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The epilepsies are now conceptualized as network disruptions: focal epilepsies are considered to have network alterations in the hemisphere of seizure onset, whilst generalized epilepsies are considered to have bi-hemispheric network changes. Increasingly, many epilepsies are also considered to be neurodevelopmental disorders, with early changes in the brain underpinning seizure biology. The development of the structure of the face is influenced by complex molecular interactions between surface ectoderm and underlying developing forebrain and neural crest cells. This influence is likely to continue postnatally, given the evidence of facial growth changes over time in humans until at least 18 years of age. In this case–control study, we hypothesized that people with lateralized focal epilepsies (i.e. unilateral network changes) have an increased degree of facial asymmetry, compared with people with generalized epilepsies or controls without epilepsy. We applied three-dimensional stereophotogrammetry and dense surface models to evaluate facial asymmetry in people with epilepsy, aiming to generate new tools to explore pathophysiological mechanisms in epilepsy. We analysed neuroimaging data to explore the correlation between face and brain asymmetry. We consecutively recruited 859 people with epilepsy attending the epilepsy clinics at a tertiary referral centre. We used dense surface modelling of the full face and signature analyses of three-dimensional facial photographs to analyse facial differences between 378 cases and 205 healthy controls. Neuroimaging around the time of the facial photograph was available for 234 cases. We computed the brain asymmetry index between contralateral regions. Cases with focal symptomatic epilepsy associated with unilateral lesions showed greater facial asymmetry compared to controls (P = 0.0001, two-sample t-test). This finding was confirmed by linear regression analysis after controlling for age and gender. We also found a significant correlation between duration of illness and the brain asymmetry index of total average cortical thickness (r = −0.19, P = 0.0075) but not for total average surface area (r = 0.06, P = 0.3968). There was no significant correlation between facial asymmetry and asymmetry of regional cortical thickness or surface area. We propose that the greater facial asymmetry in cases with focal epilepsy caused by unilateral abnormality might be explained by early unilateral network disruption, and that this is independent of underlying brain asymmetry. Three-dimensional stereophotogrammetry and dense surface modelling are a novel powerful phenotyping tool in epilepsy that may permit greater understanding of pathophysiology in epilepsy, and generate further insights into the development of cerebral networks underlying epilepsy, and the genetics of facial and neural development.

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins. ispartof: NEUROBIOLOGY OF AGING vol:92 ispartof: location:United States status: published

Altered vitamin B6 metabolism due to pathogenic variants in the gene PNPO causes early onset epileptic encephalopathy, which can be treated with high doses of vitamin B6. We recently reported that single nucleotide polymorphisms (SNPs) that influence PNPO expression in the brain are associated with genetic generalized epilepsy (GGE). However, it is not known whether any of these GGE-associated SNPs influence vitamin B6 metabolite levels. Such an influence would suggest that vitamin B6 could play a role in GGE therapy. Here, we performed genome-wide association studies (GWAS) to assess the influence of GGE associated genetic variants on measures of vitamin B6 metabolism in blood plasma in 2232 healthy individuals. We also asked if SNPs that influence vitamin B6 were associated with GGE in 3122 affected individuals and 20,244 controls. Our GWAS of vitamin B6 metabolites reproduced a previous association and found a novel genome-wide significant locus. The SNPs in these loci were not associated with GGE. We found that 84 GGE-associated SNPs influence expression levels of PNPO in the brain as well as in blood. However, these SNPs were not associated with vitamin B6 metabolism in plasma. By leveraging polygenic risk scoring (PRS), we found suggestive evidence of higher catabolism and lower levels of the active and transport forms of vitamin B6 in GGE, although these findings require further replication. Keywords: Pyridoxine, GGE, GWAS, Genetics, SNP, Pharmacogenetics

Genetic brain channelopathies result from inherited or de novo mutations of genes encoding ion channel subunits within the central nervous system. Most neurological channelopathies arise in childhood with paroxysmal or episodic symptoms, likely because of a transient impairment of homeostatic mechanisms regulating membrane excitability, and the prototypical expression of this impairment is epilepsy. Migraine, episodic ataxia and alternating hemiplegia can also occur, as well as chronic phenotypes, such as spinocerebellar ataxias, intellectual disability and autism spectrum disorder. Voltage-gated and ligand-gated channels may be involved. In most cases, a single gene may be associated with a phenotypical spectrum that shows variable expressivity. Different clinical features may arise at different ages and the adult phenotype may be remarkably modified from the syndrome onset in childhood or adolescence. Recognizing the prominent phenotypical traits of brain channelopathies is essential to perform appropriate diagnostic investigations and to provide the better care not only in the paediatric setting but also for adult patients and their caregivers. Herein, we provide an overview of genetic brain channelopathies associated with epilepsy, highlight the different molecular mechanisms and describe the different clinical characteristics which may prompt the clinician to suspect specific syndromes and to possibly establish tailored treatments.

Increasing hospital admissions and staffing pressures mean that most medical registrars find their workload is now heavy or unmanageable. Core medical trainees increasingly think the role of medical registrar is too unattractive or difficult, resulting in less competition for such posts. In autumn 2013, the Future Hospital Commission and Shape of Training outlined their vision to reform postgraduate medical training to better meet the needs of older patients with multiple comorbidities. The Future Hospital Commission proposes that there is a greater emphasis on internal medicine from medical school, with expansion of training opportunities and service provision. Shape of Training recommends a six-year training programme culminating in a Certificate of Specialty Training. New initiatives, such as broad-based training, credentialing and rotas with more continuity, are potential ways to increase training in internal medicine. It is clear that training to achieve generalist expertise is as important as training to achieve specialist expertise.

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology., SCOPUS: ar.j, info:eu-repo/semantics/published

Headache is common. Up to 5% of attendances to emergency departments and acute medical units are due to headache. Headache is classified as either primary (eg migraine, cluster headache) or secondary to another cause (eg meningitis, subarachnoid haemorrhage). Even in the acute setting the majority of cases are due to primary causes. The role of the attending physician is to take a comprehensive history to diagnose and treat benign headache syndromes while ruling out sinister aetiologies. This brief article summarises the approach to assessment of headache presenting in acute and emergency care.

Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio

Pharmacological treatment of Alzheimer’s disease is an important part of management of the condition. There are only four drugs available for treatment of the disease and none halt the disease process, however they have a benefit on cognition, behaviour, activities of daily living, and global function. Acetylcholinesterase inhibitors are thought to work by enhancing cholinergic transmission in the brain and are particularly effective in mild and moderate AD, with recent evidence suggesting donepezil is also effective in severe AD. Memantine is the only glutamate antagonist that is available for AD and is limited for use in moderate or severe AD. The choice of drug depends on route of administration, adverse effects, and medical comorbidities. There is intense research on alternative treatments especially those that may stop the underlying disease process.

There have been repeated calls from all quarters of healthcare for more clinicians to be leaders. The risks of not accepting this responsibility have been demonstrated by harrowing reports into failed care in England. Ambiguity persists over what clinical leadership encompasses, how it can be developed and how to inspire clinicians to practise it. A supportive organisational culture, dedicated resources and national support are needed to foster leadership skills among trainee clinicians. Here we discuss a possible blueprint based on the recent reviews of English NHS Trusts with high mortality rates for future initiatives in empowering medical and nursing trainees to learn from leaders and practise leadership skills.

The Glasgow coma scale (GCS) is a tool used to assess and calculate a patient’s level of consciousness. It was developed more than 40 years ago by two neurosurgeons in Glasgow and is widely applied today.1 The GCS uses a triple criteria scoring system: best eye opening (maximum 4 points), best verbal response (maximum 5 points), and best motor response (maximum 6 points). These scores are added together to provide a total score between 3 and 15 (fig 1). Fig 1 Glasgow coma scale. Score the best level of response seen for each component. Adapted from Teasdale G. Forty years on: updating the Glasgow Coma Scale. Nursing Times 2014;110:42;12-16 The GCS was initially used to assess level of consciousness in patients after head injury, but the scale is now used in many acutely unwell patients. In hospitals it is also used to monitor patients in intensive care units. During placements you may hear the GCS used to describe confused patients on care of the elderly wards, trauma patients in the emergency department, or patients seen by the “crash” medical emergency team. As a student, you might be asked to calculate the GCS score as part of the general or neurological examination of a patient, especially if the patient is confused, drowsy, or unresponsive. As you gain experience in calculating a GCS score in practice, you will become more confident and the score will become more accurate. Assessment of a GCS score can be deemed subjective, so it is best practice that two independent clinicians calculate a GCS score to mitigate subjective bias. Clinically, the GCS may help streamline trauma services through major trauma bypass protocols. In parts of the United Kingdom patients with a GCS score of 13 or less can be transported directly by ambulance to specialist major …

We present an 89-year-old man with new onset of left-sided hemiballismus affecting his face, arm and leg. He was found to have hyperglycaemia with a glucose level of 20.2 mmol/l and had started prednisolone 3 months earlier for polymyalgia rheumatica. A T2-weighted magnetic resonance scan of the brain showed a hypointense lesion of the right lentiform nucleus. At follow-up, his symptoms had improved with treatment for diabetes mellitus. To our knowledge, this is the first patient to develop hemiballismus after starting corticosteroids.

The mammalian retina contains three classes of photoreceptor. In addition to the rods and cones, a subset of retinal ganglion cells that express the putative sensory photopigment melanopsin are intrinsically photosensitive. Functional and anatomical studies suggest that these inner retinal photoreceptors provide light information for a number of non-image-forming light responses including photoentrainment of the circadian clock and the pupil light reflex. Here, we employ a newly developed mouse model bearing lesions of both rod and cone phototransduction cascades (Rho−/−Cnga3−/−) to further examine the function of these non-rod non-cone photoreceptors. Calcium imaging confirms the presence of inner retinal photoreceptors inRho−/−Cnga3−/−mice. Moreover, these animals retain a pupil light reflex, photoentrainment, and light induction of the immediate early genec-fosin the suprachiasmatic nuclei, consistent with previous findings that pupillary and circadian responses can employ inner retinal photoreceptors.Rho−/−Cnga3−/−mice also show a light-dependent increase in the number of FOS-positive cells in both the ganglion cell and (particularly) inner nuclear layers of the retina. The average number of cells affected is several times greater than the number of melanopsin-positive cells in the mouse retina, suggesting functional intercellular connections from these inner retinal photoreceptors within the retina. Finally, however, while we show that wild types exhibit an increase in heart rate upon light exposure, this response is absent inRho−/−Cnga3−/−mice. Thus, it seems that non-rod non-cone photoreceptors can drive many, but not all, non-image-forming light responses.

Challenging Concepts in Neurology reviews over twenty difficult presentations in neurology encompassing the wide spectrum of neurological disease. The cases include unusual emergency presentations such as posterior circulation stroke and non-convulsive status epilepticus, as well as important conditions that are less familiar such as dystonia, viral or autoimmune encephalitis, and neuromyelitis optica. The book covers neurological subspecialties including stroke, epilepsy, dementia, demyelination, movement disorders, infectious diseases, neuromuscular disorders, sleep disorders, uroneurology, and neurogenetics. Allied specialty cases include neurosurgery, neuro-ophthalmology, and rehabilitation medicine. Each case begins with a case history before a discussion of the topic and relevant up-to-date evidence for diagnosis, investigations, and management. Landmark trials, clinical tips, and key learning points are interspersed in the case, as well as commentaries by leading experts in the field. Figures range from photographs of anti-epileptic drug cutaneous reactions and fundi to neuroimaging and electroencephalograms. Investigations such as visual perimetry, audiograms, and sleep actigraphy are also explained to readers. The book is aimed at trainees in neurology, neurophysiology, psychiatry, neurosurgery, neuroradiology, neuropathology, and internal medicine.

Non-convulsive status epilepticus can be a challenging diagnosis as it often relies on EEG confirmation. Prognosis is largely dependent on the underlying cause and investigations should be continued until aetiology is identified. Some forms, such as absence status epilepticus, are widely considered as harmless. The aggressiveness of acute treatment should be tailored to the type of status epilepticus, the underlying cause, and the overall condition of the patient. Treatment should be conducted alongside investigations. First-line treatment comprises benzodiazepines such as lorazepam or midazolam followed by antiepileptic drugs such as phenytoin, sodium valproate, and levetiracetam. In refractory cases, treatment with anaesthetic agents may be necessary and should be balanced with the risk of complications.

This case describes the case of a person with unexplained bilateral sensorineural deafness, intracranial calcification, and a sensory peripheral neuropathy. She was found to have maternally inherited diabetes and deafness (MIDD), a mitochondrial disease. The discussion reviews mitochondrial diseases, which may present at any age with symptoms varying from ataxia to seizures. An overview of mitochondrial genetics and the currently described spectrum of mitochondrial diseases is given, before the diagnostic algorithms, investigations, and potential complications are discussed. Interpretation of common test findings is also discussed, particularly audiograms and intracranial calcification. The case is aimed at medical trainees, especially in neurology, cardiology, or clinical genetics.

Dravet syndrome has been found recently as an important underlying condition in cases of alleged vaccine encephalopathy after pertussis vaccination, where vaccination seemed to have precipitated the occurrence of the disease without modifying the long-term course. We report on a patient diagnosed with Angelman syndrome in her fifth decade, in whom the intellectual disability and epilepsy had been assumed to be caused by a vaccine encephalopathy following smallpox vaccination. Clinical features of Angelman syndrome had faded away. The history of the present patient suggests that genetic conditions other than Dravet syndrome can be associated with an alleged vaccine encephalopathy. A history of vaccine encephalopathy is rare among patients with learning disability and refractory epilepsy (1.4% in our cohort), but it should lead to consideration of a comprehensive genetic work-up if Dravet syndrome is excluded. The early history of the patient, when available, should guide the investigations. Medicolegal aspects are also discussed. (c) 2012 Elsevier Masson SAS. All rights reserved

When might it be justifiable to refuse to treat a patient? “Physicians are not bound to treat everybody who walks through their door,” except in emergencies, argued a US surgeon in 2004.1 He had proposed a resolution to the American Medical Association that doctors refuse treatment to medical malpractice lawyers in response to frustration at mounting malpractice insurance bills. Of course, the measure was denounced, with one wit responding, “What [he] is proposing is egregious, both hypocritically and Hippocratically.” But are there circumstances in which refusal to treat (apart from emergencies) is justified if alternative care is available? One accepted scenario is refusal to see new patients if a practice is already full. The American Medical Association’s guidelines state that treatment can also be refused if it is beyond the physician’s competence or if it is “scientifically invalid.”2 Physical violence and danger to self may also be valid reasons, at least legally. In 1987 a precedent was set when a US doctor successfully used the 13th Amendment (the one abolishing slavery and involuntary servitude) to argue that he should not be forced to treat an abusive …

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Kisspeptin potently stimulates gonadotrophin release in humans and therefore represents a potential therapy for disorders of reproduction. However, ex vivo studies on human tissue suggest that kisspeptin has vasoconstrictive effects. Thus it is important to determine the effects of kisspeptin on blood pressure and heart rate in humans. Furthermore, plasma kisspeptin concentrations increase markedly in pregnancy but it is currently not known if concentrations are altered in hypertensive diseases of pregnancy. WHAT THIS STUDY ADDS • This study demonstrates that states of elevated kisspeptin are not associated with changes in blood pressure or heart rate in humans. Neither are hypertensive diseases of pregnancy associated with altered circulating kisspeptin. This has implications for the future use of kisspeptin as a therapy. AIMS To investigate (i) if kisspeptin administration alters heart rate (HR) or blood pressure (BP) in healthy male and female volunteers, (ii) whether circulating plasma kisspeptin concentrations in healthy pregnant women and women with hypertensive diseases of pregnancy correlate with BP and (iii) whether women with hypertensive diseases of pregnancy have altered plasma kisspeptin concentrations. METHODS We have previously reported the effects of administration of kisspeptin-54 on gonadotrophin secretion in healthy male and female volunteers. In these studies, cardiovascular parameters were not a primary endpoint. However, data were also collected on BP and HR for 4 h post administration of kisspeptin-54. Blood samples were taken from 105 women in the third trimester of pregnancy (27 women with hypertensive diseases of pregnancy and 78 controls). Samples were assayed for plasma kisspeptin immunoreactivity (IR). RESULTS Administration of kisspeptin was not associated with significant changes in HR or BP in healthy men or women. There was no significant correlation between plasma kisspeptin concentration and BP in healthy pregnant women or in those with hypertensive diseases of pregnancy. No significant differences in plasma kisspeptin-IR concentrations were observed between women with hypertensive diseases of pregnancy and normotensive pregnant controls, plasma kisspeptin concentrations ± SE: controls 2878 ± 157 pmol l−1; pregnancy-induced hypertension 2696 ± 299 pmol l−1 (95% CI vs. controls −514, 878 pmol l−1); pre-eclampsia 3519 ± 357 (95% CI vs. controls −1644, 362 pmol l−1). CONCLUSIONS Elevation of plasma kisspeptin-IR is not associated with an alteration in BP in humans.

After several calls from high profile psychiatrists with concerns about Trump’s mental health, what does the MoCA tell us about his cognitive health?

Muscle-specific tyrosine kinase (MuSk) myasthenia gravis (MG) is a distinct and characteristic condition. We reviewed 27 MuSK-MG patients treated at the National Hospital for Neurology and Neurosurgery. Twenty-three patients were female with median age of onset of 30.5 years and median follow-up of 8.5 years. At presentation, sixteen patients had generalised weakness and eleven pure ocular involvement. In the latter group, nine became generalised and two remained ocular. At maximum severity, the pattern of involvement was: ocular (n=24) bulbar (n=22); limb (n=18); respiratory (n=18) and seven required intensive care admission. Twenty-five required long-term oral immunosuppression (prednisolone (n=24); azathioprine (n=18); mycophenolate (n=8); rituximab (n=2)). Fourteen patients received intravenous immunoglobulin, six received plasma exchange and seven underwent thymectomy. Two patients died during follow-up: One from respiratory failure and one of unrelated causes. Twelve patients were in remission, of whom eight required continuing immunosuppression. Ten had mild symptoms and three had poorly controlled MG. Five patients required long-term non-invasive ventilation, all of whom had bulbar and respiratory involvement at presentation. Most patients with MuSK-MG develop generalised weakness and there is a significant risk of respiratory involvement and myasthenic crisis. Sustained remission off medications is unusual and the majority will need long-term immunosuppression.

Acute meningococcal meningitis in adults can be complicated by cranial neuropathies and more rarely by myelopathy. A 55-year-old woman presented with acute bacterial meningitis requiring intubation and was treated with intravenous antibiotics and dexamethasone. Cerebrospinal fluid 16S PCR was positive for Neisseria meningitidis and latex agglutination confirmed the W135 serotype. Ten days after presentation she developed mild upper limb and severe lower limb weakness with hyperreflexia, despite resolution of meningism and improvement of inflammatory markers. On the next day she developed complete bilateral hearing loss and bilateral facial palsy. Magnetic resonance imaging with contrast showed bilateral enhancement of VIIth and VIIIth cranial nerves, with focal signal change within the thoracic spinal cord. Audiometry confirmed complete sensorineural deafness. She was treated with five days of intravenous methylprednisolone and continued a further nine days of intravenous antibiotics. Four weeks after onset, she remained completely deaf with mild improvement of limb and facial weakness. We report a case of acute meningococcal meningitis complicated by presumed extensive vasculitis leading to myelopathy and delayed onset of multiple cranial neuropathies. There was an unusual biphasic presentation and the vasculitis was apparently ameliorated by glucocorticoids, suggesting conventional steroid recommendations may occasionally be inadequate.

Demand for cognitive enhancement is huge and growing The prolific French novelist Honore de Balzac wrote for 15 hours a day with the help of his “precious essence.” After a dose, he said, “Ideas march into motion like battalions . . . Memories charge in . . . The cavalry of metaphor deploys with a magnificent gallop; the artillery of logic rushes up.”1 He eventually took it up to 50 times a day. As far as de Balzac was concerned, caffeine was his “smart drug.” Caffeine is still the drug of choice for many college students in search of the same effects. Most have used coffee, caffeine drinks, or caffeine tablets to help them study.2 In the United States, caffeine is now being supplanted by the prescription stimulants Adderall (amphetamine plus dextroamphetamine), methylphenidate, and modafinil. Some 5-15% of college and university students report taking these stimulants to help academic performance but most do so only occasionally (40% had used them only once or twice).3 Colleges with higher entry criteria have a higher prevalence of stimulant use. In high schools, too, 7% of …

Krishna Chinthapalli talks to the consultant neurologist and film producer behind Eddie Redmayne’s Oscar tipped portrayal of Stephen Hawking and his life with motor neurone disease

“Sin City” ranks poorly on health and has a doctor deficit. Krishna Chinthapalli investigates the reasons

Hospitals need to be prepared to avoid shutdowns In February 2016 staff at a Los Angeles hospital noticed that their computers weren’t working.1 Secretaries couldn’t access emails and had to communicate by fax or phone. Doctors couldn’t access electronic records. At least one patient had to go to another hospital. Others reported long delays. Computed tomography scans could not be done. The chief executive declared an emergency, and ambulances were diverted to other hospitals. Rumours surfaced, including that the hospital was being held to ransom for $3.4m (£2.6m; €3.1m), though the hospital denied this.23 Few people know what exactly occurred at the Hollywood Presbyterian Medical Center. It is likely to have been a “phishing” expedition in which the bait was a fake email message and the prey was a healthcare employee. The virus—or “ransomware”—then infected and locked hospital computers. IT …

There have been repeated calls from all quarters of healthcare for more clinicians to be leaders. The risks of not accepting this responsibility have been demonstrated by harrowing reports into failed care in England. Ambiguity persists over what clinical leadership encompasses, how it can be developed and how to inspire clinicians to practise it. A supportive organisational culture, dedicated resources and national support are needed to foster leadership skills among trainee clinicians. Here we discuss a possible blueprint based on the recent reviews of English NHS Trusts with high mortality rates for future initiatives in empowering medical and nursing trainees to learn from leaders and practise leadership skills.

Good and evil medical practice on the roads to Damascus On dealing with a murderous physician, Sherlock Holmes remarked, “When a doctor does go wrong he is the first of criminals. He has nerve and he has knowledge.” One doctor also has nerve agents and knowledge of how to use them. At the Western Eye Hospital in London, Bashar al-Assad’s consultant supervisor said of him, “He was an extremely kind person and a warm personality . . . He would have been a good doctor.”1 A nurse said that he was “calm at the operating table and had a wonderful manner with the patients . . . He spoke with every patient just before surgery to reassure them all would be well.” Now all is certainly not well for the millions of people under his care. Doctor Bashar—as Syrians once called him—president of Syria and a former ophthalmologist, is held indirectly or directly responsible for most of the 100 000 deaths and the two million refugees in his country’s ongoing civil war. After an incendiary bomb landed on a school last month, the head teacher, reported widely in the media, said, “There were dead people, people burning, and people running away, but where to? Where would they go? It is not safe anywhere.” He may have been thinking of the …

This month sees a new beginning for NICE, with a new chair and legal status. Krishna Chinthapalli assesses what it has achieved and the challenges it faces in the future

Use of the Liverpool care pathway for end of life care has been heavily criticised in the media. The BMJ and Channel 4’s Dispatches asked doctors for their views. Krishna Chinthapalli reports

Krishna Chinthapalli answers the key questions about personal health budgets Personal budgets were first introduced for social care in 1997 and are used by over 125 000 people in England.1 Local councils give users a means tested sum of money to spend on care of their choice, as an alternative to existing social care packages. The Department of Health now wants to use personal budgets in healthcare, initially for people who need long term NHS community care. In social care, the sum of money is given directly to users and can be used as they wish. Although direct payment may be offered to some users of NHS personal budgets, for others the primary care trusts or clinical commissioning groups will hold the budget and approve or reject users’ plans for the money. Lord Darzi’s 2008 review, High Quality Care For All , first mentioned personal health budgets “to give individual patients greater control over the services they receive.”2 Since 2009, they have been piloted in 64 primary care trusts for people with long term conditions and for preventive measures, maternity care, and end of life care. A three year study of the pilot schemes was published on 30 November, and on the same day Norman Lamb, the care minister, announced that the Department of Health would spend £1.5m (€1.8m; $2.4m) on rolling out the scheme to …

Idiopathic generalized epilepsy (IGE) is a complex disease with high heritability, but little is known about its genetic architecture. Rare copy-number variants have been found to explain nearly 3% of individuals with IGE; however, it remains unclear whether variants with moderate effect size and frequencies below what are reliably detected with genome-wide association studies contribute significantly to disease risk. In this study, we compare the exome sequences of 118 individuals with IGE and 242 controls of European ancestry by using next-generation sequencing. The exome-sequenced epilepsy cases include study subjects with two forms of IGE, including juvenile myoclonic epilepsy (n = 93) and absence epilepsy (n = 25). However, our discovery strategy did not assume common genetic control between the subtypes of IGE considered. In the sequence data, as expected, no variants were significantly associated with the IGE phenotype or more specific IGE diagnoses. We then selected 3,897 candidate epilepsy-susceptibility variants from the sequence data and genotyped them in a larger set of 878 individuals with IGE and 1,830 controls. Again, no variant achieved statistical significance. However, 1,935 variants were observed exclusively in cases either as heterozygous or homozygous genotypes. It is likely that this set of variants includes real risk factors. The lack of significant association evidence of single variants with disease in this two-stage approach emphasizes the high genetic heterogeneity of epilepsy disorders, suggests that the impact of any individual single-nucleotide variant in this disease is small, and indicates that gene-based approaches might be more successful for future sequencing studies of epilepsy predisposition., Journal Article, Research Support, N.I.H. Extramural, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Many pathogenic structural variants of the human genome are known to cause facial dysmorphism. During the past decade, pathogenic structural variants have also been found to be an important class of genetic risk factor for epilepsy. In other fields, face shape has been assessed objectively using 3D stereophotogrammetry and dense surface models. We hypothesized that computer-based analysis of 3D face images would detect subtle facial abnormality in people with epilepsy who carry pathogenic structural variants as determined by chromosome microarray. In 118 children and adults attending three European epilepsy clinics, we used an objective measure called Face Shape Difference to show that those with pathogenic structural variants have a significantly more atypical face shape than those without such variants. This is true when analysing the whole face, or the periorbital region or the perinasal region alone. We then tested the predictive accuracy of our measure in a second group of 63 patients. Using a minimum threshold to detect face shape abnormalities with pathogenic structural variants, we found high sensitivity (4/5, 80% for whole face; 3/5, 60% for periorbital and perinasal regions) and specificity (45/58, 78% for whole face and perinasal regions; 40/58, 69% for periorbital region). We show that the results do not seem to be affected by facial injury, facial expression, intellectual disability, drug history or demographic differences. Finally, we use bioinformatics tools to explore relationships between facial shape and gene expression within the developing forebrain. Stereophotogrammetry and dense surface models are powerful, objective, non-contact methods of detecting relevant face shape abnormalities. We demonstrate that they are useful in identifying atypical face shape in adults or children with structural variants, and they may give insights into the molecular genetics of facial development., Comparative Study, Journal Article, Research Support, N.I.H. Extramural, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Background:\ud \ud Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS–TEN) in the Han Chinese and other Asian populations but not in European populations.\ud Methods:\ud \ud We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions.\ud Results:\ud \ud The HLA-A*3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P=3.5×10−8). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLA-A*3101 allele (P=1.1×10−6). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS–TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18).\ud Conclusions:\ud \ud The presence of the HLA-A*3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%. (Funded by the U.K. Department of Health and others.)

To investigate (i) if kisspeptin administration alters heart rate (HR) or blood pressure (BP) in healthy male and female volunteers, (ii) whether circulating plasma kisspeptin concentrations in healthy pregnant women and women with hypertensive diseases of pregnancy correlate with BP and (iii) whether women with hypertensive diseases of pregnancy have altered plasma kisspeptin concentrations.We have previously reported the effects of administration of kisspeptin-54 on gonadotrophin secretion in healthy male and female volunteers. In these studies, cardiovascular parameters were not a primary endpoint. However, data were also collected on BP and HR for 4h post administration of kisspeptin-54. Blood samples were taken from 105 women in the third trimester of pregnancy (27 women with hypertensive diseases of pregnancy and 78 controls). Samples were assayed for plasma kisspeptin immunoreactivity (IR).Administration of kisspeptin was not associated with significant changes in HR or BP in healthy men or women. There was no significant correlation between plasma kisspeptin concentration and BP in healthy pregnant women or in those with hypertensive diseases of pregnancy. No significant differences in plasma kisspeptin-IR concentrations were observed between women with hypertensive diseases of pregnancy and normotensive pregnant controls, plasma kisspeptin concentrations ±SE: controls 2878 ± 157pmol l(-1) ; pregnancy-induced hypertension 2696 ± 299pmoll(-1) (95% CI vs. controls -514, 878pmoll(-1) ); pre-eclampsia 3519 ± 357 (95% CI vs. controls -1644, 362pmoll(-1) ).Elevation of plasma kisspeptin-IR is not associated with an alteration in BP in humans.

Kisspeptin is the product of the KISS1 1 (KiSS-1 metastasis-suppressor) gene and is the ligand for the G-protein–coupled receptor, now known as the KISS1 receptor (KISS1R)2 (1). Both kisspeptin and KISS1R play a crucial role in the regulation of reproduction and puberty(1). The KISS1 gene encodes a precursor peptide of 145 amino acid residues, which undergoes proteolytic processing to generate kisspeptins 10, 13, 14, and 54(1). These peptides all share the common C-terminal decapeptide necessary for receptor activation(1). Inactivating mutations in the human KISS1R (KISS1 receptor) gene cause hypogonadotropic hypogonadism(1). During pregnancy, circulating plasma kisspeptin concentrations rise by 7000-fold in the third trimester, compared with the concentrations in nonpregnant women(2). Plasma markers that are altered during pregnancy, such as β human chorionic gonadotropin, have been used as markers in amniotic fluid and in certain cases may be used as markers to predict fetal outcome. Kisspeptin, however, has not previously been identified in amniotic fluid. The aim of this study was to determine whether kisspeptin is present in amniotic fluid. After obtaining ethics approval (Hammersmith and Queen Charlotte’s and Chelsea Hospitals Research Ethics Committee no. 06/Q0406/12), we recruited 32 volunteers scheduled to undergo diagnostic amniocentesis at Queen Charlotte’s and Chelsea Hospital, London, UK. Indications …

More UK medical schools teach complementary medicine than sleep medicine The first known victim was an anonymous middle aged doctor from Venice. He had suffered from an inability to sleep for over a year before he experienced complete paralysis and died in 1765. Over the centuries half of his descendants succumbed to the same fate; they initially found it difficult to sleep at night and after a few months were only able to drift off into a daydreaming state for a few minutes (now known as stage 1 sleep) before waking. Eventually they developed a permanent confusional stupor, with pinpoint pupils, sweating, tachycardia, ataxia, myoclonic seizures, and akinetic mutism.1 Another doctor, Ignazio Roiter, married into this family and discovered the hereditary nature of the illness in 1979. Sadly the disease still lives up to its name: fatal familial insomnia. It is caused by deposits of misshaped prion protein in the thalamus, which destroy neurones essential for deep “slow wave” sleep (stages 3-4). Sleep is important for learning and consolidating memories. In one study participants either slept or stayed awake for three hours …

Case report Mitochondrial diseases show a broad phenotypic spectrum and are underdiagnosed. We present a 37-year-old woman referred to our neurology clinic after an incidental finding of bilateral caudate, lentiform and pulvinar calcification during workup for cochlear implant surgery. She was born at 30 weeks9 gestation with her identical twin sister and was found to have progressive sensorineural hearing loss from eight years of age. She had had no seizures, ataxia, weakness, psychosis or involuntary movements. Her mother had diabetes mellitus. On examination, she was areflexic but otherwise normal. Neurophysiology showed a mild sensory neuropathy. Mitochondrial gene testing showed heteroplasmy for m.3243A>G mutation. Discussion Our patient was seen by a number of different specialists for her deafness and the possibility of mitochondrial diseases was never explored. Pathogenic mitochondrial gene mutations are present in up to 0.5% of the general population. The m.3243A>G mutation is associated with deafness and diabetes mellitus. Neurologists see it in MELAS syndrome. Radiologically, it is associated with basal ganglia calcification. Reaching a diagnosis allows the patient and family to understand their illness and prognosis, to undergo predictive testing if wished and to undergo screening for other affected organ systems.

A blood test for 10 protein biomarkers in people with mild cognitive impairment can predict who will develop Alzheimer’s disease over the following year with a high degree of accuracy, a new study has claimed.1 Abdul Hye, lead author and a researcher at King’s College, London, said, “There are thousands of proteins in the blood, and this study is the culmination of many years’ work identifying which ones are clinically relevant. We now have a set of 10 proteins that can predict whether someone with early symptoms of memory loss, or mild cognitive impairment, will develop Alzheimer’s disease within a year, with a high level of accuracy.”2 The secretary of state for health, Jeremy Hunt, released a statement saying, “This is welcome research on …

Funding for dementia research is being greatly increased in the UK. Krishna Chinthapalli examines the challenges after a century of frustratingly slow progress

Online access to doctors’ clinic notes has been expanded to include over three million patients in the United States, a leading expert has said. Tom Delbanco, professor of primary care at Harvard Medical School and co-founder of the OpenNotes initiative for shared notes, announced the finding in a keynote speech at the International Forum on Quality & Safety in Healthcare in Paris on 10 April. “We have more than three million patients in the USA, and thousands of doctors, nurses, therapists, trainees, physician assistants, case managers, and other clinicians sharing notes,” he said. The new figure comes …