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Harald Stefanits, Vassiliki Konstantopoulou, Magnus Kuess, Ivan Milenkovic and Christian Matula

The congenital disorder of glycosylation characterized by a deficiency of phosphomannomutase 2 (PMM2-CDG) is the most common variant of congenital disorders of glycosylation. Besides typical clinical features, such as dysmorphism and abnormal body fat distribution, coagulation abnormities often lead to thromboembolic and hemorrhagic events in these patients. However, only 2 cases of intracerebral bleeding in patients with PMM2-CDG have been described so far.

A 4-year-old girl who initially presented with symptoms resulting from raised intracranial pressure underwent acute neurosurgical intervention for intracranial hemorrhage. The differential diagnoses after MRI included arteriovenous malformation and intraparenchymal brain tumor. However, clinical investigations promoted the diagnosis of PMM2-CDG, which was supported further by neuropathological findings and finally confirmed by isoelectric focusing and mutational analysis. No major complications or neurological deficits were evident after surgery, and the patient was able to attend an integrated kindergarten.

Unexplained intracranial hemorrhage should raise suspicion of a metabolic disorder and should be discussed with specialists to rule out an orphan disease such as PMM2-CDG.

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Christian Dorfer, Georgi Minchev, Thomas Czech, Harald Stefanits, Martha Feucht, Ekaterina Pataraia, Christoph Baumgartner, Gernot Kronreif and Stefan Wolfsberger

OBJECTIVE

The authors' group recently published a novel technique for a navigation-guided frameless stereotactic approach for the placement of depth electrodes in epilepsy patients. To improve the accuracy of the trajectory and enhance the procedural workflow, the authors implemented the iSys1 miniature robotic device in the present study into this routine.

METHODS

As a first step, a preclinical phantom study was performed using a human skull model, and the accuracy and timing between 5 electrodes implanted with the manual technique and 5 with the aid of the robot were compared. After this phantom study showed an increased accuracy with robot-assisted electrode placement and confirmed the robot's ability to maintain stability despite the rotational forces and the leverage effect from drilling and screwing, patients were enrolled and analyzed for robot-assisted depth electrode placement at the authors' institution from January 2014 to December 2015. All procedures were performed with the S7 Surgical Navigation System with Synergy Cranial software and the iSys1 miniature robotic device.

RESULTS

Ninety-three electrodes were implanted in 16 patients (median age 33 years, range 3–55 years; 9 females, 7 males). The authors saw a significant increase in accuracy compared with their manual technique, with a median deviation from the planned entry and target points of 1.3 mm (range 0.1–3.4 mm) and 1.5 mm (range 0.3–6.7 mm), respectively. For the last 5 patients (31 electrodes) of this series the authors modified their technique in placing a guide for implantation of depth electrodes (GIDE) on the bone and saw a significant further increase in the accuracy at the entry point to 1.18 ± 0.5 mm (mean ± SD) compared with 1.54 ± 0.8 mm for the first 11 patients (p = 0.021). The median length of the trajectories was 45.4 mm (range 19–102.6 mm). The mean duration of depth electrode placement from the start of trajectory alignment to fixation of the electrode was 15.7 minutes (range 8.5–26.6 minutes), which was significantly faster than with the manual technique. In 12 patients, depth electrode placement was combined with subdural electrode placement. The procedure was well tolerated in all patients. The authors did not encounter any case of hemorrhage or neurological deficit related to the electrode placement. In 1 patient with a psoriasis vulgaris, a superficial wound infection was encountered. Adequate physiological recordings were obtained from all electrodes. No additional electrodes had to be implanted because of misplacement.

CONCLUSIONS

The iSys1 robotic device is a versatile and easy to use tool for frameless implantation of depth electrodes for the treatment of epilepsy. It increased the accuracy of the authors' manual technique by 60% at the entry point and over 30% at the target. It further enhanced and expedited the authors' procedural workflow.

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Christian Dorfer, Thomas Czech, Susanne Aull-Watschinger, Christoph Baumgartner, Rebekka Jung, Gregor Kasprian, Klaus Novak, Susanne Pirker, Birgit Seidl, Harald Stefanits, Karin Trimmel and Ekaterina Pataraia

OBJECTIVE

The aim of this study was to present long-term seizure outcome data in a consecutive series of patients with refractory mesial temporal lobe epilepsy primarily treated with transsylvian selective amygdalohippocampectomy (SAHE).

METHODS

The authors retrospectively analyzed prospectively collected data for all patients who had undergone resective surgery for medically refractory epilepsy at their institution between July 1994 and December 2014. Seizure outcome was assessed according to the International League Against Epilepsy (ILAE) and the Engel classifications.

RESULTS

The authors performed an SAHE in 158 patients (78 males, 80 females; 73 right side, 85 left side) with a mean age of 37.1 ± 10.0 years at surgery. Four patients lost to follow-up and 1 patient who committed suicide were excluded from analysis. The mean follow-up period was 9.7 years. At the last available follow-up (or before reoperation), 68 patients (44.4%) had achieved an outcome classified as ILAE Class 1a, 46 patients (30.1%) Class 1, 6 patients (3.9%) Class 2, 16 patients (10.4%) Class 3, 15 patients (9.8%) Class 4, and 2 patients (1.3%) Class 5. These outcomes correspond to Engel Class I in 78.4% of the patients, Engel Class II in 10.5%, Engel Class III in 8.5%, and Engel Class IV in 2.0%. Eleven patients underwent a second surgery (anterior temporal lobectomy) after a mean of 4.4 years from the SAHE (left side in 6 patients, right side in 5). Eight (72.7%) of these 11 patients achieved seizure freedom.

The overall ILEA seizure outcome since (re)operation after a mean follow-up of 10.0 years was Class 1a in 72 patients (47.0%), Class 1 in 50 patients (32.6%), Class 2 in 7 patients (4.6%), Class 3 in 15 patients (9.8%), Class 4 in 8 patients (5.2%), and Class 5 in 1 patient (0.6%). These outcomes correspond to an Engel Class I outcome in 84.3% of the patients.

CONCLUSIONS

A satisfactory long-term seizure outcome following transsylvian SAHE was demonstrated in a selected group of patients with refractory temporal lobe epilepsy.

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Christina Stache, Christiane Bils, Rudolf Fahlbusch, Jörg Flitsch, Michael Buchfelder, Harald Stefanits, Thomas Czech, Udo Gaipl, Benjamin Frey, Rolf Buslei and Annett Hölsken

OBJECTIVE

In this study, the authors investigated the underlying mechanisms responsible for high tumor recurrence rates of adamantinomatous craniopharyngioma (ACP) after radiotherapy and developed new targeted treatment protocols to minimize recurrence. ACPs are characterized by the activation of the receptor tyrosine kinase epidermal growth factor receptor (EGFR), known to mediate radioresistance in various tumor entities. The impact of tyrosine kinase inhibitors (TKIs) gefitinib or CUDC-101 on radiation-induced cell death and associated regulation of survivin gene expression was evaluated.

METHODS

The hypothesis that activated EGFR promotes radioresistance in ACP was investigated in vitro using human primary cell cultures of ACP (n = 10). The effects of radiation (12 Gy) and combined radiochemotherapy on radiosensitivity were assessed via cell death analysis using flow cytometry. Changes in target gene expression were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Survivin, identified in qRT-PCR to be involved in radioresistance of ACP, was manipulated by small interfering RNA (siRNA), followed by proliferation and vitality assays to further clarify its role in ACP biology. Immunohistochemically, survivin expression was assessed in patient tumors used for primary cell cultures.

RESULTS

In primary human ACP cultures, activation of EGFR resulted in significantly reduced cell death levels after radiotherapy. Treatment with TKIs alone and in combination with radiotherapy increased cell death response remarkably, assessed by flow cytometry. CUDC-101 was significantly more effective than gefitinib. The authors identified regulation of survivin expression after therapeutic intervention as the underlying molecular mechanism of radioresistance in ACP. EGFR activation promoting ACP cell survival and proliferation in vitro is consistent with enhanced survivin gene expression shown by qRT-PCR. TKI treatment, as well as the combination with radiotherapy, reduced survivin levels in vitro. Accordingly, ACP showed reduced cell viability and proliferation after survivin downregulation by siRNA.

CONCLUSIONS

These results indicate an impact of EGFR signaling on radioresistance in ACP. Inhibition of EGFR activity by means of TKI treatment acts as a radiosensitizer on ACP tumor cells, leading to increased cell death. Additionally, the results emphasize the antiapoptotic and pro-proliferative role of survivin in ACP biology and its regulation by EGFR signaling. The suppression of survivin by treatment with TKI and combined radiotherapy represents a new promising treatment strategy that will be further assessed in in vivo models of ACP.