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

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

Clinical phenotyping and biomarker discovery for neurological involvement in Wilson’s disease

Wilson’s disease is an autosomal-recessive disorder of copper metabolism with neurological and hepatic presentations. Chelation therapy is used to 'de-copper' patients and monitoring is based on copper indices, such as serum non-caeruloplasmin-bound copper and 24-hour urinary copper output, which do not reflect neurological involvement. Biomarkers of end-organ damage, i.e. measures of the pathophysiological process in the brain, are needed to improve outcomes and prepare for clinical trials of novel therapies. In this thesis, I examine the pattern of movement disorders, cognitive deficits and psychiatric features in 40 prospectively-recruited patients before describing work identifying wet (fluid) and imaging biomarkers for neurological involvement using cross-sectional data from this cohort. The findings demonstrate that movement disorders are associated with cognitive deficits but not psychiatric features in chronically-treated patients and that some patients with hepatic presentations have subtle deficits in cognitive flexibility, associative learning and recognition memory for faces. I confirm previous observations that copper indices do not correlate with the severity of movement disorders and show that plasma neurofilament light is a promising monitoring biomarker. I also report preliminary data identifying serum proteins that might reflect neurological involvement using label-free proteomics. Using a combination of whole-brain, quantitative MRI analyses, I provide evidence that grey matter volumes in subcortical regions may serve as prognostic biomarkers and diffusivity in white matter tracts may serve as monitoring biomarkers. I identify neuroimaging correlates for serum non-caeruloplasmin-bound (‘free’) copper and demonstrate that increasing neurological severity is associated with widespread cortical iron deposition. I also determine the neuroanatomical bases for cognitive deficits and psychiatric features in Wilson’s disease, some of which relate to specific patterns of cortical volume loss or white matter pathology. These data support the idea that there is a spectrum of neurological involvement in Wilson’s disease, which I suggest can be modelled as a brain injury. I discuss next steps for validating these biomarkers and conclude by proposing a unifying theory for the evolution of neurological involvement in Wilson’s disease

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

Late presentation of chronic traumatic encephalopathy in a former association football (soccer) player

BACKGROUND: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterised 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 (soccer) 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 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 behaviour, 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 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

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

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