Thomas C. Witt

Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy.

Purpose:  We report a multicenter, double‐blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization‐related epilepsy.

A multicenter, prospective pilot study of gamma knife radiosurgery for mesial temporal lobe epilepsy: Seizure response, adverse events, and verbal memory

The safety, efficacy, and morbidity of radiosurgery (RS) must be established before it can be offered as an alternative to open surgery for unilateral mesial temporal lobe epilepsy. We report the 3‐year outcomes of a multicenter, prospective pilot study of RS.

Gamma-Knife-Based Stereotactic Radiosurgery for Uveal Melanoma

Nineteen patients with uveal melanoma were treated with Gamma-Knife-based stereotactic radiosurgery (SRS). The radiation dose was 40 Gy prescribed to the 50% isodose line for all patients. The median follow-up was 40 months. The 3- and 5-year overall survival rates were 86 and 55%, respectively. The 3- and 5-year tumor control rates were both 94%. Six of the 19 treated patients (32%) developed distant metastasis 31–75 months after SRS. Out of the 19 patients treated with SRS, 2 had improved, 4 had stable and 13 had worse vision in the treated eye. Gamma-Knife-based SRS appears to provide excellent local control of uveal melanoma. The risk of distant metastasis is significant. Effective systemic therapy is to be explored to improve the treatment outcome of uveal melanoma.

Endocrine Response after Gamma Knife-Based Stereotactic Radiosurgery for Secretory Pituitary Adenoma

Purpose: To examine treatment outcomes of Gamma Knife-based stereotactic radiosurgery (GK-based SRS) for secretory pituitary adenomas. Materials and Methods: 25 patients were treated with GK-based SRS for secretory pituitary adenomas with ≧12 months of follow-up. Results: For prolactinomas, 2 of 4 patients (50%) showed normalization of serum prolactin at a mean time of 18 months. One of 4 had a ≧50% decrease but still abnormal prolactin levels. For adrenocorticotrophic hormone-secreting tumors, 6 of 12 patients (50%) showed normalization of their endocrine levels at a median of 10 months. An additional 2 (17%) had a ≧50% decrease. For growth hormone-secreting tumors, 4 of 9 patients (44%) showed normalization of endocrine levels at a median time of 30 months. Two patients (22%) had ≧50% lower but abnormal endocrine levels. Conclusion: GK-based SRS provides a reasonable rate of endocrine normalization of secretory pituitary adenoma. The time to endocrine response is shorter than reported for fractionated external beam radiotherapy. There is a low risk of optic neuropathy.

Gamma Knife Stereotactic Radiosurgery for Low-Grade Astrocytomas

Patients with low-grade astrocytoma (LGA; 8 pilocytic astrocytomas, 2 subependymal giant cell astrocytomas, 2 fibrillary astrocytomas) were selected for treatment with gamma knife stereotactic radiosurgery (GKSRS) based on having a demarcated appearance on CT or MRI and the possibility of dose sparing of adjacent eloquent structures. A median dose of 13 Gy was prescribed to the 50% isodose line, which covered the gross tumor. The median patient age was 17.4 years. The median target volume was 4.4 cm3. With a median follow-up of 48.2 months, 4-year tumor control and overall survival were 77 and 83%, respectively. Only 2 patients experienced symptomatic treatment-related toxicity. GKSRS can provide local control in cases of unresectable or recurrent LGA with a low incidence of side effects in carefully selected patients.

Preliminary experience in the treatment of choroidal melanoma with gamma knife radiosurgery

The purpose of this paper was to note a potential source of error in magnetic resonance (MR) imaging. Magnetic resonance images were acquired for stereotactic planning for GKS of a vestibular schwannoma in a female patient. The images were acquired using three-dimensional sequence, which has been shown to produce minimal distortion effects. The images were transferred to the planning workstation, but the coronal images were rejected. By examination of the raw data and reconstruction of sagittal images through the localizer side plate, it was clearly seen that the image of the square localizer system was grossly distorted. The patient was returned to the MR imager for further studies and a metal clasp on her brassiere was identified as the cause of the distortion.A-60-year-old man with medically intractable left-sided maxillary division trigeminal neuralgia had severe cardiac disease, was dependent on an internal defibrillator and could not undergo magnetic resonance imaging. The patient was successfully treated using computerized tomography (CT) cisternography and gamma knife radiosurgery. The patient was pain free 2 months after GKS. Contrast cisternography with CT scanning is an excellent alternative imaging modality for the treatment of patients with intractable trigeminal neuralgia who are unable to undergo MR imaging.The authors describe acute deterioration in facial and acoustic neuropathies following radiosurgery for acoustic neuromas. In May 1995, a 26-year-old man, who had no evidence of neurofibromatosis Type 2, was treated with gamma knife radiosurgery (GKS; maximum dose 20 Gy and margin dose 14 Gy) for a right-sided intracanalicular acoustic tumor. Two days after the treatment, he developed headache, vomiting, right-sided facial weakness, tinnitus, and right hearing loss. There was a deterioration of facial nerve function and hearing function from pretreatment values. The facial function worsened from House-Brackmann Grade 1 to 3. Hearing deteriorated from Grade 1 to 5. Magnetic resonance (MR) images, obtained at the same time revealed an obvious decrease in contrast enhancement of the tumor without any change in tumor size or peritumoral edema. Facial nerve function improved gradually and increased to House-Brackmann Grade 2 by 8 months post-GKS. The tumor has been unchanged in size for 5 years, and facial nerve function has also been maintained at Grade 2 with unchanged deafness. This is the first detailed report of immediate facial neuropathy after GKS for acoustic neuroma and MR imaging revealing early possibly toxic changes. Potential explanations for this phenomenon are presented.In clinical follow-up studies after radiosurgery, imaging modalities such as computerized tomography (CT) and magnetic resonance (MR) imaging are used. Accurate determination of the residual lesion volume is necessary for realistic assessment of the effects of treatment. Usually, the diameters rather than the volume of the lesion are measured. To determine the lesion volume without using stereotactically defined images, the software program VOLUMESERIES has been developed. VOLUMESERIES is a personal computer-based image analysis tool. Acquired DICOM CT scans and MR image series can be visualized. The region of interest is contoured with the help of the mouse, and then the system calculates the volume of the contoured region and the total volume is given in cubic centimeters. The defined volume is also displayed in reconstructed sagittal and coronal slices. In addition, distance measurements can be performed to measure tumor extent. The accuracy of VOLUMESERIES was checked against stereotactically defined images in the Leksell GammaPlan treatment planning program. A discrepancy in target volumes of approximately 8% was observed between the two methods. This discrepancy is of lesser interest because the method is used to determine the course of the target volume over time, rather than the absolute volume. Moreover, it could be shown that the method was more sensitive than the tumor diameter measurements currently in use. VOLUMESERIES appears to be a valuable tool for assessing residual lesion volume on follow-up images after gamma knife radiosurgery while avoiding the need for stereotactic definition.This study was conducted to evaluate the geometric distortion of angiographic images created from a commonly used digital x-ray imaging system and the performance of a commercially available distortion-correction computer program. A 12 x 12 x 12-cm wood phantom was constructed. Lead shots, 2 mm in diameter, were attached to the surfaces of the phantom. The phantom was then placed inside the angiographic localizer. Cut films (frontal and lateral analog films) of the phantom were obtained. The films were analyzed using GammaPlan target series 4.12. The same procedure was repeated with a digital x-ray imaging system equipped with a computer program to correct the geometric distortion. The distortion of the two sets of digital images was evaluated using the coordinates of the lead shots from the cut films as references. The coordinates of all lead shots obtained from digital images and corrected by the computer program coincided within 0.5 mm of those obtained from cut films. The average difference is 0.28 mm with a standard deviation of 0.01 mm. On the other hand, the coordinates obtained from digital images with and without correction can differ by as much as 3.4 mm. The average difference is 1.53 mm, with a standard deviation of 0.67 mm. The investigated computer program can reduce the geometric distortion of digital images from a commonly used x-ray imaging system to less than 0.5 mm. Therefore, they are suitable for the localization of arteriovenous malformations and other vascular targets in gamma knife radiosurgery.

Stereotactic Radiosurgery and Fractionated Stereotactic Radiotherapy in the Treatment of Uveal Melanoma

Uveal melanoma is the most common primary intraocular malignant tumor. Radiation therapy has now replaced enucleation as the treatment of choice, with radioactive eye plaques and proton therapy being the two most studied radiotherapy modalities. More recently, stereotactic radiosurgery and fractionated stereotactic radiotherapy have emerged as promising, non-invasive treatments for uveal melanoma. This review summarizes the available literature on these newer treatment modalities.

Enhanced classical complement pathway activation and altered phagocytosis signaling molecules in human epilepsy

Abstract Microglia‐mediated neuroinflammation is widely associated with seizures and epilepsy. Although microglial cells are professional phagocytes, less is known about the status of this phenotype in epilepsy. Recent evidence supports that phagocytosis‐associated molecules from the classical complement (C1q‐C3) play novel roles in microglia‐mediated synaptic pruning. Interestingly, in human and experimental epilepsy, altered mRNA levels of complement molecules were reported. Therefore, to identify a potential role for complement and microglia in the synaptodendritic pathology of epilepsy, we determined the protein levels of classical complement proteins (C1q‐C3) along with other phagocytosis signaling molecules in human epilepsy. Cortical brain samples surgically resected from patients with refractory epilepsy (RE) and non‐epileptic lesions (NE) were examined. Western blotting was used to determine the levels of phagocytosis signaling proteins such as the complements C1q and C3, MerTK, Trem2, and Pros1 along with cleaved‐caspase 3. In addition, immunostaining was used to determine the distribution of C1q and co‐localization to microglia and dendrites. We found that the RE samples had significantly increased protein levels of C1q (p = 0.034) along with those of its downstream activation product iC3b (p = 0.027), and decreased levels of Trem2 (p = 0.045) and Pros1 (p = 0.005) when compared to the NE group. Protein levels of cleaved‐caspase 3 were not different between the groups (p = 0.695). In parallel, we found C1q localization to microglia and dendrites in both NE and RE samples, and also observed substantial microglia‐dendritic interactions in the RE tissue. These data suggest that aberrant phagocytic signaling occurs in human refractory epilepsy. It is likely that alteration of phagocytic pathways may contribute to unwanted elimination of cells/synapses and/or impaired clearance of dead cells. Future studies will investigate whether altered complement signaling contributes to the hyperexcitability that result in epilepsy. HighlightsLevels of complements C1q and iC3b are increased in focal cortical dysplasia.Decreased levels of Trem2 and Pros1 are evident in focal cortical dysplasia.Microglia make multiple physical contacts with dendrites in the human epileptic tissue.Altered phagocytosis‐signaling may drive microglia‐dendritic contacts in epilepsy.

Interaction of synchronized dynamics in cortex and basal ganglia in Parkinson's disease

Parkinsons disease pathophysiology is marked by increased oscillatory and synchronous activity in the beta frequency band in cortical and basal ganglia circuits. This study explores the functional connections between synchronized dynamics of cortical areas and synchronized dynamics of subcortical areas in Parkinsons disease. We simultaneously recorded neuronal units (spikes) and local field potentials (LFP) from subthalamic nucleus (STN) and electroencephalograms (EEGs) from the scalp in parkinsonian patients, and analysed the correlation between the time courses of the spike–LFP synchronization and inter‐electrode EEG synchronization. We found the (non‐invasively obtained) time course of the synchrony strength between EEG electrodes and the (invasively obtained) time course of the synchrony between spiking units and LFP in STN to be weakly, but significantly, correlated with each other. This correlation is largest for the bilateral motor EEG synchronization, followed by bilateral frontal EEG synchronization. Our observations suggest that there may be multiple functional modes by which the cortical and basal ganglia circuits interact with each other in Parkinsons disease: not only may synchronization be observed between some areas in cortex and the basal ganglia, but also synchronization within cortex and within basal ganglia may be related, suggesting potentially a more global functional interaction. More coherent dynamics in one brain region may modulate or activate the dynamics of another brain region in a more powerful way, causing correlations between changes in synchrony strength in the two regions.

Long-term radiosurgery effects in the treatment of temporal lobe epilepsy.

Epilepsy surgery is an effective treatment for medically resistant temporal lobe epilepsy (TLE). To minimize complication rates and potentially improve neuropsychology outcomes, stereotactic radiosurgery (SRS) has been explored as an alternative. Two pilot trials have demonstrated the effectiveness of SRS for the treatment of medically resistant TLE, with seizure-free outcomes for approximately 65% of patients at last follow-up. Despite encouraging results, no conclusive long-term outcomes are available for SRS. This article discusses a single patient who presented with recurrent seizures, worsening headaches, and persistent abnormal MRI findings 7 years and 8 months after SRS. This 29-year-old woman with a history of medically refractory complex partial seizures since childhood was referred for evaluation. Medical management had failed in this patient. The workup was compatible with left mesial temporal lobe onset, with MRI findings suggestive of mesial temporal sclerosis. In 2003, at the age of 23 years, she underwent Gamma Knife surgery (GKS) targeting the left temporal mesial area with a dose of 24 Gy at the 50% marginal isodose line. After GKS, the patients seizures decreased in frequency over several months, but auras were persistent. Nine months after treatment, she developed worsening headaches. A follow-up MRI study demonstrated a thick, irregular, enhancing lesion in the medial part of the temporal lobe. She was placed on corticosteroids, with resolution of her headaches. Her seizures and headaches recurred in March 2010. An MRI study showed a 2.2-cm, ill-defined, enhancing cystic lesion in the left mesial temporal lobe with T2 and FLAIR hyperintensity, which was presumably radiation induced. At that time, the patient opted for left temporal lobe resection to control her seizures. Histological examination showed moderately severe, remote, longstanding sclerosis at the level of the hippocampus. A vascular lesion was identified, and it was most consistent with radiation-induced capillary hemangioma. The entorhinal region was severely damaged, with hemorrhage, necrosis, neuronal loss, astrogliosis, and hemosiderin deposition. There was evidence of radiation vasculopathy. Radiation-induced lesions after SRS for the treatment of epilepsy are not well documented. Although GKS is a promising technique for the treatment of medically resistant TLE, the ideal candidate is not yet well defined. The selection of the appropriate technical parameters to obtain a desirable functional effect without histological damage to the surrounding neural tissue remains a challenge. This case illustrates the need for long-term follow-up when radiosurgery is used for epilepsy.