•Failure to achieve seizure control commoner in focal epilepsy.•More focal seizures were uncontrolled for a year or more before conception.•Younger age, generalized epilepsy showed lesser risk of ...seizures.•Risk of convulsive seizures commoner in generalized epilepsy.•Changing valproate before conception does not lead to seizure worsening.
To examine factors contributing to failure to achieve full seizure control during pregnancy in women with anti-seizure medication (ASM) treated generalized epilepsy compared with focal epilepsy.
Full seizure control was not attained in 51.4% of 1223 pregnancies of women with focal epilepsies in the Australian Pregnancy Register, and in 38.7% of 1026 pregnancies in women with generalized epilepsy (P < 0.05). For convulsive seizures only, the corresponding figures of 20.8% and 22.9% were reasonably similar. Where seizures had occurred in the pre-pregnancy year, 82.5% of the focal epilepsy pregnancies were seizure affected, and 70.1% of the generalized epilepsy ones (P < 0.05). Where the pre-pregnancy year was seizure free, the corresponding figures were 22.6% and 16.4% (P < 0.05), a roughly four-fold lower rate. Maternal age, epilepsy onset age, and epilepsy duration also differed between the focal and generalized epilepsy pregnancies. Multivariate regression analysis showed that generalized epilepsy and younger maternal age were associated with statistically significant decreased risks of seizure-affected pregnancy, and having seizure-affected pre-pregnancy years with an increased risk. However, for convulsive seizures only, the risk of seizure-affected pregnancy appeared increased in generalized epilepsy.
The risk of seizure-affected pregnancy appears lower in women with generalized epilepsy, independently of pre-pregnancy seizure control, itself a major determinant of the risk. The risk of having only convulsive seizures in pregnancy was not lower in generalized epilepsy than in focal epilepsy. ASM therapy seemed less effective in controlling focal than generalized epileptic seizures during pregnancy.
•Delivering first seizure clinic by telehealth is feasible.•Given the choice, 25 % of eligible patients selected telehealth over face-to-face appointments.•Clinical outcomes and satisfaction are ...similar for telehealth compared with face-to-face care.•Providing telehealth as an option improves access to care for some patients.
Prompt access to specialist assessment is critical after a first suspected seizure. We aimed to test the feasibility of providing this service via telehealth, compared with usual care (face-to-face appointment) in patients referred to a first seizure clinic.
This feasibility study was a prospective mixed-methods non-randomised controlled design in a single centre. Patients referred to the first seizure clinic chose to receive their consultation by telehealth (intervention group) or face-to-face (usual care). Demand, practicality, acceptability and limited-efficacy testing were assessed using recruitment and routinely collected clinic data, participant surveys and a clinician focus group.
Telehealth in the first seizure clinic was feasible; however, internet connection, computer hardware and software, patient confidence and organisational support impacted on practicality. Of patients who were eligible for telehealth, 25 % chose to use telehealth for their appointment, with more women taking up the opportunity. Geography and age were not factors in likelihood of uptake. There was no significant between-group difference found in acceptability and limited efficacy measures conducted.
Telehealth is a responsive and convenient way to reach some patients who face barriers in access to specialist neurology assessment following a first suspected seizure.
There are no well-validated treatments for functional seizures. While specialist psychotherapy is usually recommended, the evidence for its benefit is qualified, and it can be difficult to obtain. ...Given the association between hyperventilation and functional seizures we explored an alternative modality, breathing control training, in a multi-site open label pilot trial. Participants with functional seizures over the age of 16 received an hour of breathing training from a respiratory physiotherapist, with a half-hour booster session a month later. Seizure frequency and Nijmegen scores (a measure of hyperventilation) were reported at baseline and follow-up, 3–4 months later. Eighteen subjects were recruited, and 10 completed follow-up. Seven of these 10 had improved seizure frequency, and 3 did not (Wilcoxon signed rank test, p = 0.09), with seizure frequency correlating with Nijmegen score (Spearman's rank correlation = 0.75, p = 0.034). The intervention was well tolerated, with no adverse events reported. These preliminary results support a potentially new approach to treating functional seizures that should prove cost-effective and acceptable, though require confirmation by a randomised controlled trial.
Absence seizures are a common seizure type in children with genetic generalized epilepsy and are characterized by a temporary loss of awareness, arrest of physical activity, and accompanying ...spike-and-wave discharges on an electroencephalogram. They arise from abnormal, hypersynchronous neuronal firing in brain thalamocortical circuits. Currently available therapeutic agents are only partially effective and act on multiple molecular targets, including γ-aminobutyric acid (GABA) transaminase, sodium channels, and calcium (Ca(2+)) channels. We sought to develop high-affinity T-type specific Ca(2+) channel antagonists and to assess their efficacy against absence seizures in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model. Using a rational drug design strategy that used knowledge from a previous N-type Ca(2+) channel pharmacophore and a high-throughput fluorometric Ca(2+) influx assay, we identified the T-type Ca(2+) channel blockers Z941 and Z944 as candidate agents and showed in thalamic slices that they attenuated burst firing of thalamic reticular nucleus neurons in GAERS. Upon administration to GAERS animals, Z941 and Z944 potently suppressed absence seizures by 85 to 90% via a mechanism distinct from the effects of ethosuximide and valproate, two first-line clinical drugs for absence seizures. The ability of the T-type Ca(2+) channel antagonists to inhibit absence seizures and to reduce the duration and cycle frequency of spike-and-wave discharges suggests that these agents have a unique mechanism of action on pathological thalamocortical oscillatory activity distinct from current drugs used in clinical practice.
Summary
Purpose: Considerable information is now available concerning the risk of teratogenesis in the individual pregnancy exposed to antiepileptic drugs (AEDs). However, there is comparatively ...little information available concerning the risk in the subsequent pregnancies of women who continue to take the AED associated with a fetal malformation in a previous pregnancy. This article addresses this matter.
Methods: Analysis of data concerning fetal abnormalities in 1,243 women who had 2,637 pregnancies between mid‐1999 and 2010 recorded in the Australian Register of Antiepileptic Drugs in Pregnancy. Of the 2,637 pregnancies, 1,114 had been completed before initial enrolment in the Register.
Key Findings: Women taking any AED who had given birth to a malformed baby in their first enrolled pregnancy and who continue taking the same drug were at increased risk of having a malformed offspring in their next pregnancy (35.7% vs. 3.1%; odds ratio OR 17.6; 95% confidence interval 95% CI 4.5–68.7). Among these women, those taking valproate (VPA) were more likely to have malformed fetuses in their next pregnancies than those who had taken VPA without fetal abnormalities (57.2% vs. 7.0%, OR 17.8; 95% CI 2.7, 119.1). There were similar although not statistically significant trends in those who had taken AEDs other than VPA. Similar, although again not statistically significant, trends were found, when considering the pairings of the most recent preenrollment pregnancy and the following one. If a woman had two or more pregnancies that resulted in AED‐associated fetal malformation, the types of malformation were often different.
Significance: Women whose last pregnancy resulted in a fetal malformation have a substantially increased risk of having further malformed fetuses if they become pregnant again while taking the same AED, particularly VPA. This suggests that maternal factors, perhaps genomic, predispose to at least VPA‐associated malformations. This knowledge, together with information about the outcome of any previous pregnancy, should help in advising women with AED‐treated epilepsy who plan further pregnancies.
•Are neurite density and dispersion altered in amyotropic lateral sclerosis (ALS)?•Both measures are affected in the rNLS8 TDP-43 mouse model of ALS.•Diffusion tensor imaging metrics were also ...affected.•Group-wise changes were observed early in the disease course.•Together these diffusion imaging metrics may aid in the timelier diagnosis of ALS.
Amyotrophic lateral sclerosis (ALS) is characterized by transactive response DNA-binding protein 43 (TDP-43) pathology, progressive loss of motor neurons and muscle dysfunction. Symptom onset can be insidious and diagnosis challenging. Conventional neuroimaging is used to exclude ALS mimics, however more advanced neuroimaging techniques may facilitate an earlier diagnosis. Here, we investigate the potential for neurite orientation dispersion and density imaging and diffusion tensor imaging (DTI) to detect microstructural changes in an experimental model of ALS with neuronal doxycycline (Dox)-suppressible overexpression of human TDP-43 (hTDP-43). In vivo diffusion-weighted imaging (DWI) was acquired 1- and 3- weeks following the initiation of hTDP-43 expression (post-Dox) to investigate whether neurite density imaging (NDI) and orientation dispersion imaging (ODI) are affected early in this preclinical model of ALS and if so, how these metrics compare to those derived from the diffusion tensor. Tract-based spatial statistics at 1-week post-Dox, i.e. very early in the disease stage, demonstrated increased NDI in TDP-43 mice but no change in ODI or DTI metrics. At 3-weeks post-Dox, a reduced pattern of increased NDI was observed along with widespread increases in ODI, and decreased fractional anisotropy (FA), apparent diffusion coefficient (ADC) and axial diffusivity (AD). A hypothesis driven analysis of the bilateral corticospinal tracts demonstrated that at 1-week post-Dox, ODI was significantly increased caudally but decreased in the motor cortex of TDP-43 mice. Decreased cortical ODI had normalized by 3-weeks post-Dox and only significant increases were observed. A similar, but inverse pattern in FA was also observed. Together, these results suggest a non-monotonic relationship between DWI metrics and pathophysiological progression with TDP-43 mice exhibiting significantly altered diffusion metrics consistent with early inflammation followed by progressive axonal degeneration. Importantly, significant group-wise changes were observed in the earliest stages of disease when subtle pathology may be more elusive to traditional structural imaging techniques.
A second mild traumatic brain injury (mTBI) sustained prior to neuropathological recovery can lead to exacerbated effects. Without objective indicators of this neuropathology, individuals may return ...to activities at risk of mTBI when their brain is still vulnerable. With axonal injury recognized as a neuropathological hallmark of mTBI, we hypothesized that serum levels of neurofilament light (NfL), a highly sensitive biomarker of axonal injury, may be predictive of vulnerability to worse outcomes in the event of a second mTBI. Given this hypothesis is difficult to test clinically, we used a two-hit model of mTBI in rats and staggered inter-injury intervals by 1-, 3-, 7-, or 14-days. Repeat-mTBI rats were dichotomized into NfLhigh (NfL>median at the time of re-injury) and NfLlow (NfL<median) groups, with behavior and NfL levels analyzed throughout the 28-days, followed by ex vivo diffusion tensor imaging. NfL levels at the time of the second mTBI were found to be predictive of vulnerability to re-injury, with NfLhigh rats displaying more neurological signs and a greater potentiation of NfL levels after the second mTBI. Importantly, this potentiation phenomenon remained even when limiting analyses to rats with longer inter-injury intervals, providing evidence that vulnerability to re-injury may not be exclusively dependent on inter-injury interval. Finally, NfL levels correlated with, and were predictive of, the severity of neurological signs following the second mTBI. These findings provide evidence that measurement of NfL during mTBI recovery may be reflective of the vulnerability to a second mTBI, and as such may have utility to assist return to sport, duty and work decisions.
To examine baseline clinical features of psychogenic nonepileptic seizures (PNES) in a large cohort and to investigate outcome over a period of up to 10 years. Studies investigating PNES have been ...limited by differences in diagnostic criteria, short follow-up periods, and the use of limited outcome measures.
Patients with PNES were identified, using strict diagnostic criteria. Baseline neurological, neuropsychiatric, and neuroimaging data were obtained from medical records. Long-term outcome was assessed with ratings of seizures, psychopathology, and quality of life in a subset of the patients.
Patients with PNES (n = 221) experienced long delays in diagnosis (mu, 5.6 years; standard deviation, 7.7 years) and high rates (>60%) of prolonged treatment with antiepileptic drugs. Compared with previous studies, a relatively low proportion (8.1% to 17.9%, depending on diagnostic criteria) had comorbid epilepsy. An unexpected finding was that 22.6% of PNES patients had magnetic resonance imaging abnormalities. Patients assessed at follow-up (n = 61) exhibited poor long-term outcomes with ongoing PNES, high rates of psychopathology, low rates of specialist follow-up, poor quality of life, and poor overall levels of functioning.
These results demonstrate the need for earlier diagnosis of PNES and comorbidities and highlight the need for diagnostic and therapeutic approaches that combine neurological and psychiatric perspectives.
Summary Purpose This study assessed the comparative efficacy of pregabalin for refractory partial seizures. Methods Four-hundred and thirty-four patients with partial seizures were randomized to ...pregabalin, lamotrigine, or placebo as adjunctive therapy for 17 weeks of double-blind treatment. In phase I (11 weeks), pregabalin was titrated over 1 week and lamotrigine over 5 weeks to fixed dosages of 300 mg/day for both. In phase II (6 weeks), patients not yet seizure-free were increased to pregabalin 600 mg/day or lamotrigine 400 mg/day. Results During phase I, there was a nonsignificant trend toward a greater reduction in seizures with pregabalin versus placebo and lamotrigine. Across the 17 weeks of treatment, pregabalin showed a median percentage reduction from baseline in seizure frequency of −20.0% ( p = .001) versus placebo, and −9.7% ( p = .080) versus lamotrigine. The responder rate (≥50% reduction in seizure frequency) for pregabalin exceeded that of placebo (36% vs 21%; p = .007) and lamotrigine (36% vs 24%; p = .04). Adverse events were consistent with the known safety profiles of pregabalin and lamotrigine. Discussion Pregabalin was demonstrated to be noninferior to lamotrigine in the treatment of refractory partial seizures. Overall conclusions were complicated by an unusually large and heterogeneous placebo response.
Objective
Clinical and genetic predictors of response to antiepileptic drugs (AEDs) are largely unknown. We examined predictors of lacosamide response in a real‐world clinical setting.
Methods
We ...tested the association of clinical predictors with treatment response using regression modeling in a cohort of people with refractory epilepsy. Genetic assessment for lacosamide response was conducted via genome‐wide association studies and exome studies, comprising 281 candidate genes.
Results
Most patients (479/483) were treated with LCM in addition to other AEDs. Our results corroborate previous findings that patients with refractory genetic generalized epilepsy (GGE) may respond to treatment with LCM. No clear clinical predictors were identified. We then compared 73 lacosamide responders, defined as those experiencing greater than 75% seizure reduction or seizure freedom, to 495 nonresponders (<25% seizure reduction). No variants reached the genome‐wide significance threshold in our case‐control analysis.
Significance
No genetic predictor of lacosamide response was identified. Patients with refractory GGE might benefit from treatment with lacosamide.
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