Cognitive and behavioral effects of cannabidiol in patients with treatment-resistant epilepsy.

PURPOSE: Therapeutic use of cannabidiol (CBD) in intractable epilepsies has increased considerably over the last ten years. As more evidence for the potentially beneficial effects of CBD on different epilepsy types is emerging, it is important to monitor potential cognitive and behavioral side effects. So far, studies including standardized neuropsychological data in the context of treatment with CBD in epilepsy patients are sparse. The present open-label study examines cognitive and behavioral effects of CBD in children and adults with treatment resistant epilepsy. METHOD: Thirty-nine patients with treatment-resistant epilepsy completed the study protocol, i.e. they were tested at baseline (T0) and after three months of CBD treatment (T1). Patients completed standardized neuropsychological tests on memory, executive functions and attention if they were capable. For cognitively impaired patients who could not complete cognitive tests, caregiver interviews were conducted and caregiver questionnaires completed. RESULTS: Significant cognitive decline from T0 to T1 was observed on none of the included measures. There was a significant improvement on a measure of selective attention and on a caregiver-rated behavioral measure. More than 89% of all individual test results remained stable or showed reliable improvement from T0 to T1. Cognitive and behavioral changes from T0 to T1 were not significantly correlated with CBD dose. Improvements in short-term/working memory were significantly related to better therapy response. CONCLUSION: No adverse group-level effects of CBD treatment were detected. On an individual level, most test results remained stable or were improved. Cognitive change was not related to CBD dose. The present results show that, from a cognitive and behavioral point of view, CBD seems to have an encouraging side-effect profile. The results need to be replicated with larger samples.

Which seizure elements do patients memorize? A comparison of history and seizure documentation.

OBJECTIVE: People with epilepsy (PWE) are frequently unable to recall the core manifestation of their disease, epileptic seizures. This means that seizure frequency is often underestimated by practitioners and that seizure classification based on reports of patients or their relatives is difficult because seizure semiology remains unclear. The purpose of this study, therefore, was to prospectively explore patients' memory regarding seizure elements and to assess the role of seizure types. METHOD: Ninety patients diagnosed with focal epilepsy undergoing diagnostic electroencephalography (EEG)-video monitoring were included. The ability to memorize individual seizure elements was assessed using a questionnaire. Patient knowledge was then compared to the findings of subsequent seizure documentation during EEG-video monitoring. Seizure elements were categorized in four groups: subjective, motor, autonomic, and postictal elements. RESULTS: In all categories, the number of documented seizure elements during monitoring strongly exceeded the number of elements that were recalled. Only 45.6% of subjective elements, 5.4% of motor phenomena, 11.9% of autonomic findings, and 2.1% of postictal impairments were recalled. The ability to recall seizure elements varied significantly depending on seizure types (secondarily generalized tonic-clonic seizures [SGTCS] < complex partial seizures [CPS] < simple partial seizures [SPS]), but not on the relative timing of the element during the seizure. SIGNIFICANCE: Patients' memory of seizure semiology is almost always fragmentary. Although the rate of correctly remembered seizure elements depends on the seizure type, complete recall of a seizure is almost never obtained. Consequently, 89 of 90 patients in this cohort would only have had seizures classified as a seizure with "impaired awareness" according to the new International League Against Epilepsy (ILAE) seizure classification. The involvement of brain areas involved in memory encoding and consolidation and in the context of seizure classification schemes.

Effects of hippocampus-sparing resections in the temporal lobe: Hippocampal atrophy is associated with a decline in memory performance.

OBJECTIVE: In patients with temporal lobe epilepsy (TLE) with a nonlesional and nonepileptogenic hippocampus (HC), in order to preserve functionally intact brain tissue, the HC is not resected. However, some patients experience postoperative memory decline, possibly due to disruption of the extrahippocampal memory network and secondary hippocampal volume (HV) loss. The purpose of this study was to determine the extent of hippocampal atrophy ipsilateral and contralateral to the side of the surgery and its relation to memory outcomes. METHODS: Hippocampal volume and verbal as well as visual memory performance were retrospectively examined in 55 patients (mean age ± standard deviation [SD] 30 ± 15 years, 25 female, 31 left) before and 5 months after surgery within the temporal lobe that spared the entire HC. HV was extracted based on prespecified templates, and resection volumes were also determined. RESULTS: HV loss was found both ipsilateral and contralateral to the side of surgery (P < .001). Postoperative left HV loss was a significant predictor of postoperative verbal memory deterioration after left-sided surgery (P < .01). Together with the preoperative verbal memory performance, postoperative left HV explained almost 60% of the variance (P < .0001). However, right HV was not a clear predictor of visual memory performance. Larger resection volumes were associated with smaller postoperative HV, irrespective of side of surgery (left: P < .05, right: P < .01). SIGNIFICANCE: A disruption of the memory network by any resection within the TL, especially within the language-dominant hemisphere, may lead to HC atrophy and memory decline. These findings may further improve the counseling of patients concerning their postoperative memory outcome before TL resections sparing the entire HC.

Short- and long-term effects of rearing dairy calves with contact to their mother on their reactions towards humans.

In this Research Communication we address the hypotheses that reduced contact with humans during the first week of life would impair the relationship of dairy calves reared in dam-calf-contact systems to humans in comparison with artificially reared animals, but that this difference would vanish over time. Artificially reared calves (Artificial) that had been separated from their mother within 12 h after birth were bottle-fed with colostrum for 5 d and thereafter sucked milk from an automatic milk feeder. Animals reared with dam-calf contact (Dam-contact) were kept in the calving pen with their dam for 5 d, and then had permanent access to the cow barn and thus to their dam. Calves were weaned at an age of 12 weeks and kept in young stock groups mixed of both treatments until integration into the cow herd. We tested the animals' relationship with humans by assessing the animals' responses towards an unfamiliar person in an avoidance distance (AD) test in the home environment at 4 weeks of age, at 15 months and at 33 months. In calves, we additionally measured AD in a novel arena after a stationary person test. Artificial animals had lower AD, i.e. showed lower level of fear, than Dam-contact calves. However, the AD in Dam-contact calves decreased with increasing number of days they experienced assistance for suckling. Further, there was no significant difference in later ages. In conclusion, gentle human contact in combination with feeding during the first 5 d of life improved calves' relationship to humans leading to differences between the two treatments as well as within the Dam-contact calves. Potential effects under different conditions regarding quantity and quality of human-animal interactions need further research.

Play and social behaviour of calves with or without access to their dam and other cows.

The aim of the study reported in this Research Communication was to compare play behaviour and social interactions of dairy calves either separated from their mother and reared in a calf group (Artificial) or with access to their mother and the cow herd (cow-calf contact: Contact). Contact calves had access to a calf area and also to the cow barn where they could suckle their dam. Artificial calves were fed whole milk up to 16 kg per day via an automatic milk feeder and were only kept in the calf area. We observed the animals on 3 d during the first three months of life. Contact calves showed solitary play, consisting predominantly of locomotor play, for longer than Artificial calves and mainly in the cow barn. This indicates higher welfare in Contact calves. In addition, Artificial calves hardly experienced any agonistic interaction, while Contact calves both initiated and received agonistic interactions, which might contribute to the development of higher social competence.

Association between seizure freedom and default mode network reorganization in patients with unilateral temporal lobe epilepsy.

RATIONALE: The spontaneous synchronized activity and intrinsic organization of the Default Mode Network (DMN) has been found to be altered because of epileptic activity of temporal lobe origin. Thus, the aim of the present study was to compare DMN's topological properties in patients with seizure-free (SF) and not seizure-free (NSF) temporal lobe epilepsy (TLE). METHODS: Functional connectivity within the DMN was determined from an 8-minute resting state functional magnetic resonance imaging (fMRI) in 27 patients with TLE (12 SF, 15 NSF) and 15 healthy controls (HC). The DMN regions of interest were extracted according to the automated anatomical labeling (AAL) atlas. Network properties were assessed using standard graph-theoretical measures. RESULTS: Analyses revealed, irrespectively of focus lateralization, borderline significance for longer paths (p = 0.049) and in trend reduced local efficiency within the DMN of SF when compared with that of NSF (p = 0.075). The SF and NSF patients did not differ in global network topology from HC (p > 0.05). At the nodal network level, the degree of central hubs was significantly reduced in SF when compared with that in NSF (0.002 ≤ p ≤ 0.080) and HC (0.001 ≤ p ≤ 0.066) while simultaneously, right anterior superior temporal gyrus revealed significantly higher degree in SF than in NSF (p = 0.005) and HC (p = 0.016). CONCLUSION: Seizure freedom seems to be associated with hub redistributions that may underlie longer paths and (in trend) reduced local efficiency of the network. An associated slower system response might reduce the probability of a rapid spread of epileptic discharges over the whole network and may help to prevent hypersynchronous neuronal activity in brain networks that may result in epileptic seizures.

Viewing their own seizures improves understanding of disease in people with epilepsy.

BACKGROUND: People with epilepsy (PWE) are frequently unable to recall the core manifestation of their disease, epileptic seizures. This limits their understanding of disease severity and social reactions to it. PURPOSE: The purpose of this study was to assess the effects of video presentation (VP) of one's own seizure and the role of seizure type/severity. METHODS: Ninety patients diagnosed with focal epilepsy undergoing diagnostic video-electroencephalography (EEG) monitoring were included. All participants were presented with a seizure of their predominant seizure type on videotape. Effects of viewing seizures were assessed using a questionnaire immediately after the VP (T1), after 3 days (T2), and after 3 months (T3). RESULTS: Of the participants, 97.6%, 87.2%, and 85.2% considered VP as helpful at T1, T2, and T3, respectively. Participants who viewed a more severe seizure tended to assess the VP as more helpful, related to an improved understanding of the disease and of reaction of others to their seizures. Of the participants, 11.5% and 5.0% perceived the VP as stressful at T2 and T3, respectively. Severity of the presented seizure was positively correlated to the level of stress induced, mostly because of a feeling of helplessness based on ictal loss of control. CONCLUSIONS: The VP of the patients' own seizures is a way to improve the patients' knowledge on their disease, which was appreciated by the vast majority of participants. The VP of severe seizures was regarded more informative yet also more stressful. Further research is needed to examine possible effects on quality of life and compliance.

Cognition in epilepsy patients with hypothalamic hamartomas.

Many patients with epilepsy caused by hypothalamic hamartomas (HHs) have cognitive impairments during the course of the disease or following neurosurgical treatment. The purpose of this study was to assess cognitive function in these patients, as well as factors influencing preoperative cognitive performance and cognitive outcome after neurosurgical treatment. Using the two largest and most detailed neuropsychology datasets on HH and epilepsy from two centers, we retrospectively report on cognitive functions in 48 patients with structural epilepsy due to HH (mean age ± standard deviation [SD] 20 ± 12 years, range 5-53 years, median 16 years; disease duration mean 17 ± 11 years). Intelligence, verbal learning and recall, and speed and executive functions (processing speed and cognitive flexibility) were assessed before and on average 19 (±11) months after surgery (interstitial radiosurgery: N = 22; neurosurgical resection/disconnection: N = 26). Prior to neurosurgical treatment, 52% of patients showed impaired executive and 62% showed reduced verbal memory functions. A trend for a detrimental effect of higher drug load on cognitive functioning was found. After neurosurgical treatment, intellectual functions for the entire cohort tended to increase. This correlated with improved seizure frequency and decreased number of antiepileptic drugs (AEDs). However, postoperative outcomes for individual patients were highly variable, with significant deteriorations in 17% (processing speed) to 34% (cognitive flexibility and verbal learning), and performance increases in 17% (intellectual functioning) up to 39% (processing speed) of the patients. Higher levels of presurgical performance were significant predictors of cognitive decline after surgery. These results are highly relevant for patient consultation and may help with therapeutic decisions.

Reduced glucose metabolism in neocortical network nodes remote from hypothalamic hamartomas reflects cognitive impairment.

The clinical appearance of patients with hypothalamic hamartomas is very heterogeneous, and interindividual variability of intellectual abilities is not completely understood. We retrospectively investigated cerebral dysfunction as indicated by reduced regional glucose metabolism in 29 patients (age range 7-49 years) with epilepsy due to hypothalamic hamartomas. Brain metabolism assessed by [18 F]FDG-PET was compared between patients with and without cognitive impairment controlled for unevenly distributed hamartoma lateralization seen on magnetic resonance imaging (MRI). Due to the broad age range, the variable "age" was included in the imaging analyses as a covariate. Additional voxel-wise analysis with hamartoma volume, disease duration, seizure severity, seizure frequency, and antiepileptic drug (AED) load as well as dosage and gender as further covariates was accomplished. Furthermore, global visual ratings on laterality of hypometabolism patterns were assessed according to clinical standards and related to hamartoma lateralization on MRI as well as lateralization of electroencephalography (EEG) abnormalities. Cognitively impaired patients showed significantly reduced glucose metabolism in bilateral frontal as well as right parietal and posterior midline cortices (p < 0.005), irrespective of hamartoma lateralization seen on MRI. Additional voxel-wise analysis with the above-mentioned further covariates revealed comparable results. FDG uptake values within the main right frontal cluster obtained from group comparison were not associated with hamartoma volume, disease duration, or AED load. Irrespective of cognitive functioning, lateralization of reduced FDG uptake in global visual ratings was associated with lateralization of hypothalamic hamartomas seen on MRI (p < 0.01), but not with EEG abnormalities. We found regions of reduced glucose metabolism in cognitively impaired patients remote from the hypothalamic hamartomas in frontal and parietal regions, which have been identified as important network nodes in the human brain and are linked to higher cognitive functions.

Revised version of quality guidelines for presurgical epilepsy evaluation and surgical epilepsy therapy issued by the Austrian, German, and Swiss working group on presurgical epilepsy diagnosis and operative epilepsy treatment.

The definition of minimal standards remains pivotal as a basis for a high standard of care and as a basis for staff allocation or reimbursement. Only limited publications are available regarding the required staffing or methodologic expertise in epilepsy centers. The executive board of the working group (WG) on presurgical epilepsy diagnosis and operative epilepsy treatment published the first guidelines in 2000 for Austria, Germany, and Switzerland. In 2014, revised guidelines were published and the WG decided to publish an unaltered English translation in this report. Because epilepsy surgery is an elective procedure, quality standards are particularly high. As detailed in the first edition of these guidelines, quality control relates to seven different domains: (1) establishing centers with a sufficient number of sufficiently and specifically trained personnel, (2) minimum technical standards and equipment, (3) continuous medical education of employees, (4) surveillance by trained personnel during video electroencephalography (EEG) monitoring (VEM), (5) systematic acquisition of clinical and outcome data, (6) the minimum number of preoperative evaluations and epilepsy surgery procedures, and (7) the cooperation of epilepsy centers. These standards required the certification of the different professions involved and minimum numbers of procedures. In the subsequent decade, quite a number of colleagues were certified by the trinational WG; therefore, the executive board of the WG decided in 2013 to make these standards obligatory. This revised version is particularly relevant given that the German procedure classification explicitly refers to the guidelines of the WG with regard to noninvasive/invasive preoperative video-EEG monitoring and invasive intraoperative diagnostics in epilepsy.

Incipient preoperative reorganization processes of verbal memory functions in patients with left temporal lobe epilepsy.

We previously reported nonlinear correlations between verbal episodic memory performance and BOLD signal in memory fMRI in healthy subjects. The purpose of the present study was to examine this observation in patients with left mesial temporal lobe epilepsy (mTLE) who often experience memory decline and need reliable prediction tools before epilepsy surgery with hippocampectomy. Fifteen patients with left mTLE (18-57years, nine females) underwent a verbal memory fMRI paradigm. Correlations between BOLD activity and neuropsychological data were calculated for the i) hippocampus (HC) as well as ii) extrahippocampal mTL structures. Memory performance was systematically associated with activations within the right HC as well as with activations within the left extrahippocampal mTL regions (amygdala and parahippocampal gyrus). As hypothesized, the analyses revealed cubic relationships, with one peak in patients with marginal memory performance and another peak in patients with very good performance. The nonlinear correlations between memory performance and activations might reflect the compensatory recruitment of neural resources to maintain memory performance in patients with ongoing memory deterioration. The present data suggest an already incipient preoperative reorganization process of verbal memory in non-amnesic patients with left mTLE by simultaneously tapping the resources of the right HC and left extrahippocampal mTL regions. Thus, in the preoperative assessment, both neuropsychological performance and memory fMRI should be considered together.

Memory outcome one year after stereotactic interstitial radiosurgery in patients with epilepsy due to hypothalamic hamartomas.

Epileptic seizures caused by hypothalamic hamartomas (HHs) are highly pharmacoresistant. Resective surgical approaches have shown some efficacy in controlling seizures; however, they bear a significant risk of postoperative mnemonic deterioration due to the close anatomical proximity of the HHs to structures essential for memory functions. We report on cognitive outcome in 26 patients with structural epilepsy due to HHs one year after interstitial radiosurgery. Individually, deteriorations occurred more frequently in declarative memory functions (in 20 to 50% of the patients), whereas more than 80% of the patients revealed stable or even improved performance in attentional functions. Preoperative better memory functions were associated with higher risk of postoperative performance decline. After radiosurgery, half of the patients showed more than 50%, and some up to 90%, of seizure reduction. Hypothalamic hamartoma volumes were significantly reduced at follow-up. Transient radiogenic edema found in 10/26 patients was not associated with further cognitive decline after radiosurgery. These results are highly relevant for therapeutic decisions and patient consultation on timing and choice of nonmedical treatment options for HHs.

Transient global amnesia after the right temporal epilepsy surgery: A case report.

Transient global amnesia (TGA) is characterized by sudden and temporary memory impairment, while transient epileptic amnesia (TEA) represents amnestic attacks as the main manifestation of focal epilepsy with presumed temporal origin. We present a 48-year-old patient who experienced transient amnesia 10 weeks after right selective amygdalo-hippocampectomy for right temporal lobe epilepsy. Despite TEA being a plausible explanation for amnesia in patients with temporal lobe epilepsy, no epileptiform discharges were found during the amnestic episode and key features indicative of TGA, including long duration, isolated occurrence, and dense anterograde amnesia of the episode, argued against a diagnosis of TEA in this case. Notably, the patient has remained seizure-free (now 4,5 years) and stopped taking antiseizure medication 32 months after surgery. Although TGA clinical criteria formally exclude patients with recent active epilepsy, neurologists should be aware that TGA can occur after epilepsy surgery in the temporal lobe. Therefore, we consider it of high clinical relevance to establish a careful differential diagnosis between TGA and epileptic amnestic attacks after epilepsy surgery to avoid unnecessary reintroduction or continuation of antiseizure medication. Additionally, this case presents the first comparison of detailed neuropsychological test results before and after a presumed TGA episode, revealing a complete recovery of anterograde memory functions within 1 day. PLAIN LANGUAGE SUMMARY: A 48-year-old patient experienced an episode of transient amnesia 10 weeks after epilepsy surgery. Given the patient's history, an epileptic origin of the episode initially seemed likely. However, tests revealed no seizure activity during the episode and the characteristics matched a condition called transient global amnesia. This case highlights the importance of correctly diagnosing memory impairments after epilepsy surgery to prevent unnecessary treatment.

Dynamic facial emotion recognition and affective prosody recognition are associated in patients with temporal lobe epilepsy.

Deficits in facial emotion recognition have frequently been established in temporal lobe epilepsy (TLE). However, static, rather than dynamic emotion recognition paradigms have been applied. Affective prosody has been insufficiently studied in TLE, and there is a lack of studies investigating associations between auditory and visual emotion recognition. We wished to investigate potential deficits in a dynamic morph task of facial emotion recognition and in an affective prosody recognition task, as well as associations between both tasks. 25 patients with TLE and 24 healthy controls (CG) performed a morph task with faces continuously changing in their emotional intensity. They had to press a button, as soon as they were able to recognize the emotion expressed, and label it accordingly. In the auditory task, subjects listened to neutral sentences spoken in varying emotional tones, and labeled the emotions. Correlation analyses were conducted across both tasks. TLE patients showed significantly reduced prosody recognition compared to CG, and in the morph task, there was a statistical trend towards significantly reduced performance for TLE. Recognition rates in both tasks were significantly associated. TLE patients show deficits in affective prosody recognition, and they may also be impaired in a morph task with dynamically changing facial expressions. Impairments in basic social-cognitive tasks in TLE seem to be modality-independent.

Memory outcome after hippocampus sparing resections in the temporal lobe.

BACKGROUND AND OBJECTIVE: Epilepsy surgery within the temporal lobe of the language dominant hemisphere bears the risk of postoperative verbal memory decline. As surgical procedures have become more tailored, the question has arisen, which type of resection within the temporal lobe is more favourable for memory outcome. Since the hippocampus (HC) is known to play an essential role for long-term memory, we examined whether HC sparing resections help to preserve verbal memory functions. METHODS: We retrospectively analysed neuropsychological data (prior to and 1 year after surgery) of patients undergoing either HC sparing resections (HC-S, N=65) or resections including the hippocampus (HC-R, N=62). RESULTS: Prior to surgery, the HC-R group showed worse memory performance as compared to HC-S patients. Both patient groups revealed further deterioration over time, but in verbal learning HC-R patients demonstrated a stronger decline. Predictors for verbal learning decline were left-sided surgery, better preoperative performance, higher age at surgery, hippocampus resection, and lower preoperative IQ. In patients with spared HC, resection of the left-sided parahippocampal gyrus was rather accompanied by a decline in verbal learning performance. For visual memory, better preoperative performance best predicted deterioration after surgery. Seizure outcome was comparable between the two groups (HC-S: 66%, HC-R: 65% Engel 1a). CONCLUSIONS: Temporal lobe resections within the language dominant hemisphere can be accompanied by a decline in verbal memory performance, even if the HC is spared. Yet, HC sparing surgery is associated with a benefit in verbal learning performance. These results can help when counselling patients prior to epilepsy surgery.

Seizure control and developmental trajectories after hemispherotomy for refractory epilepsy in childhood and adolescence.

PURPOSE: To evaluate the seizure control and developmental outcomes after hemispherotomy for refractory epilepsy in childhood and to identify their predictive factors. METHODS: We retrospectively studied the clinical courses and outcomes of 52 children with refractory epilepsy who underwent hemispherotomy in the Epilepsy Center Freiburg between 2002 and 2011. KEY FINDINGS: Mean age at epilepsy onset was 1.8 years (range 0-8 years) and mean age at surgery was 6.7 years (range 6 months-18 years). The underlying etiology was congenital in 22 (42%) children, acquired in 24 (46%), and progressive in 6 (12%). At final follow-up of 1-9.8 years (mean 3.3), 43 children (83%) were seizure-free. Seizure outcome was not correlated to etiology, with the exception of hemimegalencephaly that was linked to poor seizure control. Presurgical development was impaired in all but one child. Postsurgical development highly correlated with presurgical development. Patients with acquired or progressive etiology, later epilepsy onset, and subsequent later surgery exhibited higher presurgical developmental status that substantially determined postoperative developmental outcome. Improved postsurgical development was determined by acquired etiology and seizure freedom off antiepileptic drugs. SIGNIFICANCE: In our study, most of the selected children and adolescents achieved seizure freedom, including those with congenital etiology. Developmental outcomes, however, were superior in patients with acquired etiology and older age at surgery, underscoring that it is never too late to reap the benefits of this procedure in terms of both epilepsy and development.

Impact of phosphorylation of heat shock protein 27 on the expression profile of periodontal ligament fibroblasts during mechanical strain.

PURPOSE: Orthodontic tooth movement is a complex process involving the remodeling of extracellular matrix and bone as well as inflammatory processes. During orthodontic treatment, sterile inflammation and mechanical loading favor the production of receptor activator of NF-κB ligand (RANKL). Simultaneously, expression of osteoprotegerin (OPG) is inhibited. This stimulates bone resorption on the pressure side. Recently, heat shock protein 27 (HSP27) was shown to be expressed in the periodontal ligament after force application and to interfere with inflammatory processes. METHODS: We investigated the effects of phosphorylated HSP27 on collagen synthesis (COL1A2 mRNA), inflammation (IL1B mRNA, IL6 mRNA, PTGS2 protein) and bone remodeling (RANKL protein, OPG protein) in human periodontal ligament fibroblasts (PDLF) without and with transfection of a plasmid mimicking permanent phosphorylation of HSP27 using real-time quantitative polymerase chain reaction (RT-qPCR), western blot and enzyme-linked immunosorbent assays (ELISAs). Furthermore, we investigated PDLF-induced osteoclastogenesis after compressive strain in a co-culture model with human macrophages. RESULTS: In particular, phosphorylated HSP27 increased gene expression of COL1A2 and protein expression of PTGS2, while IL6 mRNA levels were reduced. Furthermore, we observed an increasing effect on the RANKL/OPG ratio and osteoclastogenesis mediated by PDLF. CONCLUSION: Phosphorylation of HSP27 may therefore be involved in the regulation of orthodontic tooth movement by impairment of the sterile inflammation response and osteoclastogenesis.

Trends in referral patterns to presurgical evaluation at a European reference center.

PURPOSE: To determine if growing evidence for epilepsy surgery as an early treatment option is reflected in the decrease of latencies between epilepsy onset and referral for presurgical evaluation METHODS: Retrospective analysis of latencies in 1646 patients (children and adults) from the time of epilepsy diagnosis to first presurgical workup in the period from 1999 to 2019 based on electronic patient charts at a tertiary epilepsy center. Time spans 1999-2009 and 2010-2019, prior to and following the ILAE definition of pharmacoresistance, and the role of etiological factors were assessed. RESULTS: Over the whole period, the mean latency between diagnosis and a presurgical workup was 15.3 y. There was a significant reduction in the latencies between the periods 1999-2009 (16.9 y) and 2010-2019 (13.4 y), (p < 0.0001). In a linear regression analysis, the latency decreased by 2.6 months/year from 17.4 in 1999 to 13.1 y in 2019 (p < 0.001). Subgroup analyses showed significant decreases in latency to presurgical evaluation in patients with hippocampal sclerosis from 24.4 to 19.5 y, in malformations of cortical development from 16.4 to 13.2 y, and in nonlesional patients from 18.1 to 12.8 y, in contrast to patients with MR evidence for brain tumors with similar latencies across time (10.5 vs. 9.5 y, n.s.). CONCLUSION: The reduction of the time span to a first presurgical evaluation was highly significant over time, yet moderate in its degree. Overall, the aim of early diagnostic evaluation for epilepsy surgery options after established pharmacoresistance was only achieved for a minority of patients.

Epilepsy surgery in early infancy: A retrospective, multicenter study.

Although epilepsy surgery is the only curative therapeutic approach for lesional drug-resistant epilepsy (DRE), there is reluctance to operate on infants due to a fear of complications. A recent meta-analysis showed that epilepsy surgery in the first 6 months of life can achieve seizure control in about two thirds of children. However, robust data on surgical complications and postoperative cognitive development are lacking. We performed a retrospective multicenter study of infants who underwent epilepsy surgery in the first 6 months of life. 15 infants underwent epilepsy surgery at a median age of 134 days (IQR: 58) at four centers. The most common cause was malformation of cortical development, and 13 patients underwent a hemispherotomy. Two thirds required intraoperative red blood transfusions. Severe intraoperative complications occurred in two patients including death in one infant due to cardiovascular insufficiency. At a median follow-up of 1.5 years (IQR: 1.8), 57% of patients were seizure-free. Three patients where reoperated at a later age, resulting in 79% seizure freedom. Anti-seizure medication could be reduced in two thirds, and all patients improved in their development. Our findings suggest that early epilepsy surgery can result in good seizure control and developmental improvement. However, given the perioperative risks, it should be performed only in specialized centers.

Who needs a Wada test? Present clinical indications for amobarbital procedures.

INTRODUCTION: The Wada test has been the gold standard for testing cerebral language localisation during presurgical investigation in the past decades. However, during the last few years a shift has occurred in epilepsy surgery programmes towards the use of non-invasive methods, predominantly functional MRI (fMRI). However, Wada tests are still performed, albeit in a considerably smaller number of patients at many epilepsy centres. METHODS: A retrospective monocentric analysis of remaining clinical indications for performing a Wada procedure was undertaken. The clinical data of patients who participated in Wada tests (42 hemispheric and 8 superselective procedures) during recent years were retrospectively evaluated. RESULTS: Reasons for conducting a Wada test were (1) a patient's inability to perform the fMRI task due to agitation, mental disablement, or perceptual impairment, (2) validation of atypical, inconclusive or not clearly lateralised language activation shown with fMRI, (3) evaluation of propagation of ongoing interictal bilateral epileptiform EEG activity, (4) region selective testing of language and other cognitive functions, or (5) assessment of motor localisation. Patients who were not able to perform the fMRI task or in whom fMRI did not provide interpretable results were significantly younger (p<0.05). CONCLUSION: It is argued that fMRI is eligible to replace Wada tests in the majority of patients who are compliant with clearly lateralised language localisation, but in patients who are agitated or mentally impaired as well as in the case of the above-mentioned specific clinical indications and bilateral fMRI activations, Wada tests still provide additional information. Additionally, non-invasive methods less sensitive to movement artefacts are discussed as possible alternatives for these patients.