Serum Neurosteroid Levels Are Associated With Cortical Thickness in Individuals Diagnosed With Posttraumatic Stress Disorder and History of Mild Traumatic Brain Injury.

Posttraumatic stress disorder (PTSD) co-occurring with mild traumatic brain injury (mTBI) is common in veterans. Worse clinical outcome in those with PTSD has been associated with decreased serum neurosteroid levels. Furthermore, decreased cortical thickness has been associated with both PTSD and mTBI. However, it is not known whether decreased neurosteroids are associated with decreased cortical thickness in PTSD co-occurring with mTBI. This study included 141 individuals divided into the following groups: (a) mTBI group (n = 32 [10 female, 22 male] veterans with a history of mTBI); (b) PTSD + mTBI group (n = 41 [6 female, 35 male] veterans with current PTSD with a history of mTBI); and (c) control group (n = 68 [35 female, 33 male] control participants), which were acquired through the Injury and Traumatic Stress (INTRuST) Clinical Consortium. Subjects underwent clinical assessment, magnetic resonance imaging at 3 T, and serum neurosteroid quantifications of allopregnanolone (ALLO) and pregnenolone (PREGN). Group differences in cortical thickness and associations between serum neurosteroid levels and cortical thickness were investigated. Cortical thickness was decreased in the PTSD + mTBI group compared with the other groups. In the PTSD + mTBI group, decreased cortical thickness was also associated with lower serum ALLO (right superior frontal cortex) and lower serum PREGN (left middle temporal and right orbitofrontal cortex). Cortical thickness in the middle temporal and orbitofrontal cortex was associated with PTSD symptom severity. There were no significant associations between neurosteroids and cortical thickness in the mTBI or control groups. Decreased cortical thickness in individuals with PTSD + mTBI is associated with decreased serum neurosteroid levels and greater PTSD symptom severity. Causality is unclear. However, future studies might investigate whether treatment with neurosteroids could counteract stress-induced neural atrophy in PTSD + mTBI by potentially preserving cortical thickness.

Mild traumatic brain injury impacts associations between limbic system microstructure and post-traumatic stress disorder symptomatology.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a psychiatric disorder that afflicts many individuals, yet the neuropathological mechanisms that contribute to this disorder remain to be fully determined. Moreover, it is unclear how exposure to mild traumatic brain injury (mTBI), a condition that is often comorbid with PTSD, particularly among military personnel, affects the clinical and neurological presentation of PTSD. To address these issues, the present study explores relationships between PTSD symptom severity and the microstructure of limbic and paralimbic gray matter brain regions, as well as the impact of mTBI comorbidity on these relationships. METHODS: Structural and diffusion MRI data were acquired from 102 male veterans who were diagnosed with current PTSD. Diffusion data were analyzed with free-water imaging to quantify average CSF-corrected fractional anisotropy (FA) and mean diffusivity (MD) in 18 limbic and paralimbic gray matter regions. Associations between PTSD symptom severity and regional average dMRI measures were examined with repeated measures linear mixed models. Associations were studied separately in veterans with PTSD only, and in veterans with PTSD and a history of military mTBI. RESULTS: Analyses revealed that in the PTSD only cohort, more severe symptoms were associated with higher FA in the right amygdala-hippocampus complex, lower FA in the right cingulate cortex, and lower MD in the left medial orbitofrontal cortex. In the PTSD and mTBI cohort, more severe PTSD symptoms were associated with higher FA bilaterally in the amygdala-hippocampus complex, with higher FA bilaterally in the nucleus accumbens, with lower FA bilaterally in the cingulate cortex, and with higher MD in the right amygdala-hippocampus complex. CONCLUSIONS: These findings suggest that the microstructure of limbic and paralimbic brain regions may influence PTSD symptomatology. Further, given the additional associations observed between microstructure and symptom severity in veterans with head trauma, we speculate that mTBI may exacerbate the impact of brain microstructure on PTSD symptoms, especially within regions of the brain known to be vulnerable to chronic stress. A heightened sensitivity to the microstructural environment of the brain could partially explain why individuals with PTSD and mTBI comorbidity experience more severe symptoms and poorer illness prognoses than those without a history of brain injury. The relevance of these microstructural findings to the conceptualization of PTSD as being a disorder of stress-induced neuronal connectivity loss is discussed.

Stimulation-induced ictal vocalisation of left frontal lobe origin.

Pure ictal non-speech vocalisation occurs in frontal and temporal lobe epilepsies. Electrical stimulation of supplementary motor areas is reported to evoke vocalisation in selected patients. Here, we report a patient with focal epilepsy of the left anterior insula who had isolated monotonous vocalisation elicited by electrical stimulation of the left superior frontal gyrus. Quantitative analysis of audio signals was performed and compared with a former patient with left frontal lobe epilepsy who had pure ictal vocalisation. Both patients showed a comparable reduction in frequency variation indicating a monotonous voice. [Published with video sequences on www.epilepticdisorders.com].

Neuro-Metabolite Changes in a Single Season of University Ice Hockey Using Magnetic Resonance Spectroscopy.

Background: Previous research has shown evidence for transient neuronal loss after repetitive head impacts (RHI) as demonstrated by a decrease in N-acetylaspartate (NAA). However, few studies have investigated other neuro-metabolites that may be altered in the presence of RHI; furthermore, the relationship of neuro-metabolite changes to neurocognitive outcome and potential sex differences remain largely unknown. Objective: The aim of this study was to identify alterations in brain metabolites and their potential association with neurocognitive performance over time as well as to characterize sex-specific differences in response to RHI. Methods: 33 collegiate ice hockey players (17 males and 16 females) underwent 3T magnetic resonance spectroscopy (MRS) and neurocognitive evaluation before and after the Canadian Interuniversity Sports (CIS) ice hockey season 2011-2012. The MRS voxel was placed in the corpus callosum. Pre- and postseason neurocognitive performances were assessed using the Immediate Post-Concussion Assessment and Cognitive Test (ImPACT). Absolute neuro-metabolite concentrations were then compared between pre- and postseason MRS were (level of statistical significance after correction for multiple comparisons: p < 0.007) and correlated to ImPACT scores for both sexes. Results: A significant decrease in NAA was observed from preseason to postseason (p = 0.001). Furthermore, a trend toward a decrease in total choline (Cho) was observed (p = 0.044). Although no overall effect was observed for glutamate (Glu) over the season, a difference was observed with females showing a decrease in Glu and males showing an increase in Glu, though this was not statistically significant (p = 0.039). In both males and females, a negative correlation was observed between changes in Glu and changes in verbal memory (p = 0.008). Conclusion: The results of this study demonstrate changes in absolute concentrations of neuro-metabolites following exposure to RHI. Results suggest that changes in Glu are correlated with changes in verbal memory. Future studies need to investigate further the association between brain metabolites and clinical outcome as well as sex-specific differences in the brain's response to RHI.

Sex differences in white matter alterations following repetitive subconcussive head impacts in collegiate ice hockey players.

OBJECTIVE: Repetitive subconcussive head impacts (RSHI) may lead to structural, functional, and metabolic alterations of the brain. While differences between males and females have already been suggested following a concussion, whether there are sex differences following exposure to RSHI remains unknown. The aim of this study was to identify and to characterize sex differences following exposure to RSHI. METHODS: Twenty-five collegiate ice hockey players (14 males and 11 females, 20.6 ± 2.0 years), all part of the Hockey Concussion Education Project (HCEP), underwent diffusion-weighted magnetic resonance imaging (dMRI) before and after the Canadian Interuniversity Sports (CIS) ice hockey season 2011-2012 and did not experience a concussion during the season. Whole-brain tract-based spatial statistics (TBSS) were used to compare pre- and postseason imaging in both sexes for fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Pre- and postseason neurocognitive performance were assessed by the Immediate Post-Concussion Assessment and Cognitive Test (ImPACT). RESULTS: Significant differences between the sexes were primarily located within the superior longitudinal fasciculus (SLF), the internal capsule (IC), and the corona radiata (CR) of the right hemisphere (RH). In significant voxel clusters (p < 0.05), decreases in FA (absolute difference pre- vs. postseason: 0.0268) and increases in MD (0.0002), AD (0.00008), and RD (0.00005) were observed in females whereas males showed no significant changes. There was no significant correlation between the change in diffusion scalar measures over the course of the season and neurocognitive performance as evidenced from postseason ImPACT scores. CONCLUSIONS: The results of this study suggest sex differences in structural alterations following exposure to RSHI. Future studies need to investigate further the underlying mechanisms and association with exposure and clinical outcomes.

Saccades are phase-locked to alpha oscillations in the occipital and medial temporal lobe during successful memory encoding.

Efficient sampling of visual information requires a coordination of eye movements and ongoing brain oscillations. Using intracranial and magnetoencephalography (MEG) recordings, we show that saccades are locked to the phase of visual alpha oscillations and that this coordination is related to successful mnemonic encoding of visual scenes. Furthermore, parahippocampal and retrosplenial cortex involvement in this coordination reflects effective vision-to-memory mapping, highlighting the importance of neural oscillations for the interaction between visual and memory domains.

Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery.

BACKGROUND: Detailed neuropathological information on the structural brain lesions underlying seizures is valuable for understanding drug-resistant focal epilepsy. METHODS: We report the diagnoses made on the basis of resected brain specimens from 9523 patients who underwent epilepsy surgery for drug-resistant seizures in 36 centers from 12 European countries over 25 years. Histopathological diagnoses were determined through examination of the specimens in local hospitals (41%) or at the German Neuropathology Reference Center for Epilepsy Surgery (59%). RESULTS: The onset of seizures occurred before 18 years of age in 75.9% of patients overall, and 72.5% of the patients underwent surgery as adults. The mean duration of epilepsy before surgical resection was 20.1 years among adults and 5.3 years among children. The temporal lobe was involved in 71.9% of operations. There were 36 histopathological diagnoses in seven major disease categories. The most common categories were hippocampal sclerosis, found in 36.4% of the patients (88.7% of cases were in adults), tumors (mainly ganglioglioma) in 23.6%, and malformations of cortical development in 19.8% (focal cortical dysplasia was the most common type, 52.7% of cases of which were in children). No histopathological diagnosis could be established for 7.7% of the patients. CONCLUSIONS: In patients with drug-resistant focal epilepsy requiring surgery, hippocampal sclerosis was the most common histopathological diagnosis among adults, and focal cortical dysplasia was the most common diagnosis among children. Tumors were the second most common lesion in both groups. (Funded by the European Union and others.).

Seizure-associated aphasia has good lateralizing but poor localizing significance.

OBJECTIVE: To investigate the occurrence of ictal and postictal aphasia in different focal epilepsy syndromes. METHODS: We retrospectively analyzed the video-electroencephalographic monitoring data of 1,118 patients with focal epilepsy for seizure-associated aphasia (SAA). Statistical analysis included chi-square analysis and Fisher's exact test. RESULTS: We identified 102 of 1,118 patients (9.1%) in whom ictal or postictal aphasia (SAA) was part of their recorded seizures (n = 59 of 102; 57.8%) or who reported aphasia by history (n = 43; 42.2% only reported aphasia by history). Postictal aphasia was present in 18 patients (30.5%). Six of the 59 patients had both ictal and postictal aphasia (10.2%). SAA occurred either with left hemisphere seizure onset or with seizures spreading from the right to the left hemisphere. SAA was most common in patients with parieto-occipital epilepsy (10.9%; five of 46 patients), followed by patients with temporal (6.7%; 28 of 420 patients), focal (not further localized; 4.8%; 22 of 462 patients), and frontal epilepsy (2.1%; four of 190 patients; p = 0.04). SAA was more common in parieto-occipital epilepsy than in frontal epilepsy (p = 0.02). In contrast, there was no significant difference in SAA between temporal and parieto-occipital epilepsy (p = 0.36). SIGNIFICANCE: SAA has a high lateralizing but limited localizing value, as it often reflects spread of epileptic activity into speech-harboring brain regions.

Visual Auras in Epilepsy and Migraine - An Analysis of Clinical Characteristics.

OBJECTIVE: To evaluate the characteristics of visual auras (VA) in epilepsy and migraine. BACKGROUND: Both disorders are usually diagnosed on clinical grounds, but differentiation might be challenging in isolated auras or because of the similar presentation in migraine and epilepsy. METHODS: A retrospective study of two cohorts was performed to compare the VA characteristics of 27 epilepsy patients and 27 age-matched migraine patients. RESULTS: The duration of VA was significantly shorter in epilepsy (median: 56s; 1st quartile Q1: 26s; 3rd quartile Q3: 130s) than in migraine (20 min; Q1: 10 min; Q3: 30 min) (P < .0001). A cutoff duration of ≥5 minutes identified all migraine patients (100% sensitivity, 92% specificity). VAs of epileptic etiology were characterized by restriction to a visual hemifield (74.1% vs 29.6% in migraine, P = .0024) with stereotypic affection of one hemifield (55.5% vs 7.4% in migraine, P = 0.0003). Centrifugal or centripetal spread of visual phenomena only occurred in migraine (37.0%), but not in epilepsy (P = 0.0007). If present, accompanying symptoms such as nausea/vomiting (19/27) or photo-/phonophobia (17/27) identify migrainous auras (vs 0/27 in the epilepsy patients; P < .0001). Headache presented in all migraine patients, but was also observed in six of the epilepsy patients during cephalic auras or the postictal phase (P < .0001). None of the visual migrainous auras evolved into an epileptic seizure, a concept called migralepsy. CONCLUSIONS: Several clinical characteristics differentiate VA of epileptic and migrainous origin - if presenting in classical manner. Additional EEG evaluations should be performed in patients with VA of unclear etiology and epileptic VA features added to current classifications to increase their discriminatory power.

PET imaging in extratemporal epilepsy requires consideration of electroclinical findings.

OBJECTIVE: The study aimed to assess the relevance of interictal temporal glucose hypometabolism in patients with extratemporal epilepsy (ETE) by analyzing its association with a seizure semiology suggestive for temporal seizure involvement and the presence of temporal interictal epileptiform discharges (IEDs). METHODS: We retrospectively reviewed the database of our epilepsy monitoring unit for patients with ETE, in whom long-term EEG-video-monitoring and [(18)F] fluorodeoxyglucose positron emission tomography (FDG-PET) had been performed. The localization of IEDs and the glucose hypometabolism were compared. RESULTS: Almost half (46%) of the 63 ETE patients had IEDs localized in the temporal lobe. Most patients (87.5%; 7/8) with temporal IEDs and an ipsitemporal hypometabolism showed seizure semiology suggestive of temporal or limbic system involvement in contrast to only 31.0% (9/29, p=0.01) in patients without temporal IEDs nor temporal hypometabolism. Those patients also showed an ictal seizure pattern spread into the ipsitemporal lobe, compared with 75.9% (22/29, n.s.) in patients without temporal IEDs nor temporal hypometabolism. Both, extratemporal (ipsilateral in 82.1%; 23/28 patients) and temporal (ipsilateral in 78.6%; 11/14 patients) hypometabolism significantly (p<0.05) lateralized to the epileptogenic hemisphere. CONCLUSION: The common temporal glucose hypometabolism in ETE patients reflects a remote epileptic dysfunction arising from extratemporal epileptogenic zones. Thus, interpretation of interictal FDG-PET results requires consideration of EEG results and seizure semiology to avoid false localization particularly in non-lesional epilepsy.

NeuroKinect: A Novel Low-Cost 3Dvideo-EEG System for Epileptic Seizure Motion Quantification.

Epilepsy is a common neurological disorder which affects 0.5-1% of the world population. Its diagnosis relies both on Electroencephalogram (EEG) findings and characteristic seizure-induced body movements--called seizure semiology. Thus, synchronous EEG and (2D)video recording systems (known as Video-EEG) are the most accurate tools for epilepsy diagnosis. Despite the establishment of several quantitative methods for EEG analysis, seizure semiology is still analyzed by visual inspection, based on epileptologists' subjective interpretation of the movements of interest (MOIs) that occur during recorded seizures. In this contribution, we present NeuroKinect, a low-cost, easy to setup and operate solution for a novel 3Dvideo-EEG system. It is based on a RGB-D sensor (Microsoft Kinect camera) and performs 24/7 monitoring of an Epilepsy Monitoring Unit (EMU) bed. It does not require the attachment of any reflectors or sensors to the patient's body and has a very low maintenance load. To evaluate its performance and usability, we mounted a state-of-the-art 6-camera motion-capture system and our low-cost solution over the same EMU bed. A comparative study of seizure-simulated MOIs showed an average correlation of the resulting 3D motion trajectories of 84.2%. Then, we used our system on the routine of an EMU and collected 9 different seizures where we could perform 3D kinematic analysis of 42 MOIs arising from the temporal (TLE) (n = 19) and extratemporal (ETE) brain regions (n = 23). The obtained results showed that movement displacement and movement extent discriminated both seizure MOI groups with statistically significant levels (mean = 0.15 m vs. 0.44 m, p<0.001; mean = 0.068 m(3) vs. 0.14 m(3), p<0.05, respectively). Furthermore, TLE MOIs were significantly shorter than ETE (mean = 23 seconds vs 35 seconds, p<0.01) and presented higher jerking levels (mean = 345 ms(-3) vs 172 ms(-3), p<0.05). Our newly implemented 3D approach is faster by 87.5% in extracting body motion trajectories when compared to a 2D frame by frame tracking procedure. We conclude that this new approach provides a more comfortable (both for patients and clinical professionals), simpler, faster and lower-cost procedure than previous approaches, therefore providing a reliable tool to quantitatively analyze MOI patterns of epileptic seizures in the routine of EMUs around the world. We hope this study encourages other EMUs to adopt similar approaches so that more quantitative information is used to improve epilepsy diagnosis.

A novel portable, low-cost kinect-based system for motion analysis in neurological diseases.

Many neurological diseases, such as Parkinson's disease and epilepsy, can significantly impair the motor function of the patients, often leading to a dramatic loss of their quality of life. Human motion analysis is regarded as fundamental towards an early diagnosis and enhanced follow-up in this type of diseases. In this contribution, we present NeuroKinect, a novel system designed for motion analysis in neurological diseases. This system includes an RGB-D camera (Microsoft Kinect) and two integrated software applications, KiT (KinecTracker) and KiMA (Kinect Motion Analyzer). The applications enable the preview, acquisition, review and management of data provided by the sensor, which are then used for motion analysis of relevant events. NeuroKinect is a portable, low-cost and markerless solution that is suitable for use in the clinical environment. Furthermore, it is able to provide quantitative support to the clinical assessment of different neurological diseases with movement impairments, as demonstrated by its usage in two different clinical routine scenarios: gait analysis in Parkinson's disease and seizure semiology analysis in epilepsy.

Ictal asystole mimicking seizure deterioration in temporal lobe epilepsy.

We report on a patient with temporal lobe epilepsy, secondary to a left lateral temporal cavernoma, in whom the change in seizure semiology suggested recurrence of secondary generalized seizures. Anticonvulsive medication previously controlled secondary generalized seizures over a period of years but focal seizures continued at a lower rate. Continuous video-EEG monitoring revealed ictal asystole associated with myoclonic syncope and falls during focal seizures arising from the left temporal lobe. After implantation of a cardiac pacemaker, no more falls occurred during the focal seizures. In conclusion, recurrence of seizure-associated falls is typically attributed to recurrence of secondary generalized seizures, however, ictal asystole should be considered in selected epilepsy patients as a differential diagnosis of falls. [Published with video sequence].

Two Patients With Visual Aura - Migraine, Epilepsy, or Migralepsy?

BACKGROUND: The concept of migralepsy refers to visual migraine auras that seemingly evolve into epileptic seizures. It was discussed controversially ever since and scientific proof for this entity is scarce. METHODS: We report two patients with visual aura fulfilling the diagnostic criteria for migralepsy. In both patients, habitual attacks were recorded during long-term video electroencephalography (EEG) monitoring. CASE RESULTS: Both patients demonstrated unilateral occipital EEG seizure patterns during their long-lasting visual aura, which eventually evolved into versive seizures. CONCLUSION: Here, we prove the epileptic origin of the visual auras, which have been misdiagnosed as migraine or migralepsy before. Additional evaluation should be considered in patients with visual aura and hints for an epileptic origin as occipital lobe epilepsy might be missed in patients diagnosed with migraine. Based on our patients, we suggest to challenge the concept of migralepsy in current classifications.

Eye movements differ between ictal ipsilateral and contralateral head turning.

PURPOSE: This study evaluated the relation of head and eye movements during ictal ipsilateral and contralateral head turning in patients with focal epilepsies with regard to lateralization of the epileptogenic zone. METHODS: We reviewed our database and identified patients with ictal head turning ipsilateral and contralateral to the seizure onset as defined by ictal EEG. Twenty-seven seizures of 19 consecutive patients with ipsilateral and 40 seizures of 32 patients with contralateral head turning were investigated. Twenty-four patients had temporal lobe epilepsy (TLE), and 27 patients had extratemporal or multifocal epilepsy. KEY FINDINGS: Eye movement in the same direction preceded contralateral head turning in 90% (36 of 40 seizures) of the seizures, but this was the case in only 33% (9 of 27 seizures) of the ipsilateral ictal head turning. In contrary, head turning preceded the eye movements in 67% (18 of 27 seizures) of the ipsilateral ictal head turning and in only 10% of the contralateral head turning (p < 0.001). The results were similar in TLE and FLE. SIGNIFICANCE: The sequence of head and eye movements is different in ictal ipsilateral and contralateral head turning movements which likely reflects different spread patterns of epileptic activity associated with activation of different generators. The analysis of eye movements adds to the lateralization of ictal head movements.

Latency of interictal epileptiform discharges in long-term EEG recordings in epilepsy patients.

PURPOSE: To assess the latency of interictal epileptiform discharges (IED) and seizures in long-term EEG recordings of patients with epilepsy. METHOD: IED latency was measured in 210 consecutive patients (mean (SD) age 38.6 ± 13.9 years) with active epilepsy and the relationship to clinical variables was analyzed retrospectively. Median duration of EEG recording was 101.5h (95% confidence interval [CI] 92 to 117 h). RESULTS: IEDs were absent in 45 (21.4%) and present in 165 (78.6%) patients who had a longer duration (p < 0.001) and early onset (p < 0.01) of epilepsy and more often had IEDs in prior standard EEGs (p < 0.01), a structural etiology (OR 2.4, CI: 2.1-2.7), or temporal lobe epilepsy (OR 9.6, CI: 9.0-10.2). IED latency did not correlate with other clinical variables. Median latency to the emergence of the first IED was 9.3h (CI: 7.5-11.4) occurring in 7.3%, 9.7%, 74.6%, 87.9%, and 96.4% within 20 min, 30 min, 24h, 48 h, and 72 h, respectively. Seizure frequency was higher in patients with (n = 165) than without IEDs (n = 45) (72.1% vs. 46.6%, p < 0.01) and seizure latency (median 21.6h, CI: 16.8-27.3) was influenced by the presence of IEDs, whereas the presence of seizures did not influence the latency and frequency of IEDs. CONCLUSION: If present, in the majority of epilepsy patients IEDs occurred during the first 72 h of long-term video-EEG recording. Repeated video-EEG or video recordings of habitual seizures are needed to minimize false negative studies.

Seizure semiology identifies patients with bilateral temporal lobe epilepsy.

OBJECTIVE: Laterality in temporal lobe epilepsy is usually defined by EEG and imaging results. We investigated whether the analysis of seizure semiology including lateralizing seizure phenomena identifies bilateral independent temporal lobe seizure onset. METHODS: We investigated the seizure semiology in 17 patients in whom invasive EEG-video-monitoring documented bilateral temporal seizure onset. The results were compared to 20 left and 20 right consecutive temporal lobe epilepsy (TLE) patients who were seizure free after anterior temporal lobe resection. The seizure semiology was analyzed using the semiological seizure classification with particular emphasis on the sequence of seizure phenomena over time and lateralizing seizure phenomena. Statistical analysis included chi-square test or Fisher's exact test. RESULTS: Bitemporal lobe epilepsy patients had more frequently different seizure semiology (100% vs. 40%; p<0.001) and significantly more often lateralizing seizure phenomena pointing to bilateral seizure onset compared to patients with unilateral TLE (67% vs. 11%; p<0.001). The sensitivity of identical vs. different seizure semiology for the identification of bilateral TLE was high (100%) with a specificity of 60%. Lateralizing seizure phenomena had a low sensitivity (59%) but a high specificity (89%). The combination of lateralizing seizure phenomena and different seizure semiology showed a high specificity (94%) but a low sensitivity (59%). SIGNIFICANCE: The analysis of seizure semiology including lateralizing seizure phenomena adds important clinical information to identify patients with bilateral TLE.