Late Presentation of Chronic Traumatic Encephalopathy in a Former Association Football Player.

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by widespread accumulation of hyperphosphorylated tau that typically occurs in people who have suffered repetitive head impacts. To date, very few cases have been reported in association football players. Objectives: To describe the clinicopathological features of a case of CTE in an 84-year-old former football player who was clinically diagnosed as having dementia with Lewy bodies (DLB). Methods: A retrospective review of the patient's primary care and hospital medical records was performed along with a comprehensive neuropathological examination. Results: This patient presented at age 84 with symmetrical parkinsonism and cognitive impairment that was exacerbated by prochlorperazine. His condition was rapidly progressive with recurrent falls within 1 year. Other features included headaches, depression, anxiety, suicidal ideation, disturbed sleep and aggression. He received a clinical diagnosis of DLB and died approximately 2 years after the onset of symptoms. A post-mortem examination revealed stage 4 CTE. Conclusions: While the contemporaneous onset of parkinsonism and cognitive symptoms in the context of possible neuroleptic sensitivity is suggestive of DLB, the additional symptoms of aggressive behavior, depression and suicidality in a former football player are consistent with the neuropathological diagnosis of CTE. This case, which is notable for the late presentation, demonstrates that CTE may masquerade as other dementias and highlights the importance of seeking a history of repetitive head impacts.

Neuroimaging Correlates of Cognitive Deficits in Wilson's Disease.

BACKGROUND: Cognitive impairment is common in neurological presentations of Wilson's disease (WD). Various domains can be affected, and subclinical deficits have been reported in patients with hepatic presentations. Associations with imaging abnormalities have not been systematically tested. OBJECTIVE: The aim was to determine the neuroanatomical basis for cognitive deficits in WD. METHODS: We performed a 16-item neuropsychological test battery and magnetic resonance brain imaging in 40 patients with WD. The scores for each test were compared between patients with neurological and hepatic presentations and with normative data. Associations with Unified Wilson's Disease Rating Scale neurological examination subscores were examined. Quantitative, whole-brain, multimodal imaging analyses were used to identify associations with neuroimaging abnormalities in chronically treated stable patients. RESULTS: Abstract reasoning, executive function, processing speed, calculation, and visuospatial function scores were lower in patients with neurological presentations than in those with hepatic presentations and correlated with neurological examination subscores. Deficits in abstract reasoning and phonemic fluency were associated with lower putamen volumes even after controlling for neurological severity. About half of patients with hepatic presentations had poor performance in memory for faces, cognitive flexibility, or associative learning relative to normative data. These deficits were associated with widespread cortical atrophy and/or white matter diffusion abnormalities. CONCLUSIONS: Subtle cognitive deficits in patients with seemingly hepatic presentations represent a distinct neurological phenotype associated with diffuse cortical and white matter pathology. This may precede the classical neurological phenotype characterized by movement disorders and executive dysfunction and be associated with basal ganglia damage. A binary phenotypic classification for WD may no longer be appropriate. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Investigation and management of Wilson's disease: a practical guide from the British Association for the Study of the Liver.

Wilson's disease is an autosomal-recessive disorder of copper metabolism with hepatic, neurological, psychiatric, ophthalmological, haematological, renal, and rheumatological manifestations. Making a diagnosis can be challenging given that no single test can confirm or exclude the disease, and diagnostic delays are common. Treatment protocols vary and adverse effects, including paradoxical neurological worsening, can occur. In this Review, we provide a practical guide to the diagnosis of Wilson's disease. We include recommendations on indications for testing, how to interpret results, and when additional investigations are required. We also cover treatment initiation, ideally under the guidance of a specialist centre for Wilson's disease, and the principles behind long-term management. This guidance was developed by a multidisciplinary group of Wilson's disease experts formed through the British Association for the Study of the Liver. The guidance has been endorsed by the British Society of Gastroenterology and approved by the Association of British Neurologists.

Neuroimaging correlates of brain injury in Wilson's disease: a multimodal, whole-brain MRI study.

Wilson's disease is an autosomal-recessive disorder of copper metabolism with neurological and hepatic presentations. Chelation therapy is used to 'de-copper' patients but neurological outcomes remain unpredictable. A range of neuroimaging abnormalities have been described and may provide insights into disease mechanisms, in addition to prognostic and monitoring biomarkers. Previous quantitative MRI analyses have focused on specific sequences or regions of interest, often stratifying chronically treated patients according to persisting symptoms as opposed to initial presentation. In this cross-sectional study, we performed a combination of unbiased, whole-brain analyses on T1-weighted, fluid-attenuated inversion recovery, diffusion-weighted and susceptibility-weighted imaging data from 40 prospectively recruited patients with Wilson's disease (age range 16-68). We compared patients with neurological (n = 23) and hepatic (n = 17) presentations to determine the neuroradiological sequelae of the initial brain injury. We also subcategorized patients according to recent neurological status, classifying those with neurological presentations or deterioration in the preceding 6 months as having 'active' disease. This allowed us to compare patients with active (n = 5) and stable (n = 35) disease and identify imaging correlates for persistent neurological deficits and copper indices in chronically treated, stable patients. Using a combination of voxel-based morphometry and region-of-interest volumetric analyses, we demonstrate that grey matter volumes are lower in the basal ganglia, thalamus, brainstem, cerebellum, anterior insula and orbitofrontal cortex when comparing patients with neurological and hepatic presentations. In chronically treated, stable patients, the severity of neurological deficits correlated with grey matter volumes in similar, predominantly subcortical regions. In contrast, the severity of neurological deficits did not correlate with the volume of white matter hyperintensities, calculated using an automated lesion segmentation algorithm. Using tract-based spatial statistics, increasing neurological severity in chronically treated patients was associated with decreasing axial diffusivity in white matter tracts whereas increasing serum non-caeruloplasmin-bound ('free') copper and active disease were associated with distinct patterns of increasing mean, axial and radial diffusivity. Whole-brain quantitative susceptibility mapping identified increased iron deposition in the putamen, cingulate and medial frontal cortices of patients with neurological presentations relative to those with hepatic presentations and neurological severity was associated with iron deposition in widespread cortical regions in chronically treated patients. Our data indicate that composite measures of subcortical atrophy provide useful prognostic biomarkers, whereas abnormal mean, axial and radial diffusivity are promising monitoring biomarkers. Finally, deposition of brain iron in response to copper accumulation may directly contribute to neurodegeneration in Wilson's disease.

Wilson's disease: update on pathogenesis, biomarkers and treatments.

Wilson's disease is an autosomal-recessive disorder of copper metabolism caused by mutations in ATP7B and associated with neurological, psychiatric, ophthalmological and hepatic manifestations. Decoppering treatments are used to prevent disease progression and reduce symptoms, but neurological outcomes remain mixed. In this article, we review the current understanding of pathogenesis, biomarkers and treatments for Wilson's disease from the neurological perspective, with a focus on recent advances. The genetic and molecular mechanisms associated with ATP7B dysfunction have been well characterised, but despite extensive efforts to identify genotype-phenotype correlations, the reason why only some patients develop neurological or psychiatric features remains unclear. We discuss pathological processes through which copper accumulation leads to neurodegeneration, such as mitochondrial dysfunction, the role of brain iron metabolism and the broader concept of selective neuronal vulnerability in Wilson's disease. Delayed diagnoses continue to be a major problem for patients with neurological presentations. We highlight limitations in our current approach to making a diagnosis and novel diagnostic biomarkers, including the potential for newborn screening programmes. We describe recent progress in developing imaging and wet (fluid) biomarkers for neurological involvement, including findings from quantitative MRI and other neuroimaging studies, and the development of a semiquantitative scoring system for assessing radiological severity. Finally, we cover the use of established and novel chelating agents, paradoxical neurological worsening, and progress developing targeted molecular and gene therapy for Wilson's disease, before discussing future directions for translational research.

Plasma Neurofilament Light as a Biomarker of Neurological Involvement in Wilson's Disease.

BACKGROUND: Outcomes are unpredictable for neurological presentations of Wilson's disease (WD). Dosing regimens for chelation therapy vary and monitoring depends on copper indices, which do not reflect end-organ damage. OBJECTIVE: To identify a biomarker for neurological involvement in WD. METHODS: Neuronal and glial-specific proteins were measured in plasma samples from 40 patients and 38 age-matched controls. Patients were divided into neurological or hepatic presentations and those with recent neurological presentations or deterioration associated with non-adherence were subcategorized as having active neurological disease. Unified WD Rating Scale scores and copper indices were recorded. RESULTS: Unlike copper indices, neurofilament light (NfL) concentrations were higher in neurological than hepatic presentations. They were also higher in those with active neurological disease when controlling for severity and correlated with neurological examination subscores in stable patients. CONCLUSION: NfL is a biomarker of neurological involvement with potential use in guiding chelation therapy and clinical trials for novel treatments. © 2020 University College London. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Liver transplantation for late-onset presentations of acute liver failure in Wilson's disease: The UK experience over 2 decades.

BACKGROUND & AIMS: Acute liver failure as the initial presentation of Wilson's disease is usually associated with onset in childhood, adolescence or early adulthood. Outcomes after transplantation for late-onset presentations, at or after 40 years, are seldom reported in the literature. METHODS: We report a case, review the literature and provide unpublished data from the UK Transplant Registry on late-onset acute liver failure in Wilson's disease. RESULTS: We describe the case of a 62-year-old man presenting with acute liver failure who was successfully treated with urgent liver transplantation. We identified 7 cases presenting at age 40 years or over in the literature, for which individual outcomes were reported; 3 were treated with transplantation and 2 survived. We identified a further 8 cases listed for transplantation in the UK between 1995 and 2014; 7 were treated with transplantation and 6 survived. One patient was de-listed for unknown reasons. CONCLUSIONS: Wilson's disease should be considered in older adults presenting with acute liver failure. We suggest that urgent liver transplantation has good outcomes for late-onset presentations and recommend that urgent transplantation should always be considered in Wilson's disease presenting as acute liver failure. LAY SUMMARY: Wilson's disease is a rare inherited disease that causes copper accumulation in the liver and brain and usually manifests during childhood, adolescence or early adulthood. We report the case of a 62-year-old who developed acute liver failure and was successfully treated with urgent liver transplantation. We discuss the outcomes of other late-onset cases of acute liver failure due to Wilson's disease in the literature and provide additional data from the UK Transplant Registry.

Encephalomyelitis with Retinopathy in Common Variable Immunodeficiency (CVID).

Common variable immunodeficiency is the most common primary immunodeficiency and rarely causes neurological manifestations since the introduction of IVIg, but here, the authors present a case of a 31-year-old Afro-Caribbean man who after short non-adherence to his immunoglobulins, develops encephalomyelitis with retinopathy. To the authors' knowledge, this is the first case presented with retinal photographs, OCT, CT, MRI and brain biopsies.

Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches.

Hereditary spastic paraplegia (HSP) describes a heterogeneous group of genetic neurodegenerative diseases characterised by progressive spasticity of the lower limbs. The pathogenic mechanism, associated clinical features, and imaging abnormalities vary substantially according to the affected gene and differentiating HSP from other genetic diseases associated with spasticity can be challenging. Next generation sequencing-based gene panels are now widely available but have limitations and a molecular diagnosis is not made in most suspected cases. Symptomatic management continues to evolve but with a greater understanding of the pathophysiological basis of individual HSP subtypes there are emerging opportunities to provide targeted molecular therapies and personalised medicine.

Clinical presentations of Wilson disease.

The main presenting features of Wilson disease, many of which mimic common hepatic and neurologic disorders, are discussed. There is a need for specialists in these and related fields to be aware of hints from within and, more importantly, outside their area of expertise that should alert them to consider the diagnosis. Delayed diagnosis and treatment are potentially damaging for the patient. The importance of recognising and promptly investigating Wilson disease at the initial presentation should be understood by all those who assess patients with hepatic or neurologic disorders and/or train others in their specialty.

Training in neurology: lessons learnt.

There is no consensus on how to structure and deliver neurology training. The General Medical Council's annual National Training Survey indicates that the quality of UK neurology training is very variable, but does not explain this variation. We used the survey data to identify the four highest and lowest performing sites for neurology training across the UK. We conducted semistructured interviews with groups of local trainees and, separately, local trainers in an exploratory qualitative study, and identified common themes across a range of aspects of neurology training. Here we present our findings, share case studies from top-performing sites and make recommendations on how best to train a neurologist.

The BRAIN test: a keyboard-tapping test to assess disability and clinical features of multiple sclerosis.

BACKGROUND: The BRadykinesia Akinesia INcordination (BRAIN) test is an online keyboard-tapping test previously validated as a sensitive tool for detecting signs of Parkinson's disease. OBJECTIVES: To determine whether the BRAIN test can measure disability in MS and identify the presence of pyramidal or cerebellar dysfunction. METHODS: Kinesia scores (KS, number of key taps in 30 s), akinesia times (AT, mean dwell time on each key) and incoordination scores (IS, variance of travelling time between keys) were calculated in 39 MS patients. These were correlated against the Expanded Disability Status Scale (EDSS) scores, pyramidal and cerebellar functional system scores and 9-hole peg test scores. RESULTS: EDSS correlated with KS (r = - 0.594, p < 0.001), AT (r = 0.464, p = 0.003) and IS (r = 0.423, p = 0.007). 9-HPT scores strongly correlated with KS (r = 0.926, p < 0.001). Pyramidal scores correlated with KS (r = - 0.517, p < 0.001). Cerebellar scores correlated with KS (r = - 0.665, p < 0.001), AT (r = 0.567, p < 0.001) and IS (r = 0.546, p = 0.007). Receiver operating characteristic curves demonstrate that KS can distinguish between the presence or absence of pyramidal and cerebellar dysfunction with area under curve 0.840 (p < 0.001) and 0.829 (p < 0.001), respectively. CONCLUSIONS: The BRAIN test can remotely measure disability in MS. Specific scores differ according to the presence and severity of pyramidal or extrapyramidal dysfunction. It demonstrates huge potential in monitoring disease progression in clinical trials.

Cryptococcal meningitis in apparently immunocompetent patients: association with idiopathic CD4+ lymphopenia.

We present two cases of cryptococcal meningitis in people subsequently diagnosed with idiopathic CD4+ lymphopenia. Both presented with new onset headaches without sinister features and were sent home on multiple occasions from emergency departments. Cryptococcal meningitis in HIV-negative patients poses major diagnostic and management problems; the associated mortality is 9%-27%. We suggest performing blood and cerebrospinal fluid cryptococcal antigen tests in all people with lymphocytic meningitis.

Constipation preceding Parkinson's disease: a systematic review and meta-analysis.

OBJECTIVE: To systematically review published literature to estimate the magnitude of association between premorbid constipation and later diagnosis of Parkinson's disease. BACKGROUND: Constipation is a recognised non-motor feature of Parkinson's and has been reported to predate diagnosis in a number of observational studies. METHODS: A systematic review and meta-analysis was carried out following the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) criteria. A literature search was undertaken in December 2014 using PubMed and the search terms 'Parkinson's disease' and 'constipation'. Articles were screened for suitability and reviewed against inclusion and exclusion criteria. Studies were included if they assessed constipation by means of a structured questionnaire or if constipation/drugs used to treat constipation were coded in patient medical records. Data were extracted using a standardised template and effect size estimates combined using a fixed-effects model. Heterogeneity was explored with the I(2) statistic. RESULTS: 9 studies were included in the meta-analysis, with a combined sample size of 741 593 participants. Those with constipation had a pooled OR of 2.27 (95% CI 2.09 to 2.46) for developing subsequent Parkinson's disease compared with those without constipation. Weak evidence for heterogeneity was found (I(2)=18.9%, p=0.282). Restricting analysis to studies assessing constipation more than 10 years prior to Parkinson's disease gave a pooled OR of 2.13 (95% CI 1.78 to 2.56; I(2)=0.0%). CONCLUSIONS: This systematic review and meta-analysis demonstrates that people with constipation are at a higher risk of developing Parkinson's disease compared with those without and that constipation can predate Parkinson's diagnosis by over a decade.

A service development study of the assessment and management of fracture risk in Parkinson's disease.

Parkinson's disease (PD) is associated with an increased risk of fragility fracture. FRAX and Qfracture are risk calculators that estimate the 10-year risk of hip and major fractures and guide definitive investigation for osteoporosis using dual X-ray absorptiometry (DEXA) imaging. It is unclear which PD patients should be considered for fracture risk assessment and whether FRAX or Qfracture should be used. Seventy-seven patients with PD were recruited in the movement disorders clinic. Data were collected on PD-related characteristics and fracture risk scores were calculated. Patients with previous osteoporotic fractures had a higher incidence of falls (p = 0.0026) and use of bilateral walking aids (p = 0.0187) in addition to longer disease duration (p = 0.0037). Selecting patients with falls in combination with either disease duration >5 years, bilateral walking aids, or previous osteoporotic fracture distinguished patients with and without previous osteoporotic fracture with specificity 67.7 % (95 % CI 55.0-78.8) and sensitivity 100.0 % (95 % CI 73.5-100.0). Qfracture calculated significantly higher fracture risk scores than FRAX for hip (p < 0.0001) and major (p = 0.0008) fracture in PD patients. Receiver operating characteristic curves demonstrated that FRAX outperformed Qfracture with an area under the curve of 0.84 (95 % CI 0.70-0.97, p = 0.0004) for FRAX and 0.68 (95 % CI 52-86, p = 0.0476) for Qfracture major fracture risk calculators. We suggest that falls in combination with either a disease duration longer than 5 years or bilateral walking aids or previous osteoporotic fracture should be used as red flags in PD patients to prompt clinicians to perform a FRAX fracture risk assessment in the neurology clinic.