Hans Eder

An automated drug delivery system for focal epilepsy

Previous studies have demonstrated the ability to stop seizures in animal models with injection of antiepileptic medication directly onto the seizure focus. The present experiments describe automated detection and focal therapy for seizures in the laboratory setting. Focal seizures were created in Sprague-Dawley rats using bicuculline, a GABA antagonist. Computerized detection of seizures was linked to a programmable infusion pump to deliver either diazepam (DZP) or pH-balanced vehicle (VEH) directly onto the seizure focus. Mean numbers of seizures following initial delivery of drug were 2.9+/-1.45 for the VEH-treated group and 0.2+/-0.42 for the DZP-treated group (P<0.0001, Students t-test, nonpaired, one-tailed). In another series of experiments, early injection of DZP shortened seizure duration. Three DZP-treated animals died. This model provides proof-in-principle for the development of a clinically applicable treatment for intractable partial epilepsy. Such therapy might avoid some of the problems inherent to systemic administration of antiepileptic drugs.

Treatment of cerebral radionecrosis by hyperbaric oxygen therapy

Clinically observed adverse radiation effects (ARE) are rather uncommon, but modern imaging reveals that they are more common after radiosurgery than previously believed. Little is known about the pathogenesis, and current treatment is mostly empirical. The benefit of hyperbaric oxygen therapy (HBO) on radiation-induced bone and soft tissue necrosis is known in lesions in the maxillofacial area, the mouth and in the head and neck. HBO raises the tissue pO2 and initiates a cellular and vascular repair mechanism. This forms the basis for the hypothesis that it might also help alleviate the results of cerebral radionecrosis. This study is a preliminary attempt to test this hypothesis. Two patients with arteriovenous malformations (AVMs) were chosen for the study. They had been treated with Gamma Knife radiosurgery (GKRS) and had developed imaging signs consistent with ARE. They were treated by breathing 100% oxygen at 2.5 atmospheres absolute (250 kPa) in sessions of 60 minutes per day. This treatment was repeated 40 times in cycles of ten sessions. Both responded well to HBO, one lesion disappeared and the other was reduced significantly in size. No adjuvant steroids were given. These results give evidence that HBO has a potential value in treating ARE but further experience will be needed to confirm its definite benefit.

Local Perfusion of Diazepam Attenuates Interictal and Ictal Events in the Bicuculline Model of Epilepsy in Rats

Summary: Purpose: We evaluated the efficacy of local perfusion of diazepam (DZP) in suppression of EEG spikes and behavioral seizures produced by bicuculline methiodide (BMI) applied to rat sensory motor cortex and hippocampus.

Intracerebral Cavernous Hemangioma after Cranial Irradiation in Childhood

Background and Purpose:Radiotherapy is an integral part of various therapeutic regimens in pediatric and adult oncology. Endocrine dysfunction, neurologic and psychiatric deficits, secondary malignancies and radiation-induced necrosis are well-known possible late effects of cranial irradiation. However, only sporadic cases of radiation-induced cavernous hemangiomas (RICH) have been reported so far.Patients and Methods:Pediatric patients who underwent cranial radiation therapy for malignant diseases between January 1980 and December 2003 were retrospectively analyzed. After the end of therapy they entered a detailed follow-up program.Results:Of 171 patients, eight (three patients with medulloblastoma, three patients with acute lymphoblastic leukemia, and one patient each with ependymoma and craniopharyngioma) developed intracerebral cavernoma 2.9–18.4 years after irradiation representing a cumulative incidence (according to the Kaplan-Meier method) of 2.24%, 3.86%, 4.95%, and 6.74% within 5, 10, 15, and 20 years following radiation therapy, respectively. In patients treated in the first 10 years of life, RICH occurred with shorter latency and significantly more often (p = 0.044) resulting in an even higher cumulative incidence.Conclusion:These findings and previously published cases show that cavernous hemangiomas may occur after irradiation of the brain several years after the end of therapy irrespective of the radiation dose and type of malignancy. Particularly children < 10 years of age at the time of irradiation are at higher risk. Since patients with RICH frequently do not show symptoms but hemorrhage is a possible severe complication, imaging of the central nervous system should be performed routinely for longer follow- ups, particularly in patients who were treated as young children.Hintergrund und Ziel:Strahlentherapie ist ein wichtiger Bestandteil bei der onkologischen Behandlung pädiatrischer sowie erwachsener Patienten. Endokrine Dysfunktion, neurologische und psychiatrische Defizite, Sekundärmalignome und strahleninduzierte Nekrosen sind bekannte Spätfolgen nach kranieller Bestrahlung. Das Auftreten strahleninduzierter kavernöser Hämangiome (Kavernome) ist bisher nur vereinzelt beschrieben worden.Patienten und Methodik:Es wurden alle pädiatrischen Patienten, die an der eigenen Abteilung zwischen Januar 1980 und Dezember 2003 aufgrund unterschiedlicher maligner Erkrankungen einer Schädelbestrahlung unterzogen und danach in ein umfassendes Nachsorgeprogramm eingeschleust wurden, retrospektiv analysiert.Ergebnisse:Von 171 Patienten entwickelten acht (drei Patienten mit Medulloblastom, drei Patienten mit akuter lymphatischer Leukämie und je ein Patient mit Ependymom und Kraniopharyngeom) 2,9–18,4 Jahre nach der Strahlentherapie intrazerebrale Kavernome (s. Tabelle 1). Nach der Kaplan-Meier-Methode entspricht dies einer kumulativen Inzidenz von 2,24%, 3,86%, 4,95% bzw. 6,74% innerhalb von 5, 10, 15 bzw. 20 Jahren nach Strahlentherapie (s. Abbildung 1). Bei Patienten, welche in den ersten 10 Lebensjahren behandelt wurden, traten Kavernome mit kürzerer Latenzzeit und häufiger (p = 0,044) auf (s. Abbildung 2).Schlussfolgerung:Diese Ergebnisse und die bisher veröffentlichten Daten zeigen, dass Kavernome – unabhängig von der Art der Grunderkrankung und der Strahlendosis – auch viele Jahre nach kranieller Bestrahlung auftreten können. Kinder < 10 Jahre haben ein höheres Risiko, eine solche Gefäßmalformation zu entwickeln. Da Patienten mit Kavernomen häufig keine Symptome zeigen diagund Blutungen mögliche schwere Komplikationen darstellen, sollte eine regelmäßige Bildgebung des Neurokraniums im Rahmen der Nachsorge auch noch viele Jahre nach Therapieende durchgeführt werden.

Radiosurgery in Lesional Epilepsy: Brain Tumors

The purpose of this study was to examine the effects of different doses of radiation to the brain tissue immediately adjacent to tumors which were associated with epilepsy. From April 1992 to December 1995, 26 patients with medically intractable tumor epilepsy (mean duration 6.9 years, range: 1–27 years) have been treated with Gamma Knife radiosurgery (GKRS). Clinical and imaging controls were available for 24 patients with a mean follow-up of 2.25 years (range: 1–4.4 years). Tumor control had been achieved in all patients. The patients were divided into two groups according to the volume of tissue outside the tumor which had received 10 Gy or more. This volume was assessed by measuring the ratio of the tumor and the ratio of the volume within the isodose containing 10 Gy (10G/Tum ratio). 54 percent of all the 24 patients achieved an excellent result according to the Engel classification (class I or II). The patients were divided into two groups. In group I were 12 patients, and the 10G/Tum ratio was 3 or less. In group II there were 12 patients and the 10G/Tum ratio was more than 3. In group I the mean value for the 10G/Tum ratio was 2 (range 0.86 to 2.9). In group II the mean value of the ratio was 11.1 (range 3.13 to 63.2). In group I only 42% of patients achieved an excellent result compared with 66% in group II. Moreover, the location of the tumor had an effect on the results, in that temporal tumors were associated with excellent results in 64% of cases as opposed to 40% in extratemporal tumors. Finally, if the epilepsy had lasted for 2.5 years or less there were excellent results in 70% of patients, as opposed to 43% excellent results for patients who had suffered epilepsy for more than 2.5 years.

Cooling Abolishes Neuronal Network Synchronization in Rat Hippocampal Slices

Summary:  Purpose: We sought to determine whether cooling brain tissue from 34 to 21°C could abolish tetany‐induced neuronal network synchronization (gamma oscillations) without blocking normal synaptic transmission.

Efficacy and safety of radiosurgical callosotomy: a retrospective analysis.

Summary:  Purpose: Anterior callosotomy is a surgical option for the treatment of generalized tonic or atonic seizures associated with drop attacks. Besides open surgery, a radiosurgical callosal disconnection using the gamma knife (GK) also can be performed, but reliable data about tolerability and efficacy are sparse.

Interictal and ictal activity in the rat cobalt/pilocarpine model of epilepsy decreased by local perfusion of diazepam

We investigated the efficacy of focal perfusion of diazepam (DZP) in reducing seizures produced by focal cobalt and systemic pilocarpine in the rat. Cobalt chloride crystals (3.5 mg/kg) were inserted stereotactically into the left hippocampus and recording electrodes affixed to the head of 23 rats. Focal spiking was evident within 5-7 days of implantation. Occasional ictal electrographic events were observed with cobalt alone, but consistent ictal events could be produced by intraperitoneal injection of pilocarpine hydrochloride (60 mg/kg) into the cobalt-treated animals. When rhythmical spiking was observed, the animals were treated either with DZP (0.25 mg in 50 microliters) or a vehicle (VEH) delivered into the left hippocampus. Blinded spike counts before and after injection showed spiking at 133.3 +/- 53.4% of baseline (mean +/- SD, n = 8) for the VEH-treated animals and 2.7 +/- 3.3% (n = 8) for the DZP-treated animals. Ictal events occurred in seven of the eight VEH-treated and two of the eight DZP-treated rats. Mean time to the first ictal event was 5.9 +/- 6.9 min for VEH-treated animals and 24 +/- 32.6 min for DZP-treated animals. DZP injected into the hippocampus contralateral to the cobalt did not reduce spiking. Systemic levels of DZP were unmeasurable in nine of ten tested animals. Focal perfusion of DZP therefore effectively reduced spiking in this cobalt chloride/pilocarpine model of focal and secondarily generalized epilepsy. This model, while involving GABAergic mechanisms, does not entirely depend upon GABAergic mechanisms. The findings therefore broaden the possibility of using focal DZP as a treatment for partial seizures.

Gamma-Knife Radiosurgery of Mesiotemporal Tumour Epilepsy Observations and Long Term Results

PURPOSE The efficacy of radiosurgery in cases of mesiotemporal tumours associated with long standing epilepsy has not clearly been documented up to now. The authors present a retrospective analysis of 19 cases treated by Gamma-Knife radiosurgery (GKRS) for mesiotemporal tumour epilepsy. METHODS Between 1992 and 1997 19 patients (12 male and 7 female) with a mean age of 31 years (5-72) and mesiotemporal tumour-induced epilepsy of a mean duration of 8.6 years (0.9-28) were treated by GKRS. All tumours were within the mesiotemporal structures and the pathohistology proven by biopsy or resective procedure revealed 15 (79%) low grade astrocytomas, 3 (16%) gangliogliomas and 1 (5%) cavernoma. Beside tumour control, the main aim of GKRS was alleviation of epilepsy by irradiating the presumed epileptic foci outside the tumour volume. The 50% isodose volumes surrounding the tumours measured a mean of 6.2 ccm (1.1-18 ccm). Doses given at marginal isodoses ranged from 12 to 30 Gy (mean 17.3 Gy). The outcome with respect to epileptic seizures was evaluated by the Engel classification. RESULTS After a follow-up (FU) of 1.7 to 9.7 years (mean 6.5 years) 11 patients (57.9%) were significantly ameliorated (Engel I and Engel II), 7 patients (36.8%) worthwhile improved (Engel III) and 1 patient (5.3%) unchanged. In 11 patients (58%) radiosurgically induced image changes were seen on MRI. INTERPRETATION Although microsurgical approach guided by electrocorticography (EcoG) is the state of art for treatment of mesiotemporal tumour epilepsy, GKRS can be used as a non-invasive, safe and effective alternative to resective surgery for selected cases.

Automatic and Remote Controlled Ictal SPECT Injection for Seizure Focus Localization by Use of a Commercial Contrast Agent Application Pump

Summary:  Purpose: In the presurgical evaluation of patients with partial epilepsy, the ictal single photon emission computed tomography (SPECT) is a useful noninvasive diagnostic tool for seizure focus localization. To achieve optimal SPECT scan quality, ictal tracer injection should be carried out as quickly as possible after the seizure onset and under highest safety conditions possible. Compared to the commonly used manual injection, an automatic administration of the radioactive tracer may provide higher quality standards for this procedure. In this study, therefore, we retrospectively analyzed efficiency and safety of an automatic injection system for ictal SPECT tracer application.