Neurology and the histiocytoses: a case of Rosai-Dorfman-Destombes disease.

The histiocytoses are a group of rare disorders characterised by the accumulation of neoplastic or non-neoplastic activated histiocytes in various tissues. Phenotypes vary widely from cutaneous lesions or lymphadenopathy that regress spontaneously to disseminated disease with poor prognosis. Neurological symptoms can be a presenting feature or appear during the course of disease. We present a challenging diagnostic and management case of Rosai-Dorfman-Destombes disease in a 48-year-old woman with a relapsing, partially steroid-responsive syndrome comprising patchy, non-length-dependent radiculoneuropathy with diffuse pachymeningitis and widespread systemic disease, and recent dramatic response to novel mitogen-activated kinase pathway inhibition. We discuss the clinical characteristics, diagnosis, recent breakthroughs in pathogenesis and emerging treatment options for Rosai-Dorfman disease and for the histiocytoses with neurological sequelae, including Langerhans cell histiocytosis and Erdheim-Chester disease.

Learning to see the invisible: A data-driven approach to finding the underlying patterns of abnormality in visually normal brain magnetic resonance images in patients with temporal lobe epilepsy.

OBJECTIVE: To find the covert patterns of abnormality in patients with unilateral temporal lobe epilepsy (TLE) and visually normal brain magnetic resonance images (MRI-negative), comparing them to those with visible abnormalities (MRI-positive). METHODS: We used multimodal brain MRI from patients with unilateral TLE and employed contemporary machine learning methods to predict the known laterality of seizure onset in 104 subjects (82 MRI-positive, 22 MRI-negative). A visualization approach entitled "Importance Maps" was developed to highlight image features predictive of seizure laterality in both the MRI-positive and MRI-negative cases. RESULTS: Seizure laterality could be predicted with an area under the receiver operating characteristic curve of 0.981 (95% confidence interval [CI] =0.974-0.989) in MRI-positive and 0.842 (95% CI = 0.736-0.949) in MRI-negative cases. The known image features arising from the hippocampus were the leading predictors of seizure laterality in the MRI-positive cases, whereas widespread temporal lobe abnormalities were revealed in the MRI-negative cases. SIGNIFICANCE: Covert abnormalities not discerned on visual reading were detected in MRI-negative TLE, with a spatial pattern involving the whole temporal lobe, rather than just the hippocampus. This suggests that MRI-negative TLE may be associated with subtle but widespread temporal lobe abnormalities. These abnormalities merit close inspection and postacquisition processing if there is no overt lesion.

Early lipofuscin accumulation in frontal lobe epilepsy.

OBJECTIVE: This study reports on a novel brain pathology in young patients with frontal lobe epilepsy (FLE) that is distinct from focal cortical dysplasia (FCD). METHODS: Surgical specimens from 20 young adults with FLE (mean age, 30 years) were investigated with histological/immunohistochemical markers for cortical laminar architecture, mammalian target of (mTOR) pathway activation and inhibition, cellular autophagy, and synaptic vesicle-mediated trafficking as well as proteomics analysis. Findings were correlated with pre-/postoperative clinical, imaging, and electrophysiological data. RESULTS: Excessive lipofuscin accumulation was observed in abnormal dysmorphic neurones in 6 cases, but not in seven FCD type IIB and 7 pathology-negative cases, despite similar age and seizure histories. Abnormal dysmorphic neurones on proteomics analysis were comparable to aged human brains. The mTOR pathway was activated, as in cases with dysplasia, but the immunoreactivities of nucleoporin p62, DEP-domain containing protein 5, clathrin, and dynamin-1 were different between groups, suggesting that enhanced autophagy flux and abnormal synaptic vesicle trafficking contribute to early lipofuscin aggregation in these cases, compared to suppression of autophagy in cases with typical dysplasia. Cases with abnormal neuronal lipofuscin showed subtle magnetic resonance imaging cortical abnormalities that localized with seizure onset zone and were more likely to have a family history. INTERPRETATION: We propose that excess neuronal lipofuscin accumulation in young patients with FLE represents a novel pathology underlying this epilepsy; the early accumulation of lipofuscin may be disease driven, secondary to as-yet unidentified drivers accelerating autophagic pathways, which may underpin the neuronal dysfunction in this condition. Ann Neurol 2016;80:882-895.

Study protocol: Insight 46 - a neuroscience sub-study of the MRC National Survey of Health and Development.

BACKGROUND: Increasing age is the biggest risk factor for dementia, of which Alzheimer's disease is the commonest cause. The pathological changes underpinning Alzheimer's disease are thought to develop at least a decade prior to the onset of symptoms. Molecular positron emission tomography and multi-modal magnetic resonance imaging allow key pathological processes underpinning cognitive impairment - including ß-amyloid depostion, vascular disease, network breakdown and atrophy - to be assessed repeatedly and non-invasively. This enables potential determinants of dementia to be delineated earlier, and therefore opens a pre-symptomatic window where intervention may prevent the onset of cognitive symptoms. METHODS/DESIGN: This paper outlines the clinical, cognitive and imaging protocol of "Insight 46", a neuroscience sub-study of the MRC National Survey of Health and Development. This is one of the oldest British birth cohort studies and has followed 5362 individuals since their birth in England, Scotland and Wales during one week in March 1946. These individuals have been tracked in 24 waves of data collection incorporating a wide range of health and functional measures, including repeat measures of cognitive function. Now aged 71 years, a small fraction have overt dementia, but estimates suggest that ~1/3 of individuals in this age group may be in the preclinical stages of Alzheimer's disease. Insight 46 is recruiting 500 study members selected at random from those who attended a clinical visit at 60-64 years and on whom relevant lifecourse data are available. We describe the sub-study design and protocol which involves a prospective two time-point (0, 24 month) data collection covering clinical, neuropsychological, ß-amyloid positron emission tomography and magnetic resonance imaging, biomarker and genetic information. Data collection started in 2015 (age 69) and aims to be completed in 2019 (age 73). DISCUSSION: Through the integration of data on the socioeconomic environment and on physical, psychological and cognitive function from 0 to 69 years, coupled with genetics, structural and molecular imaging, and intensive cognitive and neurological phenotyping, Insight 46 aims to identify lifetime factors which influence brain health and cognitive ageing, with particular focus on Alzheimer's disease and cerebrovascular disease. This will provide an evidence base for the rational design of disease-modifying trials.

Pathophysiology, diagnosis, and management of neuroinflammation in covid-19.

Although neurological complications of SARS-CoV-2 infection are relatively rare, their potential long term morbidity and mortality have a significant impact, given the large numbers of infected patients. Covid-19 is now in the differential diagnosis of a number of common neurological syndromes including encephalopathy, encephalitis, acute demyelinating encephalomyelitis, stroke, and Guillain-Barré syndrome. Physicians should be aware of the pathophysiology underlying these presentations to diagnose and treat patients rapidly and appropriately. Although good evidence has been found for neurovirulence, the neuroinvasive and neurotropic potential of SARS-CoV-2 is limited. The pathophysiology of most complications is immune mediated and vascular, or both. A significant proportion of patients have developed long covid, which can include neuropsychiatric presentations. The mechanisms of long covid remain unclear. The longer term consequences of infection with covid-19 on the brain, particularly in terms of neurodegeneration, will only become apparent with time and long term follow-up.

The Queen Square Encephalitis Multidisciplinary Team Meeting - experience over three years, pre and post the COVID-19 pandemic.

BACKGROUND: Patients with suspected encephalitis continue to represent a diagnostic and therapeutic challenge, even in highly resourced centres. In February 2018, we set up a monthly in-person multidisciplinary team meeting (MDT). We describe the experience and outcomes of the MDT over three years. METHODS: A retrospective analysis was performed to summarise patient demographics, MDT outcomes and final diagnoses. RESULTS: Over the three-year period, 324 discussions of 238 patients took place. Cases were diverse; approximately 40% related to COVID-19 or brain infection, 40% autoimmune or other inflammatory disorders and 20% encephalitis mimics or uncertain aetiologies. Feedback from an online survey sent to referring teams and attendees highlighted the value of the MDT; 94% reported the discussion was useful and 69% reported resulting change in patient management. CONCLUSIONS: Multidisciplinary input is crucial in this challenging area, ensuring that all diagnostic avenues are explored and opening doors to novel diagnostics and therapeutics. It also supports clinicians dealing with unwell patients, including in centres where less specialist input is available, and when decisions have to be made where there is little or no evidence base.

A systematic review of brain imaging findings in neurological infection with Japanese encephalitis virus compared with Dengue virus.

OBJECTIVES: Japanese encephalitis virus (JEV) and dengue virus (DENV) represent important causes of encephalitis in Asia. Brain imaging may provide diagnostic clues about the etiology of infectious encephalitis. We performed a systematic review of brain imaging findings in Japanese encephalitis (JE) and DENV neurological infection (dengue) to identify characteristic lesions. METHODOLOGY: Five databases were searched. We included all study types and imaging techniques. Laboratory methods were categorized using diagnostic confidence levels. Imaging data were synthesized, and focal findings are presented as proportions for JE and dengue and for subgroups based on diagnostic confidence. PRINCIPAL FINDINGS: Thalamic lesions were the most reported magnetic resonance imaging finding in both diseases but appeared to occur more often in JE (74% in 23 studies) than dengue (29.4% in 58 studies). In cases diagnosed with antigen or nucleic acid tests, thalamic lesions were reported frequently in both JE (76.5% in 17 studies) and dengue (65.2% in 23 studies). SIGNIFICANCE: The results suggest that thalamic lesions frequently occur in both JE and dengue encephalitis. No radiological findings were found to be pathognomonic of either disease. Although brain imaging may support a diagnosis, laboratory confirmation with highly specific tests remains crucial.

Comprehensive Diagnosis and Management of POEMS Syndrome.

Polyneuropathy Organomegaly, Endocrinopathy, Monoclonal protein and Skin changes syndrome is a rare multisystem condition with a range of manifestations which are often overlooked as trivial comorbidities, until their whole triggers the possibility of the diagnosis. The diagnosis is typically delayed by 12-16 months, by which time patients can be severely disabled. There are no established consensus guidelines. We provide clinicians a comprehensive blueprint for managing POEMS from diagnostic suspicion through the work-up, selection of therapy, follow-up, and treatment of relapse based on published evidence and our large single-center experience. A multidisciplinary approach is essential including expert hematologists, neurologists, histopathologists, radiologists, and neurophysiologists. The aim of treatment is to eradicate the underlying plasma cell dyscrasia, but there are limited trial data to guide treatment decisions. Supportive care considerations include management of endocrinopathy, neuropathy, thrombosis, and infection. Response assessment is centered on clinical, neuropathy, hematological, vascular endothelial growth factor, and radiological criteria. Future clinical trials are welcomed in this setting where evidence is limited.

Simultaneous auditory agnosia: Systematic description of a new type of auditory segregation deficit following a right hemisphere lesion.

We investigated auditory processing in a young patient who experienced a single embolus causing an infarct in the right middle cerebral artery territory. This led to damage to auditory cortex including planum temporale that spared medial Heschl's gyrus, and included damage to the posterior insula and inferior parietal lobule. She reported chronic difficulties with segregating speech from noise and segregating elements of music. Clinical tests showed no evidence for abnormal cochlear function. Follow-up tests confirmed difficulties with auditory segregation in her left ear that spanned multiple domains, including words-in-noise and music streaming. Testing with a stochastic figure-ground task-a way of estimating generic acoustic foreground and background segregation-demonstrated that this was also abnormal. This is the first demonstration of an acquired deficit in the segregation of complex acoustic patterns due to cortical damage, which we argue is a causal explanation for the symptomatic deficits in the segregation of speech and music. These symptoms are analogous to the visual symptom of simultaneous agnosia. Consistent with functional imaging studies on normal listeners, the work implicates non-primary auditory cortex. Further, the work demonstrates a (partial) lateralisation of the necessary anatomical substrate for segregation that has not been previously highlighted.

Genomic Prognosticators and Extent of Resection in Molecularly Subtyped World Health Organization Grade II and III Gliomas-A Single-Institution, Nine-Year Data.

BACKGROUND: World Health Organization (WHO) grade II and III isocitrate dehydrogenase wild-type (IDH-wt) gliomas are often treated as WHO grade IV glioblastomas. However, cumulative evidence indicates that IDH mutation status alone is insufficient in predicting survival. The current study examines molecular and clinical markers to further prognostically stratify WHO grade II and III gliomas, in particular, IDH-wt. METHODS: A single institution's records were retrospectively reviewed for molecularly stratified WHO grade II and grade III gliomas over a 9-year period (2010-2019). Clinical data, IDH1/IDH2 status, EGFR amplification, and other molecular markers were recorded and correlated to the study outcomes. These outcomes were defined as progression-free survival (PFS), overall survival (OS), and time to malignant progression (TtMP). RESULTS: A total of 167 and 42 WHO grade II and III gliomas, respectively, were identified, totaling 209 cases with 157 IDH1/2 mutated and 52 IDH-wt tumors. The presence of IDH1/2 mutation was associated with longer OS (P < 0.0001) and PFS (P < 0.0001) but not with TtMP (P = 0.314). Lack of EGFR amplification, younger age, and greater extent of resection (EOR) (≥80%) were identified as independent, favorable OS prognostic factors. In the IDH-wt cohort, multivariate analysis indicated that older age (P = 0.003) and lesser EOR (<80%) (P = 0.007) are associated with worse OS. In addition, EGFR amplification showed a trend toward shorter OS in the IDH-wt cohort (P = 0.073). CONCLUSIONS: IDH1/2 mutation favors longer OS and PFS but does not protect from malignant progression. Lack of EGFR amplification, younger age and greater EOR are favorable OS prognosticators. In the IDH-wt cohort, older age and lesser EOR were linked to worse OS.

Relationship between Brain Tissue Oxygen Tension and Transcranial Doppler Ultrasonography.

BACKGROUND: Multimodal monitoring of intracranial pressure and brain tissue oxygen tension (PbtO2) have been increasingly used to detect delayed cerebral ischemia (DCI) after subarachnoid hemorrhage. At our center, patients who cannot be easily assessed clinically will undergo intracranial pressure and PbtO2 monitoring via a NEUROVENT-PTO bolt. We aimed to determine whether the Lindegaard ratios (LRs) computed from transcranial Doppler ultrasonography (TCDU) would correlate with, or can predict, the simultaneously recorded PbtO2 value. METHODS: Patients with aneurysmal subarachnoid hemorrhage, PbtO2 recordings from the middle cerebral artery territory, and simultaneous TCDU scans available from the ipsilateral middle cerebral artery and internal carotid artery from August 2018 to 2019 were included in the present study. The index test result was vasospasm (LR of ≥3) found on TCDU. The reference standard was the presence of regional hypoxia (PbtO2 <20 mm Hg). The PbtO2 results were compared with those from computed tomography angiography as a radiological standard. The predictive values were calculated using a contingency table and receiver operating characteristic curve. RESULTS: A total of 28 patients (6 men and 22 women; age, 59.04 ± 13.75 years) were identified with simultaneous brain tissue oxygen and TCDU recordings available. Of the 28 patients, 7 had cerebral hypoxia (PbtO2 <20 mm Hg). We found no correlation between the PbtO2 measurements and simultaneously recorded LRs (r2 = 0.048; P = 0.26). A LR of ≥3 had high specificity (95.24%) for hypoxia but relatively low sensitivity (42.86%; P = 0.037). CONCLUSION: We find TCDU to be specific for predicting cerebral hypoxia (measured via an intraparenchymal probe). Therefore, it could be a useful and noninvasive tool in the context of preventative DCI monitoring. However, given the low sensitivity, the lack of vasospasm on TCDU should not preclude the possibility of the presence of evolving DCI.

Prevalence of MRI abnormalities in people with epilepsy in rural China.

OBJECTIVE: To assess the prevalence of brain MRI abnormalities in people with epilepsy in rural China and to compare it with that of individuals in the United Kingdom. METHODS: Brain MRI scans were obtained in people with epilepsy who participated in a rural community-based program in China between July 2010 and December 2012. Individual epileptogenic lesion types were reviewed and their associations with seizure control examined. The MRI findings were compared with 2 previous similar studies in the United Kingdom. RESULTS: Among the 597 individuals (58% male, median age 38 years) with MRI scans analyzed, 488 (82%) had active epilepsy. The MRI was abnormal in 389 individuals (65%), with potentially epileptogenic lesion in 224 (38%) and nonspecific abnormalities in 165 (28%), and 108 (18%) were potentially resectable. The potentially epileptogenic lesions were less frequently detected in children (<18 years old, 12 of 68, 18%) than in adults (212 of 529, 40%; p < 0.001). In people with potentially epileptogenic lesions, 67% (150 of 224) had failed ≥2 antiseizure medications. They had higher risk of uncontrolled epilepsy than those with normal MRI (risk ratio [RR] 1.25; p < 0.001) and those with nonspecific abnormality (RR 1.15; p = 0.002) after adjustment for age and sex. The diagnostic yield of MRI was similar to that reported in community- and hospital-based studies in the United Kingdom. CONCLUSIONS: More than one-third of people with chronic epilepsy in rural China have potentially epileptogenic lesions identifiable on brain MRI, with two-thirds fulfilling the definition of pharmacoresistance. These findings highlight the magnitude of the unmet needs for epilepsy surgery in China.

Frequent central nervous system, pachymeningeal and plexus MRI changes in POEMS syndrome.

OBJECTIVE: Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) syndrome is a rare multisystem disease associated with a plasma-cell dyscrasia. Although pachymeningeal involvement has occasionally been described, MRI of the central nervous system (CNS) has not yet been extensively investigated. METHODS: We retrospectively evaluated CNS MRI in Europe's largest single-center cohort of POEMS syndrome. Of 77 patients who have been formally diagnosed with POEMS, 41 had MRI brain and 29 had MRI spine. A control group of 33 patients with chronic inflammatory demyelinating polyneuropathy (CIDP) was used as this is the major differential diagnosis. Of these CIDP patients, 12 underwent both MRI brain and spine, 7 had solely MRI brain and 14 had MRI spine. RESULTS: In 41 POEMS patients with MRI brain, we identified frequent smooth, diffuse meningeal thickening of the cerebral convexities and falx (n = 29, 71%), of which 4 had meningeal collections. 17 (41%) had vascular abnormalities including white-matter disease, of which 4 had established infarcts. Of 29 patients with MRI spine, 17 (59%) had thickening of the brachial and lumbosacral plexus. Conversely in 19 CIDP patients with MRI brain, none had meningeal thickening (p < 0.0001); however, 8 (42%) had vascular abnormalities (p = 0.85). Of 26 patients with MRI spine, 9 (35%) had brachial or lumbosacral plexus thickening (p = 0.06). CONCLUSIONS: In contrast to CIDP, POEMS patients frequently have pachymeningeal thickening. Vascular abnormalities and plexus thickening were also common but not statistically different to CIDP.

Incidental findings on brain imaging and blood tests: results from the first phase of Insight 46, a prospective observational substudy of the 1946 British birth cohort.

OBJECTIVE: To summarise the incidental findings detected on brain imaging and blood tests during the first wave of data collection for the Insight 46 study. DESIGN: Prospective observational sub-study of a birth cohort. SETTING: Single-day assessment at a research centre in London, UK. PARTICIPANTS: 502 individuals were recruited from the MRC National Survey of Health and Development (NSHD), the 1946 British birth cohort, based on pre-specified eligibility criteria; mean age was 70.7 (SD: 0.7) and 49% were female. OUTCOME MEASURES: Data regarding the number and types of incidental findings were summarised as counts and percentages, and 95% confidence intervals were calculated. RESULTS: 93.8% of participants completed a brain scan (n=471); 4.5% of scanned participants had a pre-defined reportable abnormality on brain MRI (n=21); suspected vascular malformations and suspected intracranial mass lesions were present in 1.9% (n=9) and 1.5% (n=7) respectively; suspected cerebral aneurysms were the single most common vascular abnormality, affecting 1.1% of participants (n=5), and suspected meningiomas were the most common intracranial lesion, affecting 0.6% of participants (n=3); 34.6% of participants had at least one abnormality on clinical blood tests (n=169), but few reached the prespecified threshold for urgent action (n=11). CONCLUSIONS: In older adults, aged 69-71 years, potentially serious brain MRI findings were detected in around 5% of participants, and clinical blood test abnormalities were present in around one third of participants. Knowledge of the expected prevalence of incidental findings in the general population at this age is useful in both research and clinical settings.

Pathology-MRI Correlations in Diffuse Low-Grade Epilepsy Associated Tumors.

It is recognized that IDH mutation negative, low-grade epilepsy associated tumors (LEAT) can show diffuse growth patterns and lack the diagnostic hallmarks of either classical dysembryoplastic neuroepithelial tumors (DNT) or typical ganglioglioma. "Nonspecific or diffuse DNT" and more recently "polymorphous low-grade neuroepithelial tumor of the young" have been terms used for these entities. There are few reports on the MRI recognition of these diffuse glioneuronal tumors (dGNT), which is important in planning the extent of surgical resection. In 27 LEATs T1, T2, FLAIR, and postcontrast T1 MRI were evaluated and the pathology reviewed, including immunostaining for NeuN, CD34, MAP2, and IDH1. Each case was then independently classified by pathology or MRI as simple DNT, complex DNT, or dGNT. There was agreement in 23/27 (85%; Kappa score 0.62; p < 0.01). In 4 cases, there was discrepancy in the diagnosis of simple versus complex DNT but 100% agreement achieved for dGNT. DNT showed significantly more expansion of the cortex, cystic change and ventricle extension than dGNT. dGNT showed significantly more subcortical T2w hyperintensity and focal cortical atrophy which correlated on pathology with CD34 expression, cortical neuronal loss and white matter rarefaction. There was no distinct cortical dysplasia component identified by MRI or pathology in any case. This study highlights that dGNT can be reliably discriminated on MRI from DNT.