Incidental Findings Identified on Head MRI for Investigation of Cognitive Impairment: A Retrospective Review.

INTRODUCTION: Incidental findings are common in presumed healthy volunteers but are infrequently studied in patients in a clinical context. OBJECTIVE: To determine the prevalence, nature, and management implications of incidental findings on head MRI in patients presenting with cognitive symptoms, and to quantify and describe unexpected MRI abnormalities that are of uncertain relevance to the patient's cognitive symptoms. METHODS: A single-centre retrospective review of patients attending a regional early-onset cognitive disorders clinic between March 2012 and October 2018. Medical records of consecutive patients who underwent head MRI were reviewed. Unexpected MRI findings were classified according to their severity and likelihood of being incidental. Markers of small vessel disease and cerebral atrophy were excluded. RESULTS: Records of 694 patients were reviewed (median age 60 years, 49.9% female), of whom 514 (74.1%) underwent head MRI. 54% of the patients received a diagnosis of a neurodegenerative disorder. Overall 111 incidental findings were identified in 100 patients of whom 18 patients (3.5%, 95% CI 2.2-5.6%) had 18 incidental findings classified as requiring additional medical evaluation. 82 patients (16%, 95% CI 13.0-19.5%) had 93 incidental findings without clearly defined diagnostic consequences. 17 patients (3.3%) underwent further investigations, 14 patients (2.7%) were referred to another specialist clinic and 3 patients (0.6%) were treated surgically. Two patients had MRI findings of uncertain relevance to their cognitive symptoms, necessitating prolonged clinic follow-up. CONCLUSION: Incidental findings are common in patients with cognitive impairment from this large clinic-based series; however, few required additional medical evaluation. These data could help inform discussions between clinicians and people with cognitive symptoms regarding the likelihood and potential implications of incidental imaging findings.

CT Perfusion in Acute Stroke Predicts Final Infarct Volume- Inter-observer Study.

BACKGROUND: Computed tomography perfusion (CTP) is increasingly being used in the setting of acute ischemic stroke (AIS). The aim of the current study was to compare the prognostic utility of, and inter-observer variation between, baseline appearances on non-contrast CT (using Alberta Stroke Program Early CT score(ASPECTS)) and on CTP for predicting final infarct volume. We also assessed impact of training on interpretation of these images. METHODS: Retrospectively, plain head computed tomography (CT) and CTP images at presentation and CT or diffusion imaging on follow up of patients with AIS were analyzed. The lesion volume on different CTP parameters was then correlated with the final infarct volume. This analysis was done by a Neuroradiologist, a stroke Neurologist and a medical student. Kappa statistics and Intra-class correlation coefficients were used for agreement between readers. Pearson correlation coefficients were used. RESULTS: Thirty eight patients with AIS met all inclusion criteria. There was very good agreement among all readers for the CTP parameters. There was only fair agreement for ASPECT score. Correlation coefficient (r-square) between CTP parameters and final infarct volume showed that cerebral blood volume was the best parameter to predict the final infarct volume followed by cerebral blood flow and time to peak. The best reader to predict the final infarct volume on the initial CT perfusion study was the neuroradiologist followed by medical student and stroke neurologist. CONCLUSIONS: Cerebral blood volume defect correlated the best with the final infarct volume. There was a very good inter-observer agreement for all the CTP maps in predicting the final infarct volume despite the wide variation in the experience of the readers.

Glycogen storage disease type IV without detectable polyglucosan bodies: importance of broad gene panels.

Glycogen storage disease type IV (GSD IV) is caused by mutations in the glycogen branching enzyme 1 (GBE1) gene and is characterized by accumulation of polyglucosan bodies in liver, muscle and other tissues. We report three cases with neuromuscular forms of GSD IV, none of whom had polyglucosan bodies on muscle biopsy. The first case had no neonatal problems and presented with delayed walking. The other cases presented at birth: one with arthrogryposis, hypotonia, and respiratory distress, the other with talipes and feeding problems. All developed a similar pattern of axial weakness, proximal upper limb weakness and scapular winging, and much milder proximal lower limb weakness. Our cases expand the phenotypic spectrum of neuromuscular GSD IV, highlight that congenital myopathy and limb girdle weakness can be caused by mutations in GBE1, and emphasize that GSD IV should be considered even in the absence of characteristic polyglucosan bodies on muscle biopsy.

Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus.

OBJECTIVES: Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART: NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol. METHODS: We conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer's disease, Huntington's disease, Parkinson's disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART. RESULTS: From the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART. DISCUSSION: For future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs.

Non-white cases of sporadic Creutzfeldt-Jakob disease: A 28 year review of United Kingdom National Surveillance Data.

AIMS: Descriptions of sporadic Creutzfeldt-Jakob disease (sCJD) in non-White populations are limited. Improved understanding may aid diagnoses and case ascertainment within surveillance programmes. We aimed to: 1) Ascertain the proportion of sCJD cases with non-White ethnicity in the United Kingdom (UK); 2) Compare clinical and investigation findings between non-White and White cases. METHODS: We analysed records of probable and definite sCJD cases assessed by the UK National CJD Research and Surveillance Unit over 28 years (1990-2017). Cases were stratified into White and non-White groups. Demographics, clinical features, investigation findings, and post-mortem numbers were compared. RESULTS: 1697 sCJD cases were included: 1642 (97%) White, 55 (3%) non-White (Asian/Asian British, Black/African/Caribbean). The proportion of non-Whites among sCJD cases is 7% lower than the proportion the non-White population make up in the UK (p < 0.001). This was not statistically significant when age-matched by ≥60 years (p = 0.071). Age at symptom onset was 4 years lower in the non-White population (p = 0.007). Clinical and investigation characteristics were otherwise similar between ethnic groupings. The proportion of non-Whites undergoing autopsy and classification as definite was 30% and 24% lower (p < 0.001) respectively in comparison to those for White cases. CONCLUSIONS: Approximately 3% of sCJD cases in the UK are non-White, despite non-Whites representing approximately 10% of the UK population. This difference was not statistically significant when age-matched at ≥60 years. Non-White cases tend to be younger and likelihood of autopsy is lower; relevant considerations for surveillance programmes. Reasons for these differences in non-White populations are unclear and merit further evaluation.