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J A Johnston,
J S Davies,
K Baer,
C L Hammond,
J G L Mullins,
T D Cushion,
S K Chung,
R H Thomas,
H R Morris,
C White, P E M Smith,
M I Rees
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ABSTRACT: Introduction We describe a novel GABAA receptor subunit mutation; GABRG2 R97X, segregating with febrile seizures (FS) in a borderline GEFS+ family; not found in 190 healthy controls. Structural modelling suggested the mutant polypeptide may traffic to the endoplasmic reticulum (ER), accumulate and be degraded. Methods GABAA receptor subunits were cloned and PCR-directed mutagenesis performed. A neuronal phenotype cell line was cultured and magnetofected with GABRA1, GABRB2, and GABRG2 wild type (WT) or mutant receptor subunits. Surface and intracellular distribution of mutant and WT receptors were determined by co-labelling with anti-GABRG2 and anti-GABRB2,3 subunit antibodies with confocal microscopy. Results WT GABRG2 fluorescence had a smooth distribution with clusters mainly detected on the cell surface and colocalised with GABRB2 immunoreactivity. Expression of GABRG2 R97X containing receptors resulted in less cell surface cluster immunoreactivity and more diffuse intracellular labelling. GABRG2 R97X immunoreactivity also clumped intracellularly around the nucleus in close proximity to the ER; validating the structural model. Conclusion GABAA receptor dysfunction represents a putative epilepsy mechanism for GABRG2 R97X; which alters receptor composition and distribution by reducing expression and potentially compromising trafficking. The segregation with FS suggests the mutation may experience impaired temperature dependent trafficking and a reduced sensitivity to diazepam.
Journal of neurology, neurosurgery, and psychiatry 11/2010; 81(11):e19. · 4.87 Impact Factor
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ABSTRACT: A 43-year-old woman presented with increasing daytime tiredness following a history of nocturnal events persisting from early childhood. She was told that she would wake and walk clumsily; she has no memory of the episodes, which last up to 30 min. EEG and 24-h ambulatory EEG showed no abnormality but nor did they capture any episodes. Sleep was disrupted, with stage 3 NREM (slow wave, deep) sleep only reached once that night. Her striking four-generation family history of nocturnal events raised the possibility of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) with epileptic nocturnal wandering. After many months, her husband managed to obtain video footage of an event. She walked, sometimes engaging in limited conversation or performed simple tasks such as switching on the television or opening the front door. This is truly a family disorder: not only is the parasomnia inherited in an apparently autosomal dominant manner, but it took the help of her husband-with the video-to be certain that this was NREM somnambulism. The allele HLA-DQB1*05 is overrepresented in somnambulism (35% of sleepwalkers and 13.3% controls), as well as REM sleep disorders and narcolepsy, but she was negative for this. In support of parasomnia however, she wakes in the first third of sleep, normally within an hour of going to bed. Although stereotyped, the events are too sophisticated and the duration is longer than expected for ADNFLE.
Journal of neurology, neurosurgery, and psychiatry 11/2010; 81(11):e37. · 4.87 Impact Factor
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ABSTRACT: Adolescence is a period of social, physical and psychological change that can be difficult to cope with, even for healthy teenagers. Teenagers with epilepsy therefore have unique needs that need to be specifically targeted. We performed an observational study of all referrals to a monthly teenage transitional care epilepsy clinic over a 3-year period (2006 to 2008) which receives input from a paediatric and an adult neurologist, both with a special interest in epilepsy. The retrospective notes review was a re-examination of our study of the period 1997 to 2001. Ten variables were measured including epilepsy classification, reason for referral and changes made by the consultation. 178 consultations were scheduled (121 new patients and 57 follow-ups); forty patients "did not attend" (23% of appointments). 84% were already taking antiepileptic medication. Seven teenagers were changed from sodium valproate to either lamotrigine or levetiracetam: all these were female. All teenagers received age appropriate lifestyle advice and twenty had a psychological or psychiatric co-morbidity documented (seven of whom were eventually not diagnosed with epilepsy). Although age-appropriate lifestyle advice is important, encouraging the teenager to take responsibility for their epilepsy; ensuring the correct diagnosis and most appropriate choice of drug (particularly in women) is imperative. Despite this need, bespoke teenage epilepsy clinics are still a rarity in the UK.
Journal of neurology, neurosurgery, and psychiatry 11/2010; 81(11):e47. · 4.87 Impact Factor
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ABSTRACT: Generalised (or genetic) epilepsy with febrile seizures plus (GEFS+) is a syndrome caused by mutations in SCN1A and GABRG2 genes in 10% of families. Initially the GEFS+ phenotype was tightly defined, but the borders of both epilepsy within GEFS+ families and the epilepsy caused by SCN1A mutations are increasingly blurred. Eighty families were recruited for future genetic analysis. Characteristics were ascertained via semistructured interview and the pedigrees charted. Consensus as to whether families met the criteria for GEFS+ was achieved following debate within a team of two clinical research fellows, a genetics professor, a paediatric neurologist and a genetic counsellor. Fourteen families were classified as probable and ten as borderline GEFS+; in eight families GEFS+ was unlikely and 48 had another syndrome. Borderline GEFS+ had a greater mix of epilepsies than definite GEFS+, where idiopathic generalised epilepsy comprised 80% of diagnoses that persisted into adulthood (compared with 60%, p<0.01). Febrile seizures were reported twice as often in GEFS+ or GEFS+ borderline families (p<0.005) than "unlikely" families. Identifying families with either a classic or borderline phenotype has been important for efficient targeting of resources to inform gene discovery. Atypical febrile seizures were specific (97.5%, but not sensitive) for identifying GEFS+ or GEFS+ borderline families, where they accounted for 24 and 19% of febrile seizures respectively.
Journal of neurology, neurosurgery, and psychiatry 11/2010; 81(11):e48. · 4.87 Impact Factor
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ABSTRACT: To identify and prioritise uncertainties regarding epilepsy treatment from people with epilepsy, their carers and epilepsy clinicians.
Failure to acknowledge and address genuine treatment uncertainties has caused unnecessary iatrogenic harm. The authors define an uncertainty as a question that cannot be sufficiently answered by a systematic review of the literature. The database of the uncertainties of the effects of treatment (DUETs) is a collection of 'known unknowns' that enables patient-prioritised research.
The authors organised five separate focus groups (two consisting of clinicians, three of patients and carers) to garner questions on epilepsy treatment uncertainties; these yielded 398 potential research questions. Participants were asked to rank the questions in terms of importance. The authors then performed a thematic analysis.
Patients rated questions concerning cognitive drug side effects, managing the consequences of side effects and improving public awareness about the treatment of epilepsy through improved services as most important. For clinicians, the most important themes were treatment programmes for non-epileptic attack disorder (NEAD), concerns about side effects in utero and uncertainties regarding prescribing in pregnancy.
Patient uncertainties were often focussed on very practical considerations-how to take prescribed medication, access to services and how to minimise drug side effects. Clinicians' questions were also practical but clustered around 'the challenging consultation'-for example, NEAD, sudden unexplained death in epilepsy and prescribing in pregnancy. The authors have published the research questions on NHS Evidence and are working with them to identify those questions which represent genuine uncertainties. The authors encourage other clinicians to seek patient and carers' priorities in order to shape their research agenda.
Journal of neurology, neurosurgery, and psychiatry 08/2010; 81(8):918-21. · 4.87 Impact Factor
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ABSTRACT: Who with sleep seizures is safe to drive? Driving law is controversial; ineligibility varies between individual US states and EU countries. Current UK driving law is strongly influenced by a single-centre study from 1974 where most participants were not taking antiepileptic drugs (AEDs). However, pure sleep-related epilepsy is often fully controlled on medication, and its withdrawal can provoke awake seizures. This systematic review asked, 'What is the risk of awake seizures in pure sleep-related epilepsy?' 9885 titles were identified; 2312 were excluded (not human or adult); 40 full texts were reviewed; six papers met our inclusion criteria; each of these six studies had a different pure sleep-related epilepsy definition. Using the largest prospective study, we were able to calculate next year's awake seizure chance (treated with antiepileptic medication). This was maximal in the second year: 5.7% (95% CI 3.0 to 10.4%). European licensing bodies including the UK's Driver and Vehicle Licensing Agency broadly accept a risk of less than 20% for Group 1 licensing. However, this study excluded patients with frontal-lobe epilepsies. Furthermore, follow-up (n=160) varied from 2 to 6 years, yet new awake seizures may occur even after 10-20 years of pure sleep-related epilepsy A paucity of evidence underpins present licensing law; current rulings would be difficult to defend if legally challenged. The law may be penalising people with pure sleep-related epilepsy without increased risk of awake seizures, while failing to identify subgroups at unacceptable risk of an awake seizure at the wheel.
Journal of neurology, neurosurgery, and psychiatry 02/2010; 81(2):130-5. · 4.87 Impact Factor
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ABSTRACT: The approach to epilepsy care has transformed in the last 30 years, with more and better anti-epileptic medications, improved cerebral imaging and increased surgical options. Alongside this, developments in neuroscience and molecular genetics have furthered the understanding of epileptogenesis. Future developments in pharmacogenomics hold the promise of antiepileptic drugs matched to specific genotypes. Despite this rapid progress, one-third of epilepsy patients remain refractory to medication, with their seizures impacting upon day-to-day activity, social well-being, independence, economic output and quality of life. International genome collaborations, such as HapMap and the Welcome Trust Case-Control Consortium single nucleotide polymorphism (SNP) mapping project have identified common genetic variations in diseases of major public health importance. Such genetic signposts should help to identify at-risk populations with a view to producing more effective pharmaceutical treatments. Neurological disorders, despite comprising one-fifth of UK acute medical hospital admissions, are surprisingly under-represented in these projects. Epilepsy is the commonest serious neurological disorder worldwide. Although physically, psychologically, socially and financially disabling, it rarely receives deserved attention from physicians, scientists and governmental bodies. As outlined in this article, research into epilepsy genetics presents unique challenges. These help to explain why the identification of its complex genetic traits has lagged well behind other disciplines, particularly the efforts made in neuropsychiatric disorders. Clinical beginnings must underpin any genetic understanding in epilepsy. Success in identifying genetic traits in other disorders does not make the automatic case for genome-wide screening in epilepsy, but such is a desired goal. The essential clinical approach of accurately phenotyping, diagnosing and interpreting the dynamic nature of epilepsy remains fundamental to harvesting its potential translational outcomes.
QJM: monthly journal of the Association of Physicians 04/2009; 102(7):497-9. · 2.33 Impact Factor
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ABSTRACT: Francisco Goya (1746-1828), a major Spanish artist, became profoundly deaf aged 46 years, following an acute illness. Despite this, his success continued and he eventually died aged 82 years. His illness is sketchily documented in letters written during his convalescence, describing headache, deafness, tinnitus, unsteadiness and visual disturbance with recovery (apart from deafness) over three months. There was a milder similar illness two years before, suggesting a relapsing condition. Vogt-Koyanagi-Harada syndrome, although previously accepted as Goya's diagnosis, is not supported by the limited evidence. Susac's syndrome or Cogan's syndrome, although both rare, are more likely explanations.
Practical Neurology 01/2009; 8(6):370-7.
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ABSTRACT: Three to 12 evaluations of clinical performance using the mini-clinical evaluation exercise (Mini-CEX) (n = 124) or direct observation of procedural skills (DOPS) (n = 21) were performed on 27 trainees working in an NHS neurology department. The communications/ counselling skills subdomain was scored in 64 evaluations. For Mini-CEX the focus was on gathering data (22%), diagnosis (31%), management (34%) and counselling (7%) (focus not recorded in 6%). For DOPS, lumbar puncture was the most common evaluated procedure (57%). Mini-CEX evaluations lasted 23.8 minutes (10.6) (mean, sd) and DOPS 25.9 minutes (12.6). Mini-CEX scores for overall competence and communication skills were mean 5.99 (sd 0.95, range 4-8) and 5.98 (sd 1.21, range 3-9) and for DOPS 5.71 (sd 0.90, range 4-8) both on scales of 1 to 9. Overall trainee competence and communication scores increased with year of training (p < 0.001, p < 0.004 univariate analysis). Assessors undertook up to three or four assessments in a session. Assessors and trainees considered that the observation and feedback had been 'very' or 'quite' useful in providing a relevant element of assessment. These assessments were feasible and useful in a neurology department and provided some evidence for increasing performance with trainee seniority. More assessor time (approximately one hour) than trainee time (24-26 min) was needed for each assessment undertaken.
Clinical medicine (London, England) 09/2007; 7(4):365-9. · 1.15 Impact Factor
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ABSTRACT: Variable compliance with antiepileptic drugs (AEDs) is a potentially preventable cause of sudden unexplained death in epilepsy (SUDEP). Hair AED concentrations provide a retrospective insight into AED intake variability.
We compared hair AED concentration variability in patients with SUDEP (n = 16), non-SUDEP epilepsy related deaths (n = 9), epilepsy outpatients (n = 31), and epilepsy inpatients (n = 38). AED concentrations were measured in 1 cm hair segments using high performance liquid chromatography. Individual patient hair AED concentration profiles were corrected for "washout" using linear regression analysis. The coefficient of variation (CV) of the corrected mean hair AED concentration provided an index of variability of an individual's AED taking behaviour. Hair sample numbers varied between subjects, and so weighted regression estimates of the CV were derived for each group.
The CV regression estimates for each group were: SUDEP 20.5% (standard error 1.9), non-SUDEP 15.0% (3.9), outpatients 9.6% (1.4), and inpatients 6.2% (2.7). The SUDEP group therefore showed greater hair AED concentration variability than either the outpatient or the inpatient groups (p<0.0001).
Observed variability of hair AED concentrations, reflecting variable AED ingestion over time, is greater in patients dying from SUDEP than in either epilepsy outpatients or inpatients. SUDEP, at least in a proportion of cases, appears preventable.
Journal of Neurology Neurosurgery & Psychiatry 04/2006; 77(4):481-4. · 4.76 Impact Factor
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ABSTRACT: Epilepsy is common and serious (prevalence 750 per 100 000) and has an impact upon employment, education, and driving. The diagnosis requires a detailed history including witness account. Clinicians must distinguish seizures particularly from syncope and psychogenic attacks. Electroencephalography and magnetic resonance brain scanning help to identify causes and classification of epilepsy, but alone rarely provide the diagnosis. Antiepileptic drug treatment is required long term and is potentially hazardous; patients should start treatment only after informed discussion with an epilepsy specialist. Patients require reliable written information, particularly the driving regulations, and the impact of seizures on employment, education, and leisure. Women must understand the potential drug teratogenic effects. Certain patient groups benefit from targeted epilepsy services, for example, learning disabled, children, teenagers, and elderly. People with epilepsy require long term specialist follow up. Although this is currently provided in mainly in secondary care (including nurse led clinics), improved liaison with primary care should enable improved access to epilepsy services. Epilepsy care should be multidisciplinary and long term, linking primary and secondary care, and empowering patients towards improved management of their condition.
Postgraduate medical journal 08/2005; 81(957):442-7. · 1.38 Impact Factor
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ABSTRACT: Treatments used for several neurological conditions may adversely affect the eye. Vigabatrin-related retinal toxicity leads to a visual field defect. Optic neuropathy may result from ethambutol and isoniazid, and from radiation therapy. Posterior subcapsular cataract is associated with systemic corticosteroids. Transient refractive error changes may follow treatment with acetazolamide or topiramate, and corneal deposits and keratitis with amandatine. Intraocular pressure can be elevated in susceptible individuals by anticholinergic drugs, including oxybutynin, tolterodine, benzhexol, propantheline, atropine and amitriptyline, and also by systemic corticosteroids and by topiramate. Nystagmus, diplopia and extraocular muscle palsies can occur with antiepileptic drugs, particularly phenytoin and carbamazepine. Ocular neuromyotonia can follow parasellar radiation. Congenital ocular malformations can result from in utero exposure to maternally prescribed sodium valproate, phenytoin and carbamazepine. Neurologists must be aware of potential ocular toxicity of these drugs, and appropriately monitor for potential adverse events.
European Journal of Neurology 08/2005; 12(7):499-507. · 3.69 Impact Factor
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ABSTRACT: Serum anti-epileptic drug (AED) levels are indicated to assess AED adherence or toxicity, and are applicable to only a few AEDs. Expert consensus views on the clinical role of serum AED levels are summarized in the evidence-based guidelines published by the Scottish Intercollegiate Guidelines Network.
To examine local compliance with these guidelines.
Retrospective case-note audit.
We included all serum AED level measurements requested from our hospital over two months. Our audit standards were first, that serum AED levels should be requested only for suspicion of poor AED adherence or toxicity ('indication-compliant'), and secondly, for 'full compliance', that 'indication-compliant' requests should be made only for AEDs with established dose-response and dose-toxicity relationships (phenytoin, carbamazepine, phenobarbitone).
There were 114 measurements in 102 patients. Serum AED level requests were for phenytoin (n = 50), valproate (n = 27), carbamazepine (n = 22), lamotrigine (n = 8), phenobarbitone (n = 7), and were made by physicians (n = 46), paediatricians (n = 30), neurologists (n = 15), neurosurgeons (n = 14), psychiatrists (n = 7), and intensivists (n = 2). AED toxicity was queried in 29 requests (25%), and adherence in 10 (9%); thus 34% of requests were 'indication-compliant'. However, 16 of these were for valproate or lamotrigine; thus only 23 requests (20%) were 'fully compliant'. Clinical management changed in only 17 of the 47 patients whose levels fell outside target ranges, and only two of these followed indication-compliant AED measurement.
The audit identified a failure locally to comply with standard evidence-based guidelines. If, as is likely, this reflects practice elsewhere in the UK, there are potentially major clinical management and resource implications.
QJM: monthly journal of the Association of Physicians 07/2004; 97(6):337-41. · 2.33 Impact Factor
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BMJ (Clinical research ed.). 11/2003; 327(7420):905.
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ABSTRACT: Levetiracetam is a relatively new anti-epileptic drug licensed for refractory partial epilepsy, although it may have a broad range of action. Levetiracetam's mode of action is unknown.1 Common adverse effects reported relate to the central nervous system, but recognised gastrointestinal side effects include diarrhoea and anorexia.2 We report four cases of considerable weight loss associated with using levetiracetam (table).
View this table:View PopupView InlineWeight loss in patients taking levetiracetam
No change in anti-epileptic treatment was made during the period of treatment of the four patients, and we identified no other cause of weight loss. The patients lost 2.3-7.0 kg a month, and starting levetiracetam coincided with the start of the period of weight loss. One patient stopped the treatment, and her weight increased. The other three patients decided to continue treatment because levetiracetam had improved their control of seizures. Their weight stabilised or increased after reducing the dose of levetiracetam by 250-500 mg.
The mechanism of the weight loss is unclear. None of the patients reported decreased appetite during the period of weight loss; however, one patient developed pica and craved only toast, cereal, scallops, and caviar. All cases were reported to the Committee on Safety of Medicines and the manufacturers.
We have not found any other reported cases of weight loss associated with levetiracetam. We have about 300 patients who have been prescribed levetiracetam on our epilepsy unit database. These four cases therefore represent about 1% of patients on the drug, which, for a serious adverse effect, might reasonably be regarded as common. Anti-epileptic drugs known to cause considerable weight loss include topiramate and zonisamide.3 4 Levetiracetam is also a potential cause of weight loss.
Footnotes
Funding None.
Competing interests PS has received an unrestricted research grant from UCB Pharma, manufacturer of levetiracetam, and has received payments for speaking and hospitality from UCB Pharma, GlaxoSmithKline, and Novartis. TP and SH have received unrestricted educational grants from GlaxoSmithKline, manufacturer of lamotrigine.
References↵Shorvon S. Handbook of epilepsy treatment. Oxford: Blackwell Science, 2000.↵British Medical Association, Royal Pharmaceutical Society of Great Britain. British national formulary. London: BMA, RPS, 2003: 231–2. (No 45.)↵Glanser TA. Topiramate. Epilepsia 1999; 40(suppl 5):S71–80.OpenUrl↵Faught, Ayala R, Montowris GG, Leppik IE. Randomised controlled trial of zonisamide for the treatment of refractory partial-onset seizures. Neurology 2000; 57: 1774–9.OpenUrl
BMJ. 10/2003; 327(7420):905.
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ABSTRACT: To assess the role of head up tilt testing (HUT) in diagnosing probable or possible vasovagal syncope (VVS) in patients referred from an epilepsy clinic.
One hundred thirty two patients underwent HUT over 36 months. Complete data were available on 128 patients (52 male) aged 14-80 (mean 36.7) years. The main indication for HUT (head up tilt at 70 degrees for 45 minutes) was recurrent undiagnosed blackouts, likely to be VVS. Patients were divided, prior to knowledge of the HUT results, into probable VVS, possible VVS, or probable/possible VVS associated with definite epilepsy.
HUT was positive in 72 patients (56%), and led to an alternative definite diagnosis in 31 (24%). Diagnostic change was more likely in those provisionally labelled either as possible VVS (15 of 34; 44%) or as a combination of epilepsy with possible or probable VVS (12 of 19; 63%) compared to those with probable VVS (4 of 75; 5%; P<0.01).Of the 45 patients previously treated with antiepileptic medications 27 did not have epilepsy.
HUT has an important role in confirming or refuting the diagnosis of VVS in patients presenting with undiagnosed blackouts to an epilepsy clinic, and particularly so in patients with possible rather than probable VVS, and in those thought to have a combination of epilepsy and possible or probable VVS.
Seizure 07/2003; 12(5):295-9. · 1.80 Impact Factor
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ABSTRACT: Teenagers with epilepsy are a group with special needs whom we have specifically targeted in our clinical practice. All teenagers referred to our unit between 1997 and 2001 with definite or probable epilepsy, were considered for assessment by an adult neurologist and paediatric neurologist working together in a dedicated monthly clinic. A total of 207 patients aged 11-22 (mean 16.0) years, 95 male, were seen over 46 months. Epilepsy was our diagnosis in 173 (84%), classified as generalized (n=76), focal (n=70), or unclassified (n=27). Four others had had single seizures. 'Non-epilepsy' diagnoses (n=30) included vasovagal syncope in 17, non-epileptic attack disorder in six, and migraine in three; epilepsy had been erroneously diagnosed previously in eight of these. Existing antiepileptic drug treatment, or lack of it, was considered appropriate in 165 of the 207 patients. Major changes to medication made in 42 patients included new prescriptions for those previously untreated (n=28), changing type of medication (n=6), and stopping medication (n=8). Antiepileptic medication was withheld in 21 despite epilepsy or single seizure. All patients received appropriate advice on driving, contraception, and alcohol, and were offered further specialist nurse appointments. Of the 86 females on antiepileptic medication at the time of consultation, only 12 were already taking folate supplements. The clinic had an important role in confirming diagnosis, ensuring appropriate management, information provision and aiding seamless transition to adult epilepsy care.
European Journal of Neurology 08/2002; 9(4):373-6. · 3.69 Impact Factor
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ABSTRACT: Appointments to the specialist registrar (SpR) grade depend almost entirely on performance at interview, yet standard panel interviews do not directly assess the competences required of a medical trainee. In this study, station interviews were used to select neurology SpRs. Eighteen candidates were assessed in three interviews, each involving three stations: a curriculum vitae (CV)-based interview, an interview with a simulated patient, and a discussion of scenarios based upon teaching, audit and research. Two or three assessors at each station ranked candidates independently before discussing the pooled rankings and reading written references. The CV-based interview rankings (resembling a traditional panel interview) correlated less well with the overall rankings (r=0.54) than did research (r=0.83), information giving (r=0.75), audit (r=0.70) or teaching presentation (r=0.59). Station interviews appear fairer (providing more time, more independent examiners, fresh starts at each station), although they require more planning and expense. Competency-based assessments should be more widely used in selecting medical trainees.
Clinical medicine (London, England) 6(3):279-80. · 1.15 Impact Factor
