Johann Romstöck

In vitro and ex vivo evaluation of second-generation histone deacetylase inhibitors for the treatment of spinal muscular atrophy

Among a panel of histone deacetylase (HDAC) inhibitors investigated, suberoylanilide hydroxamic acid (SAHA) evolved as a potent and non‐toxic candidate drug for the treatment of spinal muscular atrophy (SMA), an α‐motoneurone disorder caused by insufficient survival motor neuron (SMN) protein levels. SAHA increased SMN levels at low micromolar concentrations in several neuroectodermal tissues, including rat hippocampal brain slices and motoneurone‐rich cell fractions, and its therapeutic capacity was confirmed using a novel human brain slice culture assay. SAHA activated survival motor neuron gene 2 (SMN2), the target gene for SMA therapy, and inhibited HDACs at submicromolar doses, providing evidence that SAHA is more efficient than the HDAC inhibitor valproic acid, which is under clinical investigation for SMA treatment. In contrast to SAHA, the compounds m‐Carboxycinnamic acid bis‐Hydroxamide, suberoyl bishydroxamic acid and M344 displayed unfavourable toxicity profiles, whereas MS‐275 failed to increase SMN levels. Clinical trials have revealed that SAHA, which is under investigation for cancer treatment, has a good oral bioavailability and is well tolerated, allowing in vivo concentrations shown to increase SMN levels to be achieved. Because SAHA crosses the blood–brain barrier, oral administration may allow deceleration of progressive α‐motoneurone degeneration by epigenetic SMN2 gene activation.

Ictal Pleasant Sensations: Cerebral Localization and Lateralization

Summary:  Ictal pleasant feelings are a rare sign of focal epilepsies. The most popular description was performed by Dostojevskij, who reported an aura by Myshken in one of his books. No convincing evidence has been published concerning the cerebral localization of ictal happiness. In this study, the findings of 11 patients with ictal pleasant feelings are described. In eight patients, the origin of the focal epileptic activity was found in the temporal lobe (most often temporal inferior basal); in three patients, frontal or parietal lobe in addition to temporal lobe involvement was found. According to our findings ictal happiness is a localizing sign pointing to the ictal involvement of temporal mesiobasal areas. Lateralization to the right temporal lobe was found in seven and to the left temporal lobe in four patients.

Magnetic source imaging combined with image-guided frameless stereotaxy: A new method in surgery around the motor strip

OBJECTIVE In this study, information about the localization of the central sulcus obtained by magnetic source imaging (MSI) was intraoperatively translated to the brain, using frameless image-guided stereotaxy. In the past, the MSI results could be translated to the surgical space only by indirect methods (e.g., the comparison of the MSI results, displayed in surface renderings, with bony landmarks or blood vessels on the exposed brain surface). METHODS Somatosensory evoked fields were recorded with a MAGNES II biomagnetometer (Biomagnetic Technologies Inc., San Diego, CA). Using the single equivalent current dipole model, the localization of the somatosensory cortex was superimposed on magnetic resonance imaging with a self-developed contour fit program. The magnetic resonance image set containing the magnetoencephalographic dipole was then transferred to a frameless image-guided stereotactic system. Intraoperatively, the gyrus containing the dipole was identified as the postcentral gyrus, using neuronavigation, and the next anterior sulcus was regarded as the central sulcus. With intraoperative cortical recording of somatosensory evoked potentials, this assumption was verified in each case. RESULTS In all cases, the preoperatively assumed localization of the central sulcus and motor cortex with MSI agreed with the intraoperative identification of the central sulcus using the phase reversal technique. CONCLUSION The combined use of MSI and a frameless stereotactic system allows a fast orientation of eloquent brain areas during surgery. This may contribute to a safer and more radical surgery in lesions adjacent to the motor cortex.

Prediction of postoperative outcome with special respect to removal of hemosiderin fringe: A study in patients with cavernous haemangiomas associated with symptomatic epilepsy

PURPOSE In this study 30 patients with symptomatic epilepsy caused by cavernomas were investigated in a postoperative follow up study to assess predictors for postoperative outcome with respect to indications, time and approach of surgery. METHODS Thirty patients with cavernomas refractory to medical treatment were scheduled for surgery based on the findings of high-resolution MR imaging and intensive EEG-video monitoring. Postoperative outcome of epilepsy was assessed by follow-up examinations based on the basis of classification by Engel and the International League against epilepsy (ILAE). RESULTS The following variables were associated with good postoperative outcome: (1) complete resection of hemosiderin fringe surrounding the cavernoma was correlated to less postoperative seizure frequency versus incomplete resection of the hemosiderin fringe according to the outcome protocol of ILAE. (2) Lower duration of epilepsy at the time of operation was correlated to a better postoperative outcome with a benefit for recovery. (3) Absence of hemorrhage before surgery and unifocal seizure onset was a predictor for a favorable outcome, whereas bilateral or multifocal seizure onset zones showed poorer postoperative outcomes. (4) In patients with dual pathology (hippocampal sclerosis in addition to a cavernoma), lesionectomy plus hippocampectomy as opposed to lesionectomy only, had a better outcome than single lesionectomy. CONCLUSION Postoperative outcome in patients with cavernomas should be the topic of further prospective multicenter studies involving a large number of patients. In addition to the ideal operation time and handling of dual pathology the role of extended resection including perilesional hemorrhages should be taken into account.

Magnetoencephalography (MEG) predicts focal epileptogenicity in cavernomas

Objective: The aim of this study was to identify the irritative epileptic zone in patients with cavernomas by means of magnetoencephalography (MEG). Method: Among 82 patients operated for epilepsy, whose presurgical evaluation had included MEG, histological assessment of the tissue removed had confirmed cavernomas in eight. These eight patients had epilepsy since 18.6 (SD 12.7) years on average. The monitoring lasted about 2.1 (SD 1.3) hours and a median 20.9 (SD 14.3) spikes per hour were recorded. Spontaneous brain activity was recorded by means of a 74 channel dual unit MEG system (Magnes II, 4-D Neuroimaging) with simultaneous EEG recording (31 scalp electrodes). Spike analysis was performed using different source (moving dipole, current density reconstruction) and head models (spherical shells, BEM). Co-registration of neurophysiological and imaging data (MRI) was based upon anatomical landmarks. Results: In 6/8 patients co-localisation from the cavernoma and epileptic zone was found. In two patients the focus was localised in the parieto-occipital lobe, in three patients in the frontal lobe and in three patients in the temporal lobe. In one case of temporal and one case of frontal lobe focus localisation there was no spatial relationship to the cavernoma. Conclusion: In cases of focal seizures due to a single cavernoma, MEG may precisely delineate the epileptogenic tissue bordering the lesion. In patients with multiple cavernomas or dual pathology, MSI may reveal the complexity of the case, and contribute to the decision about further invasive diagnostics and more sophisticated therapeutic measures. MEG is a promising method for prediction of the epileptic zone in cavernoma related epilepsies, and thus it can contribute to decision making about and planning of epilepsy surgery.

Epilepsy surgery, resection volume and MSI localization in lesional frontal lobe epilepsy.

To verify whether interictal noninvasive information detected by magnetoencephalography (MEG) recordings can contribute to localize focal epileptic activity relevant for seizure generation in lesional frontal lobe epilepsy, magnetic source imaging (MSI) localizations of epileptic discharges were compared to the extent of neurosurgical resection and postoperative outcome. Preoperative MEG spike localizations were displayed in postoperative magnetic resonance imaging (MRI) scans to check whether dipole sites were located within the resection cavity. Moreover, MEG localizations were compared with results of prolonged video-EEG monitoring and, in three cases, with invasive EEG recordings. Our results in five cases with lesional frontal lobe epilepsy showed that good surgical outcome could be achieved in those patients where the majority of MEG spike localizations were located within the resected brain volume.

Preservation of facial nerve function after postoperative vasoactive treatment in vestibular schwannoma surgery.

OBJECTIVE:Facial nerve paresis and hearing loss are common complications after vestibular schwannoma surgery. Experimental and clinical studies point to a beneficial effect of nimodipine and hydroxyethyl starch for preservation of cochlear nerve function. A retrospective analysis was undertaken to evaluate the effect of vasoactive treatment on facial nerve outcome. PATIENTS AND METHODS:Forty-five patients with vestibular schwannoma removal, intraoperative electromyographic monitoring, and postoperative deterioration of facial nerve function were evaluated. Twenty-five patients underwent vasoactive treatment consisting of nimodipine and hydroxyethyl starch for improvement of hearing outcome. Twenty patients did not receive such treatment. Facial nerve function was evaluated before and after surgery, as well as 1 year after the surgical procedure. Patients were comparable regarding age, tumor size, and preoperative facial nerve function. RESULTS:Long-term results of facial nerve function were significantly improved in those patients who experienced severe postoperative deterioration of facial nerve function and received vasoactive treatment as compared with patients who did not receive nimodipine and hydroxyethyl starch after surgery. Treated patients showed a significantly higher rate of complete recovery compared with patients without treatment. CONCLUSION:The study points to a potential effect of vasoactive treatment for facial nerve function after vestibular schwannoma surgery. In particular, patients with postoperative disfiguring facial nerve palsy clearly benefit from intravenous hydroxyethyl starch and nimodipine with respect to a long-term socially acceptable facial nerve function.

The prognostic value of intraoperative BAEP patterns in acoustic neurinoma surgery

Based on a consecutive series of 70 hearing patients with unilateral acoustic neurinomas and intraoperative monitoring of brain-stem auditory evoked potentials (BAEP), 4 dynamic BAEP patterns could be characterized. These patterns correspond with early and late postoperative hearing outcome. All patients with stable wave V (pattern 1) showed definite hearing preservation, all patients with irreversible abrupt loss of BAEP (pattern 2) lost their hearing, despite early hearing preservation in two cases. All patients with irreversible progressive loss of either wave I or wave V (pattern 3) eventually suffered from definite postoperative hearing loss, despite early hearing preservation in two cases. Those cases with intraoperative reversible loss of BAEP (pattern 4) showed variable short and long term hearing outcome. In 34% hearing was preserved, 44% suffered from postoperative hearing loss, the remaining 22% showed postoperative hearing fluctuation, either as a delayed hearing loss or as reversible hearing loss. Postoperative hearing fluctuation indicates anatomical and functional preservation of the cochlear nerve during surgery and is suggestive of a pathophysiological mechanism initiated during the surgical procedure and continuing thereafter. Patients at risk for delayed hearing loss can be identified during surgery by a characteristic BAEP pattern and may benefit from vasoactive treatment.

Periventricular nodular heterotopia: A challenge for epilepsy surgery

Pharmacoresistant focal epilepsies due to periventricular nodular heterotopia are a diagnostic and therapeutic challenge because of the need of invasive presurgical diagnostics and the selection of an optimal surgical approach. Invasive investigations in previous studies showed that focal epileptic activity can be correlated predominantly either with one of the nodular heterotopia or with neocortical epileptogenic zones distant to the periventricular nodules. Up to now, invasive recordings were required for localization of epileptic activity and its correlation to heterotopia. The following case presentation reports on a non-invasive approach using magnetic source imaging (MSI) combined with intraoperative ECoG. MSI combines preoperative data from magnetic resonance imaging (MRI) with magnetoencephalography (MEG). The MSI data for definition of the localization of the epileptic activity and functional important areas were coregistered with the intraoperative high-field-MRI and diffusion tensor imaging-based fiber tracking (DTI) of the visual pathway using a neuronavigational system. A neuronavigation-guided surgical resection of the epileptogenic area was performed leaving the heterotopia and the visual tract fibers intact. Postoperatively preservation of the visual fields was documented and the frequency of seizures was markedly reduced.

Intraoperative brainstem auditory evoked potential pattern and perioperative vasoactive treatment for hearing preservation in vestibular schwannoma surgery

Objective: In vestibular schwannoma surgery, four different intraoperative brainstem auditory evoked potential (BAEP) patterns (stable BAEP, abrupt loss, irreversible progressive loss, reversible loss) can be identified and correlated with postoperative hearing outcome. Patients with reversible loss significantly benefit from postoperative vasoactive treatment consisting of hydroxyethyl starch and nimodipine. The present study investigates the treatment effect in the remaining three BAEP patterns. Methods: A retrospective analysis was performed in 92 patients operated on for vestibular schwannoma between 1997 and 2005. Between 1997 and 2001, only patients with reversible loss of BAEP received vasoactive medication. Subsequently, all patients operated on between 2001 and 2005 received a 10 day course of therapy, regardless of the BAEP pattern. Serial audiological examinations before, after surgery and after 1 year were performed in all patients. Results: All 30 patients with reversible loss of BAEP received medication, and postoperative hearing preservation was documented in 21 patients. All 13 patients with stable waves showed hearing preservation, regardless of treatment. In all 24 patients with abrupt loss and in all 25 patients with irreversible progressive loss, postoperative anacusis was documented, regardless of treatment. Conclusion: In patients with reversible loss of BAEP, a disturbed microcirculation of the cochlear nerve seems to be the underlying pathophysiological factor. In patients with abrupt or irreversible progressive loss, additional mechanical injury of nerve fibres determines hearing outcome. The study provides evidence that for the purpose of hearing preservation, only patients with reversible loss of BAEP benefit from vasoactive treatment.