✓ Osteopetrosis is an inherited skeletal condition of defective osteoclastic resorption of bone resulting in increased bone density. Osseous changes occur most severely at the base of the skull. Important clinical symptoms include cranial nerve palsies due to uni- or bilateral obliteration of cranial nerve foramina including deafness, facial paralysis, and optic nerve compression. Thickening of the skull and progressive diminution of the cranial capacity may lead to elevation of intracranial pressure, papilledema, and hydrocephalus. The authors present an unusual case of a patient with osteopetrosis in whom a ventriculoperitoneal shunt became obstructed at its exit from the skull by the developing bone mass. To the best of their knowledge, this has not been described.
Rachel Grossman and Zeev Feldman
Rachel Grossman, Erez Nossek, Nir Shimony, Michal Raz, and Zvi Ram
The authors report a case of primary CNS lymphoma located in the floor of the fourth ventricle that showed intense fluorescence after preoperative administration of 5-aminolevulinic acid. The authors believe that this is the first demonstration of a 5-aminolevulinic acid–induced fluorescence pattern in primary CNS lymphoma.
Rachel Grossman, Betty Tyler, Lee Hwang, Patti Zadnik, Bachchu Lal, Kashi Javaherian, and Henry Brem
Brain tumors pose many unique challenges to treatment. The authors hypothesized that Fc-endostatin may be beneficial. It is a newly synthesized recombinant human endostatin conjugated to the Fc domain of IgG with a long half-life (weeks) and unknown toxicity. The authors examined the efficacy of Fc-endostatin using various delivery methods.
Efficacy was assessed using the intracranial 9L gliosarcoma rat model treated with Fc-endostatin for use in rodents (mFc-endostatin), which was administered either systemically or locally via different delivery methods. Oral temozolomide (TMZ) was administered in combination with mFc-endostatin to determine if there was a beneficial synergistic effect.
Intracranial delivery of mFc-endostatin via a polymer or convection-enhanced delivery 5 days after tumor implantation increased median survival, compared with the control group (p = 0.0048 and 0.003, respectively). Animals treated weekly with subcutaneous mFc-endostatin (started 5 days post–tumor implantation) also had statistically improved survival as compared with controls (p = 0.0008). However, there was no statistical difference in survival between the local and systemic delivery groups. Control animals had a median survival of 13 days. Animals treated either with subcutaneous mFc-endostatin weekly or with polymer had a median survival of 18 and 15 days, respectively, and those treated with oral TMZ for 5 days (Days 5–9) had a median survival of 21 days. Survival was further increased with a combination of oral TMZ and mFc-endostatin polymer, with a median survival of 28 days (p = 0.029, compared with TMZ alone). Subcutaneous mFc-endostatin administered every week starting 18 days before tumor implantation significantly increased median survival when compared with controls (p = 0.0007), with 12.5% of the animals ultimately becoming long-term survivors (that is, survival longer than 120 days). The addition of TMZ to either weekly or daily subcutaneous mFc-endostatin and its administration 18 days before tumor implantation significantly increased survival (p = 0.017 and 0.0001, respectively, compared with TMZ alone). Note that 12.5% of the animals treated with weekly subcutaneous mFc-endostatin and TMZ were long-term survivors.
Systemically or directly (local) delivered mFc-endostatin prolonged the survival of rats implanted with intracranial 9L gliosarcoma. This benefit was further enhanced when mFc-endostatin was combined with the oral chemotherapeutic agent TMZ.
Nir Shimony, Uri Amit, Bella Minz, Rachel Grossman, Marc A. Dany, Lior Gonen, Karina Kandov, Zvi Ram, and Avi A. Weinbroum
The aim of this study was to assess in-hospital (immediate) postoperative pain scores and analgesic consumption (primary goals) and preoperative anxiety and sleep quality (secondary goals) in patients who underwent craniotomy and were treated with pregabalin (PGL). Whenever possible, out-of-hospital pain scores and analgesics usage data were obtained as well.
This prospective, randomized, double-blind and controlled study was conducted in consenting patients who underwent elective craniotomy for brain tumor resection at Tel Aviv Medical Center between 2012 and 2014. Patients received either 150 mg PGL (n = 50) or 500 mg starch (placebo; n = 50) on the evening before surgery, 1.5 hours before surgery, and twice daily for 72 hours following surgery. All patients spent the night before surgery in the hospital, and no other premedication was administered. Opioids and nonsteroidal antiinflammatory drugs were used for pain, which was self-rated by means of a numerical rating scale (score range 0–10).
Eighty-eight patients completed the study. Data on the American Society of Anesthesiologists class, age, body weight, duration of surgery, and intraoperative drugs were similar for both groups. The pain scores during postoperative Days 0 to 2 were significantly lower in the PGL group than in the placebo group (p < 0.01). Analgesic consumption was also lower in the PGL group, both immediately and 1 month after surgery. There were fewer requests for antiemetics in the PGL group, and the rate of postoperative nausea and vomiting was lower. The preoperative anxiety level and the quality of sleep were significantly better in the PGL group (p < 0.01). There were no PGL-associated major adverse events.
Perioperative use of twice-daily 150 mg pregabalin attenuates preoperative anxiety, improves sleep quality, and reduces postoperative pain scores and analgesic usage without increasing the rate of adverse effects.
Clinical trial registration no.: NCT01612832 (clinicaltrials.gov)
Assaf Berger, Gali Tzarfati, Matias Costa, Marga Serafimova, Akiva Korn, Irina Vendrov, Tali Alfasi, Dana Krill, Daniel Aviram, Shlomit Ben Moshe, Alon Kashanian, Zvi Ram, and Rachel Grossman
Ischemic complications are a common cause of neurological deficits following low-grade glioma (LGG) surgeries. In this study, the authors evaluated the incidence, risk factors, and long-term implications of intraoperative ischemic events.
The authors retrospectively evaluated patients who had undergone resection of an LGG between 2013 and 2017. Analysis included pre- and postoperative demographic, clinical, radiological, and anesthetic data, as well as intraoperative neurophysiology data, overall survival, and functional and neurocognitive outcomes.
Among the 82 patients included in the study, postoperative diffusion-weighted imaging showed evidence of acute ischemic strokes in 19 patients (23%), 13 of whom (68%) developed new neurological deficits. Infarcts were more common in recurrent and insular surgeries (p < 0.05). Survival was similar between the patients with and without infarcts. Immediately after surgery, 27% of the patients without infarcts and 58% of those with infarcts experienced motor deficits (p = 0.024), decreasing to 16% (p = 0.082) and 37% (p = 0.024), respectively, at 1 year. Neurocognitive functions before and 3 months after surgery were generally stable for the two groups, with the exception of a decline in verbal rhyming ability among patients with infarcts. Confusion during awake craniotomy was a strong predictor of the occurrence of an ischemic stroke. Mean arterial pressure at the beginning of surgery was significantly lower in the infarct group.
Recurrent surgeries and insular tumor locations are risk factors for intraoperative strokes. Although they do not affect survival, these strokes negatively affect patient activity and performance status, mainly during the first 3 postoperative months, with gradual functional improvement over 1 year. Several intraoperative parameters may suggest the impending development of an infarct.
Nadav Schellekes, Arianna Barbotti, Yael Abramov, Razi Sitt, Francesco Di Meco, Zvi Ram, and Rachel Grossman
Primary central nervous system lymphoma (PCNSL) is a rare CNS tumor with a poor prognosis. It is usually diagnosed by needle biopsy and treated mainly with high-dose chemotherapy. Resection is currently not considered a standard treatment option. A possible prolonged survival after resection of PCNSL lesions in selected patients has been suggested, but selection criteria for surgery, especially for solitary lesions, have never been established.
The authors retrospectively searched their patient database for records of adult patients (≥ 18 years) who were diagnosed and treated for a solitary PCNSL between 2005 and 2019. Patients were divided into groups according to whether they underwent resection or needle biopsy. Statistical analyses were performed in an attempt to identify variables affecting outcome and possible survival advantage and to characterize subgroups of patients who would benefit from resection of their tumor compared with undergoing biopsy only.
A total of 113 patients with a solitary lesion of PCNSL were identified; 36 patients underwent resection, and 77 had a diagnostic stereotactic biopsy only. The statically significant preoperative risk factors included age ≥ 70 years (adjusted HR 9.61, 95% CI 2.42–38.11; p = 0.001), deep-seated lesions (adjusted HR 3.33, 95% CI 1.13–9.84; p = 0.030), and occipital location (adjusted HR 4.26, 95% CI 1.08–16.78; p = 0.039). Having a postoperative Karnofsky Performance Scale (KPS) score < 80 (adjusted HR 3.21, 95% CI 1.05–9.77; p = 0.040) and surgical site infection (adjusted HR 4.27, 95% CI 1.18–15.47; p = 0.027) were significant postoperative risk factors after the adjustment and selection by means of other possible risk factors. In a subgroup analysis, patients younger than 70 years who underwent resection had a nonsignificant trend toward longer survival than those who underwent needle biopsy (median survival 35.0 months vs 15.2 months, p = 0.149). However, patients with a superficial tumor who underwent resection had significantly longer survival times than those who underwent needle biopsy (median survival 34.3 months vs 8.9 months, p = 0.014). Patients younger than 70 years who had a superficial tumor and underwent resection had significantly prolonged survival, with a median survival of 35.0 months compared with 8.9 months in patients from the same group who underwent needle biopsy (p = 0.007).
Specific subgroups of patients with a solitary PCNSL lesion might gain a survival benefit from resection compared with undergoing only a diagnostic biopsy.
Tal Gonen, Rachel Grossman, Razi Sitt, Erez Nossek, Raneen Yanaki, Emanuela Cagnano, Akiva Korn, Daniel Hayat, and Zvi Ram
Intraoperative seizures during awake craniotomy may interfere with patients' ability to cooperate throughout the procedure, and it may affect their outcome. The authors have assessed the occurrence of intraoperative seizures during awake craniotomy in regard to tumor location and the isocitrate dehydrogenase 1 (IDH1) status of the tumor.
Data were collected in 137 consecutive patients who underwent awake craniotomy for removal of a brain tumor. The authors performed a retrospective analysis of the incidence of seizures based on the tumor location and its IDH1 mutation status, and then compared the groups for clinical variables and surgical outcome parameters.
Tumor location was strongly associated with the occurrence of intraoperative seizures. Eleven patients (73%) with tumor located in the supplementary motor area (SMA) experienced intraoperative seizures, compared with 17 (13.9%) with tumors in the other three non-SMA brain regions (p < 0.0001). Interestingly, there was no significant association between history of seizures and tumor location (p = 0.44). Most of the patients (63.6%) with tumor in the SMA region harbored an IDH1 mutation compared with those who had tumors in non-SMA regions. Thirty-one of 52 patients (60%) with a preoperative history of seizures had an IDH1 mutation (p = 0.02), and 15 of 22 patients (68.2%) who experienced intraoperative seizures had an IDH1 mutation (p = 0.03). In a multivariate analysis, tumor location was found as a significant predictor of intraoperative seizures (p = 0.002), and a trend toward IDH1 mutation as such a predictor was found as well (p = 0.06). Intraoperative seizures were not associated with worse outcome.
Patients with tumors located in the SMA are more prone to develop intraoperative seizures during awake craniotomy compared with patients who have a tumor in non-SMA frontal areas and other brain regions. The IDH1 mutation was more common in SMA region tumors compared with other brain regions, and may be an additional risk factor for the occurrence of intraoperative seizures.
Betty Tyler, Kirk D. Fowers, Khan W. Li, Violette Renard Recinos, Justin M. Caplan, Alia Hdeib, Rachel Grossman, Luca Basaldella, Kimon Bekelis, Gustavo Pradilla, Federico Legnani, and Henry Brem
Paclitaxel, a cellular proliferation inhibitor/radiation sensitizer, while effective against gliomas in vitro, has poor CNS penetration and dose-limiting toxicities when administered systemically. OncoGel (paclitaxel in Re-Gel) provides controlled local paclitaxel release when placed into the CNS. The authors evaluated the safety and efficacy of OncoGel in rats with intracranial 9L gliosarcoma.
Safety studies included intracranial delivery of increasing volumes of ReGel and OncoGel containing 1.5 (OncoGel 1.5) or 6.3 (OncoGel 6.3) mg/ml paclitaxel. An in vivo radiolabeled biodistribution study was performed in 18 Fischer-344 rats to determine intracerebral distribution. Efficacy studies compared overall survival for controls, ReGel only, radiation therapy only, OncoGel 6.3, or OncoGel 6.3 in combination with radiation therapy. ReGel and OncoGel 6.3 were delivered either simultaneously with tumor implantation (Day 0) or 5 days later (Day 5). Radiation therapy was given on Day 5.
Control and ReGel animals died of tumor within 17 days. Survival significantly increased in the Onco-Gel 6.3 group on Day 0 (median 31 days; p = 0.0001), in the OncoGel 6.3 group on Day 5 (median 17 days; p = 0.02), and in the radiation therapy–only group (median 26 days; p = 0.0001) compared with controls. Animals receiving both OncoGel and radiation therapy had the longest median survival: 83 days in the group with radiation therapy combined with OncoGel 6.3 on Day 0, and 32 days in the group combined with OncoGel 6.3 on Day 5 (p = 0.0001 vs controls). After 120 days, 37.5% of the animals in the OncoGel Day 0 group, 37.5% of animals in the OncoGel 6.3 Day 0 in combination with radiation therapy group, and 12.5% of the animals in the OncoGel 6.3 on Day 5 in combination with radiation therapy group were alive. In the biodistribution study, measurable radioactivity was observed throughout the ipsilateral hemisphere up to 3 weeks after the OncoGel injection, with the most radioactivity detected 3 hours after injection. The highest dose of radioactivity observed in the contralateral hemisphere was at the Day 3 time point.
OncoGel containing 6.3 mg/ml of paclitaxel is safe for intracranial injection in rats and effective when administered on Day 0. When combined with radiation therapy, the combination was more effective than either therapy alone and should be studied clinically for the treatment of malignant glioma.