Late-onset ornithine transcarbamylase deficiency mimicking a focal opercular syndrome.

A previously healthy 27-year-old man was brought to hospital after been found late at night confused, agitated and talking incoherently. He represented 12 days later with focal seizures, progressing to anarthria and encephalopathy. MR scan of brain showed diffuse cerebral oedema and his plasma ammonia was >2000 µmol/L (12-55 µmol/L). He developed refractory status epilepticus and subsequently died. Genetic analysis identified an ornithine transcarbamylase (OTC) gene mutation on the X chromosome. We discuss this atypical presentation of OTC deficiency as a rare but treatable cause of hyperammonaemic encephalopathy.

Incidence of first seizures, epilepsy, and seizure mimics in a geographically defined area.

OBJECTIVE: To determine the incidence of first seizures, epilepsy, and seizure mimics in a geographically defined area using the updated 2014 International League Against Epilepsy (ILAE) definition, which allows an epilepsy diagnosis after a single seizure when the risk of further seizures over the next 10 years is ≈60% or greater. This replaced the 1993 definition by which epilepsy was diagnosed when a person had ≥2 seizures separated by 24 hours. METHODS: Using multiple overlapping methods of case ascertainment followed by individual case classification by an epileptologist, we identified all first seizures, new diagnosis of epilepsy, and seizure mimics occurring in a defined geographic area (population 542,868) from January 1, 2017, to December 31, 2017. Incidence was age standardized to the Standard European Population. We compared incidence rates using the 2014 and 1993 ILAE definitions. RESULTS: When the 2014 ILAE definition of epilepsy was applied, the incidence of new diagnosis of epilepsy was 62 per 100,000 (age standardized 74) compared to 41 per 100,000 (age standardized 48) when the 1993 definition was applied, and the difference was more pronounced at older ages. The incidence of all first seizures and of seizure mimics was 102 per 100,000 (age standardized 123) and 94 per 100,000 (age standardized 111), respectively. The most frequently encountered seizure mimic was syncope. CONCLUSION: Application of the 2014 ILAE definition of epilepsy resulted in a higher incidence of new diagnosis of epilepsy compared to the 1993 definition. The incidence of seizure mimics almost equals that of all first seizures. Seizures, epilepsy, and seizure mimics represent a significant burden to health care systems.

Application of Recent International Epidemiological Guidelines to a Prospective Study of the Incidence of First Seizures, Newly-Diagnosed Epilepsy and Seizure Mimics in a Defined Geographic Region in Ireland.

Studies adherent to international guidelines and epilepsy classification are needed to accurately record the incidence of isolated seizures, epilepsy and seizure-mimics within a population. Because the diagnosis of epilepsy is largely made through clinical assessment by experienced physicians, seizures and epilepsy are susceptible to misdiagnosis. Previous epidemiological studies in epilepsy have not captured "seizure mimics". We therefore sought to quantify the incidence of isolated seizures, epilepsy and seizure-mimics using the International League Against Epilepsy (ILAE) classification system. In this study multiple overlapping methods of case ascertainment were applied to a defined geographic region from January 1 to March 31, 2017 to identify all patients presenting with first seizures (provoked and unprovoked), new diagnoses of epilepsy and seizure mimics. Over a 3 month period, from a population of 542,869 adults and children, 442 potential presentations were identified, and 283 met the inclusion criteria. Radiology databases were the source of the largest number of individual cases (n = 153, 54%), while electroencephalogram (EEG) databases were the source of the highest number of unique-to-source cases (those not identified elsewhere, n = 60, 21%). No single case was picked up in every method of ascertainment. Among the 283 included presentations, 38 (13%) were classed as first provoked seizures, 27 (10%) as first unprovoked seizures, 95 (34%) as new diagnosis of epilepsy and 113 (40%) as seizure mimics. Ten (3%) presentations were indeterminate. We present and apply a rigorous study protocol for investigation of the incidence of first seizures, new diagnosis of epilepsy and seizure mimics in a geographically defined region which is adherent to recently published international guidelines for epidemiologic studies and epilepsy classification. We highlight the challenges in making a diagnosis of new-onset epilepsy in patients presenting with a first seizure using the current ILAE definition of epilepsy, when epilepsy can be diagnosed in situations where the treating physician anticipates the risk of further seizures exceeds 60%.

Giant Cell Arteritis Presenting with Bilateral Subdural Haematomas of Arterial Origin.

Giant cell arteritis or temporal arteritis is an inflammatory condition affecting medium to large sized vessels, particularly the cranial arteries. A 76-year-old man with no significant past medical history presented to the emergency department with a 3-week history of diffuse headaches associated with fever, loss of appetite, weight loss and general malaise. A CT scan of the brain showed bilateral shallow chronic low density subdural haematomas. A complete laboratory panel was unremarkable except for a raised erythrocyte sedimentation rate and elevated C-reactive protein. A transthoracic echocardiogram and CT scan of the body were unremarkable. MRI of the brain confirmed bilateral old subdural collections and showed marked vessel wall enhancement in the frontal branches of the left superficial temporal artery. A left temporal artery biopsy confirmed giant cell temporal arteritis. We speculate that a vasculitic process in the small subdural arteries may have contributed to our patient's spontaneous subdural haematomas. LEARNING POINTS: A contrast-enhanced T1 axial fat-suppressed MRI of the brain is a non-invasive modality of diagnostic value in giant cell arteritis (GCA); increased access to high resolution MRI technology may reduce the requirement for invasive temporal artery biopsy in the future.Subdural hematomas may be of arterial origin; GCA has been reported in association with subdural hematomas but causation is not proven.GCA must be suspected in patients presenting with headaches and raised inflammatory markers even in the absence of classic features or dual pathology as failure to recognize and treat promptly could lead to permanent visual loss.

TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function.

Topoisomerase II (TOP2) removes torsional stress from DNA and facilitates gene transcription by introducing transient DNA double-strand breaks (DSBs). Such DSBs are normally rejoined by TOP2 but on occasion can become abortive and remain unsealed. Here we identify homozygous mutations in the TDP2 gene encoding tyrosyl DNA phosphodiesterase-2, an enzyme that repairs 'abortive' TOP2-induced DSBs, in individuals with intellectual disability, seizures and ataxia. We show that cells from affected individuals are hypersensitive to TOP2-induced DSBs and that loss of TDP2 inhibits TOP2-dependent gene transcription in cultured human cells and in mouse post-mitotic neurons following abortive TOP2 activity. Notably, TDP2 is also required for normal levels of many gene transcripts in developing mouse brain, including numerous gene transcripts associated with neurological function and/or disease, and for normal interneuron density in mouse cerebellum. Collectively, these data implicate chromosome breakage by TOP2 as an endogenous threat to gene transcription and to normal neuronal development and maintenance.

Heritability of subcortical volumetric traits in mesial temporal lobe epilepsy.

OBJECTIVES: We aimed to 1) determine if subcortical volume deficits are common to mesial temporal lobe epilepsy (MTLE) patients and their unaffected siblings 2) assess the suitability of subcortical volumetric traits as endophenotypes for MTLE. METHODS: MRI-based volume measurements of the hippocampus, amygdala, thalamus, caudate, putamen and pallidium were generated using an automated brain reconstruction method (FreeSurfer) for 101 unrelated 'sporadic' MTLE patients [70 with hippocampal sclerosis (MTLE+HS), 31 with MRI-negative TLE], 83 unaffected full siblings of patients and 86 healthy control subjects. Changes in the volume of subcortical structures in patients and their unaffected siblings were determined by comparison with healthy controls. Narrow sense heritability was estimated ipsilateral and contralateral to the side of seizure activity. RESULTS: MTLE+HS patients displayed significant volume deficits across the hippocampus, amygdala and thalamus ipsilaterally. In addition, volume loss was detected in the putamen bilaterally. These volume deficits were not present in the unaffected siblings of MTLE+HS patients. Ipsilaterally, the heritability estimates were dramatically reduced for the volume of the hippocampus, thalamus and putamen but remained in the expected range for the amygdala. MRI-negative TLE patients and their unaffected siblings showed no significant volume changes across the same structures and heritability estimates were comparable with calculations from a healthy population. CONCLUSIONS: The findings indicate that volume deficits for many subcortical structures in 'sporadic' MTLE+HS are not heritable and likely related to acquired factors. Therefore, they do not represent suitable endophenotypes for MTLE+HS. The findings also support the view that, at a neuroanatomical level, MTLE+HS and MRI-negative TLE represent two distinct forms of MTLE.

MRI-based brain structure volumes in temporal lobe epilepsy patients and their unaffected siblings: a preliminary study.

INTRODUCTION: Investigating the heritability of brain structure may be useful in simplifying complicated genetic studies in temporal lobe epilepsy (TLE). A preliminary study is presented to determine if volume deficits of candidate brain structures present at a higher rate in unaffected siblings than controls subjects. METHODS: T1-weighted MR images was acquired for 28 TLE patients, a same-sex unaffected sibling of 12 of these and 28 normal controls. Selected brain structure volumes were measured using an automated whole brain segmentation technique. Candidate brain structure endophenotypes were determined and group differences were investigated between (1) controls and patients and (2) controls and siblings. ICC's were used to measure the quantitative volumetric association within each sibling pair. RESULTS: TLE patients demonstrated a significantly lower cerebral white matter, bilateral hippocampus, thalamus, and left entorhinal cortex volumes when compared with controls. A significant deficit in cerebral white matter (CWM) was common to patient and nonaffected siblings when compared with controls. Furthermore, a significant correlation was revealed between patients and siblings in CWM and bilateral thalamus. CONCLUSION: The findings suggest an overlap in the neurodevelopmental genes responsible for both brain structure and the expression of the disease. Further work is ongoing to confirm these findings.

Genome-wide mapping for clinically relevant predictors of lamotrigine- and phenytoin-induced hypersensitivity reactions.

AIMS: An association between carbamazepine-induced hypersensitivity and HLA-A*3101 has been reported in populations of both European and Asian descent. We aimed to investigate HLA-A*3101 and other common variants across the genome as markers for cutaneous adverse drug reactions (cADRs) attributed to lamotrigine and phenytoin. MATERIALS & METHODS: We recruited patients with lamotrigine-induced cADRs (n = 46) and patients with phenytoin-cADRs (n = 44) and the 1958 British birth cohort was used as a control (n = 1296). HLA-A*3101 was imputed from genome-wide association study data. We applied genome-wide association to study lamotrigine- and phenytoin-induced cADR, and total cADR cases combined. RESULTS: Neither HLA-A*3101 nor any other genetic marker significantly predicted lamotrigine- or phenytoin-induced cADRs. CONCLUSION: HLA-A*3101 does not appear to be a predictor for lamotrigine- and phenytoin-induced cADRs in Europeans. Our genome-wide association study results do not support the existence of a clinically relevant common variant for the development of lamotrigine- or phenytoin-induced cADRs. As a predictive marker, HLA-A*3101 appears to be specific for carbamazepine-induced cADRs.

Using atypical symptoms and red flags to identify non-demyelinating disease.

BACKGROUND: Red flags and atypical symptoms have been described as being useful in suggesting alternative diagnoses to multiple sclerosis (MS) and clinically isolated syndrome (CIS); however, their diagnostic utility has not been assessed. The aim of this study was to establish the predictive value of red flags and the typicality/atypicality of symptoms at presentation in relation to the final diagnosis of patients referred with suspected MS. METHODS: All patients referred with suspected MS over a 3-year period were assessed by the typicality of the clinical presentation and the occurrence of red flags in relation to the eventual diagnosis. The extent of agreement of trainee and consultant neurologists as to typicality of clinical presentations was determined. RESULTS: Of 244 patients referred, 119 (49%) had MS/CIS and 125 (51%) did not. 41 patients were referred because of an abnormal MRI. Of 203 with clinical symptoms, 96 patients had atypical symptoms of whom, 81 (84%) did not have MS and 15 (16%) had MS/CIS. Typical symptoms occurred in 107 patients; 10% did not have MS/CIS. Atypical symptoms had a sensitivity of 84%, specificity of 90% and positive likelihood ratio (PLR) of 8.4, whereas red flags had a sensitivity of 47%, specificity of 88% and PLR of 3.9 for the exclusion of MS/CIS. Mean percentage agreement between consultants and trainees was 73% with a range of 32-96%. CONCLUSIONS: Atypical features at presentation are more sensitive, specific and have a higher PLR than red flags to refute a diagnosis of MS/CIS.

Pharmacogenomics and epilepsy: the road ahead.

Epilepsy is one of the most common, serious neurological disorders, affecting an estimated 50 million people worldwide. The condition is typically treated using antiepileptic drugs of which there are 16 in widespread use. However, there are many different syndrome and seizure types within epilepsy and information guiding clinicians on the most effective drug and dose for individual patients is lacking. Further, all of the antiepileptic drugs have associated adverse reactions, some of which are severe and life-threatening. Here, we review the pharmacogenomic work to date in the context of these issues and comment on key aspects of study design that are required to speed up the identification of clinically relevant genetic factors.

Genomic microdeletions associated with epilepsy: not a contraindication to resective surgery.

PURPOSE: Several recent reports of genomic microdeletions in epilepsy will generate further research; discovery of more microdeletions and other important classes of variants may follow. Detection of such genetic abnormalities in patients being evaluated for surgical treatment might raise concern that a genetic defect, possibly widely expressed in the brain, will affect surgical outcome. METHODS: A reevaluation was undertaken of clinical presurgical data, histopathology of surgical specimen, and postsurgical outcome in patients with mesial temporal lobe epilepsy (MTLE) who have had surgical treatment for their drug-resistant seizures, and who have been found to have particular genomic microdeletions. KEY FINDINGS: Three thousand eight hundred twelve patients with epilepsy were genotyped and had a genome-wide screen to identify copy number variation. Ten patients with MTLE, who had resective epilepsy surgery, were found to have 16p13.11 microdeletions or other microdeletions >1 Mb. On histopathology, eight had classical hippocampal sclerosis (HS), one had nonspecific findings, and one had a hamartoma. Median postsurgical follow-up time was 48 months (range 10-156 months). All patients with HS were seizure-free after surgery, International League Against Epilepsy (ILAE) outcome class 1, at last follow-up; the patient with nonspecific pathology had recurrence of infrequent seizures after 7 years of seizure freedom. The patient with a hamartoma never became seizure-free. SIGNIFICANCE: Large microdeletions can be found in patients with "typical" MTLE. In this small series, patients with MTLE who meet criteria for resective surgery and harbor large microdeletions, at least those we have detected, can have a good postsurgical outcome. Our findings add to the spectrum of causal heterogeneity of MTLE + HS.

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.).

Pathogenic ATM mutations occur rarely in a subset of multiple myeloma patients.

Ataxia Telangiectasia (A-T) patients have biallelic inactivation of the ATM gene and exhibit a 200-fold-increased frequency of lymphoid tumours. ATM mutations have been found in a number of adult lymphoid malignancies but there is no data on the occurrence of ATM mutations in multiple myeloma tumours. The purpose of our work was to investigate the occurrence of ATM mutations in multiple myeloma and to this end we screened 45 sporadic cases for ATM mutations using denaturing high-performance liquid chromatography analysis and DNA sequencing. Pathogenic ATM mutations were identified in 2/45 of the myelomas compared with a published estimate of ATM mutant allele frequency in the UK population of 2/521 (P = 0.033). One was the missense mutation 7181C>T which was then modelled in an expression system and the S2394L protein shown to have no ATM kinase activity. The second myeloma had the pathogenic ATM splice site mutation IVS40-1G>C leading to loss of exon 41. We also report a 48-year-old ataxia telangiectasia patient who developed multiple myeloma. Taken together our study suggests that ATM mutation may play a role in the pathogenesis of a subset of multiple myelomas.

Broadening the phenotype of childhood-onset dopa-responsive dystonia.

BACKGROUND: Dopa-responsive dystonia (DRD) may cause early-onset dystonia, with extrapyramidal or pyramidal tract dysfunction. OBJECTIVE: To broaden the phenotype of DRD. SETTING: Tertiary referral university hospital. PATIENTS: We describe 4 female siblings with genetically confirmed DRD, 3 of whom presented with "unsteadiness" and 1 with scoliosis. All had dystonia and pyramidal tract signs, 3 had additional extrapyramidal features (resting tremor, bradykinesia, or rigidity), and at least 2 had definite signs of cerebellar dysfunction. MAIN OUTCOME MEASURES: The subjective response to treatment with 62.5 mg of a combination product of levodopa and carbidopa 3 times daily was assessed at both 6- and 12-month follow-up visits with the 7-item Patient's Global Impression of Change Scale as very much improved, much improved, a little improved, no different, a little worse, much worse, or very much worse. RESULTS: All patients showed a good response to levodopa therapy 41 to 49 years after symptom onset. CONCLUSION: Cerebellar signs may be observed in patients with DRD and may improve in response to levodopa.