R. Phadke

Neurofibrillary tangle pathology and Braak staging in chronic epilepsy in relation to traumatic brain injury and hippocampal sclerosis: a post-mortem study

The long-term pathological effects of chronic epilepsy on normal brain ageing are unknown. Previous clinical and epidemiological studies show progressive cognitive decline in subsets of patients and an increased prevalence of Alzheimers disease in epilepsy. In a post-mortem series of 138 patients with long-term, mainly drug-resistant epilepsy, we carried out Braak staging for Alzheimers disease neurofibrillary pathology using tau protein immunohistochemistry. The stages were compared with clinicopathological factors, including seizure history and presence of old traumatic brain injury. Overall, 31% of cases were Braak Stage 0, 36% Stage I/II, 31% Stage III/IV and 2% Stage V/VI. The mean age at death was 56.5 years and correlated with Braak stage (P < 0.001). Analysis of Braak stages within age groups showed a significant increase in mid-Braak stages (III/IV), in middle age (40–65 years) compared with data from an ageing non-epilepsy series (P < 0.01). There was no clear relationship between seizure type (generalized or complex partial), seizure frequency, age of onset and duration of epilepsy with Braak stage although higher Braak stages were noted with focal more than with generalized epilepsy syndromes (P < 0.01). In 30% of patients, there was pathological evidence of traumatic brain injury that was significantly associated with higher Braak stages (P < 0.001). Cerebrovascular disease present in 40.3% and cortical malformations in 11.3% were not significantly associated with Braak stage. Astrocytic-tau protein correlated with the presence of both traumatic brain injury (P < 0.01) and high Braak stage (P < 0.001). Hippocampal sclerosis, identified in 40% (bilateral in 48%), was not associated with higher Braak stages, but asymmetrical patterns of tau protein accumulation within the sclerotic hippocampus were noted. In over half of patients with cognitive decline, the Braak stage was low indicating causes other than Alzheimers disease pathology. In summary, there is evidence of accelerated brain ageing in severe chronic epilepsy although progression to high Braak stages was infrequent. Traumatic brain injury, but not seizures, was associated with tau protein accumulation in this series. It is likely that Alzheimers disease pathology is not the sole explanation for cognitive decline associated with epilepsy.

Loss-of-function mutations in SCN4A cause severe foetal hypokinesia or 'classical' congenital myopathy

See Cannon (doi: 10.1093/brain/awv400 ) for a scientific commentary on this article. Dominant gain-of-function mutations in SCN4A , which encodes the α-subunit of the voltage-gated sodium channel, are a common cause of myotonia and periodic paralysis. Zaharieva et al. now report recessive loss-of-function SCN4A mutations in 11 patents with congenital myopathy. The mutations cause fully non-functional channels or result in reduced channel activity.

Hereditary leukoencephalopathy with axonal spheroids: a spectrum of phenotypes from CNS vasculitis to parkinsonism in an adult onset leukodystrophy series

Background Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS) is a hereditary, adult onset leukodystrophy which is characterised by the presence of axonal loss, axonal spheroids and variably present pigmented macrophages on pathological examination. It most frequently presents in adulthood with dementia and personality change. HDLS has recently been found to be caused by mutations in the colony stimulating factor-1 receptor (CSF1R) gene. Methods In this study, we sequenced the CSF1R gene in a cohort of 48 patients from the UK, Greece and Ireland with adult onset leukodystrophy of unknown cause. Results Five pathogenic mutations were found, including three novel mutations. The presentations ranged from suspected central nervous system (CNS) vasculitis to extrapyramidal to cognitive phenotypes. The case histories and imaging are presented here, in addition to neuropathological findings from two cases with novel mutations. Conclusion We estimate that CSF1R mutations account for 10% of idiopathic adult onset leukodystrophies and that genetic testing for CSF1R mutations is essential in adult patients presenting with undefined CNS vasculitis or a leukodystrophy with prominent neuropsychiatric signs or dementia.

Strawberries on the Brain—Intracranial Capillary Hemangioma: Two Case Reports and Systematic Literature Review in Children and Adults

BACKGROUND Capillary hemangioma in the cranial cavity is rare. This report describes 2 additional cases presenting shortly after pregnancy and provides a systematic review summarizing clinical experience to date. METHODS Case reports were compiled retrospectively. Patient 1 was a 28-year-old woman who presented with a simple partial seizure associated with left-sided visual distortions that progressed to a secondary generalized tonic-clonic seizure. Imaging revealed a contrast-enhancing lesion in the right temporal region adjacent to the transverse sinus, with vasogenic edema and scalloping of the inner table. The angiographic appearance suggested the correct diagnosis. Patient 2 was a 41-year-old woman who presented with progressive visual disturbance 6 months after giving birth to her second child. Subtle symptoms of headache and visual disturbance had commenced during pregnancy. Noncontrasted imaging displayed a homogenous tumor with surrounding vasogenic edema in the occipital region. PubMed and Science Citation Index were reviewed systematically for prior publications. RESULTS Complete surgical excision was performed in both patients. Neuropathological examination confirmed benign capillary hemangioma consisting of a meshwork of capillary-sized and larger feeder vessels in both instances. Systematic review was based on 20 publications and a total of 24 patients; their clinical, radiological, and surgical features as well as management are summarized. CONCLUSIONS At follow-up, symptoms had resolved and magnetic resonance imaging confirmed complete removal in both patients. Intracranial capillary hemangioma is rare, and treatment is empirical. Review of limited published reports suggests that surgery is the most commonly used treatment and that complete excision seems most likely to prevent further recurrence.

The p.Ser107Leu in BICD2 is a mutation ‘hot spot’ causing distal spinal muscular atrophy

1 The John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK 2 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK 3 Department of Paediatric Neurology, Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust, Newcastle upon Tyne, UK

Congenital Titinopathy: Comprehensive characterization and pathogenic insights: Congenital Titinopathy

Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder.

Plurihormonal pituitary adenoma with concomitant adrenocorticotropic hormone (ACTH) and growth hormone (GH) secretion: a report of two cases and review of the literature

Plurihormonal pituitary adenomas are tumours that show immunoreactivity for more than one hormone that cannot be explained by normal adenohypophysial cytodifferentiation. The most common combinations in these adenomas include growth hormone (GH), prolactin (PRL) and one or more glycoprotein hormone sub-units (β-TSH, β-FSH, β-LH and αSU). The authors report two cases of a plurihormonal pituitary adenoma expressing the rare combination of ACTH and GH. They both underwent successful transphenoidal hypophysectomy (TSH). Long-term post-operative follow-up revealed no evidence of tumour recurrence. Due to the multiple secretions and plurihormonal characteristics clinical diagnosis of composite pituitary adenomas can be difficult. The authors discuss the diagnosis and management of composite pituitary adenomas and review the literature regarding this rare phenomenon.

P17 Whole exome sequencing in patients with congenital myopathies

Congenital myopathies (CM) are a group of disorders presenting at birth or early infancy, characterised by muscle weakness and specific changes in the muscle biopsy. During the recent decade a number of genes have been discovered, however, additional novel genes are yet to be identified as genetic diagnosis cannot be currently established in many CM patients. With the aim to identify the genetic defect in 33 CM patients, in whom mutations in suspected genes have been previously excluded, we carried out whole exome sequencing (WES). From the 33 patients, 19 have been resolved and 14 patients are still being investigated as the initial WES data analysis failed to identify possible candidate genes. Among the resolved cases, two patients with muscle biopsy suggestive of core myopathy and one with centronuclear myopathy, carried heterozygous truncating TTN mutations supporting the emerging data that TTN mutations should be investigated as causative in patients with unresolved centronuclear and core myopathy. We also identified a homozygous missense mutation in STAC3 gene in a patient with King-Denborough syndrome and core-like changes on muscle biopsy, indicating a causative role of STAC3 mutations in King–Denborough syndrome. Recently, a homozygous missense mutation in STAC3 gene was identified in patients with Native American myopathy. A patient with a severe phenotype and muscle biopsy changes suggestive of nemaline myopathy, carried a homozygous missense mutation in KLHL40. Mutations in KLHL40 have been very recently identified as a frequent cause of severe autosomal-recessive nemaline myopathy. Ten of the resolved patients carried mutations in potentially causative genes which are currently under investigation.

G.P.261

Congenital myopathies (CM) are a group of disorders presenting at birth or early infancy, characterised by muscle weakness and specific changes in the muscle biopsy. During the recent decade a number of genes have been discovered, however, additional novel genes are yet to be identified as genetic diagnosis cannot be currently established in many CM patients. With the aim to identify the genetic defect in 33 CM patients, in whom mutations in suspected genes have been previously excluded, we carried out whole exome sequencing (WES). From the 33 patients, 19 have been resolved and 14 patients are still being investigated as the initial WES data analysis failed to identify possible candidate genes. Among the resolved cases, two patients with muscle biopsy suggestive of core myopathy and one with centronuclear myopathy, carried heterozygous truncating TTN mutations supporting the emerging data that TTN mutations should be investigated as causative in patients with unresolved centronuclear and core myopathy. We also identified a homozygous missense mutation in STAC3 gene in a patient with King-Denborough syndrome and core-like changes on muscle biopsy, indicating a causative role of STAC3 mutations in King–Denborough syndrome. Recently, a homozygous missense mutation in STAC3 gene was identified in patients with Native American myopathy. A patient with a severe phenotype and muscle biopsy changes suggestive of nemaline myopathy, carried a homozygous missense mutation in KLHL40 . Mutations in KLHL40 have been very recently identified as a frequent cause of severe autosomal-recessive nemaline myopathy. Ten of the resolved patients carried mutations in potentially causative genes which are currently under investigation.

An extended chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids phenotype

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a recently described central nervous system inflammatory condition. In this case report we describe a patient initially with features consistent with this syndrome, who represented with seizures (not previously reported in this syndrome) and corresponding prominent cortical involvement on imaging (also not previously noted). Owing to diagnostic uncertainty, cerebral biopsy was performed revealing histology consistent with CLIPPERS, excluding other differentials. Following a further brainstem relapse, this patient was treated with high-dose steroids, subsequently switched to a tapering oral regime and now, azathioprine, a steroid-sparing agent. She remains well on this.