Krishna Chinthapalli

HLA-A*3101 and Carbamazepine-Induced Hypersensitivity Reactions in Europeans

BACKGROUND 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. METHODS 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. RESULTS 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). CONCLUSIONS 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.).

Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study

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 <1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies.

Uncovering genomic causes of co-morbidity in epilepsy: gene-driven phenotypic characterization of rare microdeletions.

Background Patients with epilepsy often suffer from other important conditions. The existence of such co-morbidities is frequently not recognized and their relationship with epilepsy usually remains unexplained. Methodology/Principal Findings We describe three patients with common, sporadic, non-syndromic epilepsies in whom large genomic microdeletions were found during a study of genetic susceptibility to epilepsy. We performed detailed gene-driven clinical investigations in each patient. Disruption of the function of genes in the deleted regions can explain co-morbidities in these patients. Conclusions/Significance Co-morbidities in patients with epilepsy can be part of a genomic abnormality even in the absence of (known) congenital malformations or intellectual disabilities. Gene-driven phenotype examination can also reveal clinically significant unsuspected condition.

Atypical face shape and genomic structural variants in epilepsy.

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.

Retinal nerve fibre layer thinning is associated with drug resistance in epilepsy

Objective Retinal nerve fibre layer (RNFL) thickness is related to the axonal anterior visual pathway and is considered a marker of overall white matter ‘integrity’. We hypothesised that RNFL changes would occur in people with epilepsy, independently of vigabatrin exposure, and be related to clinical characteristics of epilepsy. Methods Three hundred people with epilepsy attending specialist clinics and 90 healthy controls were included in this cross-sectional cohort study. RNFL imaging was performed using spectral-domain optical coherence tomography (OCT). Drug resistance was defined as failure of adequate trials of two antiepileptic drugs to achieve sustained seizure freedom. Results The average RNFL thickness and the thickness of each of the 90° quadrants were significantly thinner in people with epilepsy than healthy controls (p<0.001, t test). In a multivariate logistic regression model, drug resistance was the only significant predictor of abnormal RNFL thinning (OR=2.09, 95% CI 1.09 to 4.01, p=0.03). Duration of epilepsy (coefficient −0.16, p=0.004) and presence of intellectual disability (coefficient −4.0, p=0.044) also showed a significant relationship with RNFL thinning in a multivariate linear regression model. Conclusions Our results suggest that people with epilepsy with no previous exposure to vigabatrin have a significantly thinner RNFL than healthy participants. Drug resistance emerged as a significant independent predictor of RNFL borderline attenuation or abnormal thinning in a logistic regression model. As this is easily assessed by OCT, RNFL thickness might be used to better understand the mechanisms underlying drug resistance, and possibly severity. Longitudinal studies are needed to confirm our findings.

Another cause of vaccine encephalopathy: a case of Angelman syndrome.

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. Medico-legal aspects are also discussed.

Pediatric diagnosis not made until adulthood: a case of Wolf-Hirschhorn syndrome.

Wolf-Hirschhorn syndrome is a well-known clinical entity caused by a terminal deletion of the short arm of chromosome 4 (4p-). The diagnosis is usually made in childhood because of the pathognomonic facial dysmorphism, multi-organ involvement and seizures. Epilepsy is a major medical complication during the first years of life, with seizures typically being frequent, although they tend to improve or cease with age. We report on a woman diagnosed with WHS in her thirties by array-CGH. She presents with milder dysmorphic features, recognized by stereophotogrammetry and seizures persistent in adulthood.

PO190 Anti-musk positive myasthenia gravis at a tertiary centre

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.

PO002 Bacterial meningitis with myelopathy and cranial neuropathy

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.

BILATERAL INTERNAL CAROTID ARTERY DISSECTION WITH CONFUSION

Bilateral internal carotid artery (ICA) dissections are rare. Typical clinical presentation includes cerebral ischaemia, neck/headache, Horners syndrome & pulsatile tinnitus1. We present a forty-two year old right-handed man admitted to hospital with a ten day gradual onset headache, altered taste, widespread cognitive impairments, horizontal diplopia and a right Horners syndrome. There was no history of trauma. Brain magnetic resonance imaging revealed multiple small embolic infarcts in carotid territories of both cerebral hemispheres. Computed tomography angiogram (CTA) of intracranial and extracranial vessels revealed occlusion of the left ICA and attenuation of the right ICA below the skull base. Symptoms resolved within 3–5 days of starting sub-cutaneous low molecular weight heparin and he was then anticoagulated with warfarin for six months. Repeat CTA at 4 months showed persisting complete left ICA occlusion but complete recanalisation of the right ICA. This is the first description of cognitive changes following bilateral ICA artery dissections. Whilst ICA dissection presentations are usually explained by embolic phenomena or local effects upon ICA walls, the mechanism here is probably due to cerebral hypoperfusion. Cognitive assessment should be performed in all patients presenting with ICA dissection especially when it is bilateral.