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Makale 1

Celik SE, Kocaeli H, Cordan T, Bekar A. Trigeminal neuralgia due to cerebellopontine angle lipoma. Case illustration. J Neurosurg 92:889, 2000.


OBJECTIVE AND IMPORTANCE: Various intracranial abnormalities, including infectious conditions, may manifest as trigeminal neuralgia.
CLINICAL PRESENTATION: A 33-year-old man presented with a 15-day history of right-sided facial pain and numbness. Neurological examination revealed diminished corneal reflex and facial sensation in the right V1–V2 distribution. Magnetic resonance imaging revealed a contrast-enhancing lesion centered at the right pons with extension of the enhancement to the sphenoid sinus.
INTERVENTION: Broad-spectrum antibiotics were administered for 6 weeks. This resulted in alleviation of symptoms and resolution of the lesion as revealed by repeat magnetic resonance imaging.
CONCLUSION: Presentation of a pons abscess with trigeminal neuralgia is rare, and to the best of our knowledge has not been reported previously. The patient was treated successfully with antibiotics alone.

Makale 2

Yilmazlar S, Kocaeli H. Monitoring and controlling of intracranial pressure in severe head injury. Ulus Travma Derg. 7:151-7, 2001.


Uncontrolled intracranial hypertension is an important cause of mortality and morbidity in severely head injured patients. Monitoring intracranial pressure (ICP) and controlling intracranial hypertension are essential in preventing herniation and avoiding ischemic secondary brain injury. Head injured patients may require specific ICP treatment to maintain it below 20 to 25 mmHg and improve cerebral perfusion pressure (CPP) above 70 mmHg. The optimal values of ICP and CPP are vary among patients and over time. A basic goal of neurotrauma intensive care is to develop methods for treatment the various traumatic cerebral conditions for individual patients. Various methods to controlling ICP have evolved over the past two decades. Most of these therapeutic maneuvers are critical to optimizing outcomes beyond simply lowering ICP. Continuous ICP monitoring reflects the brain decompensation, allowing early detection of herniation. The present article aims to define the roles of ICP and CPP monitoring as a methods of the ICP reduction therapy after severe brain injury.

Makale 3

Yilmazlar S, Kocaeli H, Doygun M. Chance type cervical fracture and neurological deficits in ankylosing spondylitis. Ulus Travma Derg 9(1):76-8, 2003.


Prevention of sudden neck movements is vital in patients with ankylosing spondylitis of the cervical spine. We present a case of ankylosing spondylitis who sustained a cervical fracture. He presented with paraplegia after a minor car collision and died of pulmonary embolism after the operation for anterior stabilisation. We believe that the most important matter in a patient with advanced ankylosing spondylitis is the prevention of the fractures and complications. The need for neck protection in automobiles was emphasized and the literature reviewed about the occurrences of neurological deficits following trauma.

Makale 4

Yilmazlar S, Ikiz I, Kocaeli H, Tekdemir I, Adim SB. Details of fibroligamentous structures in the cervical unco-vertebral region: an obscure corner. Surg Radiol Anat. 25:50-3, 2003.


Vertebral bone, joints and ligaments on the cervical spine are structures that maintain the stability of the spine and protect the neurovascular structures. Determining the detailed anatomical location of the intervertebral foramen and unco-vertebral (UV) region with respect to the vertebral bone, joint and ligaments is critical when choosing the safest surgical approach to the cervical spine. We studied the microscopic detailed anatomy of the dural covering and posterior longitudinal ligament (PLL) in eight cadaver specimens and the relevance of these structures in the UV region from C4 to C7. The uncinate process (UP) and its covering ligaments are mechanical barriers that prevent the nerve root and the vertebral artery against unintentional surgical damage. Dissection at the posterolateral surface of the UP revealed a separate perivascular fibroligamentous tissue (PVFLT) that originates from the PLL. The recognition of the PVFLT may provide for safe surgery by protecting the neural and vascular structures during decompression in the UV region.

Makale 5

Yilmazlar S, Kocaeli H, Uz A, Tekdemir I. Clinical importance of ligamentous and osseous structures in the cervical uncovertebral foraminal region. Clin Anat 16:404-10, 2003.


The vertebral artery, cervical spinal nerves, spinal nerve roots, and the bony and ligamentous tissue related to the cervical vertebrae are structures whose anatomy determines the path of a surgical approach. Defining the anatomy and, in particular, determining the precise location of vulnerable structures at the intervertebral foramen and the uncovertebral foraminal region (UVFR), a region defined by the uncinate process anteriorly, the facet joint posteriorly and the foramen transversarium laterally, has critical significance when selecting the safest surgical approach. We studied the anatomy of the vertebral artery, cervical spinal nerves, and spinal nerve roots within the UVFR in six cadaver specimens. We also obtained measurements of bony structures in 35 dry cervical vertebral columns, from C3-C7. The uncinate process (UP) projects superiorly from the posterolateral aspect of each cervical vertebral body, except for the first and second vertebrae. Because the posterior part of the UP lies adjacent to the vertebral artery, spinal nerve, and spinal nerve roots, its resection creates sufficient space to decompress these structures directly. The posterolateral surface of the UP is covered by ligamentous tissue that originates from the posterior longitudinal ligament and protects the neural and vascular structures during their decompression in the UVFR.
Copyright 2003 Wiley-Liss, Inc.

Makale 6

Yilmazlar S, Kocaeli H, Korfali E. Primary-isolated optic nerve sarcoidosis. Acta Neurochir (Wien). 146:65-7,2004.


Sarcoidosis is a systemic, idiopathic granulomatous disorder with occasionally surprising clinical presentations. A primary involvement of the optic nerve is particularly important due to visual prognosis. We report here a patient with occult sarcoidosis who presented to us with progressive visual loss as the first and primary manifestation of the disease. The patient underwent surgery for histopathological diagnosis and decompression of the optic nerve. This case demonstrated that sarcoidosis should be considered in the differential diagnosis of any lesion involving the optic nerve.

Makale 7

Yilmazlar S, Kocaeli H, Cordan T. Sella turcica metastasis from follicular carcinoma of thyroid. Neurol Res. 26:74-8. 2004.


A case of metastasis to the sella turcica from a follicular adenocarcinoma of the thyroid gland is presented. Metastasis to this site is rare and review of the literature reveals only 12 cases of metastatic thyroid carcinoma involving the sella turcica and pituitary gland. The optimal treatment strategy is still to be determined. A 43-year-old woman presented with headache, nausea, visual impairment and galactorrhea. An MRI scan of the cranium revealed an enhancing destructive sellar lesion. The patient underwent transsphenoidal removal of the lesion to alleviate visual loss. The histological features of the sellar tumor were identical to those of a follicular adenocarcinoma partially removed from the thyroid gland 22 months earlier. Total thyroidectomy followed by three courses of iodine-131 ablation enhanced with synthetic thyrotropin and thyroid hormone suppression therapy was instituted. The post-operative course was satisfactory with improved vision and ceased galactorrhea. This case was successfully treated with a combination of surgical removal, iodine-131 ablation and hormone suppression therapy, which resulted in disease control duration of four years. Sella turcica metastases of thyroid carcinoma are exceedingly rare and currently there are no established therapeutic guidelines.

Makale 8

Yilmazlar S, Kocaeli H, Cordan T. Brain stem stroke associated with epidermoid tumours: report of two cases. J Neurol Neurosurg Psychiatry 75:1340-2, 2004.


Two cases of cerebello-pontine angle epidermoid tumour presented with the clinical findings of brain stem stroke. Preoperative imaging showed stretching of branches of the basilar artery. Brain stem stroke as a presenting feature of cerebello-pontine angle epidermoid tumour has not been reported before.

Makale 9

Bekar A, Kocaeli H, Yilmaz E, Dogan S. Trigeminal neuralgia caused by a pontine abscess : case report. Neurosurgery. 55:1450-2, 2004.


OBJECTIVE AND IMPORTANCE: Various intracranial abnormalities, including infectious conditions, may manifest as trigeminal neuralgia.
CLINICAL PRESENTATION: A 33-year-old man presented with a 15-day history of right-sided facial pain and numbness. Neurological examination revealed diminished corneal reflex and facial sensation in the right V(1)-V(2) distribution. Magnetic resonance imaging revealed a contrast-enhancing lesion centered at the right pons with extension of the enhancement to the sphenoid sinus.INTERVENTION: Broad-spectrum antibiotics were administered for 6 weeks. This resulted in alleviation of symptoms and resolution of the lesion as revealed by repeat magnetic resonance imaging.
CONCLUSION: Presentation of a pons abscess with trigeminal neuralgia is rare, and to the best of our knowledge has not been reported previously. The patient was treated successfully with antibiotics alone.

Makale 10

Dogan S, Kocaeli H, Doygun M. Oxidized regenerated cellulose as a cause of paraplegia after thoracotomy: case report and review of the literature. Spinal Cord. 43:445-7,2005.



Case report.
OBJECTIVE: To report an unusual case of paraplegia.
SETTING: University Hospital Bursa, Turkey.
CASE REPORT: A 22-year-old woman presented with paraplegia following a left-sided thoracotomy. Magnetic resonance imaging showed a dorsal epidural mass at the level of T6. The patient underwent an emergency T6/7 laminectomy and removal of a tuft of oxidised regenerated cellulose, which had migrated through the intervertebral foramen causing spinal cord compression.
CONCLUSION: In cases of neurological deficits after surgery at the posterolateral edge of a thoracotomy, the clinician should be aware of the above possibility. Urgent radiological diagnosis and decompressive laminectomy is the treatment of choice.

Makale 11

Dogan S, Kocaeli H, Sahin S, Korfali E, Saraydaroglu O. Large cavernous hemangioma of the frontal bone. Neurol Med Chir (Tokyo). 45:264-7. 2005.


A 53-year-old woman presented with a rare case of cavernous hemangioma of the frontal bone manifesting as right frontal stabbing headache and local swelling. Computed tomography revealed an extensive, well-defined, radiolucent, osteolytic lesion in the right frontal bone. The inner and outer tables of the skull were eroded and the lesion had compressed the brain parenchyma. Right frontal craniotomy was performed, and the lesion with a 1 cm-wide margin of surrounding uninvolved bone was removed. The defect was reconstructed with titanium mesh. The patient did well after the operation. The cosmetic results were satisfactory and follow up at 6 months post-surgery revealed no recurrence.

Makale 12

Yilmazlar S, Kocaeli H, Aksoy K. Quadrigeminal cistern lipoma . J Clin Neurosci 12:596-9, 2005.


Intracranial lipomas are rare benign congenital neoplasms accounting for 0.1 to 0.5% of all primary brain tumours. Approximately 50% are associated with other cerebral developmental disorders. These slow growing benign lesions are usually asymptomatic and rarely require surgery. We report the case of a 37 year old woman presented with signs of raised intracranial pressure. Computerized tomography and magnetic resonance imaging demonstrated a quadrigeminal cistern lipoma compressing the aqueduct of Sylvius. The patient underwent surgery and a distinct plane of cleavage between the lipoma and the adjacent neural structures was found, allowing total removal of the lesion. Postoperatively, the patient was relieved of her original symptoms but developed akinetic mutism which lasted for two weeks. Intracranial lipomas rarely become symptomatic and surgery is seldom required. If the lesion progresses and causes symptoms of raised intracranial pressure or compression of neural structures, surgical intervention is indicated. Total removal should not be attempted unless a plain of cleavage between the lesion and adjacent neural structures is present. Surgical manipulation should be minimised to avoid complications.

Makale 13

Yilmazlar S, Arslan E, Kocaeli H, Dogan S, Korfali E, Aksoy A, Doygun M. Cerebrospinal fluid leakage complicating skull base fractures: analysis of 81 cases. Neurosurg Rev 29:64-71, 2006.


The aim of this study was to evaluate the results of conservative and surgical management options for traumatic cerebrospinal fluid (CSF) leakage complicating skull base fractures. The subjects were 81 patients who were treated between 1996 and 2003 for CSF leaks that had persisted for 24 h or longer after head injury. For each case the medical records were reviewed, and the data collected were as follows: demographic features, clinical and radiological findings, management options, complications and outcome scores. Analysis was done with patients grouped according to Glasgow coma scale (GCS) score at admission (8), and findings for three treatment methods (conservative, CSF drainage, surgery) were evaluated. In 32 cases (39.5%), the CSF leakage resolved spontaneously, and the mean hospital stay for these patients was 14+/-11 days. Twenty-four patients (29.6%) were treated by CSF drainage, and seven of these individuals ultimately required surgery to close the leak. Hospital stay was 17+/-7 days. Twenty-five patients (30.9%) underwent surgery as the initial treatment step, and the mean hospital stay for these individuals was 15+/-9 days. The large majority (74.2%) of patients with admission GCS scores 8 resolved spontaneously. The factors that had a critical influence on outcome in this series were level of consciousness on admission and presence of additional intracranial pathology associated with CSF leakage within cases of traumatic CSF fistulae due to skull base fractures. Treatment decisions should be dictated by the severity of neurological decline during the emergency period and the presence/absence of associated intracranial lesions. The timing for surgery and CSF drainage procedures must be decided with great care and with a clear strategy. The authors offer a treatment algorithm.

Makale 14

Yilmazlar S, Kocaeli H, Aydiner F, Korfali E. Medial portion of the cavernous sinus: quantitative analysis of the medial wall. Clin Anat. 18:416-422, 2005.


Pituitary tumors invade the cavernous sinus via the medial wall. Researchers have speculated that this wall is composed of dura and that substances secreted by tumors might damage this barrier. In contrast to the lateral wall, little is known about the structure of the medial wall of the cavernous sinus (MWCS). This study provides the first detailed quantitative (thickness) and qualitative (histological) assessment of the MWCS. Eighteen sellar-parasellar tissue blocks were obtained from adult human autopsies. Ten specimens were used for microsurgical dissection and macroscopic anatomical description. Eight specimens were used for histopathological study and for recording computer measurements of MWCS thickness. Each of these eight specimens was divided into three approximately equal-sized pieces, with cuts made in the coronal plane from posterior to anterior starting at the anterior level of the pituitary stalk. Wall thicknesses were compared in the three different regions (posterior, middle, anterior), and also on the left vs. the right sides. The investigations showed that the MWCS is a distinct dural layer that forms a barrier between the medial venous space of the cavernous sinus and the pituitary gland. The mean thickness of the 48 total (left and right) MWCS observed in the 24 sections examined was 0.195 +/- 0.066 mm (range = 0.080-0.387 mm). This wall is composed of loosely arranged collagen fibers that comprise a specific layer known as "meningeal dura." The posterior third of the MWCS was significantly thinner than the middle third (P = 0.0014) or anterior third (P = 0.0001). No macro- or microscopic defects were observed in any of the MWCS in the 18 specimens. The thinness of the posterior MWCS suggests that this is the most likely path for extension of pituitary tumors into the cavernous sinus.
Copyright 2005 Wiley-Liss, Inc.

Makale 15

Yilmazlar S, Kocaeli H, Dogan S, Abas F, Aksoy K, Korfali E, Doygun M. Traumatic epidural haematomas of nonarterial origin: analysis of 30 consecutive cases. Acta Neurochir (Wien) 147:1241-8, 2005.


BACKGROUND: The purpose was to analyse the clinical and radiological findings, and management approaches used in 30 consecutive cases of traumatic epidural haematoma of nonarterial origin treated at one centre.
METHOD: Medical records for 30 patients surgically treated for epidural haematoma of nonarterial origin between 1997 and 2003 were reviewed. Epidural haematoma of nonarterial origin was diagnosed based on computed tomography (CT) and the bleeding source was confirmed intra-operatively. Admission status, outcome, fracture location, haematoma location/size/volume, and additional intracranial pathology were among the data noted. Two groups were formed for analysis: venous sinus bleeding (group 1) and other venous sources (group 2).
FINDINGS: The 30 cases accounted for 25% of the total number of traumatic epidural haematomas (n = 120) treated during the same period. The epidural haematomas of nonarterial origin locations were transverse sigmoid sinus (n = 11; 36.7%), superior sagittal sinus (n = 6; 20%), venous lakes (n = 5; 16.6%), diploë (n = 5; 0.16%), arachnoid granulations (n = 2; 6.7%), petrosal sinus (n = 1; 3.3%). There were 12 postoperative complications in 9 patients: recurrence (n = 4; 13.3% of the 30 total), pneumonia (n = 4; 13.3%), meningitis (n = 2; 6.7%), hydrocephalus (n = 1; 3.3%) and subdural effusion (n = 1; 3.3%). All recurrence cases were re-explored. Six (20%) patients died. Glasgow Outcome Scale (GOS) scores (mean follow-up 13.3 +/- 7.8 months) revealed 22 (73.3%) patients with favourable results (GOS 4-5) and 8 (26.7%) had poor results (GOS 1-3).
CONCLUSIONS: Cases of epidural haematoma of nonarterial origin differ from the more common arterial-origin epidural haematomas with respect to lesion location, surgical planning, postoperative complications, and outcome. Epidural haematoma of nonarterial origin should be suspected if preoperative CT shows a haematoma overlying a dural venous sinus or in the posterior fossa and convexity. The sinus-origin group had a high frequency of fractures which crossed the sinuses, and this might be diagnostically and surgically useful in such cases.

Makale 16

Kocaeli H, Andaluz N, Choutka O, Zuccarello M. Use of radial artery grafts in extracranial-intracranial revascularization procedures. Neurosurg Focus. 2008;24(2):E5. doi: 10.3171/FOC/2008/24/2/E5.


Cerebral revascularization procedures have been used in the clinical management of actual or threatened cerebral ischemic states and unclippable cerebral aneurysms. An alternative to a low-flow bypass graft (for example, with the superficial temporal artery) is the use of high-flow grafts created using the saphenous vein (SV) or radial artery (RA). These high-flow grafts are particularly useful when otherwise adequate collateral flow is insufficient to enable sacrifice of the parent vessel without the risk of cerebral ischemia. In their clinical series of 13 patients who underwent high-flow bypass with an RA graft, the authors describe 8 women and 5 men whose ages ranged from 44 to 69 years (mean 57.84 +/- 9.05 years). Indications for RA graft bypass were unclippable aneurysms in 10 patients and occlusive cerebrovascular disease in 3 patients. The authors review the properties of the 2 most common conduits, the SV and RA grafts. They present the technique of high-flow extracranial-intracranial bypass produced using RA grafts in the management of occlusive atherosclerotic disease and complex intracranial aneurysms that are not otherwise amenable to either clip ligation or coil occlusion.

Makale 17

Kocaeli H, Korfali E, Ozturk H, Kahveci N, Yilmazlar S. MK-801 improves neurological and histological outcomes after spinal cord ischemia induced by transient aortic cross-clipping in rats. Surg Neurol 64 Suppl 2:S22-6, 2005.


BACKGROUND: Glutamergic excitotoxicity has been shown to play a deleterious role in the pathophysiology of ischemic spinal cord injury (ISCI). The aim of this study was to investigate the neuroprotective effect of a single dose of MK-801, an antiexcitotoxic drug, in a rat model of ISCI.
METHODS: Ischemic spinal cord injury was induced for 17 minutes in Sprague-Dawley rats using direct aortic arch, just proximal to the left common carotid artery, plus left subclavian artery cross-clamping through a left-sided limited thoracotomy. Study groups were as follows: control group (n = 8) receiving only vehicle and experimental group (n = 8) receiving a single dose of MK-801 (1 mg/kg IV) 10 minutes before aortic clamping. Neurological examination was performed at 6 hours, 24 hours, and daily up to 96 hours. Rats were sacrifice at methylprenisolone socium succinate 96 hours, and spinal cords were removed for histopathology.
RESULTS: All the control rats had severe permanent neurological deficits after ISCI, whereas the MK-801-treated rats had statistically (P < .05) better neurological outcome and good recovery. Histopathology revealed severe neuronal necrosis in the lumbar gray matter of control rats, whereas MK-801-treated rats showed mild injury.
CONCLUSION: These results demonstrate that combined temporary clipping of the aortic arch (just proximal to the left common carotid artery) plus left subclavian artery for 17 minutes reproduces reliable paraplegia, and a single dose of MK-801 given before ISCI provides significant neuroprotection.

Makale 18

Kocaeli H, Yılmazlar S,Abas F, Aksoy K. Total ossification of choroid plexus papilloma mimicking petrous bone pathology. Pediatr Neurosurg 43:67-71,2007.

Makale 19

Kocaeli H, Yakut T, Bekar A, Taşkapılıoğlu Ö, Tolunay Ş. Glioblastomatous recurrence of oligodendroglioma remote from the original site: a case report. Surg Neurol 66:627-30,2006.


BACKGROUND: As in all diffuse gliomas, recurrence is an inherent feature of oligodendrogliomas, either as the same or higher grade neoplasm at the primary site. The rate of remote recurrence after surgery for the primary tumor cannot be estimated from the scarce literature, but delayed treatment of the primary tumor and genetic alterations may be associated with this phenomenon.
CASE DESCRIPTION: A 40-year-old man presented with generalized seizures. A magnetic resonance imaging scan disclosed a right frontal mass lesion showing features of a low-grade glioma for which he refused any treatment. Seven months after diagnosis upon uncontrollable seizures, he underwent a stereotactic biopsy, which was followed by a right frontal craniotomy, both of which confirmed the lesion as a grade 2 oligodendroglioma. Six months after surgery, the patient presented with a left frontal lobe GBM without evidence of recurrence at the primary site. The genetic analysis of the primary and recurrent tumors showed trisomy 7, monosomy 10, but not 1p or 19q deletions, which have been proposed as markers for favorable prognosis.
CONCLUSION: Recurrence of a frontal lobe oligodendroglioma remote from the primary site as a GBM is a rare occurrence. Single-cell invasion across the corpus callosum with subsequent or simultaneous malignant degeneration into a secondary GBM is the likely mechanism. As the genetic analysis suggests, conversion of oligodendroglioma to GBM may be associated with gain of chromosome 7, loss of chromosome 10, and other genetic markers that may represent late events in the oncogenesis of oligodendroglial tumors.

Makale 20

Hakyemez B, Yildirim N, Erdogan C, Kocaeli H, Korfali E,Parlak M. Meningiomas with conventional MRI findings resembling intraaxial tumors: can perfusion-weighted MRI be helpful in differentiation? Neuroradiology 48:695-702,2006.


INTRODUCTION: To investigate the contribution of perfusion-weighted MRI to the differentiation of meningiomas with atypical conventional MRI findings from intraaxial tumors.
METHODS: We retrospectively analyzed 54 meningiomas, 12 glioblastomas and 13 solitary metastases. We detected 6 meningiomas with atypical features on conventional MRI resembling intraaxial tumors. The regional cerebral blood flow (rCBV) ratios of all tumors were calculated via perfusion-weighted MRI. The signal intensity-time curves were plotted and three different curve patterns were observed. The type 1 curve resembled normal brain parenchyma or the postenhancement part was minimally below the baseline, the type 2 curve was similar to the type 1 curve but with the postenhancement part above the baseline, and the type 3 curve had the postenhancement part below the baseline accompanied by widening of the curve. Student's t-test was used for statistical analysis.
RESULTS: On CBV images meningiomas were hypervascular and the mean rCBV ratio was 10.58+/-2.00. For glioblastomas and metastatic lesions, the rCBV ratios were 5.02+/-1.40 and 4.68+/-1.54, respectively. There was a statistically significant difference in rCBV ratios between meningiomas and glioblastomas and metastases (P<0.001). Only one of the meningiomas displayed a type 2 curve while five showed a type 3 curve. Glioblastomas and metastases displayed either a type 1 or a type 2 curve. None of the meningiomas showed a type 1 curve and none of the glioblastomas or metastases showed a type 3 curve.
CONCLUSION: Differentiating meningiomas with atypical conventional MRI findings from malignant intraaxial tumors can be difficult. Calculation of rCBV ratios and construction of signal intensity-time curves may contribute to the differentiation of meningiomas from intraaxial tumors.

Makale 21

Bekar A, Kocaeli H, Abas F, Bozkurt M. Bilateral High Level Percutaneous Cervical Cordotomy in Cancer Pain due to Lung Cancer: A Case Report. Surg Neurol 67:504-7; 2007.


BACKGROUND: Computed tomography-guided high-level percutaneous cordotomy has been used unilaterally or bilaterally for the treatment of localized intractable pain in malignancies.
CASE DESCRIPTION: A 57-year-old man was admitted to the hospital with the complaint of intractable pain involving the left side of the chest, axillary region, and shoulder. He was operated for small cell lung cancer on the left side in December 2003 and received radiotherapy and chemotherapy. His neurological examination was normal. Magnetic resonance imaging of the thorax revealed contrast-enhancing lesions on the left side extending to mediastinum and pleura. His pain was relieved completely after the first cordotomy procedure, and he was discharged from the hospital on the second postoperative day. The patient was readmitted to the hospital with the complaint of severe unilateral chest pain like the initial pain on the right side 4 days after cordotomy. The CT-guided bilateral high-level percutaneous cordotomy was performed with a 15-day interval.
CONCLUSION: The CT-guided bilateral high-level percutaneous cordotomy can be used in the treatment of intractable upper trunk pain in patients with cancer without pulmonary dysfunction.

Makale 22

Tunca B, Bekar A, Cecener G, Egeli U, Vatan O, Tolunay S, Kocaeli H, Aksoy K. Impact of novel PTEN mutations in Turkish patients with glioblastoma multiforme. J Neurooncol 82:263-9; 2007.


Glioblastoma multiforme (GBM) represents the most common and aggressive type of primary neoplasms of the central nervous system. The PTEN (phosphatase, tensin homologue, deleted on chromosome TEN; MIM # 601728) tumor suppressor gene has an essential biological role in the formation of glioblastomas. It is known that there are variations in genetic alterations in tumors that develop in patients with different ethnic backgrounds and because there is no study evaluating PTEN mutation in Turkish patients with GBM, we aimed to realize the present study. We investigated 62 GBM tumors for mutations of the PTEN gene using single strand conformational polymorphism (SSCP) method followed by DNA sequencing. As a result of our investigation, PTEN mutations were detected in 15 of 62 tumors (24.19%). Nine different sequence variants were identified: one novel promoter site mutation (5'UTR -9C-->T), one novel intronic mutation (IVS2-2delA), four novel point mutations (61A-->G, 105T-->G, 248C-->G, and 364C-->G), two novel frameshift mutations (213delC) and 378delGATA) and one previously reported global exonic transition type mutation (129G-->A). Since the majority of PTEN mutations identified in the present study are novel, we believe that these alterations may be specific to Turkish population. Furthermore, though no significant correlation was found between PTEN mutations and histopathological properties of GBM tumors, our findings indicate that localizations of mutations in PTEN gene may have an effect on clinical aggressiveness of GBM tumors.

Makale 23

Ozay R, Bekar A, Kocaeli H, Karlı N, Tolunay S, Ulus IH. Citicoline improves functional recovery, promotes nerve regeneration and reduces postoperative scarring following peripheral nerve surgery in rats. Surg Neurol 68(6):615-622, 2007.


BACKGROUND: Citicoline has been shown to have beneficial effects in a variety of CNS injury models. The aim of this study was to test the effects of citicoline on nerve regeneration and scarring in a rat model of peripheral nerve surgery.
METHODS: Seventy adult Sprague-Dawley rats underwent a surgical procedure involving right sciatic nerve section and epineural suturing. Rats were assigned to the control or experiment groups to receive a topical application of 0.4 mL of saline or 0.4 mL (100 micromol/L) of citicoline, respectively. Macroscopic, histological, functional, and electromyographic assessments of nerves were performed 4 to 12 weeks after surgery.
RESULTS: In the control versus citicoline-treated rats, SFI was -90 +/- 1 versus -84 +/- 1 (P < .001), -76 +/- 4 versus -61 +/- 3 (P < .001), and -66 +/- 2 versus -46 +/- 3 (P < .001) at 4, 8, and 12 weeks after surgery, respectively. At 12 weeks after surgery, axon count and diameter were 16400 +/- 600 number/mm(2) and 5.47 +/- 0.25 microm versus 22250 +/- 660 number/mm(2) (P < .001) and 6.65 +/- 0.28 microm (P < .01) in the control and citicoline-treated groups, respectively. In citicoline-treated rats, histomorphological axonal organization score at the repair site was (3.4 +/- 0.1) significantly better than that in controls (2.6 +/- 0.3) (P < .001). Peripheral nerve regeneration evaluated by EMG at 12 weeks after surgery showed significantly better results in the citicoline group (P < .05). Nerves treated with citicoline demonstrated reduced scarring at the repair site (P < .001).
CONCLUSION: Our results demonstrate that citicoline promotes regeneration of peripheral nerves subjected to immediate section suturing type surgery and reduces postoperative scarring.

Makale 24

Erdogan C, Hakyemez B, Arat A, Kocaeli H, Bekar A, Parlak M. Spinal dural arteriovenous fistula in a case with lipomyelodysplasia. Br J Radiol. 2007 ;80:e98-e100. Erratum in: Br J Radiol. 80(957):771;2007. Kocaeli, H [added].


Coexistence of a spinal dural arteriovenous fistula within a dysraphic spinal lesion is a very rare situation. We report a 40-year-old man who presented with low back pain and progressive paraparesis. MR images showed an intradural high signal intensity mass at the L2-L3 level containing irregular signal void structures. Spinal angiography revealed extradural arteriovenous fistula with three connections, drained by a tortuous perimedullary vein.

Makale 25

Kocaeli H, Hakyemez B, Bekar A, Yilmazlar S, Abas F, Yilmaz E, Korfali E. Unusual complications and presentations of intracranial abscess: experience of a single institution. Surg Neurol 69(4):383-391, 2008.


BACKGROUND: Complicating events and unusual presentations associated with intracranial abscess are rare but potentially fatal conditions. This study was undertaken to shed light on the unusual complications and presentations of intracranial abscess treated at a single institution.
METHODS: We retrospectively reviewed 116 cases of intracranial abscesses that were treated at our institution over the last 10 years and identified 11 (9.4%) cases with unusual complications.
RESULTS: These complications consisted of (1) rupture within the abscess, (2) hemorrhage into the abscess, (3) hemispheric infarction due to ICA thrombosis, (4) acute visual loss due to pituitary abscess, (5) acute neurologic deterioration due to rapid gas formation within the abscess, (6) acute hydrocephalus, (7) trigeminal neuralgia, (8) fungal abscess developing secondary to intracranial extension of a temporal bone tumor, (9) Cryptococcus abscess with different morphology, (10) pontine infarction, and (11) sigmoid sinus thrombosis. Sinusitis accompanied 8 (72.7%) of the cases, and there were 5 (45.4%) mortalities. Culture results were unyielding in 4 patients, whereas Streptococcus species were identified in 4 and fungi in the rest.
CONCLUSION: Intracranial abscesses and their complications still continue to be challenging entities in the neurosurgical practice. Our experience may provide an informational source for those who are taking care of patients with intracranial abscess.

Makale 26

Dogan S, Kocaeli H, Abas F, Korfali E. Pituitary apoplexy as a cause of internal carotid artery occlusion. J Clin Neurosci 15(4):480-483, 2008.


Occlusion of intracranial arteries by pituitary apoplexy with resulting infarction is a rare occurrence. A 50-year-old man who presented with a history of sudden onset of frontal headache and visual impairment was admitted to another medical centre and MRI revealed a non-enhancing sellar lesion with suprasellar and infrasellar extension. Thereafter, the patient's consciousness deteriorated progressively and he showed signs of herniation; he was then referred to our centre for further evaluation. CT scanning revealed infarction of the left internal carotid artery territory. Transcranial resection of the tumour followed by a large decompressive craniotomy restored the blood flow in the internal carotid artery. Histological examination revealed the tumour to be a pituitary adenoma that contained formed blood elements. The patient's neurological status did not improve and he died on the ninth postoperative day despite vigorous treatment for controlling intracranial pressure. This case study documents a rare presentation of pituitary apoplexy that caused signs of raised intracranial pressure due to mechanical obstruction of an internal carotid artery with resulting infarction.

Makale 27

Kocaeli H, Taşkapılıoğlu O, Başaran E, Karaoğlu A, Bekar A. Multiple dural tuberculomas presenting as leptomeningeal carcinomatosis. Case Rep Neurol Med. 2011;2011:581230. doi: 10.1155/2011/581230.


Objective and Importance. We present the rare occurrence of multiple dural-based tuberculomas mimicking leptomeningeal carcinomatosis in a young immunocompetent patient. Clinical Presentation. A 36-year-old man presented with a 2-month history of generalized epileptic activity and altered perception. Neurological examination was remarkable for bilateral Babinski's sign. Cranial magnetic resonance imaging (MRI) revealed multiple dural-based enhancing lesions with cerebral edema. Intervention. A right frontal craniotomy was performed for diagnosis. Histological examination revealed multiple confluent necrotizing and nonnecrotizing granulomas with giant cells which was consistent with tuberculosis (TB), and the patient was placed on anti-TB therapy for 24 months. Conclusion. To the best of our knowledge isolated diffuse involvement of the dura mater by TB, mimicking leptomeningeal carcinomatosis, as the sole manifestation of disease has not been reported before. Since pachymeningeal TB is rarely suspected when atypical radiological appearance is combined with the absence of systemic disease, biopsy is inevitably required for diagnosis.

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Yilmazlar S, Kocaeli H, Eyigor O, Hakyemez B, Korfali E. Clinical importance of the basal cavernous sinuses and cavernous carotid arteries relative to the pituitary gland and macroadenomas: quantitative analysis of the complete anatomy. Surg Neurol 70(2):165-174, 2008.


BACKGROUND: It is unusual to encounter hemorrhagic complications caused by arterial or venous damage during TSS. Problems with these structures can lead to permanent disability or death. Our aim was to quantitatively analyze anatomical and radiologic relationships among the BCS, the CCA, and the pituitary gland, as these structures are accessed during TSS.
METHODS: Forty-nine formaldehyde-fixed, sellar-parasellar tissue blocks from adult cadavers were used to simulate accessing the BCSs via TSS. In each specimen, size of the pituitary gland and specific characteristics of each BCS and the horizontal segment of each CCA were recorded. Nine other specimens were used for histologic investigation and microanatomical measurements. To attest correlation between clinical data and cadaveric measurements, coronal MRI scans of 22 healthy adults as well as of 28 patients with macroadenomas were analyzed.
RESULTS: In cadaveric specimens, distances between both CCAs in the BCS were 17.1 +/- 4.0 mm anteriorly, 20.3 +/- 4.2 mm medially, and 18.8 +/- 4.6 mm posteriorly. In this study, the anterior medial space of the BCS was dominant in 12 specimens on the right side and in 5 specimens on the left; the posterior medial space of the BCS was dominant in 23 specimens on the right side and in 9 specimens on the left side. The right medial BCS was dominant in 35 specimens. On histologic coronal sections, some part of the carotid artery's (CA's) diameter was located below the line passing from the basal dural layer ranging from 5.3% to 65.4%. In normal-sella images, distances between both CCAs were 15.4 +/- 1.8 mm anteriorly, 16.0 +/- 2.8 mm medially, 16.2 +/- 3.4 mm posteriorly. On coronal normal-sella images, some part of the CA's diameter was located below the line passing from the basal dural layer ranging from 16.4% to 66.7%. In macroadenomas, distances between both CCAs were 22.0 +/- 3.6 mm anteriorly, 21.5 +/- 3.8 mm medially, and 20.7.2 +/- 3.7 mm posteriorly . On coronal images, in only 6 of 28 macroadenomas, some part of the CA's diameter was located below the line passing from the basal dural layer ranging from 12.5% to 100%.
CONCLUSIONS: Our results indicate that a working area of 15.0 +/- 2.6 x 10.3 +/- 2.1 mm is safe during TSS. The position of the CCA posterior segment was notably more caudal than the anterior segment with respect to the basal dura, which should be taken into account during extended exposure. Also, preoperative recognition of the anatomical variations is beneficial for detection of the boundaries of dissection, which is particularly important in the BCS, where variable course of CCAs may transform the anatomical configuration. Slowly growing pituitary adenomas stretch out both CCAs considerably from medial to lateral directions, and they cause widening of intercarotid distances in all segments. Processing of fixation, decalcification, and paraffin embedding for the cadaveric tissue in contrast to physiologically hydrated tissues may change the accuracy of measurements. These measurements are significantly different than those in the radiologic images when arterial blood under pressure is in the CCA as well as when venous blood fills the cavernous sinus as is the case in vivo. In clinical practice, these facts must be taken into consideration in the cadaveric measurements.

Makale 29

Kocaeli H, Korfali E. Rupture of a small middle cerebral artery aneurysm into middle fossa arachnoid cyst presenting as a chronic subdural haematoma. Acta Neurochir (Wien) 150(4):407-408, 2008.


The rupture of an aneurysm into an arachnoid cyst and subdural space is unusual. A 25-year-old man was admitted 2 weeks after having undergone a burr hole drainage for a chronic subdural haematoma elsewhere. An angiogram revealed a small aneurysm at the bifurcation of the middle cerebral artery. The aneurysm was clipped and the cyst communicated with the basal cisterns. To the best of our knowledge, this is the first report of an association of an aneurysm of the middle cerebral artery with an arachnoid cyst presenting as a chronic subdural haematoma.

Makale 30

Kocaeli H, Korfali E, Taskapilioglu O, Ozcan T. Analysis of intracranial pressure changes during early versus late percutaneous tracheostomy in a neuro-intensive care unit. Acta Neurochir (Wien) 150(12):1263-1267, 2008.


BACKGROUND: We aimed to investigate intracranial pressure (ICP) changes during early versus late bedside percutaneous tracheostomy (PT) in a neuro-intensive care unit (NICU).
METHODS: This study included 30 patients admitted to our NICU for head trauma, subarachnoid haemorrhage, intracerebral haematoma or brain tumour with a Glasgow Coma Score (GCS) less than 8. These patients also underwent ICP monitoring. Bedside PT was performed either early (within 7 days of ventilation) or late (after 7 days of ventilation) via the Griggs system. In all patients; ICP, systemic blood pressure, heart rate, oxygen saturation (Sat O(2)) and arterial blood gases were recorded 5 min before the procedure, during skin incision, during tracheal cannulation, as well as 5 min and 10 min after the procedure.
FINDINGS: Thirty patients, 18 male and 12 female, with various intracranial pathologies between ages 18 and 78 (mean 38.7 +/- 20) were identified. The admission GCS ranged between 4 and 11 (median 7). Physiological variables did not differ significantly between the two groups. In the early group, ICP values measured 5 min before the procedure, during skin incision, during tracheal cannulation, as well as 5 min and 10 min after the procedure were 15.1 +/- 5.2, 22 +/- 10.1, 28.4 +/- 13.7, 17.3 +/- 7.1, 13.8 +/- 5.0 mmHg, respectively. In the late group, these values were 14.2 +/- 4.5, 17.2 +/- 5.5, 21.5 +/- 8.0, 15.1 +/- 5.3 and 12.4 +/- 4.1 mmHg. There was no significant difference between the early or late groups in terms of ICP increases during these predetermined 5 time points.
CONCLUSIONS: In patients with decreased intracranial compliance, a relatively minimally invasive procedure such as PT may lead to significant increases in ICP. The timing of PT does not seem to influence ICP, mortality, pneumonia or early complications. During the PT procedure, ICP should be closely monitored and preventive strategies should be instituted in an attempt to prevent secondary insult to an already severely injured brain.

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Şahin S, Bekar A, Doğan Ş, Kocaeli H, Aksoy K. Critical care management of severe head injury in children. Neurosurg Q 18: 207-215, 2008.


BACKGROUND: Our aim was to analyze prognostic factors and their association with outcome among children with severe head injury.
METHODS: We conducted a retrospective study among children (n=55) with severe head injury [Glasgow Coma Score (GCS) ?8] who were admitted to our Neurosurgical Intensive Care Unit (ICU) from January 1996 to September 2003. The patients were immediately evaluated with cranial computed tomography (CT) for the severity of head injury as well as for the causes of secondary insults such as hypoxia and hypotension, metabolic and hematological alterations. Outcome analysis was assessed according to Glasgow Outcome Scale Score (GOS) six months after the injury.
RESULTS: A poor result occurred in 31 patients (57%) while 24 patients (43%) had favourable results. Multivariate analysis showed significant independent prognostic effect for admission mean systolic blood pressure, presence of hypoxia, multiple trauma, admission GCS score and multiple intracranial lesions (p<0.05). Admission WBC counts and serum glucose levels were not correlated with GOS.
CONCLUSION: This study describes clinicoradiologic findings and prognostic factors regarding severe head injury in pediatric patients. The goals of managements of pediatric patients with severe traumatic head injury include normalizing intracranial pressure, optimizing arterial blood gases and systemic blood pressure, and prevention of factors that exacerbate secondary brain injury.

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Baytan B, Evim MS, Güneş AM, Kocaeli H, Balaban S, Korfalı E, Tüzüner N. Cerebellar granulocytic sarcoma: a case report. Turk J Haematol. 2012 Jun;29(2):177-80. doi: 10.5505/tjh.2012.65002.


Granulocytic sarcoma is a rare tumor composed of immature granulocytic cells that is usually associated with acute myelogenous leukemia. Intraparenchymal cranial localization without skull, meningeal, or bone marrow invasion is extremely rare. The mechanisms of intraparenchymal cranial localization of GS remains unknown, as only 10 cases with cerebellar granulocytic sarcoma have been previously reported. Herein, we report a four year old boy with cerebellar localization of granulocytic sarcoma.

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Doğan S, Kocaeli H, Taşkapilioğlu MO, Bekar A. Stab injury of the thoracic spinal cord: case report. Turk Neurosurg. 2008 Jul;18(3):298-301.


Stab injuries of the spinal cord are rare. We report a case of a 22-year-old male who was hospitalized because of a spinal cord injury resulting from a stab wound in the posterior thoracolumbar area. On admission, the patient had 2/5 muscle strength of the right leg (monoparesis) and hypoesthesia below the L1 level. Radiological investigation revealed the retained tip of a knife that penetrated the spinal canal at the T12 level. An urgent right T12 hemilaminotomy was performed and retained knife fragment was removed. Six months after operation, the motor deficit had completely improved although hypoesthesia was still present. Surgery should be considered as the first-line treatment in cases of incomplete injuries of the spinal cord with retained metallic object.

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Kocaeli H, Korfali E, Doğan S, Savran M. Sylvian cistern dermoid cyst presenting with dysgeusia. Acta Neurochir (Wien) 151(5):561-563, 2009.


It is rare for a patient with a dermoid cyst (DC) to present with taste dysfunction. A 58-year-old man presented with an altered sense of taste. Magnetic resonance imaging of the brain showed a mass lesion in the right insula with compression effect. The tumour was resected and was found to be a DC. The postoperative course was uneventful, and the patient resumed his usual taste sensation within the early postoperative period. To the best of our knowledge, this is the first report of a sylvian cistern DC that presented with dysgeusia.

Makale 35

Bekar A, Doğan S, Abaş F, Caner B, Korfali G, Kocaeli H, Yilmazlar S, Korfali E. Risk factors and complications of intracranial pressure monitoring with a fiberoptic device. J Clin Neurosci 16(2):236-240, 2009.


We prospectively investigated the complications associated with intraparenchymal intracranial pressure (ICP) monitoring using the Camino intracranial pressure device. A fiberoptic ICP monitoring transducer was implanted in 631 patients. About half of the patients (n=303) also received an external ventricular drainage set (EVDS). The durations (mean+/-SD) of ICP monitoring in patients without and with an EVDS were 6.5+/-4.4 and 7.3+/-5.1 days, respectively. Infection occurred in 6 patients with only an ICP transducer (6/328, 1.8%) and 24 patients with an EVDS also (24/303, 7.9%). The duration of monitoring had no effect on infection, whereas the use of an EVDS for more than 9 days increased infection risk by 5.11 times. Other complications included transducer disconnection (2.37%), epidural hematoma (0.47%), contusion (0.47%), defective probe (0.31%), broken transducer (0.31%), dislocation of the fixation screw (0.15%), and intraparenchymal hematoma (0.15%). In conclusion, intraparenchymal ICP monitoring systems can be safely used in patients who either have, or are at risk of developing, increased ICP.

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Kocaeli H, Chaalala C, Abruzzo TA, Zuccarello M. Results of surgical management for posterior cerebral artery aneurysms: 7-year experience in the endovascular era. Acta Neurochir (Wien). 151(12):1583-91, 2009.


PURPOSE: Unlike most posterior circulation aneurysms, posterior cerebral artery (PCA) aneurysms can be surgically approached, we believe, without significant technical difficulty or procedural morbidity. We report our recent experience to assess procedural complications and clinical outcomes for PCA aneurysms.
METHODS: In our retrospective review of 15 consecutive patients with PCA aneurysms, six patients underwent surgical treatment, six patients had endovascular coiling, (three patients from the endovascular group also underwent surgical revascularization), and three patients were treated conservatively (medical or observation) (2001-2007). Clinical records were reviewed for: patient demographics; clinical presentation; aneurysm location, size, and morphology; treatment; procedural complications; outcome (clinical and angiographic).
RESULTS: Complete aneurysm obliteration with parent vessel or bypass patency was demonstrated by intraoperative angiography in all patients. One patient died and two patients suffered procedure-related permanent neurologic injury. Considering both surgical end endovascular treatment modalities, mortality was 8.3% and permanent morbidity was 16.6%. At mean clinical follow-up of 2-96 months (15.8 +/- 10.5 months), nine of ten patients had a Glasgow Outcome Score of 4 or 5. In patients who underwent bypass procedures, computed tomographic (CT) angiography or cerebral angiography demonstrated a patent functional bypass before the PCA occlusion.
CONCLUSIONS: Our findings for these 15 patients suggest the value of a multimodality of treatments for PCA aneurysms. Revascularization of the PCA can be performed with favorable technical results and clinical outcomes when the patency of the PCA cannot be preserved.

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Ozcelik T, Ozkalemkas F, Kocaeli H, Altundal Y, Ener B, Ali R, Ozkocaman V, Hakyemez B, Tunali A.Successful treatment of neuroaspergillosis in a patient with acute lymphoblastic leukemia: role of surgery, systemic antifungal therapy and intracavitary therapy]. Mikrobiyol Bul. 43(3):499-506, 2009 Turkish.


Cerebral aspergillosis is a rare condition that generally exhibits a poor response to conventional antifungal drugs. We report here a case of cerebral aspergillosis in a 34-years-old man with acute lymphoblastic leukaemia who was successfully treated with a combination of aggressive neurosurgery, intracavitary instillation of amphotericin B and voriconazole. We aimed to emphazise the roles of surgery, intracavitary therapy and antifungal therapy in the management of neuroaspergillosis. Under amphotericin-B therapy, the patient developed dysarthria and paralysis of the right side of his body. Brain magnetic resonance imaging demonstrated a lesion in the left parieto-occipital region, measuring 7 cm in the greatest dimension. Diagnostic surgery was interrupted due to abundant bleeding. The culture of the aspirate from the lesion yielded Aspergillus flavus. The therapy was switched to voriconazole and caspofungin combination. Due to disease progression during combination therapy, the patient had a second surgical resection resulting in a 75% reduction in lesion size. Following surgical intervention, intracavitary instillation of amphotericin B (0.3 mg/day for 15 days) was performed alongside with combination therapy (voriconazole and caspofungin). Caspofungin was stopped after 42 days, whereas the patient was continued on voriconazole for a total of 100 days. At this point, his brain lesion resolved almost completely. However, leukemia relapsed. The patient died during his treatment course because of neutropenic typhilitis occurring in the aplastic phase. It is stated that in patients with neuroaspergillosis radical neurosurgery leads to better outcomes if performed at an earlier stage. Antifungal treatment of cerebral aspergillosis requires that the drug must cross the blood brain barrier. Voriconazole has the ability to cross the blood brain barrier. The therapy should be prolonged beyond the resolution of all lesions and until reversal of the underlying predisposition. We conclude that the use of neurosurgery and voriconazole together appears to be a reliable and effective treatment modality in patients with cerebral aspergillosis.

Makale 38

Bekar A, Bilgin H,Korfalı G, Korfalı E, Kocaeli H, Taşkapılıoğlu Ö. Minimally invasive awake craniotomy using Steiner-Lindquist stereotactic laser guidance. Minim Invas Neurosurg 52(4):176-9, 2009.


INTRODUCTION: Awake craniotomy permits the continuous assessment of intraoperative neurological functions. In addition, stereotactic laser guidance aids in performing minimally invasive procedures related to the radical resection of lesions located in eloquent and non-eloquent brain regions.
METHODS: Between May 2000 and October 2006, 117 consecutive patients with various intracranial tumoral lesions underwent 141 resection procedures. The eloquent areas were determined with the aid of anatomic landmarks and/or functional MRI (fMRI) examinations. The resection of the lesions was performed under continuous neurological examination. In all cases, postoperative MRI was performed within 24-72 h.
RESULTS: Seventy-seven males and 40 females were included in this study. The mean age of the patients was 52.0+/-12.6 years. Most of the lesions were located within the parietal lobe. Of the lesions, 33 (23.4%) were located within the cortex, whereas 108 (76.5%) were subcortical. The most common pathologies were metastasis (70 cases) and glioblastome multiforme (27 cases). In 20 (14.2%) of the patients, fMRI was performed preoperatively. Of 21 patients with multiple lesions, 18 underwent 2 craniotomies and 3 underwent 3 craniotomies. The mean operation time was 72+/-0.3 min, and the mean hospital stay was 3.26+/-1.82 d. The average lesion size was 11.92+/-15.26 cm(3). In 7 cases (4.9%), the surgery caused either new neurological deficits or a worsening of the existing deficits; these deficits were permanent in 2 (1.4%) cases. One patient (0.7%) died due to the development of postoperative intracerebral hemorrhage.
CONCLUSIONS: Awake craniotomy with the aid of stereotactic laser guidance is a safe procedure that assists in performing minimally invasive resection of lesions in eloquent and non-eloquent brain regions. Although direct intraoperative stimulation was not performed, detection of the functioning areas of the brain with fMRI decreased additional postoperative neurological deficits. Overall, this method decreased the operation time and hospital stay.

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Kocaeli H, Chaalala C, Andaluz N, Zuccarello M. Spontaneous intradural vertebral artery dissection: a single-center experience and review of the literature. Skull Base. 19(3):209-18, 2009


OBJECTIVES: To define the natural history of spontaneous intracranial vertebral artery dissections (VADs) and to review current treatment strategies.
MATERIAL AND METHODS: We searched the MEDLINE database for all existing English and French literature on VADs through January 2008. Keywords employed were intradural/intracranial vertebral artery dissection, vertebral artery dissection, and vertebral artery dissection treatment. We also reviewed our series of patients with spontaneous VAD treated in the past 5 years. Data were collected, categorized, and analyzed.
RESULTS: In our sample of 457 patients, men were more frequently affected than women, and the mean age was 51.8 years. The majority of patients (79%) presented with subarachnoid hemorrhage (SAH). We experienced a high incidence (37%) of recurrent SAH, particularly within the first 24 hours after SAH first occurred. Angiographic fusiform dilatation and pearl-and-string lesions were the most common finding. Patients who presented with SAH fared worse than those who presented with ischemia.
CONCLUSIONS: Due to a high rate of recurrent bleeding, we concluded that early treatment by either surgical or endovascular route is indicated in patients who present with SAH secondary to spontaneous intradural VADs. Treatment decisions should take into account the site and type of dissection, vertebral artery dominance, and involvement of posterior inferior cerebellar artery.

Makale 40

Turkkan A, Alkan T, Goren B, Kocaeli H, Akar E, Korfali E.Citicoline and postconditioning provides neuroprotection in a rat model of ischemic spinal cord injury. Acta Neurochir (Wien). 152(6):1033-42, 2010.


BACKGROUND: Ischemic spinal cord injury is a chain of events caused by the reduction and/or cessation of spinal cord blood flow, which results in neuronal degeneration and loss. Ischemic postconditioning is defined as a series of intermittent interruptions of blood flow in the early phase of reperfusion and has been shown to reduce the infarct size in cerebral ischemia. Our study aimed to characterize the relationship between the neuronal injury-decreasing effects of citicoline and ischemic postconditioning, which were proven to be effective against the apoptotic process.
METHOD: Spinal cord ischemia was produced in rats using an intrathoracic approach to implement the synchronous arcus aorta and subclavian artery clipping method. In our study, 42 male Sprague-Dawley rats (309 +/- 27 g) were used. Animals were divided into sham operated, spinal ischemia, citicoline, postconditioning, and postconditioning citicoline groups. Postconditioning was generated by six cycles of 1 min occlusion/5 min reperfusion. A 600 mmol/kg dose of citicoline was given intraperitoneally before ischemia in the citicoline and postconditioning citicoline groups. All rats were sacrificed 96 h after reperfusion. For immunohistochemical analysis, bcl-2, caspase 3, caspase 9, and bax immune staining were performed. Caspase 3, caspase 9, bax, and bcl-2 were used as apoptotic and antiapoptotic markers, respectively.
FINDINGS: The blood pressure values obtained at the onset of reperfusion were significantly lower than the preischemic values. A difference in immunohistochemical scoring was detected between the caspase 3, caspase 9, bax, and bcl-2 groups. When comparisons between the ischemia (groups 2, 3, 4, and 5) and sham groups (group 1) were performed, a significant increase in caspase 3, caspase 9, bax, and bcl-2 was detected. When comparing the subgroups, the average score of caspase 9 was found to be significantly higher in ischemia group 2. The average score of bcl-2 was also found to be significantly higher in postconditioning and citicoline group 5.
CONCLUSIONS: It is thus thought that combining citicoline with postconditioning provides protection by inhibiting the caspase pathway and by increasing the antiapoptotic proteins.

Makale 41

Aslan E, Kocaeli H, Bekar A, Tolunay S, Ulus IH.CDP-choline and its endogenous metabolites, cytidine and choline, promote the nerve regeneration and improve the functional recovery of injured rat sciatic nerves. Neurol Res. 33(7):766-73, 2011.


OBJECTIVE: Topical cytidine-5'-diphosphocholine (CDP-choline) has been shown to improve the functional recovery and promote the nerve regeneration of injured sciatic nerves in rats. The aims of this study were to test whether CDP-choline was effective at promoting nerve healing when the surgery to repair an injury was delayed and to determine whether the cytidine and/or the choline moieties of CDP-choline contribute to its beneficial actions.
METHODS: One hundred and fifty Sprague-Dawley rats underwent a surgical procedure that involved damaging the right sciatic nerve and suturing the epineurium. The injured sciatic nerve was either repaired immediately (on the first day) or on the third day after surgery. Rats were assigned to one of five groups and received a topical application of either 0.4 ml of saline (control) or 0.4 ml of 100 μM CDP-choline, cytidine, choline, or cytidine+choline.
RESULTS: The sciatic function index (SFI) of the rats in both groups (those who had their nerve repair immediately versus those on day 3) improved gradually by 4, 8, and 12 weeks after surgery. The percentage recovery in SFI score was significantly higher in rats treated with CDP-choline or cytidine+choline at all time points. Axon count increased by ∼50% in rats treated either with CDP-choline or cytidine+choline. Treatment with CDP-choline or cytidine+choline reduced scar formation and decreased nerve adherence when the sciatic nerve was repaired immediately, and rats treated with CDP-choline or cytidine+choline had better axonal organization than control rats. Treatment with choline or cytidine alone led to a less marked improvement in SFI score and failed to increase axon count.
CONCLUSION: Our results demonstrate that CDP-choline, as well as the combination of its metabolites, cytidine+choline, improves the functional recovery and promotes the regeneration of injured sciatic nerves treated with immediate or delayed surgical repair in rats.

Makale 42

Kocaeli H, Korfalı E, Savran M, Yilmazlar S, Bekar A, Dogan S. Early surgical management of middle cerebral artery aneurysms associated with intarcerebral hematomas: The Uludag University experience. Neurosurg Q 21: 26-32, 2011

Makale 43

Dusak A, Hakyemez B, Kocaeli H, Bekar A.Magnetic Resonance Spectroscopy Findings of Pyogenic, Tuberculous, and Cryptococcus Intracranial Abscesses. Neurochem Res. 37(2):233-7, 2012.


Proton magnetic resonance spectroscopy (MRS) complements conventional methods used to differentiate intracranial cystic lesions. We report MRS findings of three cases that were diagnosed as pyogenic, tuberculous, and Cryptococcus abscesses before instituting any medical or surgical therapy. The pyogenic brain abscess had typical specific spectral findings (i.e., the demonstration of amino acids). Lactate and lipid peaks were visible in the tuberculous abscess. Cryptococcus neoformans can appear differently in different brain regions, which may lead to different spectral findings.

Makale 44

Serrone J, Kocaeli H, Douglas Mast T, Burgess MT, Zuccarello M. The potential applications of high-intensity focused ultrasound (HIFU) in vascular neurosurgery.J Clin Neurosci. 19(2):214-21, 2012.


This review assesses the feasibilty of high-intensity focused ultrasound (HIFU) in neurosurgical applications, specifically occlusion of intact blood vessels. Fourteen articles were examined. In summary, MRI was effective for HIFU guidance whereas MR angiography assessed vessel occlusion. Several studies noted immediate occlusion of blood vessels with HIFU. Long-term data, though scarce, indicated a trend of vessel recanalization and return to pre-treatment diameters. Effective parameters for extracranial vascular occlusion included intensity ranges of 1,690-8,800 W/cm(2), duration <15 seconds, and 0.68-3.3 MHz frequency. A threshold frequency-intensity product of 8,250 MHzW/cm(2) was needed for vascular occlusion with a sensitivity of 70% and a specificity of 86%. Complications include skin burns, hemorrhage, and damage to surrounding structures. With evidence that HIFU can successfully occlude extracranial blood vessels, refinement in applications and demonstrable intracranial occlusion are needed. Copyright © 2011 Elsevier Ltd. All rights reserved.

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Kocaeli H, Yilmazlar S, Kuytu T, Korfali E. The artery of Percheron revisited: a cadaveric anatomical study.Acta Neurochir (Wien). 155(3):533-9, 2013.


BACKGROUND: The artery of Percheron (AOP) is a single thalamoperforating arterial trunk that provides bilateral supply to the paramedian thalami and the rostral midbrain. As this rare anatomical variant artery may be involved in endovascular procedures or encountered surgically during basilar terminus aneurysms, the present study was warranted.
METHOD: Thirty-four adult (20 male and 14 female) formalin-fixed cadaveric brains underwent dissection of the 68 posterior cerebral arteries. Observations were made of the presence and the variations of the thalamoperforating arteries as well as the presence of the AOP.
FINDINGS: Thalamoperforating arteries arose from the superior or posterior surfaces of the P1 segment at a mean of a 1.87 mm (range, 0.39-5.25 mm) distance from the basilar apex and entered the brain through the posterior perforated substance. The average number was 4.25 (range 1-9), and the mean diameter was 0.73 mm (range 0.46-1.16 mm). Thalamoperforating arteries were classified into four different types according to their origin at the P1 segment: type I (bilateral multiple, n = 19), 55.8 %; type II (unilateral multiple, unilateral single, n = 4), 11.7 %; type III (bilateral single, n = 7), 20.5 %; type IV [one side with a single branch, the other side with no branches (the AOP), n = 4], 11.7 %. In three separate specimens with ruptured basilar artery aneurysms, the origin of the thalamoperforating arteries was incorporated not only into the posterior aspect of the aneurysm neck but also into the fundus.
CONCLUSIONS: In about one tenth of cases the possibility of the presence of a single arterial trunk that supplies the two paramedian thalamic territories should be taken into consideration during treatment planning of basilar terminus aneurysms. Furthermore, our data show that the thalamoperforating arteries may take off from both the aneurysm neck and the fundus.

Makale 46

Kerr RG, Tobler WD, Leach JL, Theodosopoulos PV, Kocaeli H, Zimmer LA, Keller JT. Anatomic variation of the optic strut: classification schema, radiologic evaluation, and surgical relevance. J Neurol Surg B Skull Base. 2012 ;73(6):424-9.


Objective Anatomic variability of the optic strut in location, orientation, and dimensions is relevant in approaching ophthalmic artery aneurysms and tumors of the anterior cavernous sinus, medial sphenoid wing, and optic canal. Methods In 84 dry human skulls, imaging studies were performed (64-slice computed tomography [CT] scanner, axial view, aligned with the zygomatic arch). Optic strut location related to the prechiasmatic sulcus was classified as presulcal, sulcal, postsulcal, and asymmetric. Morphometric analysis was performed. Results The optic strut was presulcal in 11.9% specimens (posteromedial margin bilaterally anterior to limbus sphenoidale), sulcal in 44% (posteromedial part adjacent to the sulcus's anterior two thirds bilaterally), postsulcal in 29.8% (posteromedial margin posterior to the sulcus's anterior two thirds), and asymmetric (left/right) in 14.3%. Optic strut length, width, and thickness measured 6.54 ± 1.69 mm, 4.23 ± 0.69 mm, and 3.01 ± 0.79 mm, respectively. Optic canal diameter was 5.14 ± 0.47 mm anteriorly and 4.79 ± 0.64 mm posteriorly. Angulation was flat (>45 degrees) in 13% or acute (<45 degrees) in 87% specimens. Conclusions Anatomical variations in the optic strut are significant in planning for anterior clinoidectomy and optic-canal decompression. Our optic strut classification considers these variations relative to the prechiasmatic sulcus on preoperative imaging.

Makale 47

Buyukkaya R, Yıldırım N, Cebeci H, Kocaeli H, Dusak A, Ocakoğlu G, Erdoğan C, Hakyemez B. The relationship between perimesencephalic subarachnoid hemorrhage and deep venous system drainage pattern and calibrations. Clin Imaging. 2014 May-Jun;38(3):226-30.


BACKGROUND AND PURPOSE: The purpose of this study is to investigate the relationship between Rosenthal basal vein (BVR) type and diameter and perimesencephalic nonaneurysmal subarachnoid hemorrhage (P-SAH).
MATERIALS AND METHODS: Aneurysmal subarachnoid hemorrhage (A-SAH), P-SAH, and control groups were evaluated, and BVRs were classified by type. BVR diameters in patients were measured.
RESULTS: There was a statistically significant difference of BVR drainage types between groups (P=.002). BVR diameters of patients with normal drainage pattern in P-SAH group were significantly smaller than those in both other groups (P<.001).
CONCLUSION: There is a relationship between P-SAH and BVR primitive drainage type. P-SAH risk increases in parallel with decreasing caliber of BVR in patients with normal drainage pattern.
Copyright © 2014 Elsevier Inc. All rights reserved.

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Tezcan G, Tunca B, Bekar A, Preusser M, Berghoff AS, Egeli U, Cecener G, Ricken G, Budak F, Taskapılıoglu MO, Kocaeli H, Tolunay S. microRNA expression pattern modulates temozolomide response in GBM tumors with cancer stem cells. Cell Mol Neurobiol. 2014 Jul;34(5):679-92.


Temozolomide (TMZ) is widely used to treat glioblastoma multiforme (GBM). Although the MGMT gene methylation status is postulated to correlate with TMZ response, some patients with a methylated MGMT gene still do not benefit from TMZ therapy. Cancer stem cells (CSCs) may be one of the causes of therapeutic resistance, but the molecular mechanism underlying this resistance is unclear. microRNA (miRNA) deregulation has been recognized as another chemoresistance modulating mechanism. Thus, we aimed to evaluate the miRNA expression patterns associated with chemoresistance that is dependent on the CSC status in GBM tumors to identify therapeutic biomarkers. CSCs were identified in 5 of 20 patients' tumor tissues using magnetic separation. CSC (+) tumors displayed a significant induction of CpG island methylation in the MGMT gene promoter (p = 0.009). Using real-time reverse transcription polymerase chain reaction (qRT-PCR), 9 miRNAs related to GBM (mir-181b, miR-153, miR-137, miR-145, miR-10a, miR-10b, let-7d, miR-9, and miR-455-3p), which are associated with cell cycle and invasion was analyzed in tumor samples. Low miR-181b and high miR-455-3p expression levels were detected (p = 0.053, p = 0.004; respectively) in CSC (+) tumors. Analysis revealed a significant correlation between miR-455-3p expression and Smad2 protein levels as analyzed by immunohistochemistry in CSC (+) tumors (p = 0.002). Thus, miR-455-3p may be involved in TMZ resistance in MGMT methylated CSC (+) GBM patients. Further studies and evaluations are required, but this miRNA may provide novel therapeutic molecular targets for GBM treatment and new directions for the development of anticancer drugs.

Makale 49

Cebeci H, Aydin O, Ozturk-Isik E, Gumus C, Inecikli F, Bekar A, Kocaeli H, Hakyemez B.Assesment of perfusion in glial tumors with arterial spin labeling; comparison with dynamic susceptibility contrast method. Eur J Radiol. 2014 Oct;83(10):1914-9.


PURPOSE: Arterial spin labeling perfusion imaging (ASL-PI) is a non-invasive perfusion imaging method that can be used for evaluation and quantification of cerebral blood flow (CBF). Aim of our study was to evaluating the efficiency of ASL in histopathological grade estimation of glial tumors and comparing findings with dynamic susceptibility contrast perfusion imaging (DSC-PI) method.
METHODS: This study involved 33 patients (20 high-grade and 13 low-grade gliomas). Multiphase multislice pulsed ASL MRI sequence and a first-passage gadopentetate dimeglumine T2*-weighted gradient-echo single-shot echo-planar sequence were acquired for all the patients. For each patient, perfusion relative signal intensity (rSI), CBF and relative CBF (rCBF) on ASL-PI and relative cerebral blood volume (rCBV) and relative cerebral blood flow (rCBF) values on DSC-PI were determined. The relative signal intensity of each tumor was determined as the maximal SI within the tumor divided by SI within symetric region in the contralateral hemisphere on ASL-PI. rCBV and rCBF were calculated by deconvolution of an arterial input function. Relative values of the lesions were obtained by dividing the values to the normal appearing symmetric region on the contralateral hemisphere. For statistical analysis, Mann-Whitney ranksum test was carried out. Receiver operating characteristic curve (ROC) analysis was performed to assess the relationship between the rCBF-ASL, rSI-ASL, rCBV and rCBF ratios and grade of gliomas. Their cut-off values permitting best discrimination was calculated. The correlation between rCBV, rCBF, rSI-ASL and rCBF-ASL and glioma grade was assessed using Spearman correlation analysis.
RESULTS: There was a statistically significant difference between low and high-grade tumors for all parameters. Correlation analyses revealed significant positive correlations between rCBV and rCBF-ASL (r=0.81, p<0.001). However correlation between rCBF and rCBF-ASL was weaker (r=0.64, p<0.001).
CONCLUSION: Arterial spin labeling is an employable imaging technique for evaluating tumor perfusion non-invasively and may be useful in differentiating high and low grade gliomas. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Makale 50

Tezcan G, Tunca B, Bekar A, Budak F, Sahin S, Cecener G, Egeli U, Taskapılıoglu MO, Kocaeli H, Tolunay S, Malyer H, Demir C, Tumen G. Olea europaea leaf extract improves the treatment response of GBM stem cells by modulating miRNA expression.Am J Cancer Res. 2014 Sep 6;4(5):572-90.


The stem-like cells of Glioblastoma multiforme (GBM) tumors (GSCs) are one of the important determinants of recurrence and drug resistance. The aims of the current study were to evaluate the anticancer effect of Olea europaea leaf extract (OLE) on GBM cell lines, the association between OLE and TMZ responses, and the effect of OLE and the OLE-TMZ combination in GSCs and to clarify the molecular mechanism of this effect on the expression of miRNAs related to cell death. The anti-proliferative activity of OLE and the effect of the OLE-TMZ combination were tested in the T98G, U-138MG and U-87MG GBM cell lines using WST-1 assay. The mechanism of cell death was analyzed with Annexin V/FITC and TUNEL assays. The effects of OLE on the expression levels of miR-181b, miR-153, miR-145 and miR-137 and potential mRNA targets were analyzed in GSCs using RT-qPCR. OLE exhibited anti-proliferative effects via apoptosis and necrosis in the GBM cell lines. In addition, OLE significantly induced the expression of miR-153, miR-145, and miR-137 and decreased the expression of the target genes of these miRNAs in GSCs (p < 0.05). OLE causes cell death in GBM cells with different TMZ responses, and this effect is synergistically increased when the cells are treated with a combination of OLE and TMZ. This is the first study to indicate that OLE may interfere with the pluripotency of GSCs by modulating miRNA expression. Further studies are required, but we suggest that OLE may have a potential for advanced therapeutic cancer drug studies in GBM.

Makale 51

Buyukkaya R, Kocaeli H, Yildirim N, Cebeci H, Erdogan C, Hakyemez B. Treatment of complex intracranial aneurysms using flow-diverting silk® stents. An analysis of 32 consecutive patients. Interv Neuroradiol. 2014 Dec;20(6):729-35.


This study describes the peri-procedural and late complications and angiographic follow-up results of 32 patients with 34 complex aneurysms treated with flow diverter Silk stents in a single centre. In this retrospective study, 40 Silk stents (SS) were implanted in 34 complex intracranial aneurysms in 32 patients. In our series, 20 (58.8%) carotid-ophthalmic internal carotid artery (ICA), six (17.6%) cavernous ICA, two (5.9%) supraclinoid ICA, two (5.9%) petrosal ICA (the same patient- bilateral) and four (11.8%) posterior circulation aneurysms were treated. One of the posterior circulation lesions was a fenestrated-type aneurysm. Twenty wide-necked, saccular; eight neck remnant; four fusiform and two blister-like aneurysms were included in our series. SS were successfully implanted in all patients (100%). Misdeployment occurred in 17.6% of patients. In two of these patients adequate stent openness was achieved via Hyperglide balloon dilatation. Coil embolization in addition to SS placement was utilized in four aneurysms. One patient (3%) experienced transient morbidity due to a thromboembolic event and there was one mortality (3%) due to remote intraparenchymal haemorrhage. Complete occlusion of 27/33 (81.8 %) and 29/33 (87.9 %) aneurysms was achieved six and 12 months after the procedure, respectively. In-stent intimal hyperplasia was detected in 6.1 % patients. Flow-diverter Silk stent implantation is an effective method of treating complex aneurysms with acceptable mortality and morbidity rates. Complete occlusion is achieved in most of the complex aneurysms.

Makale 52

Kacar E, Nas OF, Kaya A, Erdogan C, Kocaeli H, Hakyemez B. The gently pull-back technique for neck bypass in treatment of wide-necked internal carotid artery aneurysms: A report of three cases and review of the literature. Neuroradiol J. 2015 Dec;28(6):604-8.


Neck bypass failure in endovascular treatment of wide-necked internal carotid artery (ICA) aneurysms may adversely affect the technical success of the procedure. We used the gently pull-back technique to bypass the aneurysm neck and access the distal parent artery during endovascular treatment in patients with wide-necked ICA aneurysms. In this technique, a loop was made in the aneurysm and the distal parent artery was reached by using a small diameter microguidewire and a microcatheter. After providing reliable distal access, the microguidewire was removed and the whole system which consists of the microcatheter was gently pulled back. Finally the microcatheter was straightened and the aneurysm neck was passed. After crossing the aneurysm neck, a flow-diverting stent treatment and stent-assisted coiling were performed in three cases with wide-necked ICA aneurysm. The gently pull-back technique is a simple and effective method which requires no extra intravascular device and helps to bypass the aneurysm neck through a small diameter microguidewire and a microcatheter. This technique may be useful for neck aneurysm bypass in endovascular treatment of wide-necked ICA aneurysms.

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Trial of Decompressive Craniectomy for Traumatic Intracranial Hypertension. Hutchinson PJ, Kolias AG, Timofeev IS, Corteen EA, Czosnyka M, Timothy J, Anderson I, Bulters DO, Belli A, Eynon CA, Wadley J, Mendelow AD, Mitchell PM, Wilson MH, Critchley G, Sahuquillo J, Unterberg A, Servadei F, Teasdale GM, Pickard JD, Menon DK, Murray GD, Kirkpatrick PJ; RESCUEicp Trial Collaborators. N Engl J Med. 2016 Sep 22;375(12):1119-30.


Background The effect of decompressive craniectomy on clinical outcomes in patients with refractory traumatic intracranial hypertension remains unclear. Methods From 2004 through 2014, we randomly assigned 408 patients, 10 to 65 years of age, with traumatic brain injury and refractory elevated intracranial pressure (>25 mm Hg) to undergo decompressive craniectomy or receive ongoing medical care. The primary outcome was the rating on the Extended Glasgow Outcome Scale (GOS-E) (an 8-point scale, ranging from death to "upper good recovery" [no injury-related problems]) at 6 months. The primary-outcome measure was analyzed with an ordinal method based on the proportional-odds model. If the model was rejected, that would indicate a significant difference in the GOS-E distribution, and results would be reported descriptively. Results The GOS-E distribution differed between the two groups (P<0.001). The proportional-odds assumption was rejected, and therefore results are reported descriptively. At 6 months, the GOS-E distributions were as follows: death, 26.9% among 201 patients in the surgical group versus 48.9% among 188 patients in the medical group; vegetative state, 8.5% versus 2.1%; lower severe disability (dependent on others for care), 21.9% versus 14.4%; upper severe disability (independent at home), 15.4% versus 8.0%; moderate disability, 23.4% versus 19.7%; and good recovery, 4.0% versus 6.9%. At 12 months, the GOS-E distributions were as follows: death, 30.4% among 194 surgical patients versus 52.0% among 179 medical patients; vegetative state, 6.2% versus 1.7%; lower severe disability, 18.0% versus 14.0%; upper severe disability, 13.4% versus 3.9%; moderate disability, 22.2% versus 20.1%; and good recovery, 9.8% versus 8.4%. Surgical patients had fewer hours than medical patients with intracranial pressure above 25 mm Hg after randomization (median, 5.0 vs. 17.0 hours; P<0.001) but had a higher rate of adverse events (16.3% vs. 9.2%, P=0.03). Conclusions At 6 months, decompressive craniectomy in patients with traumatic brain injury and refractory intracranial hypertension resulted in lower mortality and higher rates of vegetative state, lower severe disability, and upper severe disability than medical care. The rates of moderate disability and good recovery were similar in the two groups. (Funded by the Medical Research Council and others; RESCUEicp Current Controlled Trials number, ISRCTN66202560 .).