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Highlights • Patients showed showed widespread connectome alterations relative to controls. • Relative to controls, patients /w seizure-freedom (SF) had increased diffusivity. • Patients /w persistent seizures (PS) had increased diffusivity relative to controls. • Subgroup-specific connectomes were found for both patient groups (SF vs PS). • Patients with generalized seizures and those without had altered connectomes., Despite an expanding literature on brain alterations in patients with longstanding epilepsy, few neuroimaging studies investigate patients with newly diagnosed focal epilepsy (NDfE). Understanding brain network impairments at diagnosis is necessary to elucidate whether or not brain abnormalities are principally due to the chronicity of the disorder and to develop prognostic markers of treatment outcome. Most adults with NDfE do not have MRI-identifiable lesions and the reasons for seizure onset and refractoriness are unknown. We applied structural connectomics to T1-weighted and multi-shell diffusion MRI data with generalized q-sampling image reconstruction using Network Based Statistics (NBS). We scanned 27 patients within an average of 3.7 (SD = 2.9) months of diagnosis and anti-epileptic drug treatment outcomes were collected 24 months after diagnosis. Seven patients were excluded due to lesional NDfE and outcome data was available in 17 patients. Compared to 29 healthy controls, patients with non-lesional NDfE had connectomes with significantly decreased quantitative anisotropy in edges connecting right temporal, frontal and thalamic nodes and increased diffusivity in edges between bilateral temporal, frontal, occipital and parietal nodes. Compared to controls, patients with persistent seizures showed the largest effect size (|d|>=1) for decreased anisotropy in right parietal edges and increased diffusivity in edges between left thalamus and left parietal nodes. Compared to controls, patients who were rendered seizure-free showed the largest effect size for decreased anisotropy in the edge connecting the left thalamus and right temporal nodes and increased diffusivity in edges connecting right frontal nodes. As demonstrated by large effect sizes, connectomes with decreased anisotropy (edge between right frontal and left insular nodes) and increased diffusivity (edge between right thalamus and left parietal nodes) were found in patients with persistent seizures compared to patients who became seizure-free. Patients who had persistent seizures showed larger effect sizes in all network metrics than patients who became seizure-free when compared to each other and compared to controls. Furthermore, patients with focal-to-bilateral tonic-clonic seizures (FBTCS, N = 11) had decreased quantitative anisotropy in a bilateral network involving edges between temporal, parietal and frontal nodes with greater effect sizes than those of patients without FBTCS (N = 9). NBS findings between patients and controls indicated that structural network changes are not necessarily a consequence of longstanding refractory epilepsy and instead are present at the time of diagnosis. Computed effect sizes suggest that there may be structural network MRI-markers of future pharmacoresistance and seizure severity in patients with a new diagnosis of focal epilepsy.

Purpose: Status epilepticus (SE) is a severe condition of unrelenting seizures requiring urgent identification and treatment. SE may be unprovoked, occurring in someone with epilepsy, or may be provoked by acute intracranial disease or metabolic derangement. Increasingly encephalitis, particularly autoimmune types, is reported to cause refractory seizures. Whilst convulsive SE is readily identified, non-convulsive SE (NCSE) can be difficult to identify clinically, and electroencephalography (EEG) is required. Therefore, it is critical to identify the key clinical features associated with NCSE on EEG to inform future use of EEG. Methods: We conducted a multicentre, retrospective analysis of EEG requests from four general and one specialist neurology hospital in the Northwest of England (2015-2018). Cases were identified from EEG requests for patients with suspected NCSE or other indications such as encephalopathy. We compared demographic and clinical characteristics between EEG-confirmed cases of NCSE and a randomly selected sample of negative controls. Results: 358 EEGs were reviewed, and 8 positive cases of NCSE were identified. Epilepsy was identified as the aetiology in 2 of these cases, and autoimmune encephalitis another 2 cases (one patient with N-methyl-d-aspartate receptor antibodies and another with voltage gated potassium channel antibodies). Previous alcohol excess (p = 0.005) and subtle motor signs (p = 0.047) on examination were observed more frequently in patients with NCSE compared to controls. Conclusion: Physicians should have a low threshold for urgent EEG in patients with suspected or previous encephalitis, especially if autoimmunity is suspected or subtle motor signs are present. info:eu-repo/semantics/publishedVersion

Highlights • Tractography approaches showed moderate to good agreement for tract morphology. • Along- and whole-tract diffusivity was significantly correlated across approaches. • Whole-tract AFQ but not manual tract diffusivity correlated with clinical variables. • Absence of excellent agreement between approaches warrants caution., Objective To investigate the agreement between manually and automatically generated tracts from diffusion tensor imaging (DTI) in patients with temporal lobe epilepsy (TLE). Whole and along-the-tract diffusivity metrics and correlations with patient clinical characteristics were analyzed with respect to tractography approach. Methods We recruited 40 healthy controls and 24 patients with TLE who underwent conventional T1-weighted imaging and 60-direction DTI. An automated (Automated Fiber Quantification, AFQ) and manual (TrackVis) deterministic tractography approach was used to identify the uncinate fasciculus (UF) and parahippocampal white matter bundle (PHWM). Tract diffusion scalar metrics were analyzed with respect to agreement across automated and manual approaches (Dice Coefficient and Spearman correlations), to side of onset of epilepsy and patient clinical characteristics, including duration of epilepsy, age of onset and presence of hippocampal sclerosis. Results Across approaches the analysis of tract morphology similarity revealed Dice coefficients at moderate to good agreement (0.54 - 0.6) and significant correlations between diffusion values (Spearman's Rho=0.4–0.9). However, within bilateral PHWM, AFQ yielded significantly lower FA (left: Z = 4.4, p

Summary Background Despite progress in understanding the genetics of rare epilepsies, the more common epilepsies have proven less amenable to traditional gene-discovery analyses. We aimed to assess the contribution of ultra-rare genetic variation to common epilepsies. Methods We did a case-control sequencing study with exome sequence data from unrelated individuals clinically evaluated for one of the two most common epilepsy syndromes: familial genetic generalised epilepsy, or familial or sporadic non-acquired focal epilepsy. Individuals of any age were recruited between Nov 26, 2007, and Aug 2, 2013, through the multicentre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine (New York, USA) between Feb 6, 2013, and Aug 18, 2015. To identify epilepsy risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples with no known epilepsy or epilepsy comorbidity sequenced through unrelated studies. Findings We separately compared the sequence data from 640 individuals with familial genetic generalised epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3877 controls, and found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalised epilepsy: odd ratio [OR] 2·3, 95% CI 1·7–3·2, p=9·1 × 10 −8 ; familial non-acquired focal epilepsy 3·6, 2·7–4·9, p=1·1 × 10 −17 ). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals. For the individuals with familial non-acquired focal epilepsy, we found that five known epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious variation. After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy. Our analyses showed that no individual gene was significantly associated with familial genetic generalised epilepsy; however, known epilepsy genes had lower p values relative to the rest of the protein-coding genes (p=5·8 × 10 −8 ) that were lower than expected from a random sampling of genes. Interpretation We identified excess ultra-rare variation in known epilepsy genes, which establishes a clear connection between the genetics of common and rare, severe epilepsies, and shows that the variants responsible for epilepsy risk are exceptionally rare in the general population. Our results suggest that the emerging paradigm of targeting of treatments to the genetic cause in rare devastating epilepsies might also extend to a proportion of common epilepsies. These findings might allow clinicians to broadly explain the cause of these syndromes to patients, and lay the foundation for possible precision treatments in the future. Funding National Institute of Neurological Disorders and Stroke (NINDS), and Epilepsy Research UK.

Refractory status epilepticus (RSE) is a medical and neurologic emergency. Patients who do not respond to standard treatment regimens for status epilepticus are considered to have RSE. The occurrence of RSE has been mostly associated with acute and potentially fatal underlying causes, such as encephalitis, massive stroke, or progressive primary brain tumors. An imbalance of the inhibitory activity of the neurotransmitter γ-aminobutyric acid and the excitatory activity of the neurotransmitter glutamate is suspected as the underlying pathophysiology of seizure perpetuation in status epilepticus. RSE once developed, requires early, effective, and more aggressive treatment as it is associated with higher mortality and morbidity. Patients should be treated in the intensive care unit, as artificial ventilation and hemodynamic support is required. Coma is induced with anesthetic drugs to achieve complete control of seizure activity, and the initial choice is restricted to three groups of compounds: propofol, thiopental, and midazolam.

Publisher Summary This chapter focuses primarily on data from epidemiological studies and randomized controlled trials that have addressed prognosis and outcome for patients with single seizures and early epilepsy. For patients with a single seizure or early epilepsy, when compared to deferred treatment, immediate treatment with one of the current firstline antiepileptic drugs reduces the risk of seizure recurrence, but has no impact on the longer-term seizure outcome in epilepsy. Consensus holds that antiepileptic drug treatment should be initiated for the majority of patients who have had two or more seizures, as the risk of recurrence is high, although the aim of treatment is to control seizures rather than influence the natural history of epilepsy. For patients with a single seizure, the recurrence risk is generally low, and there is a trade-off between preventing seizures and adverse effects of antiepileptic drugs such that neither policy is associated with overall quality-of-life gains. Patients can be identified at a low, medium, and high risk of seizure recurrence to aid patients and clinicians in discussions regarding the pros and cons of starting antiepileptic drug treatment following a single seizure.