Epilepsy surgery and the evolution of clinical and translational science.

GENERAL SCIENTIFIC SESSION 2 (HONORED GUEST LECTURE) GENERAL SCIENTIFIC SESSION 2 (HONORED GUEST LECTURE)

Epilepsy Surgery and the Evolution of Clinical and Translational Science Johannes Schramm, MD, PhD Professor emeritus, Medical Faculty, Bonn University, Bonn, Germany Correspondence: Professor Johannes Schramm, MD, PhD, Bonn University, Medical Center, Sigmund-Freud-Str 25, 53105 Bonn, Germany. E-mail: Johannes.Schramm@ukb. uni-bonn.de Copyright © 2014 by the Congress of Neurological Surgeons.

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his article will review some classical and recent advances in epilepsy surgery and describes the complex relationship between progress in clinical epilepsy surgery, the multiple small advancements introduced into the field, and the evolution in clinical sciences related to epilepsy surgery from a personal perspective. The specific advantages of clinical research and its connection with basic science groups within the framework of the neurosciences and related specialties will be described. In this context, the unique opportunity to do research when epilepsy surgery is considered as a “window to the brain” will be outlined. The important place the neurosurgeon can have in a neuroscience network based on direct access to the brain or living brain tissue will be illustrated.

HISTORIC ADVANCES BASED ON EPILEPSY SURGERY In order to gain the right perspective on recent progress, it is worth being aware of important past advances. Early brain surgery at the end of the 19th century frequently consisted of surgery for chronic epilepsy. And from these early stages onward, neurosurgeons have used the opportunity of exposing the living brain to do research, 1 famous example being the evaluation of electrical stimulation methods of the cerebral cortex. One of the first topographic maps of the somatotropic organization of the motor cortex was obtained by Fedor Krause and published in his famous book in 1911 (Figure 1).1 Wilder Penfield, who had spent some time with Otfried Foerster, who performed brain surgery in general (as a neurologist!), perfected these techniques, resulting in the famous map of somatic motor and sensory representation in the cerebral cortex (Figure 2).2 Not only in its infancy, but also later, surgery for epilepsy has been an avenue for research,

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frequently with ground-breaking results. A more modern example is Ojemann’s work on the topography and the variability of cortical speech representation.3 Modern techniques of intraoperative localization of eloquent cortex, which now seem indispensible for the surgery of brain tumors close to eloquent areas, still rely on the techniques developed by epilepsy surgeons. This is one example of the interrelation between epilepsy surgery and tumor surgery, which will be discussed in more detail below. Another advance in which research by neuropathologists and neurologists led to the development of newer resection techniques is the discovery of the significance of hippocampal sclerosis as an etiological factor in chronic temporal lobe epilepsy, which led to the development of selective mesiotemporal lobe surgery for seizure relief.4,5

RECENT CLINICAL ADVANCES IN EPILEPSY SURGERY The past 20 to 25 years have seen considerable progress and development in the practice of epilepsy surgery both related to diagnostic methodology and the spectrum of procedures performed to treat drug-resistant epilepsy. In the clinical area, a most significant step forward was made by Wiebe et al6 in 2001 with the first randomized, controlled trial of surgery for temporal lobe epilepsy (TLE). He demonstrated a 58% seizure freedom rate for operated patients vs 8% seizure freedom for nonoperated patients after 1 year. In the area of surgical technique, a number of innovations have occurred, such as the use of disconnection techniques instead of resection, the use of radiosurgery for TLE, and the introduction of augmentative techniques. In the field of TLE surgery, a trend to go away from standard anterior lobe resections to smaller resection types such as corticouncoamygdalectomy and selective amygdalohippocampectomy is noted. The augmentative techniques include vagal nerve stimulation and, very recently, deep brain stimulation7,8 and responsive cortical stimulation.9 The recent trial with closed-loop

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Epilepsy Surgery and the Evolution of Clinical Science

FIGURE 1. Reproduction of Figure 66 from the book “Die Chirurgie des Gehirns und Rückenmarks” by Fedor Krause, demonstrating an early example of using brain surgery for research. Published in 1911 by Urban und Schwarzenberg Verlag (reproduced with permission of Elsevier, Munich).

stimulation provided class I evidence for a significant reduction in seizure frequency for 12 weeks.9 The use of radiosurgery for mesial TLE can now be assessed a bit better with results from a large center10 and a prospective study comparing 2 dose schemes.11 It appears that seizure freedom rates are very similar to resective series, but one should be aware that to achieve it may take 8 to 18 months during which a temporary increase in auras is very frequently observed. Quite a number of patients need to take steroids, frequently for several months. A recent study claims that the cognitive tests showed no decline compared with pretreatment baseline values.12 The use of deep brain stimulation only rarely leads to seizure freedom,7 so it may best be qualified as a palliative technique, but in some countries (eg, Germany) it has been admitted in the catalogue of procedures being paid for by health care providers and insurance companies. The trend for disconnection can be observed on the small scale in the form of multiple subpial transection.13 In recent years, the

CLINICAL NEUROSURGERY

first series have appeared where, instead of doing a temporal lobe resection, a temporal lobe disconnection was done.14,15 Trials of multiple transections of the hippocampus for treatment of mesial TLE have been performed,16 most recently even combining both techniques.17 It can be observed on the macroanatomic scale in the change from anatomic hemispherectomy to modern hemispherectomy techniques.18 Already in the 1970s, the principle of lobar disconnection was introduced in the so-called functional hemispherotomy, which was a combination of resection with the disconnection of the frontal and occipitoparietal lobes. In modern hemispherectomy techniques, only a very limited amount of brain is resected, for example, parts of the operculum over the insula or just the hippocampus, whereas most of the brain tissue is disconnected from the basal ganglia bloc by performing a disconnection through a transventricular entry. Disconnection instead of resection was also applied for hypothalamic hamartomas. A stereotactic-guided radiofrequency lesioning has also been used for hypothalamic hamartoma, but

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FIGURE 2. Reproduction of a more detailed figure from Penfield and Boldrey’s article on “somatic motor and sensory representation in the cerebral cortex of men as studied by electrical stimulation.” It can be seen that stimulation of the precentral cortex can also evoke sensations and not only movements. Published in Brain 1937;60(4):389-443, reproduced with permission from Oxford University Press.

is now also tried out for other lesions, such as tiny deep-seated focal dysplasias or heterotopic intraventricular nodules.19 It seems that focused ultrasound guided by magnetic resonance imaging (MRI) may be used for circumscribed deep-seated tissue destruction.20 The spectrum of epilepsy surgery procedures in comparison with the late 1980s now contains procedures that just did not exist at that time or had hardly been tried, such as vagal nerve stimulation, multiple subpial transections, hemispherotomies, or deep brain stimulation (Table 1), already constituting more than 20% of all interventions for drug-resistant epilepsy. The introduction of newer technologies and new surgical strategies over the past 20 to 22 years has been amazing. It includes the combination of well-known techniques like stereotaxy with modern imaging, the use of intraoperative MRI for


eloquent located epileptogenic lesions, the use of intracerebral stimulation, and radiosurgery. In a recent review by Jacobs and colleagues21 the authors pointed out that 2 clinical conditions have been identified that are associated with a later risk of TLE: brain injury and febrile seizures of childhood. Alterations in MRI reveal changes that may be associated with epileptogenesis and may thus serve as noninvasively obtainable biomarkers and trigger interventions.

ADVANCES IN PRESURGICAL DIAGNOSTICS Those recent advances include improved imaging, eg, ictal single-photon emission computed tomography (SPECT), subtraction ictal SPECT coregistered with MRI (SISCOM), MRI




TABLE 1. Spectrum of Epilepsy Surgery Procedures Between 1989 and 2012a,b Resective procedures Temporal resections Extratemporal resections Disconnective procedures Hemispherectomy Callosotomy Palliative procedures Multiple subpial transsection (1061) Vagal nerve stimulation Deep brain stimulation

1941 1485 456 190 127 (17) 46 461 28 425 8

75% 57% 18% 7%

18%

a

MST, multiple subpial transsection. Percentages refer to total case numbers. Numbers in italics refer to procedures only introduced during the 1990s or later. The number of MST designated with (1) refers to add-on MSTs, the lower number show MST-only procedures.

b

volumetrics, and morphometric analysis. The well-known SPECT procedure has been modified for epilepsy surgery as ictal SPECT, where the isotope is injected during the seizure. An even more refined variant is SISCOM, which allows the isolation of the ictal SPECT activity by subtracting the normal SPECT image from the ictal SPECT in order to later fuse the resulting picture with a morphological MRI data set (Figure 3). Other modern methods to identify the ictogenic area are the (usually nonictal) recording of interictal spikes in magnetoencephalography, now in a multi-

channel version, or the 3-dimensional (3-D) reconstruction of the dipoles produced by an interictal spike, reconstructed in a 3-D fashion after electroencephalogram (EEG) recording with many electrodes. The resulting dipoles (from interictal spikes) are transposed into a 3-D morphological MRI. These more refined evaluation techniques are especially important in so-called nonlesional epilepsy cases. This means patients with drugresistant epilepsy where MRI does not show a recognizable lesion. MRI volumetrics and MRI postprocessing with morphometric analysis can give indirect hints pointing to suspicious areas of the brain. Hippocampal atrophy diagnosed with MRI points to the side of affected mesiotemporal lobe.22 In the nonlesional epilepsy cases, subtle morphological changes may be present that are hard to recognize or may be even outright undetectable. Of specific value among the new developments are some of the MRI postprocessing techniques. The morphometric analysis by voxel-based 3-D MRI analysis compares a 3-D MRI data set of the patient with a suspected cortical dysplasia and compares the grey/white matter junction and grey matter extension and thickness with a data set of more than 200 normal brain MRIs (Figure 4).23 This MAP (morphometric analysis programme) technique described by Huppertz et al in 200523 has been demonstrated to be instrumental in detecting tiny focal cortical dysplasias that were overlooked or virtually impossible to detect in conventional MRI24 (Figure 5). These new developments have direct effects on effectiveness and outcome of epilepsy surgery. The use of SISCOM, positron emission tomography, SPECT, MRI spectroscopy, and magnetoencephalography increased the rate of noninvasive focus

FIGURE 3. The use of SISCOM in presurgical evaluation to identify the ictogenic zone. Three representative slices from a SPECT examination obtained in a seizure-free period (Left) and an ictal SPECT, obtained after injection of the tracer during a seizure (Middle) and of a morphological MRI with the seizure activity projected into the MRI slice, after having subtracted the normal SPECT from the ictal SPECT image. This technique is used when the EEG gives no hints as to in which area of the brain the seizures arises, and when there is no abnormal structure detectable in the MRI. The resulting SISCOM picture is helpful for deciding where to place invasive electrodes for seizure monitoring. Pictures provided by C.E. Elger (Department of Epileptology, Bonn University Medical Center). SPECT, single-photon emission computed tomography; SISCOM, subtraction ictal SPECT coregistered with MRI; EEG, electroencephalogram; MRI, magnetic resonance imaging.




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FIGURE 4. The morphometric analysis technique described by Huppertz et al23 applied to an own case. The T1-weighted images (Left column) and the postanalysis image of junction and extension show the areas suggestive of a focal cortical dysplasia. The lesion was later reproduced in the high-resolution FLAIR image (Right column) but had previously been unrecognizable on standard coronal and axial FLAIR -images with 3-mm and 4-mm slice thickness. FLAIR, fluid attenuated inversion recovery. From J. Wellmer et al24: Integrating magnetic resonance imaging postprocessing results into neuronavigation for electrode implantation and resection of subtle focal cortical dysplasia in previously cryptogenic epilepsy. Neurosurgery 2010;66:187-195. Reproduced with permission from Lippincott Williams & Wilkins.

detections.25,26 MRI postprocessing helps to detect previously unrecognizable lesions; the combination of diffusion tensor imaging for visualization of fiber tracts with the use of grid mapping for eloquently located tumors (instead of awake surgery), combined with median nerve somatosensory evoked potential phase reversal are all now used to maximize the extent of tumor resection for tumors in difficult locations. The combination of more precise determination of the ictal onset zone by these modern methods with the use of microsurgery and better guided resection techniques appears to have led to an improvement in the seizure freedom rate in extratemporal lobe epilepsy surgery


from around 60% to around 70% over the past 25 years. It has also made risky surgeries possible and may have helped to lower morbidity.

EPILEPSY SURGERY AND ITS SPECIFIC VALUE FOR RESEARCH The major advantage with regard to use of epilepsy surgery for scientific exploration is the opportunity to use epilepsy surgery as a “window to the brain.” Principally, epilepsy and its underlying syndromes may be considered as a model for studying normal and




FIGURE 5. Same case as in Figure 4. The MAP (morphometric analysis programme) results are used to plan electrode implantation, including depth electrodes into the suspected focal cortical dysplasia. Schematic implantation plan (A) and screen shots of the presurgical implantation planning in the stereotaxy system (B-E). The final ROI (circumlined in magenta, filled arrows) is located only slightly posterior to a developmental venous abnormality (DVA) (open arrow). The trajectories of the 2 depth electrodes target the ROI (the suspected and later proven focal cortical dysplasia) without crossing sulci or the DVA. L, left side; ROI, region of interest. Taken from J. Wellmer et al: Integrating magnetic resonance imaging postprocessing results into neuronavigation for electrode implantation and resection of subtle focal cortical dysplasia in previously cryptogenic epilepsy. Neurosurgery 2010;66:187-195. Reproduced with permission from Lippincott Williams & Wilkins.

abnormal brain function. Crick, in an article on consciousness coauthored with I. Fried,27 quoted a lecture by Penfield stating that “the neurosurgeon has a unique opportunity for psychological study when he exposes the brain. . ..and it is his duty to give account of such observations. . .” to the psychologist. These authors also pointed out that the neurosurgeon “can contribute to an understanding of consciousness in 2 ways, by reporting his observations and by recording brain activity (EEG), singleneuron and multiple-neuron activity, and local field potentials directly from the human brain.” So the concept of cooperation between clinician and scientist and of using epilepsy surgery as a window to brain function is by no means a new one.27 Since the chance to study both normal and abnormal conditions, to study the epileptic brain is not only opening a perspective on disease, but also direct access to the brain. Using the particular


opportunities of presurgical diagnostic procedures and the necessary craniotomy and exposure of the brain surface, epilepsy surgery is like opening several windows to the brain. Researchers have access to recordings from the brain surface; from the depths of the brain, they can correlate electrophysiological findings with pathological findings (from resected tissue) and MRI findings. The results from cognitive testing can be correlated to neuropathological findings and imaging findings. The relationship between the various specialties involved in research around the disease entities encountered in epilepsy surgery are not only one-way or straight-line relationships, but there is also crossfertilization between the various specialties (Figure 6). Access to living brain tissue, both diseased and normal (as obtainable during access to lesions), provides unique chances to do research on living brain tissue. In this way, it has become possible to do



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FIGURE 6. Schematic depiction of the potential connections and relationships between several neuroscience fields dealing with the patients who has chronic epilepsy and the results obtained during the examination of these patients and the research done with the tissue obtained during surgery. The upper half is meant to show that the collaboration and transfer of data and knowledge do not only happen as the predictable interaction between epileptology and the epilepsy surgeon or between the neuropathologist and the epilepsy surgeon in a 1-way direction, but may frequently be bidirectional. At the same time, it points out that there are similar relationships between subspecialties dealing with only 1 aspect of the patient who has chronic epilepsy (eg, imaging or neuropathology). A multitude of collaborations between the specialties is possible. The lower half of the graph shows that results from clinical science in combination with results from basic science lead to results that may have feedback on the clinical practice and thus constitute translational science.

electrophysiological recordings, including single-cell recordings from cortical areas and human hippocampus. The involvement of basic science is thus not limited to neuropathology or molecular neuropathology, but can also involve cellular physiology (neuronal and glial) and network physiology. The combination of basic science and clinical science offers the opportunity to feed back the results into clinical use and, in this sense constitutes true translational science. These specific research-friendly factors around epilepsy surgery include the application of long-term EEG recording with or without test paradigms, and the access to single-cell recordings from human brain or brain tissue slices. These single-cell recordings are not only valuable for researchers investigating properties of the various ion channels or the connectivity between different cell types, for example, in the human hippocampus, they have also been used to investigate the basic properties of networks. Similar investigations have been done, of course, in numerous animal experiments, but having a chance to verify experimental findings in slice preparations of human cortex or hippocampus provides new chances.28,29

BASIC SCIENCE AND CLINICAL SCIENCE Basic science and clinical science are frequently considered as 2 different poles. Clinical research is focused on the evaluation of


normal physiology or pathological conditions in a single patient or in a group of patients, or the examination of therapeutic interventions. Basic science is devoted to investigations of basic cellular mechanisms, physiological properties, and network interaction mainly in an experimental setup. The requirements of a busy clinical practice usually make it very hard or close to impossible for a clinical neurosurgeon to be involved in basic science, and it is frequently believed that it is a mutually exclusive condition that a brilliant clinical neurosurgeon at the same time can be a productive and successful basic scientist. In daily life, one can frequently observe a natural antagonism between these 2 groups, one of them occupied with his clinical responsibilities, the necessity to keep up with new developments, and the busy operative schedule, whereas the other seems to be in the enviable position of being able to spend 5 full working days a week (if not 6 or 7) devoted to the basic science laboratory and the organization of funding and supervising the people in the laboratory. There is no question that certain kinds of scientific endeavors can not be performed at the same level by the clinicians in comparison with a full-time basic scientist, for example, molecular biological investigations, single-cell recordings, and other time-intensive laboratory work. There is also the impression, certainly in my country, that grant institutions favor giving money to wellestablished laboratories compared with clinicians and clinical studies. In addition, there is competition at the faculty level for funding, space, and staff positions. Clinicians find it much harder to spend the necessary time (sometime weeks) to develop a research project, or write a well-founded grant application. The basic scientist has certain advantages in his favor, such as a reliable source of his experimental subjects (eg, rats or mice) with a very homogenous background (ie, a certain strain or breed or a certain knocked out gene) and he can apply a well-established experimental protocol to these subjects of his research. The clinician is confronted with the need to collect his cases over a long period of time and is then confronted with an inhomogeneous group, that is, inhomogeneity in many aspects: sex, age, concomitant disease, variable duration of disease, different educational level, different cognitive abilities, different individual genetic background, etc. Despite undeniable considerable differences between these 2 types of scientists, the question arises, whether collaboration can be fruitful and result in good partnership with an associated increase in results. The conditions to achieve a good and productive collaboration include personal factors such as open-mindedness and the willingness to cooperate and invest time. To add are the presence of several different but related research groups in close proximity (ideally in the same building), competent and successful grant acquisition, flexibility in setting up new research directions, founding new groups, and, finally, support from the dean—in short, the formation of a neuroscience center. In such an environment, the epilepsy surgeon as the clinician and basic scientists can collaborate, and it is even possible that the epilepsy surgeon himself can intensively be involved with research of a very basic character. I must be forgiven for describing mainly




experiences from our neurocenter, although many other groups successfully use similar strategies, to name but a few.28-31 Over 2 decades such collaboration in our center made it possible to provide tissue to neuropharmacologists to study cerebral 5hydroxytryptamine receptors, to endocrinologists to study cerebral hormone synthesis, to neuroanatomists to study GABA-ergic synapses, to molecular physiologists to study hippocampal glia, to cellular neuroscientists to study glial ion channels, to neurochemists to study mitochondrial dysfunction in neurons, and to experimental epileptologists to study hippocampal network activity. Now it was possible to look after very basic physiological mechanisms such as the properties of K1 channels in the human hippocampus.30 Bedner and Steinhäuser in 201332 identified changes in K1-channel-mediated K1 buffering in patients with hippocampal sclerosis, which may contribute to the epileptogenicity of the sclerotic hippocampus, a finding also seen by Heuser et al.30 Among the interesting findings in human tissue was the observation that alterations in expression, localization, and function of astroglial K1 channels as well as impaired K1 buffering occurred in patients with pharmacoresistant TLE. One of the potential consequences of this finding is that dysfunctional astrocytes “should be considered promising targets for new therapeutics strategies.”32 This rather surprising recent discovery of the functional importance of human hippocampal astrocytes is a significant result and it was not obtained in the rat brain. This was possible because clinicians and basic scientists collaborated, carefully collecting specimens from patients who agreed to support the scientific evaluation by allowing their resected tissue to be examined in the laboratory. In order to make this kind of research possible, close collaboration is necessary. Timing of surgery has to be interleaved with a well-prepared laboratory, ready to do examinations on the tissue for many hours. The resection technique has to be adapted so that a well-prepared hippocampal structure can reach the laboratory in time in good condition. The exchange of data between the 2 groups must work properly, and, as a third part, the neuropathologist will be involved and several years of patient work will be necessary. Examples of close collaboration between clinicians and basic scientists can be found in other big epilepsy surgery centers as well.28-31 Lee et al33 in 2012 and Baek et al34 in 2013 reviewed the molecular genetics of cortical malformations, and the group of Koch and Fried used the necessity to do depth recordings to obtain single-cell recordings from human hippocampal cells, resulting in ground-breaking discoveries on the role of single cells in visual memory.31 Among many surprising findings, they were able to identify a hippocampal neuron during a test series of visual memory that only spiked when the subject was shown pictures of a well-known female actress, even if that actress was shown with her face visible from a lateral perspective only. In this kind of collaboration, it has been questioned whether the contribution of the neurosurgeon deserves to be honored by a coauthorship. A common opinion on this contribution is that


“neurosurgeons only give us what they have to remove anyway.” That is, of course, a nice misunderstanding, as illustrated by the following episode. A very well-known surgeon loved to collect 5 to 6 TLE epilepsy cases and then did them all within 2 days, making it impossible for the physiologist hoping to examine hippocampal slices from his resections. This was for 2 reasons: he was using the an ultrasonic aspirator or the ring forceps destroying the hippocampus and, even if he had bothered to take out the hippocampus en bloc, the physiologist would be busy with 1 case well into the night and instead of having a chance to examine 6 different specimens, could have done a maximum of 2 in those 2 days. The collaborative neurosurgeon, however, adjusts the timing of the surgery to the available laboratory capacity, develops a resection technique that allows for long enough viable hippocampal specimens, and takes care that the laboratory is well informed when the surgery takes place and is ready to cut up the slices. In addition, the neurosurgeon coauthors the ethics vote application, codesigns the informed consent form, fits the experimenter’s dream to the surgical reality, explains the experimental design to the patient and the family, and obtains informed consent. He keeps the documentation and, if necessary, provides clinical data to the specimen including follow-up data and the precise location of the specimen. In the operating room, he organizes the logistics of transportation and decides on the ethically correct site and extent of tissue samples after having adjusted his surgical technique to obtain viable specimens and having provided an en bloc specimen. And he continues to do so for years in a reliable way. His contribution is similar to the contribution of the PhD student or post doc performing the chores in the laboratory beautifully for a year or more. Nobody will question the right for a coauthorship for the laboratory guy, but why would anybody question the right for a coauthorship for the neurosurgeon in the team?

SYNERGY BETWEEN TUMOR AND EPILEPSY SURGERY The specific pathologies associated with drug-resistant epilepsy lead to the collection of pathological processes in high numbers, which are otherwise rarely seen, such as rare tumors. The term “long-term epilepsy associated tumors” has been created for these specific tumors35 and unique studies on extremely rare tumors have been possible. The collaboration between epilepsy surgeons and neuropathology on the topic of rare tumors frequently found in chronic epilepsy cases constitutes a nice example of joint clinical research between 2 neighboring fields with some involvement of molecular genetics. It was soon evident that otherwise rare tumor entities were frequently seen in the epilepsy surgery patients. So the basis was laid for investigations on clinical and neuropathological aspects and finally on molecular genetic examinations of these rare tumor entities.36-38 Our group in Bonn was able to collect over 180 gangliogliomas and a large number of dysembryoplastic neuroepithelial tumors.39,40 Because of large case numbers, it was possible to work out the



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incidence of the rarely occurring malignization of these principally very benign tumors.41 Because roughly a third of the resective cases in the epilepsy surgery series were operations for brain tumors, we were able to describe long-term observations on tumors that ordinarily occur only in the 1% to 3% range in normal brain tumor series. The detailed examination of a large series of long-term epilepsy-associated tumors led to the description of a new astrocytoma subtype with an extremely benign clinical course42 (Figure 7). One could describe this effect as the synergy of epilepsy surgery and tumor surgery. Another aspect of this synergy is seen in the transfer of techniques originally developed for epilepsy surgery into tumor surgery, a process that was already started decades ago by Goldring,43,44 who was one of the first to use median nerve somatosensory evoked potential phase reversal to locate the central sulcus and thus the motor cortex. Starting with the pioneering work of George Ojemann (1989)3 on cortical language localization, the use of direct cortical stimulation to describe the topography and variability of eloquent cortices, such as the sensory-, motor-, and language-associated cortices, was refined and systematically researched, soon to be used by many groups in tumor surgery45,46 and soon combined with diffusion tensor imaging of motor pathways.

Transfer of techniques used for tumor surgery into epilepsy surgery also happened, such as the use of diffusion tensor imaging of motor tracts and monitoring of motor and sensory potentials during the surgery of difficultly located epileptogenic lesions (tumors and dysplasias) during epilepsy surgery. Not only direct cortical stimulation during awake surgery was transferred into the area of tumor surgery, the technique of subdural grid implantation for the localization of the epileptogenic zone frequently used in eloquently located epileptogenic lesions was also transferred in the tumor surgery cases, where it was now used to locate eloquent cortex close to tumors as an alternative to awake craniotomy.47 The cortical mapping can be combined with subcortical mapping of fiber tracts.48,49

PROFITING FROM MULTISPECIALIST RESEARCH ON A COMMON TOPIC The patients with drug-resistant epilepsy, the clinical manifestations, the etiological factors, the cognitive manifestations of disease and therapeutic intervention, the electrophysiological manifestations and virtually every aspect of chronic epilepsy are continuously researched in many centers worldwide. This paragraph, however, deals with the chances and benefits that

FIGURE 7. Graphs illustrating the benign behavior of a subgroup of extremely benign grade II astrocytomas, the so-called isomorphic subtype identified in a larger cohort of long-term epilepsy-associated low-grade tumors. Gemisto, gemistocytic astrocytoma; iso, isomorphic subtype. The upper panel is based on a figure from Schramm J, et al: Evidence for a clinically distinct new subtype of grade II astrocytomas in patients with long-term epilepsy. Neurosurgery. 2004;55(2):340-347. Reproduced with permission from Lippincott Williams & Wilkins.





multilayered research efforts, involving many aspects of clinical and basic neuroscience, can have if the local constellation permits. These factors include enough support from faculty and dean, flexibility with regard to forming new research fields and creating positions for competent researchers, and all that based on a unique substrate, the patients undergoing resections for drug-resistant epilepsy. And, of course, topics like brain tumors, cavernomas, intracranial pressure, or neurotrauma have been used successfully as foci of similar research networks in various academic neurosurgery departments. This may be illustrated by the example of the neurocenter in Bonn, where, within about 10 to 15 years, a considerable increase in the number and quality of publications was achieved, and a remarkable increase in research grants from the large national funding institutions such as the Deutsche Forschungsgemeinschaft or the German Cancer Society was obtained. Two large collaborative research grants were funded for over 10 years each, having between 18 and 21 funded projects. Many of these projects were devoted to epilepsy aspects, one of them involving 3 epilepsy surgery centers in Germany. Within 10 years, 8 professorial positions in the Bonn neurocenter were created: 1 for neuropathology, 5 in epileptology, and 2 in neurosurgery. The research performed there was related specifically to epilepsy in 2 of these and to basic neuroscience aspects in 4 of them (eg, cellular neurophysiology, molecular physiology); 2 were devoted to the aspects of cognition. Soon enough, each of these newly recruited professors acquired outside grants and increased the number of researchers in their own group and, of course, did research outside the narrower area of chronic epilepsy. Amazing new results were obtained by some of these groups such as the discovery that white matter axons may release vesicular glutamate. Kukley et al50 in 2007 were able to show in the rat brain that the neurotransmitter glutamate is also released at discrete sites along axons in white matter. They hypothesized that this is a mechanism for activitydependant signaling at the axon-glial interface in white matter. This is contrary to the classical belief that fast transmitter release is restricted to nerve terminals in grey matter. Similar patterns of collaborating research groups within a local neuroscience community are possible and found regularly. For them to happen, the clinician must find the time and must be able to distance himself enough from his daily clinical workload to attend the meetings of a steering committee and to retreat from the daily treadmill in order to find the time to write a demanding grant proposal. And he is well advised to do this in collaboration with several others. Designing a good study or developing an intelligent hypothesis can be made easier by collaboration. Neurosurgeons who are able to blend into the collaborative dealings of a neuroscience center and manage to put enough effort into joint research proposals have been known to profit immensely from the collaboration with basic science-oriented research groups. It is all about intra- and extramural networking, even international collaboration. Table 2 demonstrates a few examples where epilepsy surgeons or a group were able to produce publications in top-ranking journals. Considering the well-known limiting


TABLE 2. Some Examples of Successful Publishinga

Epilepsy surgeon 1 Epilepsy surgeon 2 Epilepsy surgeon 3 Epileptologist Epilepsy surgery group Epilepsy surgeon 4

Natureb

Science

1 1 4 6 4 15

2 2 1 4

Lancetb 3 4 2

a

The table demonstrates that publications in high-ranking journals by researchers involved with chronic epilepsy or epilepsy surgery is possible. b Includes publications in main journal and subeditions.

factors for clinicians to become involved with time-consuming and very difficult experimental basic science and the occasional mild grin with which our “cousins” from the basic science community occasionally look at the clinicians, it is good to see that surgeons are able to produce articles accepted in renowned journals. And there is more than 1 case where not just 1 article in Nature, Science, or Lancet was produced.

ADAPTING TRENDS IN ORGANIZATION OF SCIENCE The funding of science has changed considerably over the past 2 decades. So has the grant system in many countries changed, usually with the result of decreasing acceptance rates for grant applications. The influence of “scientometrics” plays an important role. The potential “usefulness” of an applicant for a professorial position is more and more judged also by the number of publications, the amount of acquired grant money, and the presumed quality of journals in which he managed to publish his articles. The problems of judging the potential value of a clinical or basic researcher in this way are well-known and need not be discussed here. In parallel, there is a trend by the grant-providing institutions to favor or even request collaboration between various groups. A typical example is the Transregional Sonderforschungsbereich (transregional collaborative research group) as defined by the Deutsche Forschungsgemeinschaft (German Research Council), where the pre-requisite is that a number of research groups join together under the umbrella of the common topic, write a grant application together, go through the assessment procedure by the funding institution as a group, and, if successful, may be rewarded with funding for up to 12 years for the whole group (provided regular and successful reexamination and reassessment). As shown in Figure 8, the organization of scientific projects is going away from the classical group of 2 to 3 neurosurgeons; it may include a basic scientist or even 1 or 2 neighboring groups. For some topics, it will be necessary to collaborate on a national scale or even internationally. The European Union has instituted a grant institution for funding science where the international collaboration



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LIMITATIONS These reflections were originally presented at the 2013 annual meeting of the Congress of Neurological Surgeons. It is a review containing a very personal and subjective view. Many examples for the general trends described in the article were taken from the experiences of the author at the neurocenter in Bonn for purely practical reasons. It is obvious that similar research collaborations exist in many other universities. It was impossible to acknowledge important contributions of all the groups who contributed to the clinical advances and the progress in epilepsy research.

CONCLUSION FIGURE 8. The arrow indicates a tendency in organizing science as observed by the author over the past 2 decades.

between several groups from different countries within the European Union is a pre-requisite. Competition is extremely hard, and I have known cases where people have taken off several months to be the leading organizer and author of the grant application. To come back to specific experiences with a typical example of collaboration within the local neuroscience center, Pernhorst et al51 involved a total of seven different institutions that were using funding from 9 different organizations and patients from 1 epilepsy surgery center. One example of an international multicenter study52 also involving epilepsy surgeons was a genome-wide association study including 1018 patients with hippocampal sclerosis, 7552 control subjects, and validation of results in an independent sample of 959 people with hippocampal sclerosis and 3591 control subjects. This trend to the international organization of research is also reflected in the establishment of a European Epilepsy Brain Bank by Ingmar Blümcke,53 which now holds 6000 histological specimens, including 1200 long-term epilepsy-associated tumors. Many future research areas can be recognized, in both basic and clinical sciences and on the crossroads between the 2. Just to outline 3 in an exemplary fashion: exploring the connectivity of neural networks using optogenetic methods in the living brain; or working out the consequences after the realization that astrocytic malfunction in epileptic insults precedes neuronal changes; or third, exploring the significance of the detection of gliotransmitters, ie, astrocytes that are involved in synaptic signaling. By just reading the last 3 sentences, it becomes clear that the whole understanding of the pathophysiology of seizure generation may completely change in the future. Similarly, new clinical research areas exist, like the whole field of new developments (eg, deep brain stimulation) with the potential to provide relief to hitherto untreatable chronic epilepsy; albeit, this may frequently not be associated with seizure freedom, but with the palliation of seizure frequency.


Clinical research on patients who have chronic epilepsy and epilepsy surgery has progressed to include large databases, multicenter studies, and randomized studies. The instruments to obtain class I evidence have improved. The results of clinical research, frequently incorporating new technologies and methods from outside neurosurgery, influence surgical planning and resection. The cooperation with nonsurgical and basic science groups, ie, opening the window to brain cells and brain function for others, has led to exciting discoveries and will undoubtedly continue to do so. These results translate into better understanding of chronic epilepsy and may modify therapy and epilepsy surgery. The 2013 Congress of Neurological Surgeons Annual Meeting presentation on which this article is based is available at: http://bit. ly/1f02ppl. Disclosure The author has no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.

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