Inappropriate antidiuretic hormone secretion in amyotrophic lateral sclerosis.

Only a few cases of syndrome of inappropriate antidiuretic hormone secretion (SIADH) in the setting of amyotrophic lateral sclerosis (ALS) have been described in the literature. We present the case of an 81-year-old male who developed severe hyponatremia following elective total hip replacement. His past medical history included prostate cancer, which was under surveillance, and ischemic heart disease. He reported recent weight loss, worsening shortness of breath, and lethargy. SIADH was diagnosed on the basis of hyponatremia, elevated urinary sodium, and decreased serum osmolality, presumed secondary to surgery. Investigations revealed no occult malignancy and no other cause for hyponatremia. He was discharged when sodium levels had normalized, however, he then had several further admissions for hyponatremia, general fatigue, and breathlessness. His condition continued to decline, and he developed dysphagia, weakness, and tongue fasciculations. Neurological examination showed globally decreased power, increased tone, and fasciculations. MRI of the brain was normal. He did not respond to neostigmine treatment, and a presumed diagnosis of motor neuron disease was made. The patient passed away shortly after this, and a post-mortem confirmed the diagnosis of ALS. Drug, post-operative, and cancer-related causes were precluded by the timing of onset of hyponatremia. We present this case and an analysis of previously published cases alongside a discussion on the potential causative mechanisms.

Muscle biopsy: what and why and when?

Skeletal muscle biopsy remains an important investigative tool in the diagnosis of a variety of muscle disorders. Traditionally, someone with a limb-girdle muscle weakness, myopathic changes on electrophysiology and raised serum creatine kinase (CK) would have a muscle biopsy. However, we are living through a genetics revolution, and so do all such patients still need a biopsy? When should we undertake a muscle biopsy in patients with a distal, scapuloperoneal or other patterns of muscle weakness? When should patients with myositis, rhabdomyolysis, myalgia, hyperCKaemia or a drug-related myopathy have a muscle biopsy? What does normal muscle histology look like and what changes occur in neurogenic and myopathic disorders? As with Kipling's six honest serving men, we hope that by addressing these issues we can all become more confident about when to request a muscle biopsy and develop clearer insights into muscle pathology.

Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy.

Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators.

The impact of MGMT methylation and IDH-1 mutation on long-term outcome for glioblastoma treated with chemoradiotherapy.

BACKGROUND: Increasingly, biomarkers have been identified that correlate with improved overall and progression-free survival (OS and PFS) in glioblastoma, including MGMT methylation status and mutations in the IDH1 gene. In this study, we investigated the clinical and biological factors associated with long-term survival in glioblastoma patients treated with chemoradiotherapy. METHOD: Demographic and clinical data were collected for all patients with glioblastoma diagnosed between May 2004 and September 2007, treated with chemoradiotherapy and with associated tissue samples available for biomarker analysis. MGMT methylation was determined by pyrosequencing. IDH1 mutation was identified by R132H immunohistochemistry. Univariate Cox regression analysis of factors associated with survival and Kaplan-Meier survival analysis was performed using the SPSS statistics package. RESULTS: One hundred patients were included in the study. Median follow-up was 12.2 months (range 1.6-102.4). Median OS was 12.1 months (95 % CI: 10.8-13.3) and median PFS was 8.2 months (95 % CI: 6.8-9.5). The 2-, 3- and 5-year survival was 18, 9 and 6 % respectively. Three patients are still alive at 7.4, 8.3 and 8.5 years after diagnosis. Cox proportional-hazards regression identified independent prognostic factors for OS, female (p = 0.019), MGMT methylation (p < 0.0001) and IDH1 mutation (p = 0.023), and for PFS, MGMT methylation (p = 0.001) and IDH1 mutation (p = 0.018). Kaplan-Meier survival analysis showed that MGMT(methylated)/IDH1(+ve) was associated with a significantly longer OS 66.8 months (95 % CI: 0.0-167.8) and PFS 16.9 months (95 % CI: 11.1-22.7) when compared with MGMT(methylated)/IDH1(-ve) OS 15.5 months (95 % CI: 11.6-19.4) and PFS 9.4 months (95 % CI: 8-10.8) (log-rank, P = 0.000) and MGMT(unmethylated)/IDH1(-ve) OS 11.1 months (95 % CI: 8.5-13.7) and PFS 6.3 months (95 % CI: 4.4-8.3) (log-rank, p = 0.000). CONCLUSIONS: While the importance of MGMT methylation is well established, we demonstrate that the combination of MGMT(methylated)/IDH1(+ve) is associated with considerably longer OS and PFS in this series of chemoradiotherapy-treated glioblastoma tumours. The long-term cognitive function and quality of life in these long-term survivors warrant investigation.

Accumulation of dipeptide repeat proteins predates that of TDP-43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene.

AIMS: Frontotemporal lobar degeneration (FTLD) and motor neurone disease are linked by the possession of a hexanucleotide repeat expansion in C9ORF72, and both show neuronal cytoplasmic inclusions within cerebellar and hippocampal neurones which are TDP-43 negative but immunoreactive for p62 and dipeptide repeat proteins (DPR), these being generated by a non-ATG RAN translation of the expanded region of the gene. METHODS: Twenty-two cases of FTLD from Newcastle were analysed for an expansion in C9ORF72 by repeat primed PCR and Southern blot. Detailed case note analysis was performed, and blinded retrospective clinical impressions were achieved by review of clinical histories. Sections from all major brain regions were immunostained for TDP-43, p62 and DPR. The extent of TDP-43 and DPR pathology in expansion bearers was compared with that in 13 other previously identified cases from the Manchester Brain Bank with established disease. RESULTS: Three Newcastle patients bearing an expansion in C9ORF72 were identified. These three patients died prematurely, two from bronchopneumonia within 10 months and 3 years of onset, and one from myocardial infarction 3 years after onset. In all three, DPR were plentiful throughout all cerebral cortical regions, hippocampus and cerebellum, but TDP-43 pathological changes were sparse. The severity of DPR pathological changes in these three patients was similar to that in the Manchester series, although the extent of TDP-43 pathology was significantly less. CONCLUSION: Widespread accumulation of DPR within nerve cells may occur much earlier than that of TDP-43 in patients with FTLD bearing expansion in C9ORF72.

Atypical benign melanotic thoracic intradural schwannoma.

We discuss the 8th known case of a patient who presented with an intradural intramedullary spinal melanocytic schwannoma. In this report we will discuss the hypothesis regarding the pathogenesis of the development of intradural schwannomas, the imaging modality of choice and treatment options.

Psychiatric presentation of sporadic Creutzfeldt-Jakob disease: a challenge to current diagnostic criteria.

Pathological diagnosis remains the gold standard for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD), but being able to differentiate between CJD and non-prion diseases clinically is important because many of the non-prion, rapidly progressive dementias are treatable. Diagnostic criteria need both high sensitivity and specificity while remaining applicable to clinical practice. Despite extensive updates to the clinical criteria for sCJD, there remains a heavy emphasis on neurological signs. We describe a psychiatric presentation of sCJD that did not fulfill the diagnostic criteria until very late in a prolonged disease course and required biopsy for diagnosis.

Characterization of the human primary visual cortex and cerebellum proteomes using shotgun mass spectrometry-data-independent analyses.

We present the first characterization of the human occipital lobe (primary visual cortex) and cerebellum proteomes. Proteins were identified using a combination of gel electrophoresis and data-independent nanoflow liquid chromatography mass spectrometry (nLC-MS(E) ). The resulting data sets comprised 391 and 330 unique proteins in occipital lobe and cerebellum, respectively, present in at least 75% of the analyzed samples with 297 proteins found in common. These proteins have been associated previously with conditions, such as neurological disorder, progressive motor neuropathy, Parkinson's disease and schizophrenia. The unique proteins identified in the occipital lobe included the interesting finding of growth hormone and several members of the Ca²âº-dependent calmodulin kinase and serine/threonine protein phosphatase families. The complete mapping of these and other brain proteomes may help in the elucidation of neurological processes and identify potential targets for therapeutic strategies.

Proteomic analysis identifies dysfunction in cellular transport, energy, and protein metabolism in different brain regions of atypical frontotemporal lobar degeneration.

Frontotemporal lobar degeneration (FTLD) is an umbrella term for a heterogeneous group of young-onset dementias of uncertain prevalence and incidence worldwide. Atypical cases of FTLD with fused in sarcoma inclusions (aFTLD-U) have been described recently, but their molecular characterization is still due. Using shotgun mass spectrometry, we identified a total of 107 differentially expressed proteins in the prefrontal cortex, cerebellum and occipital lobe from aFTLD-U patients compared to controls. These proteins are involved in a range of biological pathways such as cellular transport in the prefrontal cortex, energy metabolism in the cerebellum, and protein metabolism in the occipital lobe. In addition, they were validated by selective reaction monitoring (SRM). Comparison of the aFTLD-U proteomic findings with similar studies of Alzheimer's disease and schizophrenia led to identification of proteins that may be related to dementias and psychoses, respectively. Further studies of aFTLD-U and other FTLD subtypes are warranted, although this will require intensive biobanking efforts.

Longitudinally extensive transverse myelitis as the sole presentation of neuro-Behçet's disease responding to infliximab.

CONTEXT: Isolated involvement of the spinal cord is an uncommon presentation of neuro-Behçet's disease (NBD) and it is associated with a poor prognosis for functional recovery. METHOD: A case report of an 18-year-old Turkish man who presented with a progressive paraparesis and bladder dysfunction secondary to a longitudinally extensive transverse myelitis as the sole presentation of NBD. FINDINGS: Examination revealed a spastic paraparesis and a T7 sensory level. Magnetic resonance imaging revealed multiple enhancing lesions throughout the thoracic cord and cerebrospinal fluid showed intense neutrophilia. On further enquiry a family history of Behçet's disease was elicited. The patient subsequently reported a history of recurrent oral ulceration and intermittent occular inflammation. A diagnosis of NBD was made and intravenous high-dose steroids commenced with poor response. In view of the poor prognosis for functional recovery associated with spinal NBD the patient was treated with infliximab, an anti-tumour necrosis factor-alpha monoclonal antibody, leading to excellent recovery of function. CONCLUSION/CLINICAL RELEVANCE: Early treatment with infliximab may facilitate a favourable functional recovery and should be considered in cases of NBD with spinal cord involvement.

Pathological correlates of frontotemporal lobar degeneration in the elderly.

Frontotemporal lobar degeneration (FTLD) is generally recognised as a disorder with presenile onset (that is before 65 years of age) with only occasional cases presenting later than this. We set out to determine what proportion of cases of FTLD had late onset of disease and whether such cases of FTLD had distinctive clinical and neuropathological features as compared to cases with presenile onset. Within a combined Manchester and Newcastle autopsy series of 117 cases with pathologically confirmed FTLD (109/117 cases also met Lund Manchester clinical criteria for FTLD), we identified 30 cases (onset age range 65-86 years), comprising 25% of all FTLD cases ascertained in these two centres over a 25-year period. Neuropathologically, the 30 elderly cases presented features of several FTLD histological subgroups [FTLD-TDP (types 1, 2 and 3, 19 cases (63%)], FLTD-tau [MAPT, PiD and CBD, 10 cases (33%)] and FTLD-UPS (1 case), similar in range of phenotypes to that seen in the presenile group, though patients with MAPT, but not PGRN, mutation, or FUS pathology, were notably absent or fewer in the elderly group. Hippocampal sclerosis (HS) was present in 13/30 of the elderly FTLD cases (43%) compared with 14/79 (18%) (P = 0.012) in the presenile FTLD patients. Lobar atrophy present in most of the younger patients was prominent in only 25% of the elderly subjects. Prospective and retrospective psychiatric and medical case note analysis showed that the majority of the elderly FTLD patients, like their younger counterparts, had behavioural features consistent with frontotemporal dementia. FTLD is common amongst elderly persons and all or most of the major clinical and histological subtypes present in younger individuals can be seen in the older group.

The most common type of FTLD-FUS (aFTLD-U) is associated with a distinct clinical form of frontotemporal dementia but is not related to mutations in the FUS gene.

Frontotemporal lobar degeneration (FTLD) is clinically, pathologically and genetically heterogeneous. Recent descriptions of a pathological sub-type that is ubiquitin positive, TDP-43 negative and immunostains positive for the Fused in Sarcoma protein (FUS) raises the question whether it is associated with a distinct clinical phenotype identifiable on clinical grounds, and whether mutations in the Fused in Sarcoma gene (FUS) might also be associated with FTLD. Examination of a pathological series of 118 cases of FTLD from two centres, showing tau-negative, ubiquitin-positive pathology, revealed FUS pathology in five patients, four classified as atypical FTLD with ubiquitin inclusions (aFTLD-U), and one as neuronal intermediate filament inclusion disease (NIFID). The aFTLD-U cases had youthful onset (22-46 years), an absence of strong family history, a behavioural syndrome consistent with frontotemporal dementia (FTD) and severe caudate atrophy. Their cognitive/behavioural profile was distinct, characterised by prominent obsessionality, repetitive behaviours and rituals, social withdrawal and lack of engagement, hyperorality with pica, and marked stimulus-bound behaviour including utilisation behaviour. They conformed to the rare behavioural sub-type of FTD identified previously by us as the "stereotypic" form, and linked to striatal pathology. Cognitive evaluation revealed executive deficits in keeping with subcortical-frontal dysfunction, but no cortical deficits in language, perceptuospatial skills or praxis. The patient with NIFID was older and exhibited aphasia and dyspraxia. No patient had clinical evidence of motor neurone disease during life, or a mutation in the FUS gene. In the complementary clinical study of 312 patients with clinical syndromes of FTLD, genetic analysis revealed a 6 bp deletion in FUS in 3 patients, of questionable significance. One presented a prototypical picture of FTD, another expressive language disorder, and the third semantic dementia. None showed the early onset age or distinctive 'stereotypic' picture of patients with aFTLD-U. We conclude that aFTLD-U is associated with a distinct clinical form of frontotemporal dementia, potentially allowing identification of such patients in life with a high degree of precision. Whether mutations in the FUS gene cause some cases of FTLD remains unresolved.

In-frame seven amino-acid duplication in AIP arose over the last 3000 years, disrupts protein interaction and stability and is associated with gigantism.

OBJECTIVE: Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are associated with pituitary adenoma, acromegaly and gigantism. Identical alleles in unrelated pedigrees could be inherited from a common ancestor or result from recurrent mutation events. DESIGN AND METHODS: Observational, inferential and experimental study, including: AIP mutation testing; reconstruction of 14 AIP-region (8.3 Mbp) haplotypes; coalescent-based approximate Bayesian estimation of the time to most recent common ancestor (tMRCA) of the derived allele; forward population simulations to estimate current number of allele carriers; proposal of mutation mechanism; protein structure predictions; co-immunoprecipitation and cycloheximide chase experiments. RESULTS: Nine European-origin, unrelated c.805_825dup-positive pedigrees (four familial, five sporadic from the UK, USA and France) included 16 affected (nine gigantism/four acromegaly/two non-functioning pituitary adenoma patients and one prospectively diagnosed acromegaly patient) and nine unaffected carriers. All pedigrees shared a 2.79 Mbp haploblock around AIP with additional haploblocks privately shared between subsets of the pedigrees, indicating the existence of an evolutionarily recent common ancestor, the 'English founder', with an estimated median tMRCA of 47 generations (corresponding to 1175 years) with a confidence interval (9-113 generations, equivalent to 225-2825 years). The mutation occurred in a small tandem repeat region predisposed to slipped strand mispairing. The resulting seven amino-acid duplication disrupts interaction with HSP90 and leads to a marked reduction in protein stability. CONCLUSIONS: The c.805_825dup allele, originating from a common ancestor, associates with a severe clinical phenotype and a high frequency of gigantism. The mutation is likely to be the result of slipped strand mispairing and affects protein-protein interactions and AIP protein stability.

Lack of relationship between cellular density and either capillary density or metabolic rate in different regions of the brain.

Whereas a pronounced correlation exists between local cerebral glucose utilization (LCGU) and capillary density in different regions of the brain, it is not known whether these parameters also correlate with the overall density of nuclei (cellularity). Therefore, cellularity was determined by diamidino-phenylindol (DAPI) fluorescent staining of nuclei in acetone-fixed frozen sections of the rat brain. A comparison of the density of nuclei in different brain regions showed much less variation than that observed in LCGU and capillary density. No correlation was found between nuclear density and either LCGU or capillary densities. In conclusion the cellular density is not a determinant of variation in LCGU and capillary density.

Anti-N-Methyl-D-Aspartate Receptor Encephalitis In A Young Child With Histological Evidence On Brain Biopsy Of Coexistent Herpes Simplex Virus Type 1 Infection.

We report a 3-year-old boy with anti-N-methyl-D-aspartate receptor encephalitis with a typical syndrome of movement disorder and encephalopathy and evidence of herpes simplex virus (HSV) type 1 infection on brain biopsy. HSV type 1 infection and anti-N-methyl-D-aspartate receptor encephalitis are temporally linked in some cases: this case suggests that prodromal HSV type-1 infection may be clinically subtle and easily missed.

Low grade glioma in an adult patient with Sotos syndrome.

Sotos syndrome is a rare overgrowth syndrome with an increased risk of tumorigenesis. To our knowledge we report the first case of astrocytoma in an adult patient with Sotos syndrome and describe the clinical course.