Patricia Dugan

Comparing neurostimulation technologies in refractory focal-onset epilepsy

For patients with pharmacoresistant focal epilepsy in whom surgical resection of the epileptogenic focus fails or was not feasible in the first place, there were few therapeutic options. Increasingly, neurostimulation provides an alternative treatment strategy for these patients. Vagal nerve stimulation (VNS) is well established. Deep brain stimulation (DBS) and cortical responsive stimulation (CRS) are newer neurostimulation therapies with recently published long-term efficacy and safety data. In this literature review, we introduce these therapies to a non-specialist audience. Furthermore, we compare and contrast long-term (5-year) outcomes of newer neurostimulation techniques with the more established VNS. A search to identify all studies reporting long-term efficacy (>5 years) of VNS, CRS and DBS in patients with refractory focal/partial epilepsy was conducted using PubMed and Cochrane databases. The outcomes compared were responder rate, percentage seizure frequency reduction, seizure freedom, adverse events, neuropsychological outcome and quality of life. We identified 1 study for DBS, 1 study for CRS and 4 studies for VNS. All neurostimulation technologies showed long-term efficacy, with progressively better seizure control over time. Sustained improvement in quality of life measures was demonstrated in all modalities. Intracranial neurostimulation had a greater side effect profile compared with extracranial stimulation, though all forms of stimulation are safe. Methodological differences between the studies mean that direct comparisons are not straightforward. We have synthesised the findings of this review into a pragmatic decision tree, to guide the further management of the individual patient with pharmacoresistant focal-onset epilepsy.

Auras in generalized epilepsy

Objective: We studied the frequency of auras in generalized epilepsy (GE) using a detailed semistructured diagnostic interview. Methods: In this cross-sectional study, participants with GE were drawn from the Epilepsy Phenome/Genome Project (EPGP). Responses to the standardized diagnostic interview regarding tonic-clonic (grand mal) seizures were then examined. This questionnaire initially required participants to provide their own description of any subjective phenomena before their “grand mal seizures.” Participants who provided answers to these questions were considered to have an aura. All participants were then systematically queried regarding a list of specific symptoms occurring before grand mal seizures, using structured (closed-ended) questions. Results: Seven hundred ninety-eight participants with GE were identified, of whom 530 reported grand mal seizures. Of these, 112 (21.3%) reported auras in response to the open-ended question. Analysis of responses to the closed-ended questions suggested that 341 participants (64.3%) experienced at least one form of aura. Conclusions: Auras typically associated with focal epilepsy were reported by a substantial proportion of EPGP subjects with GE. This finding may support existing theories of cortical and subcortical generators of GE with variable spread patterns. Differences between responses to the open-ended question and closed-ended questions may also reflect clinically relevant variation in patient responses to history-taking and surveys. Open-ended questions may underestimate the prevalence of specific types of auras and may be in part responsible for the underrecognition of auras in GE. In addition, structured questions may influence participants, possibly leading to a greater representation of symptoms.

Ketamine Continuous Infusion for Refractory Status Epilepticus in a Patient With Anticonvulsant Hypersensitivity Syndrome

Objective: Refractory status epilepticus (RSE) requires aggressive management with multiple antiepileptic drugs (AEDs) often requiring the initiation of continuous infusions of propofol, midazolam, or pentobarbital to achieve adequate control in addition to intermittent agents. Ketamine has been implicated in several case reports as a successful agent for treating RSE given that it blocks the N-methyl-D-aspartate receptor, which is overexpressed in prolonged status epilepticus. Case Summary: We describe a previously healthy 27-year-old woman who presented with prolonged RSE requiring the initiation of multiple AEDs, including high-dose propofol and midazolam continuous infusions. As a result of hypotension from propofol and inadequate seizure control with midazolam, the patient was successfully transitioned to a pentobarbital infusion in combination with multiple AEDs. Although the patient achieved control of her RSE, her course was complicated by the development of an anticonvulsant hypersensitivity syndrome (AHS) with transaminitis. Limited with the options of AED that could have been used, it was decided to initiate the patient on a continuous ketamine infusion plus midazolam and slowly wean the patient off pentobarbital as well as to avoid further use of phenytoin and phenobarbital. Discussion: The patient was successfully transitioned off pentobarbital to a ketamine infusion plus midazolam with complete seizure control after several dose escalations. Her AHS and transaminitis resolved on a ketamine infusion for a total of 12 days, and she was successfully discharged from the hospital after 60 days in the ICU. Conclusion: This is the first case report to describe a successful transition to a ketamine infusion in a patient with AHS and transaminitis.

Prefrontal lobe structural integrity and trail making test, part B: converging findings from surface-based cortical thickness and voxel-based lesion symptom analyses

Surface-based cortical thickness (CT) analyses are increasingly being used to investigate variations in brain morphology across the spectrum of brain health, from neurotypical to neuropathological. An outstanding question is whether individual differences in cortical morphology, such as regionally increased or decreased CT, are associated with domain-specific performance deficits in healthy adults. Since CT studies are correlational, they cannot establish causality between brain morphology and cognitive performance. A direct comparison with classic lesion methods is needed to determine whether the regional specificity of CT-cognition correlations is similar to that observed in patients with brain lesions. We address this question by comparing the neuroanatomical overlap of effects when 1) whole brain vertex-wise CT is tested as a correlate of performance variability on a commonly used neuropsychological test of executive function, Trailmaking Test Part B (TMT-B), in healthy adults and 2) voxel-based lesion-symptom mapping (VBLSM) is used to map lesion location to performance decrements on the same task in patients with frontal lobe lesions. We found that reduced performance on the TMT-B was associated with increased CT in bilateral prefrontal regions in healthy adults and that results spatially overlapped in the left dorsomedial prefrontal cortex with findings from the VBLSM analysis in patients with frontal brain lesions. Findings indicate that variations in the structural integrity of the left dorsomedial prefrontal lobe, ranging from individual CT differences in healthy adults to structural lesions in patients with neurological disorders, are associated with poor performance on the TMT-B. These converging results suggest that the left dorsomedial prefrontal region houses a critical region for the complex processing demands of TMT-B, which include visuomotor tracking, sequencing, and cognitive flexibility.

Sex differences in seizure types and symptoms.

BACKGROUND Despite the increasing interest in sex differences in disease manifestations and responses to treatment, very few data are available on sex differences in seizure types and semiology. The Epilepsy Phenome/Genome Project (EPGP) is a large-scale, multi-institutional, collaborative study that aims to create a comprehensive repository of detailed clinical information and DNA samples from a large cohort of people with epilepsy. We used this well-characterized cohort to explore differences in seizure types as well as focal seizure symptoms between males and females. METHODS We reviewed the EPGP database and identified individuals with generalized epilepsy of unknown etiology (GE) (n = 760; female: 446, male: 314), nonacquired focal epilepsy (NAFE) (n = 476; female: 245, male: 231), or both (n = 64; female: 33, male: 31). Demographic data along with characterization of seizure type and focal seizure semiologies were examined. RESULTS In GE, males reported atonic seizures more frequently than females (6.5% vs. 1.7%; p < 0.001). No differences were observed in other generalized seizure types. In NAFE, no sex differences were seen for seizure types with or without alteration of consciousness or progression to secondary generalization. Autonomic (16.4% vs. 26.6%; p = 0.005), psychic (26.7% vs. 40.3%; p = 0.001), and visual (10.3% vs. 19.9%; p = 0.002) symptoms were more frequently reported in females than males. Specifically, of psychic symptoms, more females than males endorsed déjà vu (p = 0.001) but not forced thoughts, derealization/depersonalization, jamais vu, or fear. With corrections for multiple comparisons, there were no significant differences in aphasic, motor, somatosensory, gustatory, olfactory, auditory, vertiginous, or ictal headache symptoms between sexes. CONCLUSIONS Significant differences between the sexes were observed in the reporting of atonic seizures, which were more common in males with GE, and for autonomic, visual, and psychic symptoms associated with NAFE, which were more common in females.

Epilepsy: Guidelines on vagus nerve stimulation for epilepsy.

An evidence-based guideline update on vagus nerve stimulation for treatment of epilepsy supports consideration of its use in children, in patients with Lennox–Gastaut syndrome, and to improve mood in adults. Its efficacy may also increase over prolonged treatment. These conclusions are tentative, however, highlighting our knowledge gaps.

Derivation and initial validation of a surgical grading scale for the preliminary evaluation of adult patients with drug-resistant focal epilepsy

Presently, there is no simple method at initial presentation for identifying a patients likelihood of progressing to surgery and a favorable outcome. The Epilepsy Surgery Grading Scale (ESGS) is a three‐tier empirically derived mathematical scale with five categories: magnetic resonance imaging (MRI), electroencephalography (EEG), concordance (between MRI and EEG), semiology, and IQ designed to stratify patients with drug‐resistant focal epilepsy based on their likelihood of proceeding to resective epilepsy surgery and achieving seizure freedom.

Why is mesial temporal lobe epilepsy with Ammon's horn sclerosis becoming less common?

We read the article ‘Temporal lobe surgery in Germany from 1988 to 2008: diverse trends in etiological subgroups’ [1] with great interest. The authors found that the age and duration of epilepsy of patients with mesial temporal lobe epilepsy with Ammon’s horn sclerosis (mTLE + AHS) undergoing epilepsy surgery increased over time, supporting a hypothesis of a decreasing incidence of mTLE + AHS. This confirms the impression of many epileptologists. To explain this apparent decrease in the ‘supply’ of patients with mTLE + AHS, the authors speculate that vaccinations, improved treatment of childhood infections and better seizure control with newer antiepileptic drugs may be modifying the epileptogenic disease process. We agree with this, and would like to suggest another potentially relevant factor: increased use of ibuprofen in children. Inflammation is now known to play a role in epilepsy and epileptogenesis [2,3] and ibuprofen is a potent non-steroidal anti-inflammatory agent (NSAID) that can reduce inflammation in the brain [4]. Ibuprofen became available in the UK in1969, and was made over-the-counter in the UK in 1983 and in the USA in 1984 [5]. Whilst ibuprofen and other NSAIDs have complex effects on epileptogenesis in animal models [6] and do not prevent febrile seizure recurrence in children in the short term [7], long-term studies have not to our knowledge been performed. Could increased use of ibuprofen to treat fever and febrile seizures in children starting in the 1980s account for the decreased incidence of current patients with pharmacoresistant mTLE + AHS? Testing this speculation epidemiologically and/or in animal models could have important public health implications since even a modest antiepileptogenic effect of ibuprofen could contribute significantly to decreasing the worldwide burden of epilepsy given the established safety and low cost of this widely available medication.

Replay of large-scale spatio-temporal patterns from waking during subsequent NREM sleep in human cortex

Animal studies support the hypothesis that in slow-wave sleep, replay of waking neocortical activity under hippocampal guidance leads to memory consolidation. However, no intracranial electrophysiological evidence for replay exists in humans. We identified consistent sequences of population firing peaks across widespread cortical regions during complete waking periods. The occurrence of these “Motifs” were compared between sleeps preceding the waking period (“Sleep-Pre”) when the Motifs were identified, and those following (“Sleep-Post”). In all subjects, the majority of waking Motifs (most of which were novel) had more matches in Sleep-Post than in Sleep-Pre. In rodents, hippocampal replay occurs during local sharp-wave ripples, and the associated neocortical replay tends to occur during local sleep spindles and down-to-up transitions. These waves may facilitate consolidation by sequencing cell-firing and encouraging plasticity. Similarly, we found that Motifs were coupled to neocortical spindles, down-to-up transitions, theta bursts, and hippocampal sharp-wave ripples. While Motifs occurring during cognitive task performance were more likely to have more matches in subsequent sleep, our studies provide no direct demonstration that the replay of Motifs contributes to consolidation. Nonetheless, these results confirm a core prediction of the dominant neurobiological theory of human memory consolidation.

Parahippocampal and entorhinal resection extent predicts verbal memory decline in an epilepsy surgery cohort

The differential contribution of medial-temporal lobe regions to verbal declarative memory is debated within the neuroscience, neuropsychology, and cognitive psychology communities. We evaluate whether the extent of surgical resection within medial-temporal regions predicts longitudinal verbal learning and memory outcomes. This single-center retrospective observational study involved patients with refractory temporal lobe epilepsy undergoing unilateral anterior temporal lobe resection from 2007 to 2015. Thirty-two participants with Engel Class 1 and 2 outcomes were included (14 left, 18 right) and followed for a mean of 2.3 years after surgery (±1.5 years). Participants had baseline and postsurgical neuropsychological testing and high-resolution T1-weighted MRI scans. Postsurgical lesions were manually traced and coregistered to presurgical scans to precisely quantify resection extent of medial-temporal regions. Verbal learning and memory change scores were regressed on hippocampal, entorhinal, and parahippocampal resection volume after accounting for baseline performance. Overall, there were no significant differences in learning and memory change between patients who received left and right anterior temporal lobe resection. After controlling for baseline performance, the extent of left parahippocampal resection accounted for 27% (p = .021) of the variance in verbal short delay free recall. The extent of left entorhinal resection accounted for 37% (p = .004) of the variance in verbal short delay free recall. Our findings highlight the critical role that the left parahippocampal and entorhinal regions play in recall for verbal material.