patients with Class 2 outcome (equivalent to Barrow Neurological Institute Grades IV and V) treatment was considered to have failed.

Results

A good treatment outcome from initial GKS was achieved in 31 (58.5%) patients for whom the mean follow-up period was 48 months (range 36–66 months). Outcomes at last follow-up were reflected by class status: Class 1A, 32.1% of patients; 1B, 1.9%; 1C, 3.8%; 1D, 20.8%; and Class 2, 41.5%. Statistical analysis showed no difference in outcomes between patients previously treated with microvascular decompression or rhizotomy compared with patients with no previous surgical treatments. Thirty-six percent of patients reported some degree of posttreatment facial numbness. Anesthesia dolorosa did not develop in any patient.

Conclusions

Despite a time-dependent deterioration in the success rate of GKS for medically intractable TN, the authors' study showed that > 50% of patients can be expected to have a good outcome based on their scoring system, with ~ 33% having an ideal outcome (pain free with no need for medications). Long-term data, as those presented here, are important when counseling patients on their treatment options.