Publications by authors named "Hannah Cock"

60 Publications

Invitation to participate in a prospective case-control study of sudden unexpected death in epilepsy.

Epilepsia 2021 May;62(5):1280-1281

School of Population Health, Grafton Campus, University of Auckland, Auckland, New Zealand.

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http://dx.doi.org/10.1111/epi.16898DOI Listing
May 2021

Patterns of benzodiazepine underdosing in the Established Status Epilepticus Treatment Trial.

Epilepsia 2021 03 10;62(3):795-806. Epub 2021 Feb 10.

Department of Experimental and Clinical Pharmacology, College of Pharmacy and Center for Orphan Drug Research, University of Minnesota, Minneapolis, Minnesota, USA.

Objective: This study was undertaken to describe patterns of benzodiazepine use as first-line treatment of status epilepticus (SE) and test the association of benzodiazepine doses with response to second-line agents in patients enrolled in the Established Status Epilepticus Treatment Trial (ESETT).

Methods: Patients refractory to an adequate dose of benzodiazepines for the treatment of SE were enrolled in ESETT. Choice of benzodiazepine, doses given prior to administration of second-line agent, route of administration, setting, and patient weight were characterized. These were compared with guideline-recommended dosing. Logistic regression was used to determine the association of the first dose of benzodiazepine and the cumulative benzodiazepine dose with the response to second-line agent.

Results: Four hundred sixty patients were administered 1170 doses of benzodiazepines (669 lorazepam, 398 midazolam, 103 diazepam). Lorazepam was most frequently administered intravenously in the emergency department, midazolam intramuscularly or intravenously by the emergency medical services personnel, and diazepam rectally prior to ambulance arrival. The first dose of the first benzodiazepine (N = 460) was lower than guideline recommendations in 76% of midazolam administrations and 81% of lorazepam administrations. Among all administrations, >85% of midazolam and >76% of lorazepam administrations were lower than recommended. Higher first or cumulative benzodiazepine doses were not associated with better outcomes or clinical seizure cessation in response to second-line medications in these benzodiazepine-refractory seizures.

Significance: Benzodiazepines as first-line treatment of SE, particularly midazolam and lorazepam, are frequently underdosed throughout the United States. This broad and generalizable cohort confirms prior single site reports that underdosing is both pervasive and difficult to remediate. (ESETT ClinicalTrials.gov identifier: NCT01960075.).
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http://dx.doi.org/10.1111/epi.16825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075113PMC
March 2021

Early Exposure of Fosphenytoin, Levetiracetam, and Valproic Acid After High-Dose Intravenous Administration in Young Children With Benzodiazepine-Refractory Status Epilepticus.

J Clin Pharmacol 2021 06 12;61(6):763-768. Epub 2021 Jan 12.

Center for Orphan Drug Research, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.

Fosphenytoin (FOS) and its active form, phenytoin (PHT), levetiracetam (LEV), and valproic acid (VPA) are commonly used second-line treatments of status epilepticus. However, limited information is available regarding LEV and VPA concentrations following high intravenous doses, particularly in young children. The Established Status Epilepticus Treatment Trial, a blinded, comparative effectiveness study of FOS, LEV, and VPA for benzodiazepine-refractory status epilepticus provided an opportunity to investigate early drug concentrations. Patients aged ≥2 years who continued to seizure despite receiving adequate doses of benzodiazepines were randomly assigned to FOS, LEV, or VPA infused over 10 minutes. A sparse blood-sampling approach was used, with up to 2 samples collected per patient within 2 hours following drug administration. The objective of this work was to report early drug exposure of PHT, LEV, and VPA and plasma protein binding of PHT and VPA. Twenty-seven children with median (interquartile range) age of 4 (2.5-6.5) years were enrolled. The total plasma concentrations ranged from 69 to 151.3 μg/mL for LEV, 11.3 to 26.7 μg/mL for PHT and 126 to 223 μg/mL for VPA. Free fraction ranged from 4% to 19% for PHT and 17% to 51% for VPA. This is the first report in young children of LEV concentrations with convulsive status epilepticus as well as VPA concentrations after a 40 mg/kg dose. Several challenges limited patient enrollment and blood sampling. Additional studies with a larger sample size are required to evaluate the exposure-response relationships in this emergent condition.
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http://dx.doi.org/10.1002/jcph.1801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089035PMC
June 2021

Testing blood and CSF in people with epilepsy: a practical guide.

Epileptic Disord 2020 Aug;22(4):381-398

Institute of Medical & Biomedical Education, St George's University of London, UK, Molecular & Clinical Sciences Research Institute, Clinical Neurosciences, St George's University of London, UK, Atkinson Morley Regional Epilepsy Network, George's University Hospitals NHS Foundation Trust, London, UK.

Laboratory investigations, whilst not essential to the diagnosis of seizures or of epilepsy, can be fundamental to determining the cause and guiding management. Over 50% of first seizures have an acute symptomatic cause, including a range of metabolic, toxic or infectious cause. The same triggers can precipitate status epilepticus, either de novo or as part of a deterioration in control in individuals with established epilepsy. Some, such as hypoglycaemia or severe hyponatraemia, can be fatal without prompt identification and treatment. Failure to identify seizures associated with recreational drug or alcohol misuse can lead to inappropriate AED treatment, as well as a missed opportunity for more appropriate intervention. In individuals with established epilepsy on treatment, some laboratory monitoring is desirable at least occasionally, in particular, in relation to bone health, as well as in situations where changes in AED clearance or metabolism are likely (extremes of age, pregnancy, comorbid disorders of renal or hepatic function). For any clinician managing people with epilepsy, awareness of the commoner derangements associated with individual AEDs is essential to guide practice. In this article, we review indications for tests on blood, urine and/or cerebrospinal fluid in patients presenting with new-onset seizures and status epilepticus and in people with established epilepsy presenting acutely or as part of planned monitoring. Important, but rare, neurometabolic and genetic disorders associated with epilepsy are also mentioned.
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http://dx.doi.org/10.1684/epd.2020.1191DOI Listing
August 2020

Corrigendum to "Medical management of status epilepticus: Emergency room to intensive care unit" [Seizure: Eur. J. Epilep. 75 (2020) 145-152].

Seizure 2020 Aug 4;80:282. Epub 2020 Jun 4.

Professor of Epilepsy & Medical Education, Consultant Neurologist, Atkinson Morley Regional Neuroscience Centre, St George's University Hospitals NHS Foundation Trust, and Institute of Medical & Biomedical Education, St George's University of London, London, UK. Electronic address:

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http://dx.doi.org/10.1016/j.seizure.2020.05.021DOI Listing
August 2020

The association of patient weight and dose of fosphenytoin, levetiracetam, and valproic acid with treatment success in status epilepticus.

Epilepsia 2020 06 18;61(6):e66-e70. Epub 2020 May 18.

Department of Experimental and Clinical Pharmacology and Center for Orphan Drug Research, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota.

The Established Status Epilepticus Treatment Trial was a blinded, comparative-effectiveness study of fosphenytoin, levetiracetam, and valproic acid in benzodiazepine-refractory status epilepticus. The primary outcome was clinical seizure cessation and increased responsiveness without additional anticonvulsant medications. Weight-based dosing was capped at 75 kg. Hence, patients weighing >75 kg received a lower mg/kg dose. Logistic regression models were developed in 235 adults to determine the association of weight (≤ or >75 kg, ≤ or >90 kg), sex, treatment, and weight-normalized dose with the primary outcome and solely seizure cessation. The primary outcome was achieved in 45.1% and 42.5% of those ≤75 kg and >75 kg, respectively. Using univariate analyses, the likelihood of success for those >75 kg (odds ratio [OR] = 0.9, 95% confidence interval [CI] = 0.54-1.51) or >90 kg (OR = 0.85, 95% CI = 0.42-1.66) was not statistically different compared with those ≤75 kg or ≤90 kg, respectively. Similarly, other predictors were not significantly associated with primary outcome or clinical seizure cessation. Our findings suggest that doses, capped at 75 kg, likely resulted in concentrations greater than those needed for outcome. Studies that include drug concentrations and heavier individuals are needed to confirm these findings.
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http://dx.doi.org/10.1111/epi.16534DOI Listing
June 2020

Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial.

Lancet 2020 04 20;395(10231):1217-1224. Epub 2020 Mar 20.

Department of Emergency Medicine, Neuro Emergencies Research, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Background: Benzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT) we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here we describe our results after extending enrolment in children to compare outcomes in three age groups.

Methods: In this multicentre, double-blind, response-adaptive, randomised controlled trial, we recruited patients from 58 hospital emergency departments across the USA. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalised convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 min after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group (<18 years, 18-65 years, and >65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analysed by intention to treat. This study is registered in ClinicalTrials.gov, NCT01960075.

Findings: Between Nov 3, 2015, and Dec 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged <18 years), 186 adults (18-65 years), and 51 older adults (>65 years). 175 (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenyltoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41-62) of children, 44% (33-55) of adults, and 37% (19-59) of older adults; with fosphenytoin in 49% (38-61) of children, 46% (34-59) of adults, and 35% (17-59) of older adults; and with valproate in 52% (41-63) of children, 46% (34-58) of adults, and 47% (25-70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age group.

Interpretation: Children, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus.

Funding: National Institute of Neurological Disorders and Stroke, National Institutes of Health.
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http://dx.doi.org/10.1016/S0140-6736(20)30611-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241415PMC
April 2020

Valproate risk form-Surveying 215 clinicians involving 4775 encounters.

Acta Neurol Scand 2020 Jun 10;141(6):483-490. Epub 2020 Mar 10.

Cornwall Partnership NHS Foundation Trust, Truro, UK.

Objectives: Annual completion of a Valproate Risk Acknowledgement Form (RAF) is mandated in the United Kingdom due to neurodevelopmental risks of in utero valproate exposure. The number of women of childbearing potential taking valproate, the uptake of the RAF within this population and their clinical outcomes is not known or monitored. This study surveyed responses of clinicians administering the RAF to women of childbearing potential taking valproate medications.

Materials And Methods: Study design-national online survey distributed to clinical specialists throughout the United Kingdom via their national organizations. Participants-clinicians qualified to counsel and administer the valproate RAF (as defined by the Medicines and Healthcare products Regulatory Agency). Main outcome measures-quantitative and qualitative responses regarding identification, uptake, effects and reactions to the RAF. Trial registration-registered at the Clinical Governance and Audit Committee at Royal Free London NHS Foundation Trust Hospital.

Results: 215 respondents covering more than 4775 patient encounters were captured. Most patients continued on valproate, 90% with epilepsy as the indication. Respondents reported that seizure control deteriorated when switched to levetiracetam (33%) and lamotrigine (43%), compared to 7% when continuing valproate (P < .001).

Conclusions: 33%-43% of clinicians reported seizure control deterioration in women changed to alternatives to valproate. Informed consent requires women considering a change are given this information. Systematic capture of data automated through online RAFs and linked to patient outcomes is needed. There remains little data on valproate given for indications other than epilepsy.
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http://dx.doi.org/10.1111/ane.13231DOI Listing
June 2020

Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus.

N Engl J Med 2019 11;381(22):2103-2113

From the Department of Neurology, University of Virginia, Charlottesville (J.K., N.F.); the Data Coordination Unit, Department of Public Health Sciences, Medical University of South Carolina, Charleston (J.E., C.M.); the Division of Emergency Medicine, Children's National Medical Center, Washington, DC (J.M.C.); the Department of Emergency Medicine, University of Michigan, Ann Arbor (W.B., R.S.); the College of Pharmacy, Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis (J.C.); the Department of Neurology, University of California, San Francisco, San Francisco (D.L.); the Departments of Neurology and Pediatrics, Albert Einstein College of Medicine, Montefiore Medical Center, New York (S.S.); the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (R.C.); St. George's University of London and St. George's University Hospitals NHS Foundation Trust, London (H.C.); and ConfluenceStat (J.T.C.) and the University of Central Florida College of Medicine (J.T.C.) - both in Orlando.

Background: The choice of drugs for patients with status epilepticus that is refractory to treatment with benzodiazepines has not been thoroughly studied.

Methods: In a randomized, blinded, adaptive trial, we compared the efficacy and safety of three intravenous anticonvulsive agents - levetiracetam, fosphenytoin, and valproate - in children and adults with convulsive status epilepticus that was unresponsive to treatment with benzodiazepines. The primary outcome was absence of clinically evident seizures and improvement in the level of consciousness by 60 minutes after the start of drug infusion, without additional anticonvulsant medication. The posterior probabilities that each drug was the most or least effective were calculated. Safety outcomes included life-threatening hypotension or cardiac arrhythmia, endotracheal intubation, seizure recurrence, and death.

Results: A total of 384 patients were enrolled and randomly assigned to receive levetiracetam (145 patients), fosphenytoin (118), or valproate (121). Reenrollment of patients with a second episode of status epilepticus accounted for 16 additional instances of randomization. In accordance with a prespecified stopping rule for futility of finding one drug to be superior or inferior, a planned interim analysis led to the trial being stopped. Of the enrolled patients, 10% were determined to have had psychogenic seizures. The primary outcome of cessation of status epilepticus and improvement in the level of consciousness at 60 minutes occurred in 68 patients assigned to levetiracetam (47%; 95% credible interval, 39 to 55), 53 patients assigned to fosphenytoin (45%; 95% credible interval, 36 to 54), and 56 patients assigned to valproate (46%; 95% credible interval, 38 to 55). The posterior probability that each drug was the most effective was 0.41, 0.24, and 0.35, respectively. Numerically more episodes of hypotension and intubation occurred in the fosphenytoin group and more deaths occurred in the levetiracetam group than in the other groups, but these differences were not significant.

Conclusions: In the context of benzodiazepine-refractory convulsive status epilepticus, the anticonvulsant drugs levetiracetam, fosphenytoin, and valproate each led to seizure cessation and improved alertness by 60 minutes in approximately half the patients, and the three drugs were associated with similar incidences of adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ESETT ClinicalTrials.gov number, NCT01960075.).
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http://dx.doi.org/10.1056/NEJMoa1905795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098487PMC
November 2019

A perspective on cannabinoids for treating epilepsy: Do they really change the landscape?

Neuropharmacology 2020 06 23;170:107861. Epub 2019 Nov 23.

Institute of Molecular and Clinical Sciences, St George's University of London, SW17 0RE, UK; Atkinson Morley Regional Epilepsy Network, St George's University Hospitals NHS Foundation Trust, Blackshaw Road, London, SW17 0QT, UK. Electronic address:

With the licensing of cannabidiol for drug resistant seizures in Dravet and Lennox Gastaut syndromes in the United states in 2018, interest in the potential for cannabis-based-medicinal products to meet currently unmet needs for people with epilepsy continues to grow. This review summarizes current knowledge and discusses the implications for future research and practice. Both cannabidiol and tetrahydrocannabinol, the main components, have been extensively studied in animal models, with multimodal mechanisms of action proposed. Only pure cannabidiol formulations have been rigorously evaluated in controlled trials thus far, with modest but significant improvements in motor seizures. Adverse effects include diarrhoea, somnolence and reduced appetite, with mostly acceptable tolerability, but a not insignificant (up to 1 in 23) risk of serious adverse events. Recognized drug interactions include with valproate (increased risk of hepatotoxicity) and clobazam (contributing to somnolence, increased secretions, probably chest infections, and potentially efficacy). Whilst there is public (and producer) interest in products also containing tetrahydrocannabinol, clinicians have justifiable concerns about exposing a group already vulnerable to mental health and neurobehavioural comorbidities to the associated additional risks in these domains. Artisanal preparations, with often inconsistent/unknown constituents are frequently used but not recommended. A gulf exists between the actual evidence, including a lack of comparative studies and public beliefs, fuelled by media and anecdote. Continued education of the public, policymakers, researchers and healthcare providers about what is and isn't yet known, together with on-going good quality research is essential to mitigate against future potential risks, particularly in relation to vulnerable populations. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'.
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http://dx.doi.org/10.1016/j.neuropharm.2019.107861DOI Listing
June 2020

Medical management of status epilepticus: Emergency room to intensive care unit.

Seizure 2020 Feb 24;75:145-152. Epub 2019 Oct 24.

Professor of Epilepsy & Medical Education, Consultant Neurologist. Atkinson Morley Regional Neuroscience Centre, St George's University Hospitals NHS Foundation Trust, and Institute of Medical & Biomedical Education, St George's University of London, London, UK. Electronic address:

In convulsive status epilepticus (SE), achieving seizure control within the first 1-2 hours after onset is a significant determinant of outcome. Treatment is also more likely to work and be cost effective the earlier it is given. Initial first aid measures should be accompanied by establishing intravenous access if possible and administering thiamine and glucose if required. Calling for help will support efficient management, and also the potential for video-recording the events. This can be done as a best interests investigation to inform later management, provided adequate steps to protect data are taken. There is high quality evidence supporting the use of benzodiazepines for initial treatment. Midazolam (buccal, intranasal or intramuscular) has the most evidence where there is no intravenous access, with the practical advantages of administration outweighing the slightly slower onset of action. Either lorazepam or diazepam are suitable IV agents. Speed of administration and adequate initial dosing are probably more important than choice of drug. Although only phenytoin (and its prodrug fosphenytoin) and phenobarbitone are licensed for established SE, a now considerable body of evidence and international consensus supports the utility of both levetiracetam and valproate as options in established status. Both also have the advantage of being well tolerated as maintenance treatment, and possibly a lower risk of serious adverse events. Two adequately powered randomized open studies in children have recently reported, supporting the use of levetiracetam as an alterantive to phenytoin. The results of a large double blind study also including valproate are also imminent, and together likely to change practice in benzodiazepine-resistant SE.
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http://dx.doi.org/10.1016/j.seizure.2019.10.006DOI Listing
February 2020

Epilepsy deaths: Learning from health service delivery and trying to reduce risk.

Epilepsy Behav 2020 02 23;103(Pt B):106473. Epub 2019 Oct 23.

St George's, University of London SW17 0RE, UK; Atkinson Morley Regional Epilepsy Network, St George's University Hospitals NHS Foundation Trust, London SW17 0QT, UK. Electronic address:

Two recent UK reports have highlighted data of concern in relation to potentially preventable epilepsy deaths. Public Health England, an executive agency of the Government Department of Health, using National Health Service data from 2001 to 2014 reported a rise in direct age-standardised mortality for epilepsy-associated deaths, in contrast to a reduction in all-cause deaths over the same period. Premature death was seen in people aged below 50 years, especially in men, and where epilepsy was a contributory cause rather than an association. The Scottish Epilepsy Deaths Study, analysing deaths between 2009 and 2016, similarly found death in those with epilepsy was significantly higher than the matched population below the age of 54, especially between the ages of 16 and 24 (6 times higher). Sudden unexpected death in epilepsy accounted for 38% of epilepsy-related deaths under the age of 45. Both studies found a strong relationship between risk of death and deprivation; we discuss the implications of these and other data for planning service delivery and improving epilepsy care. This paper is for the Special Issue: Prevent 21: SUDEP Summit - Time to Listen.
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http://dx.doi.org/10.1016/j.yebeh.2019.106473DOI Listing
February 2020

Lessons from the Established Status Epilepticus Treatment Trial.

Epilepsy Behav 2019 12 22;101(Pt B):106296. Epub 2019 Oct 22.

Department of Neurology (Fountain, Kapur), Brain Institute, University of Virginia, Charlottesville, VA, USA; Department of Neuroscience (Kapur), Brain Institute, University of Virginia, Charlottesville, VA, USA.

Convulsive status epilepticus (SE) is a relatively common emergency condition affecting individuals of all ages. The primary goal of treatment is prompt termination of seizures. Where first-line treatment with benzodiazepine has failed to achieve this, a condition known as established SE (ESE), there is uncertainty about which agent to use next. The Established Status Epilepticus Treatment Trial (ESETT) is a 3-arm (valproate (VPA), fosphenytoin (FOS), levetiracetam (LEV)), phase III, double-blind randomized comparative effectiveness study in patients aged 2 years and above with established convulsive SE. Enrollment was completed in January 2019, and the results are expected later this year. We discuss lessons learnt during the conduct of the study in relation to the following: ethical considerations; trial design and practical implementation in emergency settings, including pediatric and adult populations; quality assurance; and outcome determination where treating emergency clinicians may lack specialist expertise. We consider that the ESETT is already informing both clinical practice and future trial design. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".
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http://dx.doi.org/10.1016/j.yebeh.2019.04.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944752PMC
December 2019

Implementing clinical guidelines.

Pract Neurol 2019 Dec 12;19(6):529-535. Epub 2019 Jun 12.

Institute of Medical and Biomedical Education, University of London Saint George's, London, UK

Clinical guidelines that support practice and improve care are essential in this era of evidence-based medicine. However, implementing this guidance often falls short in practice. Sharing knowledge and auditing practice are important, but not sufficient to implement change. This article brings together evidence from the study of behaviour, education and clinical practice and offers practical tips on how practising neurologists might bring about change in the healthcare environment. Common themes include the importance of team working, multidisciplinary engagement, taking time to identify who and what needs changing, and selecting the most appropriate tool(s) for the job. Engaging with the challenge is generally more rewarding than resisting and is important for the effective provision of care.
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http://dx.doi.org/10.1136/practneurol-2017-001814DOI Listing
December 2019

Hiding in Plain Sight: Functional Neurological Disorders in the News.

J Neuropsychiatry Clin Neurosci 2019 23;31(4):361-367. Epub 2019 May 23.

The Department of Neurology, University Hospital Knappschaftskrankenhaus, Ruhr University Bochum, Bochum, Germany (Popkirov); the Section of Cognitive Neuropsychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London (Nicholson); the Department of Neurology, Radboud University Medical Centre, Donders Institute for Brain, Cognition, and Behaviour, Nijmegen, the Netherlands (Bloem); the Institute of Medical and Biomedical Education, St. George's University of London and Atkinson Morley Regional Neuroscience Centre, St. George's University Hospitals NHS Foundation Trust, London (Cock); the Department of Clinical Neurosciences, Western General Hospital, Edinburgh, United Kingdom (Derry); the Department of Neurology, University of Otago, Christchurch, New Zealand (Duncan); the Department of Neurology, Edward B. Bromfield Epilepsy Program, Brigham and Women's Hospital, Harvard Medical School, Boston (Dworetsky); the Institute of Molecular and Clinical Sciences, St. George's University of London (Edwards, Morgante); the Department of Neurology, Gardner Family Center for Parkinson Disease and Movement Disorders, University of Cincinnati (Espay); the Human Motor Control Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Md. (Hallett); the Morton and Gloria Shulman Movement Disorders Clinic and Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, Toronto (Lang); Queen Elizabeth University Hospital, University of Glasgow, Glasgow, United Kingdom (Leach); the Mater Centre for Neurosciences and School of Medicine, University of Queensland, Brisbane, Australia (Lehn); the Institut de Neurosciences des Systèmes, INSERM, Aix-Marseille Université, Marseille, France; the Department of Clinical Neurophysiology, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, France (McGonigal); the Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy (Morgante); the Departments of Neurology and Psychiatry, Functional Neurology Research Group, Massachusetts General Hospital, Harvard Medical School, Boston (Perez); the Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield, United Kingdom (Reuber); the Institute of Psychiatry, Psychology and Neuroscience, Kings College London (Richardson); the Department of Neurology, Alan Richens Epilepsy Unit, University Hospital of Wales, Cardiff, United Kingdom (Smith); the HYGEIA Hospital, Athens, Greece (Stamelou); the Neurology Clinic, Philipps University Marburg, Marburg, Germany (Stamelou); the University of Athens, Greece (Stamelou); the Department of Neurology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (Tijssen); the Neurology Unit, Movement Disorders Division, University of Verona, Verona, Italy (Tinazzi); and the Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom (Carson, Stone).

Objective: Functional movement and seizure disorders are still widely misunderstood and receive little public and academic attention. This is in stark contrast to their high prevalence and levels of associated disability. In an exploratory observational study, the authors examined whether the relative lack of media coverage of functional neurological disorders is in part due to misidentification in "human interest" news stories.

Methods: Thirteen recent news stories from high-impact English-language media outlets that portrayed patients with complex symptoms either attributed to other diagnoses or presented as medical mysteries were identified using online keyword searches. All selected news stories contained video or still images displaying relevant symptoms. Cases were categorized into movement disorders or seizure disorders and were then independently assessed by 10 respective expert raters. For each category, one story of a patient whose symptoms were due to a well-recognized neurological disease was also included. Both the diagnostic category and the respective confidence level were reported by each rater for each case. The interrater agreement was calculated for each group of disorders.

Results: The raters confirmed almost unanimously that all presented news stories except the negative control cases portrayed misidentified functional movement or seizure disorders. The interrater agreement and average diagnostic confidence were high.

Conclusions: Functional neurological disorders are often wrongly considered a rare medical curiosity of the past. However, these findings suggest that, while they are largely absent from public discourse, they often appear in the news incognito, hiding in plain sight.
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http://dx.doi.org/10.1176/appi.neuropsych.19010025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291360PMC
March 2020

Valproate and the Pregnancy Prevention Programme: exceptional circumstances.

Br J Gen Pract 2019 Apr;69(681):166-167

Cornwall Partnership NHS Foundation Trust, Cornwall; Honorary Associate Clinical Professor, University of Exeter Medical School, Exeter.

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http://dx.doi.org/10.3399/bjgp19X701897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428457PMC
April 2019

Seizure-alerting behavior in dogs owned by people experiencing seizures.

Epilepsy Behav 2019 05 18;94:104-111. Epub 2019 Mar 18.

Laboratory for Ethology, Department of Nutrition, Genetics and Ethology, Faculty of Veterinary Medicine, Ghent University, Belgium.

Introduction: The unpredictability of epileptic seizures is considered an important threat to the quality of life of a person with epilepsy. Currently, however, there are no tools for seizure prediction that can be applied to the domestic setting. Although the information about seizure-alert dogs - dogs that display changes in behavior before a seizure that are interpreted by the owner as an alert - is mostly anecdotal; living with an alerting dog (AD) has been reported to improve quality of life of the owner by reducing the stress originating from the unpredictability of epileptic seizures and, sometimes, diminishing the seizure frequency.

Aim Of The Study: The aim of the study was to investigate, at an international level, the behaviors displayed by trained and untrained dogs that are able to anticipate seizures and to identify patient- and dog-related factors associated with the presence or absence of alerting behavior.

Methodology: An online questionnaire for dog owners with seizures was designed. Information about the participants (demographics, seizure type, presence of preictal symptoms) and their dogs (demographics, behavior around the time of seizures) was collected. In addition, two validated scales were included to measure the human-dog relationship (Monash Dog-Owner Relationship scale (MDORS)) and five different traits of the dogs' personality (Monash Canine Personality Questionnaire refined (MCPQ-R)).

Results: Two hundred and twenty-seven responses of people experiencing seizures were received from six participant countries: 132 from people with dogs that had started alerting spontaneously, 10 from owners of trained AD, and the rest from owners of dogs that did not display any alerting behavior (nonalerting dog (NAD)). Individuals' gender, age, or seizure type did not predict the presence of alerting behavior in their dogs. People who indicated that they experience preictal symptoms were more likely to have a spontaneously AD. The owner-dog bond was significantly higher with ADs compared with NADs, and ADs scored significantly higher than NADs in the personality traits "Amicability", "Motivation", and "Training focus".

Conclusion: This study collected a large group of dog owners with seizures reporting behavioral changes in their dogs before their seizures occurred. This was associated with the presence of preictal symptoms. The seizure-alerting behavior of the dog may have a positive influence on the bond between the owner and the dog.
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http://dx.doi.org/10.1016/j.yebeh.2019.02.001DOI Listing
May 2019

Valproate MHRA Guidance: Limitations and Opportunities.

Front Neurol 2019 20;10:139. Epub 2019 Feb 20.

Cornwall Partnership NHS Foundation Trust, Threemilestone Industrial Estate, Truro, United Kingdom.

Recent publication of the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom has strengthened the regulatory measures for valproate medicines. It highlights the importance of making women of childbearing age with epilepsy aware of the teratogenic risks of valproate and encourages the withdrawal of it from those currently prescribed. While a significant directive, it raises concerns of not having considered the impact on special populations such as women with Intellectual Disability (ID). While it is important that women with ID are not excluded from such safety initiatives, due caution needs to be taken on a case by case basis preferably, to ensure their best interests are central to the decision making. Many women with moderate to profound ID cannot have informed consented sexual relationships not to mention cognitive incapability to make informed choices on medication suitability. These women are at potential risk of having their epilepsy control undermined due to the MHRA directives. Around 30% of people with moderate to profound ID have seizures of which 60% are considered treatment resistant. In this vulnerable population changes to medication without clear clinical and social insights could lead to increased harm levels. This paper enumerates the challenges of application of the new directive to these special populations and proposes a pathway based on individual cognitive ability to provide informed consent to facilitate the continuation or removal of valproate. It is important not to lose sight of individual circumstances and the importance of working collaboratively toward providing person center care.
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http://dx.doi.org/10.3389/fneur.2019.00139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391862PMC
February 2019

Brivaracetam in adults with drug-resistant epilepsy and psychiatric comorbidities.

Epilepsy Behav 2019 01 22;90:129-131. Epub 2019 Jan 22.

Atkinson Morley Regional Neuroscience Centre, St George's University Hospitals NHS Foundation Trust, London, UK; Institute of Medical and Biomedical Education, St George's University of London, UK. Electronic address:

This is a case series of 25 patients with drug-resistant epilepsy and psychiatric comorbidities who started on brivaracetam (BRV) at St George's University Hospitals and Frimley Health in London. Median BRV dose was 150 mg for a median follow-up period of 8 months. Twenty had focal epilepsy, four had generalized epilepsies, and one had unclassified epilepsy; 76% had mood disorders (either depression or bipolar disorder), 12% intellectual disabilities with autism spectrum disorder and challenging behavior, and 12% psychoses. Forty percent of patients presented at least 50% seizure reduction, but none of them became seizure-free. A total of 44% of patients discontinued BRV, 20% because of adverse events, 20% because of inefficacy, and 4% because of both. Depression was reported by 8%, aggressive behavior by 8%, while 4% reported both. A total of 91.6% had received levetiracetam (LEV) before, in whom LEV was discontinued because of psychiatric adverse events (PAEs) in half. Seventy-seven percent of patients who developed PAEs with LEV did not do so on BRV suggesting that BRV is better tolerated than LEV in complex patients with psychiatric comorbidities and that the synaptic vesicle glycoprotein 2A (SV2A) protein modulation is unlikely to be implicated in LEV-related PAEs.
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http://dx.doi.org/10.1016/j.yebeh.2018.11.032DOI Listing
January 2019

Functional neurological disorders: acute presentations and management.

Clin Med (Lond) 2018 10;18(5):414-417

Institute of Molecular and Clinical Sciences, St George's University of London, London, UK

Functional neurological disorders (FND) are common and associated with significant morbidity and healthcare costs. Patients with FND often present acutely, particularly with dissociative seizures (resembling epilepsy) or persistent weakness resembling a stroke. History and careful observation and examination are critical to diagnosis, as investigations will often be normal or non-contributory. The nature of convulsive movements in dissociative seizures often differs from that in epilepsy, and long duration of individual events, waxing and waning, closed eyes and high reported frequency in an apparently well individual are all suggestive. In those with stroke-like episodes, demonstration of normal power even briefly (eg Hoover's sign, 'give way' weakness) together with distractability are positive physical features indicating a functional disorder. A positive diagnosis and clear non-judgemental explanation, backed up by reliable information sources associated with prompt onward referral to a neurologist can greatly reduce distress and ultimately improve outcomes.
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http://dx.doi.org/10.7861/clinmedicine.18-5-414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334101PMC
October 2018

Valproate, women, and exceptional circumstances.

BMJ 2018 Aug 28;362:k3625. Epub 2018 Aug 28.

Atkinson Morley Regional Epilepsy Network, St George's University Hospital NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1136/bmj.k3625DOI Listing
August 2018

Learning from an exceptional boy.

Authors:
Hannah R Cock

Pract Neurol 2018 04 1;18(2):170-171. Epub 2018 Feb 1.

Atkinson Morley Regional Epilepsy Network, St George's University Hospitals NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1136/practneurol-2017-001853DOI Listing
April 2018

Vitamin D supplementation.

Pract Neurol 2018 Feb 25;18(1):35-42. Epub 2017 Sep 25.

Department of Neurology, Royal London Hospital, Barts Health NHS Trust, London, UK.

Vitamin D testing and supplementation is of great interest to neurologists and their patients. Recommended nutritional intakes of vitamin D in the UK remain focused on bone health, despite increasing evidence for a role outside this area. Here we discuss how neurologists might approach vitamin D testing and supplementation, focusing on two conditions associated with vitamin D deficiency that have an increased risk of downstream complications resulting from these: multiple sclerosis and epilepsy. We set out a rationale for testing serum 25-hydroxyvitamin D concentrations and discuss our personal practice in terms of supplementation, with evidence where available.
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http://dx.doi.org/10.1136/practneurol-2017-001720DOI Listing
February 2018

Non-hyperammonaemic valproate encephalopathy after 20 years of treatment.

Epilepsy Behav Case Rep 2017 21;8:9-11. Epub 2017 Apr 21.

Atkinson Morley Regional Neuroscience Centre, St Georges University Hospitals NHS Foundation Trust, London SW17 0QT, United Kingdom.

Sodium valproate is a commonly used antiseizure drug with broad indications for different seizuretypes and epilepsy syndromes. Well-recognised side effects include weight gain, tremor, dizziness, and unsteadiness. Non-hyperammonaemic parkinsonism, with or without cognitive impairment, is a rare adverse effect of sodium valproate. We present the case of a sixty year-old lady with a generalized seizure disorder, treated with phenytoin, valproate, lamotrigine and clonazepam. Following withdrawal of phenytoin she developed an akinetic-rigid syndrome, with ataxia and marked cognitive impairment. Extensive investigation failed to identify a cause. Serum ammonia and valproate levels were normal. Hypothesizing this might be valproate encephalopathy, valproate was rapidly substituted with levetiracetam. Her severe motor symptoms resolved within two weeks and cognitive impairment markedly improved. Valproate-induced encephalopathy, with or without hyperammonaemia and liver toxicity are typically recognizable for their temporal relation between the start of therapy with valproate and emergence of the clinical syndrome. Reversible disorders of motor function and cognition attributable to valproate are well described, but few cases have been reported presenting years after starting treatment. Given the insidious progression, delayed onset, lack of association with drug levels or presence of hyperammonaemia, a high index of suspicion is needed to make the diagnosis.
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http://dx.doi.org/10.1016/j.ebcr.2017.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470621PMC
April 2017

Fatigue during treatment with antiepileptic drugs: A levetiracetam-specific adverse event?

Epilepsy Behav 2017 07 29;72:17-21. Epub 2017 May 29.

Epilepsy Group, Atkinson Morley Regional Neuroscience Centre, St George's University Hospitals NHS Foundation Trust, London, United Kingdom; Institute of Medical and Biomedical Education, St George's University of London, United Kingdom; Department of Neuropsychiatry, South West London & St George's Mental Health Trust, London, United Kingdom.

Purpose: To examine the prevalence and clinical correlates of fatigue as an adverse event (AE) of antiepileptic drug (AED) treatment in patients with epilepsy.

Methods: Data from 443 adult outpatients with epilepsy assessed with the Adverse Event Profile (AEP) and the Neurological Disorder Depression Inventory for Epilepsy (NDDIE) were analysed.

Results: Fatigue is reported by 36.6% of patients as always a problem during AED treatment. Fatigue is more likely to be reported by females (64.8% vs. 35.2%; Chi-Square=16.762; df=3; p=0.001) and during treatment with levetiracetam (42.3% vs. 33.2%; Chi-Square=11.462; df=3; p=0.009). The associations with the female gender and levetiracetam treatment were not mediated by depression, as identified with the NDDIE, and could not be simply explained by the large number of subjects on levetiracetam treatment, as analogous figures resulted from the analysis of a monotherapy subsample (41.7% vs. 30.3%; Chi-Square=11.547; df=3; p=0.009).

Conclusions: One third of patients with epilepsy reports fatigue as a significant problem during AED treatment. Fatigue is more likely to be reported by females and seems to be specifically associated with LEV treatment. However, fatigue is not mediated by a negative effect of LEV on mood.
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http://dx.doi.org/10.1016/j.yebeh.2017.04.030DOI Listing
July 2017

Medical student perceptions of clinical neurosurgery teaching in an undergraduate medical school curriculum.

Br J Neurosurg 2017 Dec 31;31(6):727-730. Epub 2017 May 31.

b Institute of Medical and Biomedical Education , St George's University of London , London , UK.

Aim: The aim of this study was to evaluate undergraduate medical student perceptions as to the value of different types of neurosurgical teaching to their general neuroscience education, delivered in the penultimate year of a U.K medical school.

Methods: We surveyed penultimate-year medical students at St George's Hospital Medical School, University of London (SGUL), who were undertaking their clinical neuroscience attachment from August 2014 to July 2015. A questionnaire comprising closed Likert scale questions and an open question inviting participants to comment freely was used to assess student perception about the value of Neurosurgical sessions within their overall neuroscience education.

Results: Of the 316 students in the year we surveyed 247 (78.2%), of whom 201 responded (response rate 81.4%). On average, 82.8% of students either agreed or strongly agreed that neurosurgical teaching sessions made a valuable contribution to their learning. In particular, lectures by neurosurgeons, clinical teaching on the Glasgow Coma Scale in neuro-ITU, bedside teaching and neurosurgical clinics were considered the most beneficial. The majority of students felt the sessions improved their understanding of neurological examination, signs, and 'red-flags'. The sessions were also beneficial for learning neuro-imaging and understanding of neurosurgical emergencies. Over two thirds felt that theatre sessions were beneficial, significantly more so amongst students invited to 'scrub-in'.

Conclusions: Students rated neurosurgical sessions highly and valued the contribution they made not only to their learning of neurosurgical conditions and emergencies, but also to their learning of general neurology and clinical neurosciences overall. Student perceived learning from theatre sessions was significantly correlated with whether or not the student had been invited to 'scrub-in'. Expert neurosurgical teaching can make a valuable, and arguably essential contribution to the undergraduate medical curriculum.
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http://dx.doi.org/10.1080/02688697.2017.1335856DOI Listing
December 2017

Screening of anxiety and quality of life in people with epilepsy.

Seizure 2017 Feb 6;45:107-113. Epub 2016 Dec 6.

St George's University of London, London, UK; Department of Neurology 1, Neuromed Campus, Kepler Universitaetsklinikum, Linz, Austria. Electronic address:

Purpose: Up to 60% of people with epilepsy (PwE) have psychiatric comorbidity including anxiety. Anxiety remains under recognized in PwE. This study investigates if screening tools validated for depression could be used to detect anxiety disorders in PWE. Additionally it analyses the effect of anxiety on QoL.

Method: 261 participants with a confirmed diagnosis of epilepsy were included. Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) and Emotional Thermometers (ET), both validated to screen for depression were used. Hospital Anxiety and Depression Scale-Anxiety (HADS-A) with a cut off for moderate and severe anxiety was used as the reference standard. QoL was measured with EQ5-D. Sensitivity, specificity, positive and negative predictive value and ROC analysis as well as multivariate regression analysis were performed.

Results: Patients with depression (n=46) were excluded as multivariate regression analysis showed that depression was the only significant determinant of having anxiety in the group. Against HADS-A, NDDI-E and ET-7 showed highest level of accuracy in recognizing anxiety with ET7 being the most effective tool. QoL was significantly reduced in PwE and anxiety.

Conclusion: Our study showed that reliable screening for moderate to severe anxiety in PwE without co-morbid depression is feasible with screening tools for depression. The cut off values for anxiety are different from those for depression in ET7 but very similar in NDDI-E. ET7 can be applied to screen simultaneously for depression and "pure" anxiety. Anxiety reduces significantly QoL. We recommend screening as an initial first step to rule out patients who are unlikely to have anxiety.
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http://dx.doi.org/10.1016/j.seizure.2016.11.026DOI Listing
February 2017

eLearning resources to supplement postgraduate neurosurgery training.

Acta Neurochir (Wien) 2017 02 5;159(2):325-337. Epub 2016 Dec 5.

Department of Neurosurgery, Leeds Teaching Hospitals NHS Trust, Leeds, UK.

Background: In an increasingly complex and competitive professional environment, improving methods to educate neurosurgical residents is key to ensure high-quality patient care. Electronic (e)Learning resources promise interactive knowledge acquisition. We set out to give a comprehensive overview on available eLearning resources that aim to improve postgraduate neurosurgical training and review the available literature.

Material And Methods: A MEDLINE query was performed, using the search term "electronic AND learning AND neurosurgery". Only peer-reviewed English-language articles on the use of any means of eLearning to improve theoretical knowledge in postgraduate neurosurgical training were included. Reference lists were crosschecked for further relevant articles. Captured parameters were the year, country of origin, method of eLearning reported, and type of article, as well as its conclusion. eLearning resources were additionally searched for using Google.

Results: Of n = 301 identified articles by the MEDLINE search, n = 43 articles were analysed in detail. Applying defined criteria, n = 28 articles were excluded and n = 15 included. Most articles were generated within this decade, with groups from the USA, the UK and India having a leadership role. The majority of articles reviewed existing eLearning resources, others reported on the concept, development and use of generated eLearning resources. There was no article that scientifically assessed the effectiveness of eLearning resources (against traditional learning methods) in terms of efficacy or costs. Only one article reported on satisfaction rates with an eLearning tool. All authors of articles dealing with eLearning and the use of new media in neurosurgery uniformly agreed on its great potential and increasing future use, but most also highlighted some weaknesses and possible dangers.

Conclusion: This review found only a few articles dealing with the modern aspects of eLearning as an adjunct to postgraduate neurosurgery training. Comprehensive eLearning platforms offering didactic modules with clear learning objectives are rare. Two decades after the rise of eLearning in neurosurgery, some promising solutions are readily available, but the potential of eLearning has not yet been sufficiently exploited.
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http://dx.doi.org/10.1007/s00701-016-3042-7DOI Listing
February 2017

Depression correlates with quality of life in people with epilepsy independent of the measures used.

Epilepsy Behav 2016 09 6;62:246-50. Epub 2016 Aug 6.

Epilepsy Group, Atkinson Morley Regional Neuroscience Centre, St George's Hospital, London, UK; Institute of Medical and Biomedical Sciences, St George's University of London, UK.

Purpose: A number of studies have suggested that depressed mood is one of the most important predictors of quality of life (QoL) in patients with epilepsy. However, the QoL measure used in previous studies was limited to the Quality of Life in Epilepsy (QOLIE) scales. It could be questioned whether correlation of QOLIE with measures of depression is influenced by the properties of the instruments used rather than being a valid effect. By using visual analogue scales, the current study aimed to clarify whether depression and QoL are truly correlated in patients with epilepsy.

Methods: Data from a sample of 261 outpatients with epilepsy attending the Epilepsy Clinics of the Atkinson Morley Outpatient Department, St George's Hospital in London, were analyzed. Patients were screened using the European Quality-of-Life scale (EQ-5D-3L) which includes an overall visual analogue score (EQ-VAS), the Emotional Thermometer (ET7), the Beck Depression inventory-II (BDI-II), the Hospital Anxiety and Depression scale (HADS), and the Major Depression inventory (MDI).

Results: Depression was found to significantly correlate with EQ-VAS score with r coefficient ranging from 0.42 to 0.51 and r(2) coefficients ranging between 0.18 and 0.26. In addition, we identified patients who were depressed according to DSM-IV criteria (MD) and those with atypical forms of depression (AD). The EQ-5D-3L scores in these subjects compared with those without depression (ND) showed a different impact of AD and MD on QoL.

Conclusions: The relationship between depression and QoL in people with epilepsy has been demonstrated to be a robust and valid effect, not a result of potential bias of the specific measures used. However, the strength of the association is influenced by the individual instrument. Atypical or subsyndromic forms of depression are as relevant as DSM-based depression in terms of impact on QoL.
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http://dx.doi.org/10.1016/j.yebeh.2016.07.020DOI Listing
September 2016
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