Update: Cerebellar glioblastoma multiforme

Cerebellar glioblastoma multiforme (GBM) is rare in adults, accounting for <1% of all patients with glioblastoma multiforme (GBM).

Clinical Presentation

Presents with increased intracranial pressure and cerebellar syndrome.


The accurate diagnosis of cGBM is important for establishing a suitable therapeutic schedule. However, the diagnosis of cerebellar GBM is not usually suspected preoperatively because of its rarity.

Some evaluated cases of cerebellar GBM did not exhibit the common CT, MRI, and PET findings of supratentrial GBM, leading to considerable difficulty with preoperative differential diagnosis 1).


The recommended treatment is radical resection, if possible, with radiation and chemotherapy.


In view of their rarity, a metaanalysis is required to assess the pathogenesis and prognostic factors affecting overall survival 2).

Case series


Kikuchi et al., retrospectively reviewed seven patients with cerebellar GBM (six men and one woman: mean age: 56 years, range: 18-73 years). They reviewed medical records and radiological data, including preoperative CT, MRI and PET. All patients underwent CT and MRI. DWI data were acquired in four patients. Three patients underwent FDG- and MET-PET examinations. All patients underwent total or subtotal tumor resection and received pathological diagnoses.

Four patients had imaging findings consistent with GBM and received preoperative cerebellar GBM diagnoses. Two patients exhibited homogeneous patchy and nodular enhancement without necrosis on MRI, which resembled malignant lymphoma and metastasis. One case exhibited Lhermitte-Duclos disease-like parallel linear striations (i.e.,“tiger-striped” appearance). Although the imaging findings of these three patients were inconsistent with GBM, pathological diagnosis confirmed cerebellar GMB.

Some evaluated cases of cerebellar GBM did not exhibit the common CT, MRI, and PET findings of supratentrial GBM, leading to considerable difficulty with preoperative differential diagnosis 3).


Five adult patients with cerebellar GBM was evaluated and their outcome was assessed. They observed local failure in patients who reported back with recurrence. The presence of brainstem infiltration was a significant factor influencing progression-free survival. The overall prognosis was worse than for patients with supratentorial GBM. In view of their rarity, a meta-analysis is required to assess the pathogenesis and prognostic factors affecting overall survival in patients with cerebellar GBM 4).

Case reports


Gao S et al., reported a cerebellar glioblastoma multiforme patient, with his clinical presentations and imaging characteristics mimicking a vestibular schwannoma. To the best of authors knowledge, this is the first reported patient of cGBM mimicking a vestibular schwannoma 5).


A 53-year-old man presented with hypertensive cerebellar bleeding and a 2-day history of severe headaches, nausea, vomiting, gait instability, and elevated blood pressure. Computed tomography (CT) showed a left cerebellar hematoma with no obstruction of cerebrospinal fluid and no hydrocephalus. CT angiography showed no signs of pathologic blood vessels in the posterior cranial fossa. The patient was observed in the hospital and discharged. Subsequent CT showed complete hematoma resorption. Two weeks later, he developed headaches, nausea, and worsening cerebellar symptoms. Magnetic resonance imaging (MRI) showed a 4-cm diameter tumor in the left cerebellar hemisphere where the hemorrhage was located. The tumor was radically resected and diagnosed as GBM. The patient underwent radiation and chemotherapy. At a follow-up of 1.5 years, MRIs showed no tumor recurrence.

Hypertensive cerebellar hemorrhage may be the first presentation of underlying tumor, specifically cerebellar glioblastoma. Patients undergoing surgery for cerebellar hemorrhage should have clot specimens sent for histologic examination and have pre- and postcontrast MRIs. Patients not undergoing surgery should have MRIs done after hematoma resolution to rule out underlying tumor 6).


Hernandez-Gonzalez et al., report a case of cerebellar GBM in a 27-year-old woman. Magnetic resonance imaging (MRI) showed a 3×3.6 cm-sized, ill-defined, heterogeneously enhancing mass in the left cerebellum. GBM was histologically confirmed following radical surgery. Postoperative radiotherapy with concomitant and adjuvant temozolomidechemotherapy was subsequently administrated. She has no evidence of recurrence and is in good clinical conditions up-to date, three years after surgery 7).


A 69-year-old man. Neurologic examination revealed the presence of cerebellar signs. Magnetic resonance imaging (MRI) showed a 4.5 x 3.6 cm-sized, ill-defined, heterogeneously enhancing mass in the left cerebellum and two patchy hyperintense lesions in the right cerebellum with minimal enhancement. After operation, glioblastoma was histologically confirmed. Postoperative radiotherapy with concomitant and adjuvant temozolomide chemotherapy was subsequently followed. Here, a case of unusual GBM in the cerebellum is reported with review of literature regarding the pathogenesis, the differential diagnosis and prognosis. There was no evidence of recurrence during postoperative one year. This patient showed a good prognosis in spite of the multiple lesions 8).


Two cases of unusual de novo cerebellar glioblastomas, one of which is the giant-cell variant 9).


A 39-year-old woman. Postoperative irradiation to the posterior fossa enabled her to work for the next 5 1/2 years. At readmission, progressive pontocerebellar signs were observed. In spite of repeated irradiation and intrathecal chemotherapy, she died after 1 month. Autopsy revealed extensive tumorous infiltration of the right cerebellar hemisphere, pons, and medulla. Both the biopsy and autopsy specimens showed typical features of GM. Tumorous propagation resulted in extreme enlargement of the right inferior olive. Electron microscopic analysis disclosed characteristic bundles of glial filaments, cytoplasmic inclusions lying within nuclear folds, and intracytoplasmic granules of uncertain nature. The possible cause of the long survival is discussed and a comparison is made with previously reported cases 10).


Kopelson G. Cerebellar glioblastoma. Cancer. 1982 Jul 15;50(2):308-11. PubMed PMID: 6282439 11).


Approximately 38 cases of cerebellar glioblastoma have been reported. The authors report a case which seems to be the first report of such in the Brazilian literature 12)

1) , 3) Kikuchi K, Hiratsuka Y, Kohno S, Ohue S, Miki H, Mochizuki T. Radiological features of cerebellar glioblastoma. J Neuroradiol. 2016 Jul;43(4):260-5. doi: 10.1016/j.neurad.2015.10.006. Epub 2015 Dec 28. PubMed PMID: 26740386.
2) , 4) Gopalakrishnan CV, Dhakoji A, Nair S, Menon G, Neelima R. A retrospective study of primary cerebellar glioblastoma multiforme in adults. J Clin Neurosci. 2012 Dec;19(12):1684-8. doi: 10.1016/j.jocn.2011.12.035. Epub 2012 Oct 16. PubMed PMID: 23084346.
5) Gao S, Liu X, Cheng P, Yuan X, Niu J, Bai Y, Xi B. A Primary Cerebellar Glioblastoma Multiforme Mimicking Vestibular Schwannoma. J Craniofac Surg. 2016 Aug 10. [Epub ahead of print] PubMed PMID: 27513787.
6) Lakičević G, Arnautović K, Mužević D, Chesney T. Cerebellar glioblastoma multiforme presenting as hypertensive cerebellar hemorrhage: case report. J Neurol Surg Rep. 2014 Aug;75(1):e117-21. doi: 10.1055/s-0034-1376198. Epub 2014 May 28. PubMed PMID: 25097829.
7) Hernandez-Gonzalez G, Marchione P, De Angelis F, Giannone C, Kouleridou A, Spallone A. Long-term survival in cerebellar glioblastoma multiforme. Case report. J Neurosurg Sci. 2012 Dec;56(4):379-81. PubMed PMID: 23111300.
8) Hur H, Jung S, Jung TY, Kim IY. Cerebellar glioblastoma multiforme in an adult. J Korean Neurosurg Soc. 2008 Apr;43(4):194-7. doi: 10.3340/jkns.2008.43.4.194. Epub 2008 Apr 20. PubMed PMID: 19096643; PubMed Central PMCID: PMC2588262.
9) Demir MK, Hakan T, Akinci O, Berkman Z. Primary cerebellar glioblastoma multiforme. Diagn Interv Radiol. 2005 Jun;11(2):83-6. PubMed PMID: 15957093.
10) Hegedüs K, Molnár P. Primary cerebellar glioblastoma multiforme with an unusually long survival. Case report. J Neurosurg. 1983 Apr;58(4):589-92. PubMed PMID: 6298382.
11) Kopelson G. Cerebellar glioblastoma. Cancer. 1982 Jul 15;50(2):308-11. PubMed PMID: 6282439.
12) Aun RA, Stavale JN, Silva Junior D. [Glioblastoma multiforme of the cerebellum. Report of a case]. Arq Neuropsiquiatr. 1981 Sep;39(3):350-4. Portuguese. PubMed PMID: 6275825.

Update: Heparin induced thrombocytopenia in Neurosurgery

Heparin-induced thrombocytopenia (HIT) is a complication of heparin therapy.


There are two types of HIT. Type 1 HIT presents within the first 2 days after exposure to heparin, and the platelet count normalizes with continued heparin therapy. Type 1 HIT is a nonimmune disorder that results from the direct effect of heparin on platelet activation.

Type 2 HIT is an immune-mediated disorder that typically occurs 4-10 days after exposure to heparin and has life- and limb-threatening thrombotic complications. In general medical practice, the term HIT refers to type 2 HIT.

HIT must be suspected when a patient who is receiving heparin has a decrease in the platelet count, particularly if the fall is over 50% of the baseline count, even if the platelet count nadir remains above 150 x 109/L. Clinically, HIT may manifest as skin lesions at heparin injection sites or by acute systemic reactions (eg, chills, fever, dyspnea, chest pain) after administration of an intravenous bolus of heparin.

Unlike other forms of thrombocytopenia, HIT is generally not marked by bleeding; instead, venous thromboembolism (eg, deep venous thrombosis, pulmonary embolism) is the most common complication. Less often, arterial thrombosis (eg, myocardial infarction) may occur. For that reason, the disorder is sometimes termed heparin-induced thrombocytopenia and thrombosis (HITT).

Diagnosis of HIT is based on the combination of clinical findings, thrombocytopenia characteristics, and laboratory studies of HIT antibodies. Treatment of HIT begins with discontinuation of all heparin products (including heparin flushes of intravenous catheters). The patient should then be started on an alternative anticoagulant 1).

The incidence of heparin induced thrombocytopenia (HIT) in neurological patients continues to increase with expansion of indication for neurointerventional procedures. The pathophysiology of HIT is related to a hypersensitivity reaction against complex platelet factor 4. The diagnosis is mostly clinical and is often confirmed by laboratory testing. Patients with HIT have a higher rate of thromboembolic complications, both arterial and venous, and with worse neurological outcomes at the time of discharge. Early diagnosis and heparin cessation are essential in the management of those patients. Both immediate and prolonged alternative anticoagulation are necessary. Understanding of the mechanism of action, indication and drug interaction of the alternative anticoagulants (direct thrombin inhibitors, fondaparinux and danaparoid) and warfarin is essential during management of these patients 2).

Venous thromboembolism (VTE) is associated with heparin induced thrombocytopenia (HIT) infrequently (< 1%) in low molecular weight heparin (LMWH) treated patients, yet often (approximately one in eight cases) in unfractionated heparin-treated patients. Physicians should suspect the possibility of HIT if VTE develops during or soon after unfractionated heparin use; if thrombocytopenia is present, alternative anticoagulation should be used until HIT is excluded 3).

Heparin-induced thrombocytopenia type II correlates with a worse outcome and higher risk of thromboembolic complications in aneurysmal subarachnoid hemorrhage patients. In addition, HIT II was strongly associated with the number of angiographic procedures performed during the same hospitalization 4).

The presence of HIT in SAH has adverse consequences and is more likely in female patients who have undergone aneurysm clipping and require multiple endovascular vasospasm treatments 5).

SAH patients with isolated heparin induced thrombocytopenia and heparin induced thrombocytopenia with thrombotic syndrome did not differ in the incidence of new thromboses, incidence of hemorrhage, or hospice/death. Patients with isolated heparin induced thrombocytopenia had fewer “poor treatment-related effects” than heparin induced thrombocytopenia with thrombotic syndrome patients 6).

Studies reveal a high occurrence of overdiagnosis of heparin-induced thrombocytopenia in surgical patients with critical illness. The optimal criteria for diagnosis of heparin-induced thrombocytopenia remain unclear, contributing to unnecessary treatment.

Overtreatment of heparin-induced thrombocytopenia in the surgical ICU continues even with recent increased caution encouraging a higher antiplatelet factor 4/heparin enzyme-linked immunosorbent assay optical density threshold before initiating treatment. More stringent criteria should be used to determine when to order serologic testing and when the results of such testing should prompt a change in anticoagulant treatment. If antiplatelet factor 4/heparin enzyme-linked immunosorbent assay is used to consider immediate treatment, an optical density greater than or equal to 2.0 may be a more appropriate threshold 7).

Case series

During a 3.5-year period (January 2000-June 2003), 389 consecutive SAH patients were treated at our center. We retrospectively reviewed their laboratory data and medical records and used accepted clinical criteria for the diagnosis of HIT II to determine the incidence of HIT II, thrombotic complications, management, and outcome.

Fifty-nine patients (15%) met the clinical diagnostic criteria for HIT II. The average platelet count nadir in the HIT II patients was 68,600 +/- 25,300/microl (mean +/- standard deviation). Female patients and patients with Fisher Grade 3 were more likely to develop HIT II (P < 0.01). Thirty-six patients (61%) underwent a neuroendovascular procedure. The rate of systemic thrombotic complications in the HIT II patients was 37 versus 7% in SAH patients without HIT II (P < 0.001), and the rate of new hypodensities on head computed tomographic scans was 66% in the HIT II patients versus 40% in the SAH patients without HIT II (P < 0.001). Clinical outcomes were worse in the HIT II patients. The outcome was favorable for 38% in the HIT II patients versus 52% in all SAH patients (P < 0.05), and deaths were more common (29%) in the HIT II patients than in all SAH patients (12%, P < 0.001).

The incidence of HIT II in SAH patients at a single center was 15%. The SAH patients with HIT II had significantly higher rates of thrombotic complications, new hypodensities on head computed tomographic scans, more deaths, and significantly less favorable outcomes. This is the first report of the incidence of HIT II in a neurosurgical patient population 8).

Case reports


A 63-year-old man with HIT and multiple medical comorbidities underwent emergent coronary artery bypass grafting, postoperative imaging revealed plaque at the origin of the left internal carotid artery with 80%-99% stenosis and minimal contralateral internal carotid artery disease. During the patient’s evaluation to undergo CEA for symptomatic high-grade carotid stenosis, enzyme-linked immunosorbent assay revealed persistent platelet factor 4 antibodies.

The endarterectomy was successfully performed while the patient received argatroban, both as a continuous infusion and intermittent irrigation during dissection of the plaque. Postoperatively, the drip was continued for 24 hours, and the patient was discharged day 2 on a daily dose of 325 mg of aspirin. At the 6-month examination, Doppler ultrasound revealed normal anterograde velocities with no evidence of stenosis, and the patient noted no subsequent ischemic events.

Serrone et al., now recommend systemic intravenous and local argatroban irrigation to prevent thromboembolic complications in CEA cases with HIT and renal insufficiency. Bivalirudin for both systemic intravenous use and local irrigation may be safer in patients without renal insufficiency because of its shorter half-life 9).


Kruljac et al., report a case of an elderly female who received prophylactic fractionated heparin therapy due to sepsis, consequent rhabdomyolysis, and overt disseminated intravascular coagulation. On the seventh day of heparin therapy, she reported sudden vision loss, ptosis, diplopia, and severe headache. Severe thrombocytopenia and positive antibodies to the complex of platelet factor 4 and heparin confirmed heparin-induced thrombocytopenia type 2 (HIT). Magnetic resonance imaging disclosed a homogenous pituitary tumor mass with pronounced sphenoid sinus mucosa thickening and two hypointense zones within the tumor mass on contrast-enhanced images consistent with focal ischemic necrosis. The tumor was confirmed to be squamous cell carcinoma with no signs of necrosis. Ischemic necrosis was found within marginal pituitary tissue. This is the first reported case of ischemic PA associated with pituitary metastasis and the first case in which HIT triggered PA. Our case demonstrates that prothrombotic states such as HIT can precipitate ischemic PA. Pituitary metastasis can present with ischemic PA, but radiological features differ from those described in pituitary adenomas. Segregated low-signal intensity zones within the tumor mass on postcontrast images indicate partial infarction of the tumor, which could be a special feature of ischemic PA in pituitary metastasis and has never been described in pituitary adenomas. These are all novel findings and might enlighten the pathogenesis of PA 10).


A 58-year-old woman presented with right supplementary motor area glioblastoma multiforme and deep venous thrombosis in her legs. The tumor was resected after temporary inferior vena cava filter placement, considering that increased thrombosis during and after the operation would cause fatal pulmonary embolism. After anticoagulation with unfractionated heparin, thrombocytopenia was aggravated, and computed tomography showed filter catheter-related thrombosis in the inferior vena cava. The diagnosis was heparin-induced thrombocytopenia, and argatroban and urokinase were administered. Thrombolysis with urokinase was completed and the temporary inferior vena cava filter catheter was removed without complication 11).

A case of bifrontal intracerebral haemorrhage in a patient with heparin-induced thrombocytopenia type II (HIT II). HIT II was induced by treatment with low-molecular-weight heparin for recurrent deep vein thrombosis caused by essential thrombocytosis and accompanied by hepatic thromboembolism. This patient was treated with platelet substitution and neurosurgical haematoma evacuation. Anticoagulation with 2500 units danaparoid per day was sufficient for therapy of thrombosis and no rebleeding occurred 12).

A 61-year-old woman treated for cerebral venous thrombosis (CVT) leading to diagnosis of essential thrombocythemia (ET). During treatment with unfractionated heparin, after initial improvement of clinical state, signs of cerebral hypertension reappeared. Although the platelet count decreased, heparin-induced thrombocytopenia (HIT) was only suspected 2 days later when it dropped below the standard 150 × 10(9) L(-1) threshold. HIT diagnosis was confirmed by the presence of anti-PF4/heparin IgG. This late finding was the cause of the extension of CVT with worsening of cerebral hypertension necessitating decompressive craniectomy. Elevated basal platelet count due to ET can delay diagnosis and treatment of HIT. In this case, physicians should be more attentive to platelet count variations rather than thrombocytopenia threshold 13).


A patient with heparin-induced thrombocytopenia type II and pulmonary embolism who was anticoagulated with argatroban and, later, with fondaparinux. No intracranial bleeding was detected when anticoagulation was performed with argatroban and, later, fondaparinux 14).

A case of intratumor haemorrhage in the cavernous sinus 1 week after cardiac surgery. The pathogenesis may be venous thrombosis and haemorrhagic infarct caused by HIT following cardiopulmonary bypass surgery 15).


The development of cerebral sinus thrombosis as a complication of heparin-induced thrombocytopenia is very rare. A 59-year-old patient with cerebral sinus thrombosis secondary to type II heparin-induced thrombocytopenia 16).


Doty et al., report the clinical course of two patients who in the immediate postoperative period developed heparin-associated thrombocytopenia that resulted in significant morbidity. In these two cases, the origin of the heparin was in “flush” solutions used to maintain the patency of indwelling vascular catheters and was infused at a dose of 250 to 500 units/day. The minimal daily dose previously reported to result in thrombocytopenia is 9000 units/day administered in divided doses subcutaneously. The case reports indicate that heparin in “flush” solutions should be considered as a cause for unexpected thrombocytopenia and that platelet counts should be monitored in patients receiving heparin in any amount 17).

2) Alaraj A, Wallace A, Tesoro E, Ruland S, Amin-Hanjani S, Charbel FT, Aletich V. Heparin induced thrombocytopenia: diagnosis and management. J Neurointerv Surg. 2010 Dec;2(4):371-8. doi: 10.1136/jnis.2010.002840. Epub 2010 Jul 23. Review. PubMed PMID: 21990651.
3) Levine RL, McCollum D, Hursting MJ. How frequently is venous thromboembolism in heparin-treated patients associated with heparin-induced thrombocytopenia? Chest. 2006 Sep;130(3):681-7. PubMed PMID: 16963663.
4) Alaraj A, Wallace A, Mander N, Aletich V, Charbel FT, Amin-Hanjani S. Risk factors for heparin-induced thrombocytopenia type II in aneurysmal subarachnoid hemorrhage. Neurosurgery. 2011 Nov;69(5):1030-6. doi: 10.1227/NEU.0b013e3182284a81. PubMed PMID: 21670717.
5) Mehta BP, Sims JR, Baccin CE, Leslie-Mazwi TM, Ogilvy CS, Nogueira RG. Predictors and outcomes of suspected heparin-induced thrombocytopenia in subarachnoid hemorrhage patients. Interv Neurol. 2014 Aug;2(4):160-8. doi: 10.1159/000362189. PubMed PMID: 25337085; PubMed Central PMCID: PMC4188165.
6) Benken ST, Tesoro EP, Kim KS, Mucksavage JJ. Treatment outcomes of heparin-induced thrombocytopenia in subarachnoid hemorrhage patients: a 4-year, retrospective single-center review. Neurocrit Care. 2012 Oct;17(2):177-82. doi: 10.1007/s12028-012-9725-x. PubMed PMID: 22692920.
7) Harada MY, Hoang DM, Zaw AA, Murry JS, Volod O, Sun BJ, Nuño M, Mason R, Margulies DR, Ley EJ. Overtreatment of Heparin-Induced Thrombocytopenia in the Surgical ICU. Crit Care Med. 2016 Aug 4. [Epub ahead of print] PubMed PMID: 27513533.
8) Hoh BL, Aghi M, Pryor JC, Ogilvy CS. Heparin-induced thrombocytopenia Type II in subarachnoid hemorrhage patients: incidence and complications. Neurosurgery. 2005 Aug;57(2):243-8; discussion 243-8. PubMed PMID: 16094152.
9) Serrone JC, Andaluz N, Brink V, Zuccarello M, Ware SL. Systemic infusion and local irrigation with argatroban effective in preventing clot formation during carotid endarterectomy in a patient with heparin-induced thrombocytopenia. World Neurosurg. 2013 Jul-Aug;80(1-2):222.e15-8. doi: 10.1016/j.wneu.2013.01.037. Epub 2013 Jan 12. PubMed PMID: 23321376.
10) Kruljac I, Cerina V, Pećina HI, Pažanin L, Matić T, Božikov V, Vrkljan M. Pituitary metastasis presenting as ischemic pituitary apoplexy following heparin-induced thrombocytopenia. Endocr Pathol. 2012 Dec;23(4):264-7. doi: 10.1007/s12022-012-9224-9. PubMed PMID: 23129546.
11) Nitta N, Shitara S, Nozaki K. Heparin-induced thrombocytopenia in a glioblastoma multiforme patient with inferior vena cava filter placement for deep venous thrombosis. Neurol Med Chir (Tokyo). 2011;51(6):445-8. PubMed PMID: 21701111.
12) Hertle DN, Hähnel S, Richter GM, Unterberg A, Sakowitz OW, Kiening KL. The use of danaparoid to manage coagulopathy in a neurosurgical patient with heparin-induced thrombocytopenia type II and intracerebral haemorrhage. Br J Neurosurg. 2011 Feb;25(1):117-9. doi: 10.3109/02688697.2010.502266. Epub 2010 Aug 13. PubMed PMID: 20707682.
13) Richard S, Perrin J, Lavandier K, Lacour JC, Ducrocq X. Cerebral venous thrombosis due to essential thrombocythemia and worsened by heparin-induced thrombocytopenia and thrombosis. Platelets. 2011;22(2):157-9. doi: 10.3109/09537104.2010.527399. Epub 2010 Dec 8. PubMed PMID: 21142409.
14) Kerz T, Schinzel H. Anticoagulation in a Neurosurgical Patient with Heparin-Induced Thrombocytopenia Type II with Argatroban and Fondaparinux after Clipping of an Intracranial Aneurysm. Transfus Med Hemother. 2009;36(2):141-143. Epub 2009 Mar 13. PubMed PMID: 20823996; PubMed Central PMCID: PMC2928829.
15) Tsai HC, Yen HC, Hsu JC, Lin CL. Heparin-induced thrombocytopenia associated with intra-tumour haemorrhage in cavernous sinus after cardiac myxoma surgery. Br J Neurosurg. 2009 Feb;23(1):95-6. doi: 10.1080/02688690802272164. PubMed PMID: 19234918.
16) Fountas KN, Faircloth LR, Hope T, Grigorian AA. Spontaneous superior sagittal sinus thrombosis secondary to type II heparin-induced thrombocytopenia presenting as an acute subarachnoid hemorrhage. J Clin Neurosci. 2007 Sep;14(9):890-5. Epub 2007 Jun 19. PubMed PMID: 17582771.
17) Doty JR, Alving BM, McDonnell DE, Ondra SL. Heparin-associated thrombocytopenia in the neurosurgical patient. Neurosurgery. 1986 Jul;19(1):69-72. PubMed PMID: 3748340.

Update: Low dose computed tomography in neurosurgery

The implementation of a low-dose head CT protocol substantially reduced the amount of ionizing radiation exposure in a preselected population of pediatric neurosurgical patients. Image quality and diagnostic utility were not significantly compromised 1).

In a cohort of patients in the neurosurgical intensive care unit, dedicated ultra-low-dose CT for surveillance head CT imaging led to a significant dose reduction while maintaining adequate image quality 2).

Although replacing a CT with magnetic resonance imaging is ideal to completely avoid ionizing radiation, this is not always practical or preferred. Therefore, it is important to have CT protocols in place that minimize radiation dose without sacrificing diagnostic quality 3).

The evaluation of children with suspected ventriculoperitoneal shunt malfunction has evolved into a diagnostic dilemma. This patient population is vulnerable not only to the medical risks of hydrocephalus and surgical complications but also to silent but harmful effects of ionizing radiation secondary to imaging used to evaluate shunt efficacy and patency. The combination of increased medical awareness regarding ionizing radiation and public concern has generated desire to reduce the reliance on head computed tomography (CT) for the evaluation of VPS malfunction. Many centers have started to investigate the utility of low dose computed tomography and alternatives, such as fastmagnetic resonance imaging for the investigation of VP shunt malfunction in order to keep radiation exposure as low as reasonably achievable.

A pilot study demonstrates that utilization of limited head CT scan in the evaluation of children with suspected VP shunt malfunction is a feasible strategy for the evaluation of the ventricular size 4).

In the study of Afat et al., low-dose computed tomography (LD-CT) provides excellent sensitivity and higher diagnostic confidence with lower radiation exposure compared with radiographic shunt series (SS) 5).

1) Morton RP, Reynolds RM, Ramakrishna R, Levitt MR, Hopper RA, Lee A, Browd SR. Low-dose head computed tomography in children: a single institutional experience in pediatric radiation risk reduction: clinical article. J Neurosurg Pediatr. 2013 Oct;12(4):406-10. doi: 10.3171/2013.7.PEDS12631. Epub 2013 Aug 23. PubMed PMID: 23971634.
2) Corcuera-Solano I, Doshi AH, Noor A, Tanenbaum LN. Repeated head CT in the neurosurgical intensive care unit: feasibility of sinogram-affirmed iterative reconstruction-based ultra-low-dose CT for surveillance. AJNR Am J Neuroradiol. 2014 Jul;35(7):1281-7. doi: 10.3174/ajnr.A3861. Epub 2014 Feb 20. PubMed PMID: 24557704.
3) Albert GW, Glasier CM. Strategies for Computed Tomography Radiation Dose Reduction in Pediatric Neuroimaging. Neurosurgery. 2015 Aug;77(2):228-32; discussion 232. doi: 10.1227/NEU.0000000000000764. PubMed PMID: 25856110.
4) Park DB, Hill JG, Thacker PG, Rumboldt Z, Huda W, Ashley B, Hulsey T, Russell WS. The Role of Limited Head Computed Tomography in the Evaluation of Pediatric Ventriculoperitoneal Shunt Malfunction. Pediatr Emerg Care. 2016 Jun 14. [Epub ahead of print] PubMed PMID: 27299297.
5) Afat S, Pjontek R, Hamou HA, Herz K, Nikoubashman O, Bamberg F, Brockmann MA, Nikolaou K, Clusmann H, Wiesmann M, Othman AE. Imaging of Ventriculoperitoneal Shunt Complications: Comparison of Whole Body Low-Dose Computed Tomography and Radiographic Shunt Series. J Comput Assist Tomogr. 2016 Aug 16. [Epub ahead of print] PubMed PMID: 27529684.

Update: Planum sphenoidale meningioma

Planum sphenoidale meningioma

J.Sales-Llopis; J.Abarca-Olivas; R. López-García

Neurosurgery Department, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Alicante, Spain

Planum sphenoidale meningiomas are anterior cranial fossa meningiomas, overlying the area of the cribriform plate of the ethmoid bone, sphenofrontal suture, and planum sphenoidale.

The tumors are usually bilateral based on their midline origin, although they can also be unilateral.

A universally accepted classification system predicting surgical risk and outcome is still lacking.


Planum sphenoidale meningiomas account for 5-10% of all intracranial meningiomas.

Clinical features

They are typically slow-growing tumors, explaining why some patients remain asymptomatic and, therefore, un-diagnosed for extended periods of time. The ensuing growth of the extra-axial neoplasm can cause displacement of the optic apparatus resulting in visual disturbances. It is, therefore, imperative that patient undergoes formal neuro-ophthalmological testing before any surgical intervention. A headache, although present in many patients with this neoplasm, is a non-specific finding.

A patient with a planum sphenoidale meningioma mimicking a classic case of pituitary apoplexy is reported 1).


Delay in the diagnosis of meningiomas of the tuberculum sellae and planum sphenoidale is detrimental to the patient in terms of visual recovery, morbidity and mortality. Early accurate diagnosis of these tumors is possible through the use of neuroimaging which is recommended for all patients with unexplained impairment of vision 2).

Neuroimaging characteristics on CT include a homogenously and avidly contrast-enhancing, extra-axial mass, with a well-defined border and broad dural attachment and/or dural tail. The tumor is associated with moderate circumferential edema and mass effect. There may be an area of central calcification within the tumour and hyperostosis of adjacent bony structures may be evident.

On MRI, the meningioma appears hypo to isointense on T1-weighted imaging and possesses variable signal intensity on T2-weighted images. Gadolinium MR imaging demonstrates intense homogeneous or heterogeneous-enhancement of the tumor, with well-circumscribed margins.

Differential diagnosis

Tuberculum sellae meningiomas are located not only on the limited surface between the prechiasmatic sulcus and diaphragm sellae, but also on the limbus sphenoidalis, chiasmatic sulcus and diaphragma sellae.

Planum sphenoidale meningiomas are located more anterior and in proximity of the olfactory groove location.

A 45-year-old gentleman who presented with signs of raised intracranial hypertension, secondary optic atrophy and a contrast-enhancing mass arising from the planum sphenoidale. Postoperatively, mass was diagnosed as aspergilloma on histopathology and culture. Despite antifungal treatment, patient could not be saved due to large artery infarcts in the immediate postoperative period 3).

Hemangioblastomas are rarely seen in the suprasellar region, arising from the optic apparatus or pituitary stalk, mimicking meningiomas on the preoperative MRI scan. They may be suspected in the presence of large flow voids and the absence of a dural tail. Intraoperatively, the extreme vascularity and compressibility of the tumour with no dural attachment should alert the surgeon to the diagnosis. A complete resection with preservation of vision may be successfully attempted because of the well-demarcated tumour-nerve interface 4).

Two cases of intracranial leiomyosarcoma revealed a mass at the left cavernous sinus involving prepontine cistern in one case and two lesions in the other case showing masses with dural based appearance at the region of the planum sphenoidale and the posterior aspect of the falx cerebri which mimiced a meningioma. The leiomyosarcoma should be included in the differential diagnosis of extra-axial CNS lesions in HIV-infected patients 5).

Adenoid cystic carcinoma (ACC) is rarely encountered by the neurosurgeon; however it should always be considered in the differential diagnosis of skull base tumors. Interdisciplinary surgical approaches represent the major advance in the treatment of these complex neoplasms 6).


Midline anterior skull base lesions are becoming amenable for total surgical excision with minimal morbidities and mortalities. Most preferred surgical routes are thesubfrontal approach and the pterional approach 7).

Small and midsize olfactory groove, planum sphenoidale, and tuberculum sellae meningiomas can be removed via an endonasal endoscopic approach, an alternative option to the transcranial microsurgical approach. The choice of approach depends on tumor size and location, involvement of important neurovascular structures, and, most importantly, the surgeon’s preference and experience. In most meningiomas, the endonasal approach has no advantage compared with the transcranial approach. Disadvantages of the endonasal approach are the discomfort after surgery and the prolonged recovery phase because of the nasal morbidity, which requires intensive nasal care. Compared with the eyebrow approach, the trauma to the nasal cavity, paranasal sinuses, and skull base is greater, and the risk of cerebrospinal fluid leak is higher 8).

A combination of different surgical and endovascular techniques before resection of hypervascular giant planum sphenoidale meningiomas should always be considered. Microsurgical extracranial ligation of anterior and sometimes posterior ethmoidal arteries provides a safe and feasible option to limit blood loss during anterior skull base surgery 9).


Like most meningiomas, meningiomas of the anterior cranial base are typically benign and potentially curable. Thus, the extent of surgical resection is the most important predictor of recurrence.

Despite the benign pathology, their recurrence rates 10 years after surgical resection have ranged from 10 to 41%.

These high rates have been attributed to the difficulty in removing the tumor cells that invade the base of skull and paranasal sinuses.


It is well known that it is difficult to remove the planum sphenoidale without damaging the optic nerves. The visual outcome after this operation has been unacceptable in such tumors, especially in large ones.


Case series


Mortazavi et al., conducted a retrospective review of the patients who between 2005 and March 2015 underwent a craniotomy or endoscopic surgery for the resection of meningiomas involving the suprasellar region. Operative nuances of a modified frontotemporal craniotomy and orbital osteotomy technique for meningioma removal and reconstruction are described.

Twenty-seven patients were found to have tumors arising mainly from the planum sphenoidale or the tuberculum sellae; 25 underwent frontotemporal craniotomy and tumor removal with orbital osteotomy and bilateral optic canal decompression, and 2 patients underwent endonasal transphenoidal resection. The most common presenting symptom was visual disturbance (77%). Vision improved in 90% of those who presented with visual decline, and there was no permanent visual deterioration. Cerebrospinal fluid leak occurred in one of the 25 cranial cases (4%) and in 1 of 2 transphenoidal cases (50%), and in both cases it resolved with treatment. There was no surgical mortality.

An orbitotomy and early decompression of the involved optic canal are important for achieving gross total resection, maximizing visual improvement, and avoiding recurrence. The visual outcomes were excellent. A new classification system that can allow the comparison of different series and approaches and indicate cases that are more suitable for an endoscopic transsphenoidal approach is presented 10).

In patients treated with endonasal endoscopic meningioma surgery. Sughrue et al., believe that very low rates of morbidity can be achieved in carefully selected patients, thus avoiding brain manipulation 11).


7 PSMs (23.3%) of midline anterior skull base meningiomas 12).

12 planum/jugum sphenoidale meningioma 13).


Zygourakis et al., retrospectively identified 44 patients with planum/olfactory meningiomas treated at our institution from 1996 to 2006. We used univariate and multivariate regression models to analyze the effect of several magnetic resonance imaging characteristics (tumor volume, distance to optic chiasm, anterior cerebral artery encasement, paranasal sinus invasion, and sellar invasion) on preoperative symptoms and postoperative outcomes, including complication rate and tumor recurrence.

Only brain tumor volume (>42 cm(3)), but not distance to the optic chiasm, is independently associated with an increased likelihood of preoperative visual symptoms. Tumors with nasal sinus invasion are significantly more likely to cause postoperative surgical complications, and tumors with anterior cerebral artery encasement are associated with a greater likelihood of both postoperative complications and tumor recurrence.

Tumors larger than 3.4 cm in diameter and those whose posterior edge is within 6-8 mm of the optic chiasm should be recommended for early surgical intervention. In terms of predicting surgical complications, nasal sinus invasion and anterior cerebral artery encasement are associated with greater-risk profiles when surgery becomes necessary. Thus, it is prudent to take these specific variables into consideration when advising patients about the risks of observation and surgery for olfactory/planum meningiomas 14).


Perera et al., retrospectively reviewed the clinical records of 17 patients with planum sphenoidale meningiomas who were admitted between 2004 and 2011. Patients had formal visual assessments (including Humphrey’s visual field testing) pre- and postoperatively.

The mean age at presentation was 62.3 years; there were 11 women and 6 men. The meningiomas ranged in diameter from 17 mm to 70 mm (mean diameter 37.2 mm). Twelve of the patients had neurosurgical intervention (seven of these had a pterional approach, three had a bicoronal frontal approach, and two had the tumor resected via the transglabellar frontal approach). Histological analysis showed nine of the cases were WHO grade I and the remaining three were grade II.

Ten of the patients demonstrated improvement in their visual acuity assessment, and four of the patients had no demonstrable visual impairment preoperatively.

Conclusions: Prevention of visual deterioration and/or improvement of visual function remain benefits that could be attained by resection of planum sphenoidale meningioma. Pre- and postoperative formal ophthalmological assessments should be an integral component in the management of these tumors.


A review propounds a strategy to secure visual acuity through operation. A total of eight cases are summarized. In five midline symmetrical meningiomas, the tumors compressed the nerves at the portion of the optic chiasma, causing a typical bitemporal hemianopsia. Four large tumors were resected by the frontobasal interhemispheric approach to minimize the intraoperative damage to the optic chiasma, and a small one was removed by the pterional approach. Visual disturbances were recovered immediately after the operation in all cases without any surgical complications. Three meningiomas were attached to the lateral part of the planum sphenoidale ortuberculum sellae. Although the sizes were relatively small in all cases, they caused ipsilateral severe visual loss by direct compression to optic nerves. MRI and three-dimensional CT angiography showed the tumor extension into the optic canal. The ipsilateral pterional approach was selected in these cases. To avoid additional nerve damage, we tried to reduce the tension of nerves which were compressed by the tumors. Uede et al., removed the anterior clinoid process and opened the optic canal before surgical manipulation of the tumor. In two cases, tumors severely compressed the optic nerves from the medial side, and nerves were stretched laterally. Great care was required to separate the optic nerves from tumors in those two cases. In contrast, the resection seemed to be very easy in one of the cases where the optic nerve was displaced infero-medially. Visual symptoms were improved in all cases, although one case became worse temporarily. Although planum sphenoidale and tuberculum sellae meningiomas are still troublesome, appropriate preoperative management would allow us to expect an excellent visual outcome. Especially, selection of the surgical approach should be based on the anatomical analysis of the nerve displacement 15).


In this article 105 cases of meningiomas of the planum sphenoidale and tuberculum sellae are reviewed. In only five cases was the diagnosis made within three months of the onset of the symptoms 16).


Meningiomas of the tuberculum sellae and planum sphenoidale. A review of 83 cases 17).

Case reports


Coincidental pituitary adenoma and planum sphenoidale meningioma mimicking a single tumor 18).


A 60-year-old male presented with complaints of dizziness, which worsened with fatigue and a sense his balance was ‘off’. Initial physical examination was negative and the laboratory testing was unremarkable. Within weeks, the patient developed bilateral visual field defects. MRI revealed an extra-axial mass which extended into the pituitary fossa and caused compression of the pituitary gland. The pituitary stalk was displaced posteriorly and the optic chiasm was compressed with displacement superiorly and posteriorly. The patient underwent a surgical resection. Diabetes insipidus developed postoperatively requiring a vasopressin drip. He also developed hypopituitarism after the resection with hypothyroidism, hypoadrenalism and hypogonadism. The patient requires testosterone, levothyroxine and hydrocortisone replacement and has mild residual bitemporal hemianopsia 19).


A previously healthy 31-year-old man presented with an extremely rare case of small meningioma associated with cerebral infarction preceded by recurrent transient ischemic attacks manifesting as a 3-day history of recurrent and transient weakness of the left lower limb lasting several minutes for each episode. The symptoms became persistent and complete on the following day. Magnetic resonance imaging revealed acute cerebral infarction in the right frontal lobe and a 20 mm diameter tumor in the planum sphenoidale encasing the right anterior cerebral artery. Cerebral angiography demonstrated occlusion of the right A(2) portion. The patient underwent surgery and the tumor was gross totally removed. The histological diagnosis was meningothelial meningioma. Cases of meningioma causing cerebral infarction are very rare, but the possibility should be considered even if the tumor is small 20).


A 66-year-old woman who developed a planum sphenoidale meningioma. Histologically, the tumor was composed of meningothelial cells arranged in fascicles and whorls, typical of a well-differentiated meningioma. Many tumor cells contained round intracytoplasmic eosinophilic inclusions that were periodic acid Schiff-negative and red on Masson trichrome. The inclusions were immunopositive for vimentin, and were immunonegative for epithelial membrane antigen, smooth muscle actin, desmin and type IV collagen. Ultrastructural examination showed the inclusions were composed of round to oval, well-demarcated, non-membrane-bound, osmiophilic granular material. The inclusions within this tumor had histochemical, immunohistochemical and ultrastructural properties not described in other reported meningiomas with eosinophilic granular or granulofilamentous inclusions 21).

1) Marano SR, Sonntag VK, Spetzler RF. Planum sphenoidale meningioma mimicking pituitary apoplexy: a case report. Neurosurgery. 1984 Dec;15(6):859-62. PubMed PMID: 6514160.
2) , 16) Kadis GN, Mount LA, Ganti SR. The importance of early diagnosis and treatment of the meningiomas of the planum sphenoidale and tuberculum sellae: a retrospective study of 105 cases. Surg Neurol. 1979 Nov;12(5):367-71. PubMed PMID: 515934.
3) Verma R, Singh P, Kumar A, Paliwal VK. Cranial aspergilloma masquerading as meningioma. BMJ Case Rep. 2013 Jan 9;2013. pii: bcr2012008118. doi: 10.1136/bcr-2012-008118. PubMed PMID: 23307467; PubMed Central PMCID: PMC3604443.
4) Prabhu K, Daniel RT, Chacko G, Chacko AG. Optic nerve haemangioblastoma mimicking a planum sphenoidale meningioma. Br J Neurosurg. 2009;23(5):561-3. doi: 10.1080/02688690902965964. PubMed PMID: 19718547.
5) Lerdlum S, Lalitanantpong S, Numkarunarunrote N, Chaowanapanja P, Suankratay C, Shuangshoti S. MR imaging of CNS leiomyosarcoma in AIDS patients. J Med Assoc Thai. 2004 Sep;87 Suppl 2:S152-60. PubMed PMID: 16083180.
6) Brunori A, Scarano P, Iannetti G, Chiappetta F. Dumbbell tumor of the anterior skull base. Meningioma? No, adenoid cystic carcinoma! Surg Neurol. 1998 Nov;50(5):470-4. PubMed PMID: 9842875.
7) , 12) Refaat MI, Eissa EM, Ali MH. Surgical management of midline anterior skull base meningiomas: experience of 30 cases. Turk Neurosurg. 2015;25(3):432-7. doi: 10.5137/1019-5149.JTN.11632-14.2. PubMed PMID: 26037184.
8) Schroeder HW. Indications and limitations of the endoscopic endonasal approach for anterior cranial base meningiomas. World Neurosurg. 2014 Dec;82(6 Suppl):S81-5. doi: 10.1016/j.wneu.2014.07.030. Review. PubMed PMID: 25496640.
9) Cecchini G. Anterior and Posterior Ethmoidal Artery Ligation in Anterior Skull Base Meningiomas: A Review on Microsurgical Approaches. World Neurosurg. 2015 Oct;84(4):1161-5. doi: 10.1016/j.wneu.2015.06.005. Epub 2015 Jun 11. Review. PubMed PMID: 26072460.
10) Mortazavi MM, Brito da Silva H, Ferreira M Jr, Barber JK, Pridgeon JS, Sekhar LN. Planum Sphenoidale and Tuberculum Sellae Meningiomas: Operative Nuances of a Modern Surgical Technique with Outcome and Proposal of a New Classification System. World Neurosurg. 2016 Feb;86:270-86. doi: 10.1016/j.wneu.2015.09.043. Epub 2015 Sep 25. PubMed PMID: 26409085.
11) Sughrue M, Bonney P, Burks J, Hayhurst C, Gore P, Teo C. Results with Expanded Endonasal Resection of Skull Base Meningiomas: Technical Nuances and Approach Selection Based on an Early Experience. Turk Neurosurg. 2016 Jan 25. doi: 10.5137/1019-5149.JTN.16105-15.3. [Epub ahead of print] PubMed PMID: 27337239.
13) Brunworth J, Padhye V, Bassiouni A, Psaltis A, Floreani S, Robinson S, Santoreneos S, Vrodos N, Parker A, Wickremesekera A, Wormald PJ. Update on endoscopic endonasal resection of skull base meningiomas. Int Forum Allergy Rhinol. 2015 Apr;5(4):344-52. doi: 10.1002/alr.21457. Epub 2014 Dec 22. PubMed PMID: 25533175.
14) Zygourakis CC, Sughrue ME, Benet A, Parsa AT, Berger MS, McDermott MW. Management of planum/olfactory meningiomas: predicting symptoms and postoperative complications. World Neurosurg. 2014 Dec;82(6):1216-23. doi: 10.1016/j.wneu.2014.08.007. Epub 2014 Aug 7. PubMed PMID: 25108294.
15) Uede T, Ohtaki M, Nonaka T, Tanabe S, Hashi K. [Characteristics of visual impairment complicated with planum sphenoidale and tuberculum sellae meningiomas and their surgical results]. No Shinkei Geka. 1996 Dec;24(12):1093-8. Japanese. PubMed PMID: 8974091.
17) Finn JE, Mount LA. Meningiomas of the tuberculum sellae and planum sphenoidale. A review of 83 cases. Arch Ophthalmol. 1974 Jul;92(1):23-7. PubMed PMID: 4835973.
18) Ruiz-Juretschke F, Iza B, Scola-Pliego E, Poletti D, Salinero E. Coincidental pituitary adenoma and planum sphenoidale meningioma mimicking a single tumor. Endocrinol Nutr. 2015 Jun-Jul;62(6):292-4. doi: 10.1016/j.endonu.2015.03.003. Epub 2015 May 8. PubMed PMID: 25963837.
19) Lutwak N, Dill C, Wieczorek R. Planum sphenoidale meningioma leading to visual disturbance. BMJ Case Rep. 2011 Aug 31;2011. pii: bcr0720114511. doi: 10.1136/bcr.07.2011.4511. PubMed PMID: 22679053; PubMed Central PMCID: PMC3176386.
20) Masuoka J, Yoshioka F, Ohgushi H, Kawashima M, Matsushima T. Meningioma manifesting as cerebral infarction. Neurol Med Chir (Tokyo). 2010;50(7):585-7. PubMed PMID: 20671387.
21) Alexander RT, McLendon RE, Cummings TJ. Meningioma with eosinophilic granular inclusions. Clin Neuropathol. 2004 Nov-Dec;23(6):292-7. PubMed PMID: 15584214.

Update: Low molecular weight heparin- Brain Edema

Evidence suggests low molecular weight heparin reduces brain edema and improves neurological recovery following stroke and traumatic brain injury (TBI), through blunting of cerebral leukocyte (LEU) recruitment. It remains unknown if unfractionated heparin (UFH) similarly affects brain inflammation and neurological recovery post TBI.

Prophylaxis was associated with decreased risk of pulmonary embolism and deep vein thrombosis, but no increase in risk of late neurosurgical intervention or death. Early prophylaxis may be safe and should be the goal for each patient in the context of appropriate risk stratification 6).

Unfractionated heparin (UFH) after TBI reduces LEU recruitment, microvascular permeability and brain edema to injured brain. Lower UFH doses concurrently improve neurological recovery while higher UFH may worsen functional recovery. Further study is needed to determine if this is due to increased bleeding from injured brain with higher UFH doses 7).

Mirroring Enoxaparin (ENX), HMGB1 signaling blockade reduces LEU recruitment, cerebrovascular permeability, and brain edema following TBI. ENX further reduced lung edema indicating a multifaceted effect beyond HMGB1 blockade. Further study is needed to determine how ENX may play a role in blunting HMGB1 signaling in brain injury patients 8).

Update: Curcumin

Curcumin (Cur), is a natural polyphenol of Curcuma longa.

Plant extract therapy has been the cornerstone of cancer treatment for many years. The natural component curcumin demonstrated antineoplastic effects on different type of tumor cells.

Due to its poor aqueous solubility and low biological availability, the clinical application of Cur is quite limited.

(/ˈkərkjuːmən/) is a diarylheptanoid. It is the principal curcuminoid of turmeric, which is a member of the ginger family (Zingiberaceae). Turmeric’s other two curcuminoids are desmethoxycurcumin and bis-desmethoxycurcumin. The curcuminoids are natural phenols that are responsible for the yellow color of turmeric. Curcumin can exist in several tautomeric forms, including a 1,3-diketo form and two equivalent enol forms. The enol form is more energetically stable in the solid phase and in solution.

Curcumin has a bright-yellow color and may be used as a food coloring. As a food additive, its E number is E100.

Results suggest that curcumin not only protects astrocytes from H2O2-induced oxidative stress but also reverses the mitochondrial damage and dysfunction induced by oxidative stress. A study also provides evidence for protective role of curcumin on astrocytes by showing its effects on attenuating reactive astrogliosis and inhibitingapoptosis 1).

Results of investigations proved that curcumin is a natural compound potentially useful in the fight against glioblastoma (GB) 2).

Mukherjee et al., used the non-invasive strategy of intranasal (IN) delivery of a glioblastoma-directed adduct of curcumin (CC), CC-CD68Ab, into the brain of mouse GBM GL261-implanted mice to study the effect of CC on tumor remission and on the phenotype of the tumor-associated microglial cells (TAMs). The treatment caused tumor remission in 50% of GL261-implanted GBM mice. A similar rescue rate was also achieved through intraperitoneal infusion of a lipid-encapsulated formulation of CC, Curcumin Phytosome, into the GL261-implanted GBM mice. Most strikingly, both forms of CC elicited a dramatic change in the tumor-associated Iba1+ TAMs, suppressing the tumor-promoting Arginase1high , iNOSlow M2-type TAM population while inducing the Arginase1low , iNOShigh M1-type tumoricidal microglia. Concomitantly, we observed a marked induction and activation of microglial NF-kB and STAT1, which are known to function in coordination to cause induction of iNOS. Therefore, our novel findings indicate that appropriately delivered CC can directly kill GBM cells and also repolarize the TAMs to the tumoricidal M1 state 3).

Nanomicelles loaded with Cur were formulated by a self-assembly method with biodegradable monomethoxy poly(ethylene glycol)-poly(lactide) copolymers (MPEG-PLAs). After encapsulation, the cellular uptake was increased and Cur could be released from MPEG-PLA micelles in a sustained manner. The Cur-loaded MPEG-PLA micelles (Cur/MPEG-PLA micelles) exhibited an enhanced toxicity on C6 and U251 glioma cells and induced more apoptosis on C6 glioma cells compared with free Cur. Moreover, the therapy efficiency of Cur/MPEG-PLA micelles was evaluated at length on a nude mouse model bearing glioma. The Cur/MPEG-PLA micelles were more effective on suppressing tumor growth compared with free Cur, which indicated that Cur/MPEG-PLA micelles improved the antiglioma activity of Cur in vivo. The results of immunohistochemical and immunofluorescent analysis indicated that the induction of apoptosis, antiangiogenesis, and inhibition of cell proliferation may contribute to the improvement in antiglioma effects. Our data suggested that Cur/MPEG-PLA may have potential clinic applications in glioma therapy 4).

Primary cortical neurons were cultured and were injured by ferrous chloride, z.vad.fmk was applied to block apoptosis, curcumin was administrated to protect neurons, necrostatin-1 was applied to inhibit necroptosis if needed. Cell viability was measured by detecting lactate dehydrogenase activity in lysates of surviving cells, and assessed by cell counting kit-8. The expression of receptor interacting protein 1 was detected by immunoblot and immunofluorescence. Results showed that necroptosis mainly occurred in the concentrations of ferrous chloride ranging from 100 to 200μM, curcumin attenuated necroptosis in a dose-dependent manner. Furthermore, curcumin decreased expression of receptor interacting protein 1 in a dose- and time-dependent manner. Taken together, these findings suggest that curcumin protects against iron induced neurotoxicity in primary cortical neurons by attenuating necroptosis 5).

Case series

Thirteen glioblastoma patients ingested 70 mg micellar curcuminoids [57.4 mg curcumin, 11.2 mg demethoxycurcumin (DMC), and 1.4 mg bis-demethoxycurcumin (BDMC)] three times per day for 4 days (total amount of 689 mg curcumin, 134 mg DMC, and 17 mg BDMC) prior to planned resection of their respective brain tumors. Tumor and blood samples were taken during the surgery and analyzed for total curcuminoid concentrations. (31)P magnetic resonance spectroscopic imaging was performed before and after curcuminoid consumption.

Ten patients completed the study. The mean intratumoral concentration of curcumin was 56 pg/mg of tissue (range 9-151), and the mean serum concentration was 253 ng/ml (range 129-364). Inorganic phosphate was significantly increased within the tumor (P = 0.034). The mean ratio of phosphocreatine to inorganic phosphate decreased, and the mean intratumoral pH increased (P = 0.08) after curcuminoid intervention.

Oral treatment with micellar curcuminoids led to quantifiable concentrations of total curcuminoids in glioblastomas and may alter intratumoral energy metabolism 6).

1) Daverey A, Agrawal SK. Curcumin alleviates oxidative stress and mitochondrial dysfunction in astrocytes. Neuroscience. 2016 Oct 1;333:92-103. doi: 10.1016/j.neuroscience.2016.07.012. Epub 2016 Jul 14. PubMed PMID: 27423629.
2) Alexandru O, Georgescu AM, Ene L, Purcaru SO, Serban F, Popescu A, Brindusa C, Tataranu LG, Ciubotaru V, Dricu A. The effect of curcumin on low-passage glioblastoma cells in vitro. J Cancer Res Ther. 2016 Apr-Jun;12(2):1025-32. doi: 10.4103/0973-1482.167609. PubMed PMID: 27461692.
3) Mukherjee S, Baidoo J, Fried A, Atwi D, Dolai S, Boockvar J, Symons M, Ruggieri R, Raja K, Banerjee P. Curcumin Changes the Polarity of Tumor-Associated Microglia and Eliminates Glioblastoma. Int J Cancer. 2016 Aug 20. doi: 10.1002/ijc.30398. [Epub ahead of print] PubMed PMID: 27543754.
4) Zheng S, Gao X, Liu X, Yu T, Zheng T, Wang Y, You C. Biodegradable micelles enhance the antiglioma activity of curcumin in vitro and in vivo. Int J Nanomedicine. 2016 Jun 9;11:2721-36. doi: 10.2147/IJN.S102450. eCollection 2016. PubMed PMID: 27354801; PubMed Central PMCID: PMC4907711.
5) Dai MC, Zhong ZH, Sun YH, Sun QF, Wang YT, Yang GY, Bian LG. Curcumin protects against iron induced neurotoxicity in primary cortical neurons by attenuating necroptosis. Neurosci Lett. 2013 Mar 1;536:41-6. doi: 10.1016/j.neulet.2013.01.007. Epub 2013 Jan 14. PubMed PMID: 23328441.
6) Dützmann S, Schiborr C, Kocher A, Pilatus U, Hattingen E, Weissenberger J, Geßler F, Quick-Weller J, Franz K, Seifert V, Frank J, Senft C. Intratumoral Concentrations and Effects of Orally Administered Micellar Curcuminoids in Glioblastoma Patients. Nutr Cancer. 2016 Aug-Sep;68(6):943-8. doi: 10.1080/01635581.2016.1187281. Epub 2016 Jun 24. PubMed PMID: 27340742.

New Book: Astrocytes and Epilepsy

Astrocytes and Epilepsy
By Jacqueline A. Hubbard, Devin K. Binder

Astrocytes and Epilepsy

List Price: $125.00


Epilepsy is a devastating group of neurological disorders characterized by periodic and unpredictable seizure activity in the brain.  There is a critical need for new drugs and approaches given than at least one-third of all epilepsy patients are not made free of seizures by existing medications and become “medically refractory“.  Much of epilepsy research has focused on neuronal therapeutic targets, but current antiepileptic drugs often cause severe cognitive, developmental, and behavioral side effects. Recent findings indicate a critical contribution of astrocytes, star-shaped glial cells in the brain, to neuronal and network excitability and seizure activity.  Furthermore, many important cellular and molecular changes occur in astrocytes in epileptic tissue in both humans and animal models of epilepsy.  The goal of Astrocytes and Epilepsy is to comprehensively review exciting findings linking changes in astrocytes to functional changes responsible for epilepsy for the first time in book format.  These insights into astrocyte contribution to seizure susceptibility indicate that astrocytes may represent an important new therapeutic target in the control of epilepsy.

Astrocytes and Epilepsy includes background explanatory text on astrocyte morphology and physiology, epilepsy models and syndromes, and evidence from both human tissue studies and animal models linking functional changes in astrocytes to epilepsy.  Beautifully labelled diagrams are presented and relevant figures from the literature are reproduced to elucidate key findings and concepts in this rapidly emerging field.  Astrocytes and Epilepsy is written for neuroscientists, epilepsy researchers, astrocyte investigators as well as neurologists and other specialists caring for patients with epilepsy.

  • Presents the first comprehensive book to synthesize historical and recent research on astrocytes and epilepsy into one coherent volume
  • Provides a great resource on the field of astrocyte biology and astrocyte-neuron interactions
  • Details potential therapeutic targets, including chapters on gap junctions, water and potassium channels, glutamate and adenosine metabolism, and inflammation

Product Details

  • Published on: 2016-08-08
  • Original language: English
  • Number of items: 1
  • Dimensions: 9.25″ h x 1.02″ w x 7.52″ l, .0 pounds
  • Binding: Hardcover
  • 394 pages

About the Author

Jacqueline A. Hubbard received her B.S. in biochemistry from the University of Vermont. Her M.S. and Ph.D. were both completed at the University of California, Riverside. She has been working in Devin Binder’s laboratory since 2011 and her research focuses on characterizing astrocytic changes in epilepsy. Specifically, she uses in vivo and in vitro techniques to characterize changes in aquaporin-4 (AQP4) and glutamate transporter 1 (GLT1) expression during epileptic pathogenesis that could ultimately be used to develop novel therapeutic strategies. She has presented her research at a number of national and international conferences and has co-authored a review article, a book chapter, and original research articles. She has also won awards for outstanding teaching, excellent presentations, as well as travel awards to attend international conferences.

Originally from the Bay Area, Devin K. Binder went to Harvard University as an undergraduate, where he studied biology, anthropology, and neuroscience. He was awarded the Hoopes Prize at Harvard for his summa cum laude senior honors thesis “Serotonin and behavioral state.” Deciding to pursue both neuroscience and clinical medicine, he enrolled in the M.D./Ph.D. program at Duke University. At Duke, he graduated 1st in his medical school class, and contributed to epilepsy neuroscience with his Ph.D. dissertation “The functional role of neurotrophins in the kindling model of epilepsy.” Subsequently, Binder completed a one-year internship in general surgery at the University of California, San Francisco, and a six-year residency in neurological surgery at UCSF. At UCSF, he did a one-year fellowship in the laboratory of Dr. Alan Verkman, leader in the field of aquaporin biology. Following residency, Binder was awarded the Van Wagenen neurosurgical fellowship for one year of neuroscience and neurosurgery at the University of Bonn. There, he did another fellowship in the laboratory of Dr. Christian Steinhäuser, Director of the Institute for Cellular Neuroscience at the University of Bonn. Following a three-year stint at the University of California, Irvine, in the Departments of Neurological Surgery and Anatomy & Neurobiology, Binder joined the Division of Biomedical Sciences at the University of California, Riverside School of Medicine in January 2010. Binder runs the NIH-funded Translational Neuroscience Laboratory, and conducts research on astrocytes, epilepsy, and neurophotonics. Binder has been publishing in the epilepsy field since the 1990s, and has publications since 2004 relevant to astrocyte contribution to seizures and epilepsy. He is the previous co-author of 3 books, 2 related to epilepsy, currently holds 2 NIH grants related to epilepsy, and sits on leadership committees of the American Epilepsy Society.

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