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Functional status (FSt) describes the phenomenon of prolonged non-epileptic attacks that may be misidentified as Status Epilepticus (SE). The early differentiation between epileptic and functional status is crucial in order to avoid unnecessarily invasive and costly medical escalation in the latter group, including the hazards of overmedication, intubation and intensive care admission. The authors conducted a literature review of available studies describing cases of functional status to extract the common aspects of FSt seizure semiology, investigations used to differentiate from SE, and guidance for managing FSt. A search was carried out using Medline, Embase and PsychInfo databases and 3909 papers were extracted for review. 30 papers were found relevant for inclusion, describing 260 cases of FSt. FSt was found to occur more commonly in younger, female patients with a family history of epilepsy, co-morbid psychiatric diagnosis and following a recent traumatic event. Common clinical features of FSt during and after, the events were identified. While video-EEG remains the gold standard investigation for differentiating FSt from SE, many of the included studies considered the utility of other investigation modalities including serum markers and neuroimaging. One key shortcoming identified within the literature reviewed was a lack of well-defined guidance on the acute management of FSt. We offer an A-F step management plan for the immediate and longer term assessment and treatment of FSt.

Epilepsy is a common neurological condition, affecting over 70 million individuals worldwide.The present paper reviews current and future (under preclinical and clinical development) pharmacotherapy options for the treatment of drug-resistant focal and generalized epilepsies.Current pharmacotherapy options for drug-resistant epilepsy include perampanel, brivaracetam and the newly approved cenobamate for focal epilepsies; cannabidiol (Epidiolex) for Lennox-Gastaut Syndrome (LGS), Dravet and Tuberous Sclerosis Complex (TSC); fenfluramine for Dravet syndrome and ganaxolone for seizures in Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder. Many compounds are under clinical development and may hold promise for future pharmacotherapies. For adult focal epilepsies, padsevonil and carisbamate are at a more advanced Phase III stage of clinical development followed by compounds at Phase II like selurampanel, XEN1101 and JNJ-40411813. For specific epilepsy syndromes, XEN 496 is under Phase III development for potassium voltage-gated channel subfamily Q member 2 developmental and epileptic encephalopathy (KCNQ2-DEE), carisbamate is under Phase III development for LGS and Ganaxolone under Phase III development for TSC. Finally, in preclinical models several molecular targets including inhibition of glycolysis, neuroinflammation and sodium channel inhibition have been identified in animal models although further data in animal and later human studies are needed.

BackgroundPatients with functional seizures (FS) can experience dissociation (depersonalisation) before their seizures. Depersonalisation reflects disembodiment, which may be related to changes in interoceptive processing. The heartbeat-evoked potential (HEP) is an electroencephalogram (EEG) marker of interoceptive processing.AimTo assess whether alterations in interoceptive processing indexed by HEP occur prior to FS and compare this with epileptic seizures (ES).MethodsHEP amplitudes were calculated from EEG during video-EEG monitoring in 25 patients with FS and 19 patients with ES, and were compared between interictal and preictal states. HEP amplitude difference was calculated as preictal HEP amplitude minus interictal HEP amplitude. A receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic performance of HEP amplitude difference in discriminating FS from ES.ResultsThe FS group demonstrated a significant reduction in HEP amplitude between interictal and preictal states at F8 (effect size rB=0.612, false discovery rate (FDR)-corrected q=0.030) and C4 (rB=0.600, FDR-corrected q=0.035). No differences in HEP amplitude were found between states in the ES group. Between diagnostic groups, HEP amplitude difference differed between the FS and ES groups at F8 (rB=0.423, FDR-corrected q=0.085) and C4 (rB=0.457, FDR-corrected q=0.085). Using HEP amplitude difference at frontal and central electrodes plus sex, we found that the ROC curve demonstrated an area under the curve of 0.893, with sensitivity=0.840 and specificity=0.842.ConclusionOur data support the notion that aberrant interoception occurs prior to FS. Changes in HEP amplitude may reflect a neurophysiological biomarker of FS and may have diagnostic utility in differentiating FS and ES.

Objectives/AimsPatients with functional seizures (FS) can experience dissociation (depersonalisation) before their seizures. Depersonalisation encompasses a feeling of disembodiment, putatively caused by reduced afferent visceral mapping, that is, changes in interoceptive processing. The heartbeat-evoked potential (HEP) is an electroencephalographic (EEG) index of synchronised neural responses to individual heartbeats, and a marker interoceptive representation. HEP amplitude is reported to be reduced in patients with depersonalisation-derealisation disorder. The objective of this study was to assess whether alterations in interoceptive processing indexed by the HEP occur prior to FSs, and compare this with epileptic seizures (ES).MethodsHEP amplitudes were calculated from EEG during video-EEG monitoring in 25 patients with FS and 19 patients with ES, and compared between interictal and preictal states. HEP amplitudes were calculated at frontal and central EEG electrodes. HEP amplitude difference was calculated as a composite measure of preictal HEP amplitude minus interictal HEP amplitude. A Receiver Operating Characteristic (ROC) curve analysis was later used to evaluate the diagnostic performance of the HEP amplitude difference measure in discriminating functional cases from epilepsy cases.ResultsThe FS group demonstrated a significant reduction in HEP amplitude between interictal and preictal states at F8 (effect size rB=0.612, p=0.006) and C4 (rB=0.600, p=0.007). No differences in HEP amplitude were found between interictal and preictal states in the ES group. Between diagnostic groups, HEP amplitude difference was significantly different between the FS and ES group at C4 (rB=0.457, p=0.009) and F8 (rB=0.423, p=0.017). These findings were not related to heart rate, mean ECG or QRS amplitudes, which did not differ between interictal/preictal states, or groups. There was no difference in age between FS and ES groups, however there were a greater proportion of females compared to males in the FS group as compared to the ES group. Using HEP amplitude difference at frontal and central electrodes plus sex as variables, the ROC curve demonstrated an area under the curve (AUC) of 0.893, with sensitivity=0.840 and specificity=0.842 (p=0.000).ConclusionsOur data support the notion that aberrant interoception underpins disembodiment prior to dissociative FS. Changes in HEP amplitude may therefore reflect a neurophysiological biomarker of FS. HEP amplitude difference between interictal and preictal states may have diagnostic utility in differentiating FS and ES.

BackgroundPatients with functional seizures (FS) can experience dissociation (depersonalisation) before their seizures. Depersonalisation encompasses a feeling of disembodiment, putatively caused by reduced afferent visceral mapping, that is, changes in interoceptive processing. The heartbeat-evoked potential (HEP) is an electroencephalographic (EEG) index of synchronised neural responses to individual heart- beats, and a marker of interoceptive representation. HEP amplitude is reported to be reduced in dep- ersonalisation-derealisation disorder.PurposeTo assess whether alterations in interoceptive processing indexed by the HEP occur prior to FSs, and compare this with epileptic seizures (ES).MethodsHEP amplitudes were calculated from EEG during video-EEG monitoring in 25 patients with FS and 19 patients with ES, and compared between interictal and preictal states.ResultsThe FS group demonstrated a significant reduction in HEP amplitude between interictal and preictal states at F8 (rB=0.612, p=0.006) and C4 (rB=0.600, p=0.007). No differences in HEP amplitude were found between interictal and preictal states in the ES group. Findings were not related to heart rate, mean ECG or QRS amplitudes, which did not differ between states or groups.ConclusionOur data support the notion that aberrant interoception underpins disembodiment prior to dissociative FS. Changes in HEP amplitude may reflect a neurophysiological biomarker of FS.

BackgroundHead Injury (HI) is a common presentation to the Emergency Department (ED). Most injuries are mild and patients are often discharged directly from ED. However, persistent symptoms and failure to return-to-work are common. Comprehensive advice and a clear pathway if symptoms persist are critical to prevent unnecessary morbidity.ObjectivesTo audit the discharge advice and follow-up of patients discharged from an ED with a HI.MethodologyA Data Collection Tool was used to audit the advice and follow-up guidance given to patients attending St George’s Hospital ED in December 2018 with a HI. Data was audited against the NICE Guidelines for Head Injury: Assessment and Early Management (CG176).Results149 patients were identified. 41 (27.5%) were provided with written advice; 53 (35.6%) had no documentation of any HI advice being given; 55 (36.9%) had some documentation of HI advice but no documentation that written material was provided.ConclusionsA need for improvement in the quality of HI Discharge Advice from ED and access to spe- cialist HI outpatient assessment was identified. Improvements implemented included education of ED staff, new patient information sheet, and direct referral system to a specialist HI clinic. Re-audit is planned following these improvements.Samia.Elkommos@nhs.net

BackgroundPatients with chronic focal epilepsy may have atrophy of brain structures important for the generation and maintenance of seizures. However, little research has been conducted in patients with newly diagnosed focal epilepsy (NDfE), despite it being a crucial point in time for understanding the underlying biology of the disorder. We aimed to determine whether patients with NDfE show evidence of volumetric abnormalities of subcortical structures.MethodsEighty-two patients with NDfE and 40 healthy controls underwent MRI scanning using a standard clinical protocol. Volume estimation of the left and right hippocampus, thalamus, caudate nucleus, putamen and cerebral hemisphere was performed for all participants and normalised to whole brain volume. Volumes lower than two standard deviations below the control mean were considered abnormal. Volumes were analysed with respect to patient clinical characteristics, including treatment outcome 12 months after diagnosis.ResultsVolume of the left hippocampus (P(FDR-corr) = 0.04) and left (P(FDR-corr) = 0.002) and right (P(FDR-corr) = 0.04) thalamus were significantly smaller in patients relative to controls. Relative to the normal volume limits in controls, 11% individual patients had left hippocampal atrophy, 17% had left thalamic atrophy and 9% had right thalamic atrophy. We did not find evidence of a relationship between volumes and future seizure control or with other clinical characteristics of epilepsy.ConclusionsVolumetric abnormalities of structures known to be important for the generation and maintenance of focal seizures are established at the time of epilepsy diagnosis and are not necessarily a result of the chronicity of the disorder.

Objective Depression is a relatively common comorbidity in people with epilepsy with a lifetime history identified in 1 in 4 individuals. In this paper, we aimed to provide a systematic review of structural and functional brain region-specific group differences of adults with epilepsy and depression and to discuss existing evidence as compared to that in people with depression. Methods We undertook a systematic review of neuroimaging studies of depression in adults with epilepsy through MEDLINE/PubMed, Embase and PsycInfo searches until June 2020. Results A total of 44 studies were included in the qualitative synthesis: 21 on structural neuroimaging, 9 on functional, and 14 on pharmaco/metabolic neuroimaging. Almost all studies focused on temporal lobe epilepsy (TLE). Patterns of changes in the hippocampi and subcortical structures seem to be different from those reported in depression outside epilepsy. Cortical changes are grossly similar as well as the lack of any laterality effect. Serotonin dysfunction seems to be due to different mechanisms with reduced synaptic availability for depression in epilepsy as compared to reduced 5HT1 receptor density outside epilepsy. Depressive symptoms seem to correlate with a dysfunction in temporolimbic structures contralateral to the epileptogenic zone especially in patients with de novo postsurgical depression. Conclusions Depression, at least in TLE, seems to be associated with a different pattern of brain changes as compared to major depression, potentially supporting the notion of phenomenological peculiarities of depression in epilepsy.

The fetal brain shows accelerated growth in the latter half of gestation, and these changes can be captured by 2D and 3D biometry measurements. The aim of this study was to quantify brain growth in normal fetuses using Magnetic Resonance Imaging (MRI) and to produce reference biometry data and a freely available centile calculator (https://www.developingbrain.co.uk/fetalcentiles/). A total of 127 MRI examinations (1.5 T) of fetuses with a normal brain appearance (21–38 gestational weeks) were included in this study. 2D and 3D biometric parameters were measured from slice-to-volume reconstructed images, including 3D measurements of supratentorial brain tissue, lateral ventricles, cortex, cerebellum and extra-cerebral CSF and 2D measurements of brain biparietal diameter and fronto-occipital length, skull biparietal diameter and occipitofrontal diameter, head circumference, transverse cerebellar diameter, extra-cerebral CSF, ventricular atrial diameter, and vermis height, width, and area. Centiles were constructed for each measurement. All participants were invited for developmental follow-up. All 2D and 3D measurements, except for atrial diameter, showed a significant positive correlation with gestational age. There was a sex effect on left and total lateral ventricular volumes and the degree of ventricular asymmetry. The 5th, 50th, and 95th centiles and a centile calculator were produced. Developmental follow-up was available for 73.1% of cases [mean chronological age 27.4 (±10.2) months]. We present normative reference charts for fetal brain MRI biometry at 21–38 gestational weeks. Developing growth trajectories will aid in the better understanding of normal fetal brain growth and subsequently of deviations from typical development in high-risk pregnancies or following premature delivery. Electronic supplementary material The online version of this article (doi:10.1007/s00429-016-1342-6) contains supplementary material, which is available to authorized users.

Mild cerebral ventricular enlargement is associated with schizophrenia, autism, epilepsy, and attention-deficit/hyperactivity disorder. Fetal ventriculomegaly is the most common central nervous system (CNS) abnormality affecting 1% of fetuses and is associated with cognitive, language, and behavioral impairments in childhood. Neurodevelopmental outcome is partially predictable by the 2-dimensional size of the ventricles in the absence of other abnormalities. We hypothesized that isolated fetal ventriculomegaly is a marker of altered brain development characterized by relative overgrowth and aimed to quantify brain growth using volumetric magnetic resonance imaging (MRI) in fetuses with isolated ventriculomegaly. Fetal brain MRI (1.5 T) was performed in 60 normal fetuses and 65 with isolated ventriculomegaly, across a gestational age range of 22-38 weeks. Volumetric analysis of the ventricles and supratentorial brain structures was performed on 3-dimensional reconstructed datasets. Fetuses with isolated ventriculomegaly had increased brain parenchyma volumes when compared with the control cohort (9.6%, P < 0.0001) with enlargement restricted to the cortical gray matter (17.2%, P = 0.002). The extracerebral cerebrospinal fluid and third and fourth ventricles were also enlarged. White matter, basal ganglia, and thalamic volumes were not significantly different between cohorts. The presence of relative cortical overgrowth in fetuses with ventriculomegaly may represent the neurobiological substrate for cognitive, language, and behavioral deficits in these children.

Highlights • We studied patients with refractory temporal lobe epilepsy who underwent surgery. • Hippocampal internal architecture (HIA) did not correlate with seizure outcome. • HIA correlated with hippocampal neuronal density, Wyler grades, and hippocampal volume. • HIA on MRI has a histopathological basis. • Postoperative seizure outcome cannot be predicted by HIA on MRI., Purpose Semi-quantitative analysis of hippocampal internal architecture (HIA) on MRI has been shown to be a reliable predictor of the side of seizure onset in patients with temporal lobe epilepsy (TLE). In the present study, we investigated the relationship between postoperative seizure outcome and preoperative semi-quantitative measures of HIA. Methods We determined HIA on high in-plane resolution preoperative T2 short tau inversion recovery MR images in 79 patients with presumed unilateral mesial TLE (mTLE) due to hippocampal sclerosis (HS) who underwent amygdalohippocampectomy and postoperative follow up. HIA was investigated with respect to postoperative seizure freedom, neuronal density determined from resected hippocampal specimens, and conventionally acquired hippocampal volume. Results HIA ratings were significantly related to some neuropathological features of the resected hippocampus (e.g. neuronal density of selective CA regions, Wyler grades), and bilaterally with preoperative hippocampal volume. However, there were no significant differences in HIA ratings of the to-be-resected or contralateral hippocampus between patients rendered seizure free (ILAE 1) compared to those continuing to experience seizures (ILAE 2-5). Conclusions This work indicates that semi-quantitative assessment of HIA on high-resolution MRI provides a surrogate marker of underlying histopathology, but cannot prospectively distinguish between patients who will continue to experience postoperative seizures and those who will be rendered seizure free. The predictive power of HIA for postoperative seizure outcome in non-lesional patients with TLE should be explored.

Although temporal lobe surgery is an effective treatment for patients with intractable mesial temporal lobe epilepsy (mTLE), a third of patients will continue to experience seizures at 2 years after surgery. The reasons are unknown. One suggestion is that patients with abnormalities of the entorhinal cortex might have a subtype of mTLE that is resistant to surgery. We investigated the association between presurgical entorhinal cortex volume and postoperative outcome in patients with mTLE.78 patients with intractable mTLE and unilateral hippocampal sclerosis underwent comprehensive presurgical evaluation at the Department of Epileptology, University Hospital Bonn, Germany. Patients and 76 age-matched healthy controls received an MP-RAGE T1-weighted MRI. We determined left and right entorhinal cortex volume, masked to participant identity, using rigorous manual techniques. All patients had complex partial seizures, underwent amygdalohippocampectomy, and received postoperative outcome assessment.There was a significant effect of group (controls, left mTLE, right mTLE) on the volume of the left (univariate ANOVA F=29·6, p0·001) and right (F=8·3, p0·001) entorhinal cortex, and entorhinal asymmetry (F=92·6, p0·001). Post-hoc analysis with Bonferroni correction revealed that patients with left (p0·001) and right (p=0·01) mTLE had significantly reduced volume of the ipsilateral entorhinal cortex relative to controls, and patients with right mTLE also had volume reduction of the contralateral entorhinal cortex (p=0·01). We found no significant differences in entorhinal cortex volumes and clinical data between patients (n=48, 62%) surgically rendered seizure free (ILAE I-II) and patients (n=30, 38%) with persistent seizures (ILAE III-VI).These data indicate that gross atrophy of the entorhinal cortex is not a predictor of postoperative outcome in patients with intractable mTLE. We are evaluating whether alterations in entorhinal cortex connectivity and extent of resection are related to postoperative outcome in our series of patients.This work was supported by a UK Medical Research Council grant awarded to SSK.

Studies of newly-diagnosed epilepsy (NDE) will provide important insight into the underlying neurobiology in the early stages of epilepsy and development of imaging biomarkers for seizure and cognitive outcomes. However, patients with NDE are rarely studied using imaging techniques. This study investigated whether volumetric changes in subcortical nuclei are present in patients with newly diagnosed focal epilepsy (NDfE). 101 patients with NDfE and 40 healthy controls received T1-weighted MRI. Quantitative MRI volume measurements of the thalamus, caudate nucleus and putamen were performed. The left (p=0.001) and right (p=0.015) thalami were significantly smaller in patients relative to controls. Eleven patients (11%) had thalamic volumes below the ‘normal range’. There were no statistically significant differences between patients and controls in volume of the left (p=0.701) or right (p=0.546) putamen and left (p=0.328) or right (p=0.426) caudate nucleus. This study reports the first evidence for the presence of thalamic atrophy in patients with NDfE, and suggests that previously reported thalamic abnormalities in patients with refractory epilepsy are not necessarily due to the chronicity of the condition. Subcortical atrophy in patients with NDfE could structurally compromise patients at the point of diagnosis, predisposing these patients to seizures and cognitive dysfunction.

Objective There are competing explanations for persistent postoperative seizures after temporal lobe surgery. One is that 1 or more particular subtypes of mesial temporal lobe epilepsy (mTLE) exist that are particularly resistant to surgery. We sought to identify a common brain structural and connectivity alteration in patients with persistent postoperative seizures using preoperative quantitative magnetic resonance imaging and diffusion tensor imaging (DTI). Methods We performed a series of studies in 87 patients with mTLE (47 subsequently rendered seizure free, 40 who continued to experience postoperative seizures) and 80 healthy controls. We investigated the relationship between imaging variables and postoperative seizure outcome. All patients had unilateral temporal lobe seizure onset, had ipsilateral hippocampal sclerosis as the only brain lesion, and underwent amygdalohippocampectomy. Results Quantitative imaging factors found not to be significantly associated with persistent seizures were volumes of ipsilateral and contralateral mesial temporal lobe structures, generalized brain atrophy, and extent of resection. There were nonsignificant trends for larger amygdala and entorhinal resections to be associated with improved outcome. However, patients with persistent seizures had significant atrophy of bilateral dorsomedial and pulvinar thalamic regions, and significant alterations of DTI‐derived thalamotemporal probabilistic paths bilaterally relative to those patients rendered seizure free and controls, even when corrected for extent of mesial temporal lobe resection. Interpretation Patients with bihemispheric alterations of thalamotemporal structural networks may represent a subtype of mTLE that is resistant to temporal lobe surgery. Increasingly sensitive multimodal imaging techniques should endeavor to transform these group‐based findings to individualize prediction of patient outcomes. Ann Neurol 2015;77:760–774

Background Transverse myelitis (TM) associated with neuromyelitis optica (NMO) has many unusual characteristics compared with TM in Multiple Sclerosis (MS): long centrally located lesions that cause significant motor-sensory (including tonic spasms) and autonomic dysfunction. We wish to report a symptom not previously described in neurological literature, neuropathic post ejaculatory pain (PEP). Methods We will present videos of 3 male patients with AQP4-IgG +ve NMO describing post-ejaculatory pain (PEP). Results All patients were recovering from long thoracic TM and had autonomic dysfunction at nadir. None had preexisting urological symptoms. The pain occurred immediately after orgasm and ejaculation and was severe, brief ( Conclusion PEP has not been described in neurological disorders and maybe a unique feature of NMO associated myelitis.

IntroductionIt is unknown why over one-third of patients with mesial temporal lobe epilepsy (mTLE) and hippocampal sclerosis (HS) continue to experience seizures despite temporal lobe surgery. We investigated the relationship between hippocampal internal architecture (HIA) on preoperative MRI, and postoperative seizure outcome in patients with refractory mTLE and HS.MethodsHIA was assessed on preoperative T2-STIR MR images using a published scoring system1 for 79 patients undergoing evaluation at University Hospital Bonn, Germany. Patients underwent amygdalohippocampectomy and received postoperative outcome assessment using the International League Against Epilepsy (ILAE) classification. Hippocampal volumes were obtained using 3D T1-weighted images. Quantitative histopathological assessment was performed on resected hippocampal specimens.ResultsNo significant differences in ipsilateral or contralateral HIA ratings, or HIA score asymmetry, were found between patients rendered seizure free (ILAE I) compared to those continuing to experience postoperative seizures (ILAE II-VI). HIA significantly correlated with neuronal density in CA3 and CA4 in the pathologic hippocampus, and hippocampal volumes bilaterally. There was no significant correlation between HIA and clinical variables.ConclusionAlthough valuable in determining seizure laterality, HIA does not predict postoperative outcome.AcknowledgementsThis work was supported by a UK MRC grant awarded to SSK (Grant Number: MR/K023152/1). References:1Ver Hoef 2013