Structural and functional investigations of vigabatrin toxicity

The purpose of this thesis was to investigate visual dysfunction arising from vigabatrin (VGB) toxicity: structural investigation utilising optical coherence tomography (OCT) and functional investigation using multifocal electrophysiology. OCT of the retinal nerve fibre layer (RNFL) based upon a fixed diameter circle scan and enabling reference to the manufacturers' large proprietary normative database, revealed a specific finding associated with vigabatrin-attributed visual field loss (VAVFL) namely, a characteristic pattern of nasal quadrant attenuation with a normal temporal quadrant thickness. This was present in all 11 individuals (including 2 learning-disabled adults) with VAVFL. A further 4 of 16 (including 3 learning- disabled adults and three children) VGB-exposed individuals with normal visual fields (VGB-E) also manifested this pattern as did two of three individuals (one learning-disabled adult and two children) exposed to VGB but unable to undertake perimetry. The pattern was absent in all 13 individuals treated with non-gabaergic anti-epileptic drugs manifesting normal fields and in 9 normal children. OCT is readily achievable in children as young as 3 years and in learning-disabled adults and should be essential for identifying VAVFL. A re-analysis of RNFL thickness for quadrant/sector differences by OCT and by scanning laser ophthalmoscopy (Heidelberg Retinal Tomography (HRT)) on 13 individuals with VAVFL, 8 VGB-E and 21 normal individuals previously published (Wild et al., 2006) confirmed the abnormal nasal/normal temporal pattern of attenuation. Four children, exposed to VGB in utero, from three mothers (two with VAVFL and nasal RNFL attenuation) yielded normal visual fields and RNFL thicknesses. The amplitudes and implicit times of the mfERG waveform were normal in all 5 VAVFL and in 9 VGB-E, when compared to 13 normal individuals. This suggests that neither bipolar cell nor photoreceptor cell dysfunction, respectively, is implicated in VGB toxicity. The mfVEP amplitudes were normal in all 5 VAVFL and in all 9 VGB-E, when compared to 16 normal individuals. The lack of abnormality may arise from the mismatch between cortical functional topography and the characteristics of VAVFL and the technical limitations associated with the monocular analysis of the mfVEP

Exploring seizure management in hospitals, unmet need, and the impact of the COVID-19 pandemic on seizure presentations to hospital

Purpose This study assesses investigations, referrals and admissions in patients presenting to the Emergency Department (ED) with seizures, and the effect of the COVID-19 pandemic on such management. Outcomes in patients with learning disabilities, active significant mental health concerns, and from the most socioeconomically deprived areas were compared to those of the general cohort. Methods Investigations, referrals and admissions were recorded for 120 patients across two cohorts; pre-pandemic (September 2019) and during the pandemic (December 2020). Retrospective review of individual patient electronic health care records was used for data collection. Results There was a decrease in patient numbers from 2019 to 2020. A greater proportion of patients presented with organic cause seizures and fewer presented with non-epileptic attacks. Frequent use of CT heads (45%) is likely to represent improper use of limited resources. There were low referral rates, both to acute neurology (28%) and to the adult epilepsy team (32%). Patients with active significant mental health concerns were significantly less likely to be referred to neurology or admitted. Conclusions Despite a greater proportion of admissions during the Covid-19 pandemic, referrals to acute neurology and the epilepsy team remained low. Failure to refer prevents the most vulnerable seizure patients from receiving appropriate support, as seen in patients with active significant mental health concerns. Neurology staff were unaware of a significant number of patients presenting with seizures, which is of concern in an already over-stretched department. This offers an opportunity to improve care for people with epilepsy

The SANAD II study of the effectiveness and cost-effectiveness of levetiracetam, zonisamide, or lamotrigine for newly diagnosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial

Background: Levetiracetam and zonisamide are licensed as monotherapy for patients with focal epilepsy, but there is uncertainty as to whether they should be recommended as first-line treatments because of insufficient evidence of clinical effectiveness and cost-effectiveness. We aimed to assess the long-term clinical effectiveness and cost-effectiveness of levetiracetam and zonisamide compared with lamotrigine in people with newly diagnosed focal epilepsy. Methods: This randomised, open-label, controlled trial compared levetiracetam and zonisamide with lamotrigine as first-line treatment for patients with newly diagnosed focal epilepsy. Adult and paediatric neurology services across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked focal seizures. Participants were randomly allocated (1:1:1) using a minimisation programme with a random element utilising factor to receive lamotrigine, levetiracetam, or zonisamide. Participants and investigators were not masked and were aware of treatment allocation. SANAD II was designed to assess non-inferiority of both levetiracetam and zonisamide to lamotrigine for the primary outcome of time to 12-month remission. Anti-seizure medications were taken orally and for participants aged 12 years or older the initial advised maintenance doses were lamotrigine 50 mg (morning) and 100 mg (evening), levetiracetam 500 mg twice per day, and zonisamide 100 mg twice per day. For children aged between 5 and 12 years the initial daily maintenance doses advised were lamotrigine 1·5 mg/kg twice per day, levetiracetam 20 mg/kg twice per day, and zonisamide 2·5 mg/kg twice per day. All participants were included in the intention-to-treat (ITT) analysis. The per-protocol (PP) analysis excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analysis included all participants who received one dose of any study drug. The non-inferiority limit was a hazard ratio (HR) of 1·329, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on lamotrigine. The trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64). Findings: 990 participants were recruited between May 2, 2013, and June 20, 2017, and followed up for a further 2 years. Patients were randomly assigned to receive lamotrigine (n=330), levetiracetam (n=332), or zonisamide (n=328). The ITT analysis included all participants and the PP analysis included 324 participants randomly assigned to lamotrigine, 320 participants randomly assigned to levetiracetam, and 315 participants randomly assigned to zonisamide. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission versus lamotrigine (HR 1·18; 97·5% CI 0·95–1·47) but zonisamide did meet the criteria for non-inferiority in the ITT analysis versus lamotrigine (1·03; 0·83–1·28). The PP analysis showed that 12-month remission was superior with lamotrigine than both levetiracetam (HR 1·32 [97·5% CI 1·05 to 1·66]) and zonisamide (HR 1·37 [1·08–1·73]). There were 37 deaths during the trial. Adverse reactions were reported by 108 (33%) participants who started lamotrigine, 144 (44%) participants who started levetiracetam, and 146 (45%) participants who started zonisamide. Lamotrigine was superior in the cost-utility analysis, with a higher net health benefit of 1·403 QALYs (97·5% central range 1·319–1·458) compared with 1·222 (1·110–1·283) for levetiracetam and 1·232 (1·112, 1·307) for zonisamide at a cost-effectiveness threshold of £20 000 per QALY. Cost-effectiveness was based on differences between treatment groups in costs and QALYs. Interpretation: These findings do not support the use of levetiracetam or zonisamide as first-line treatments for patients with focal epilepsy. Lamotrigine should remain a first-line treatment for patients with focal epilepsy and should be the standard treatment in future trials. Funding: National Institute for Health Research Health Technology Assessment programme

The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial

Background: Valproate is a first-line treatment for patients with newly diagnosed idiopathic generalised or difficult to classify epilepsy, but not for women of child-bearing potential because of teratogenicity. Levetiracetam is increasingly prescribed for these patient populations despite scarcity of evidence of clinical effectiveness or cost-effectiveness. We aimed to compare the long-term clinical effectiveness and cost-effectiveness of levetiracetam compared with valproate in participants with newly diagnosed generalised or unclassifiable epilepsy. Methods: We did an open-label, randomised controlled trial to compare levetiracetam with valproate as first-line treatment for patients with generalised or unclassified epilepsy. Adult and paediatric neurology services (69 centres overall) across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked generalised or unclassifiable seizures. Participants were randomly allocated (1:1) to receive either levetiracetam or valproate, using a minimisation programme with a random element utilising factors. Participants and investigators were aware of treatment allocation. For participants aged 12 years or older, the initial advised maintenance doses were 500 mg twice per day for levetiracetam and valproate, and for children aged 5–12 years, the initial daily maintenance doses advised were 25 mg/kg for valproate and 40 mg/kg for levetiracetam. All drugs were administered orally. SANAD II was designed to assess the non-inferiority of levetiracetam compared with valproate for the primary outcome time to 12-month remission. The non-inferiority limit was a hazard ratio (HR) of 1·314, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on valproate. All participants were included in the intention-to-treat (ITT) analysis. Per-protocol (PP) analyses excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analyses included all participants who received one dose of any study drug. This trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64). Findings: 520 participants were recruited between April 30, 2013, and Aug 2, 2016, and followed up for a further 2 years. 260 participants were randomly allocated to receive levetiracetam and 260 participants to receive valproate. The ITT analysis included all participants and the PP analysis included 255 participants randomly allocated to valproate and 254 randomly allocated to levetiracetam. Median age of participants was 13·9 years (range 5·0–94·4), 65% were male and 35% were female, 397 participants had generalised epilepsy, and 123 unclassified epilepsy. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission (HR 1·19 [95% CI 0·96–1·47]); non-inferiority margin 1·314. The PP analysis showed that the 12-month remission was superior with valproate than with levetiracetam. There were two deaths, one in each group, that were unrelated to trial treatments. Adverse reactions were reported by 96 (37%) participants randomly assigned to valproate and 107 (42%) participants randomly assigned to levetiracetam. Levetiracetam was dominated by valproate in the cost-utility analysis, with a negative incremental net health benefit of −0·040 (95% central range −0·175 to 0·037) and a probability of 0·17 of being cost-effectiveness at a threshold of £20 000 per quality-adjusted life-year. Cost-effectiveness was based on differences between treatment groups in costs and quality-adjusted life-years. Interpretation: Compared with valproate, levetiracetam was found to be neither clinically effective nor cost-effective. For girls and women of child-bearing potential, these results inform discussions about benefit and harm of avoiding valproate. Funding: National Institute for Health Research Health Technology Assessment Programme

Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice

Nasal retinal nerve fiber layer attenuation: A biomarker for vigabatrin toxicity

Purpose To investigate whether nasal peripapillary retinal nerve fiber layer (RNFL) attenuation is associated with visual field loss attributed to the anti-epileptic drug vigabatrin. Design Prospective cross-sectional observational study. Participants Twenty-seven individuals with focal-onset epilepsy exposed to vigabatrin and 13 individuals with focal-onset epilepsy exposed to non-GABAergic anti-epileptic drug monotherapy. Methods At one visit, suprathreshold perimetry of the central and peripheral field (3-zone, age-corrected Full Field 135 Screening Test) and threshold perimetry of the central field (Program 30-2 and the FASTPAC strategy) were undertaken using the Humphrey Field Analyzer (Carl Zeiss Meditech, Dublin, CA). At a second visit, ocular coherence tomography was undertaken for the right eye using the 3.4 RNFL thickness protocol of the StratusOCT (Carl Zeiss Meditech). Main Outcome Measures The magnitude, for each individual, of the RNFL thickness, averaged across the 4 oblique quadrants, and for each separate quadrant. Results Of the 27 individuals exposed to vigabatrin, 11 (group I) exhibited vigabatrin-attributed visual field loss, 15 exhibited a normal field, and 1 exhibited a homonymous quadrantanopia (group II). All 13 individuals exposed to non-GABAergic therapy had normal fields (group III). All individuals in group I exhibited abnormal average and nasal quadrant RNFL thicknesses in the presence of a normal temporal quadrant thickness. Most also exhibited additional RNFL attenuation in either the superior or inferior quadrant, or both. Four individuals in group II exhibited an identical pattern of RNFL attenuation suggesting that nasal RNFL thinning is a more sensitive marker for vigabatrin toxicity than visual field loss. None of the 13 individuals in group III exhibited nasal quadrant RNFL attenuation. Conclusions Vigabatrin-attributed visual field loss is associated with a characteristic pattern of RNFL attenuation: nasal quadrant thinning and normal temporal quadrant thickness with, or without, superior or inferior quadrant involvement. Nasal attenuation may precede visual field loss. Ocular coherence tomography of the peripapillary RNFL should be considered in patients previously exposed to vigabatrin. It should also be considered at baseline and follow-up in those commencing vigabatrin for treatment of epilepsy or in trials for anti-addiction therapy. The pattern of RNFL thinning seems to be a useful biomarker to identify vigabatrin toxicity

In utero exposure to vigabatrin: No indication of visual field loss

The purpose of the study was to determine whether in utero exposure to vigabatrin caused visual field loss. Three mothers with four children who had been exposed to vigabatrin in utero and who were subsequently formula fed were identified. All seven individuals underwent perimetry and imaging of the retinal nerve fiber layer (RNFL). All individuals yielded reliable outcomes to perimetry and RNFL images of acceptable quality. Two of the three mothers exhibited vigabatrin-attributed visual field loss and an abnormally attenuated RNFL. The third exhibited an upper left quadrantanopia, consistent with previous temporal lobe surgery, and a normal RNFL. All four children yielded normal visual fields and RNFL thicknesses. The presence of the normal findings for the children is reassuring and, if representative, suggests a lack of vigabatrin visual toxicity and therefore obviates the need for ophthalmological examination of those exposed to vigabatrin prenatally