[Good medicinal practice in epilepsy in the elderly]. / Les bonnes pratiques médicamenteuses en cas d'épilepsie de la personne âgée.

Epilepsy is a frequent disease in the elderly. Diagnosis must be precise and systematic. Initiation of treatment must be assessed according to epileptic risk and comorbidities. Several treatments exist, but there is no miracle solution. Epileptic patients must be monitored regularly, and their tolerance of treatment monitored. The efficacy of the proposed treatments is generally good.

Genetic cooperativity in multi-layer networks implicates cell survival and senescence in the striatum of Huntington's disease mice synchronous to symptoms.

MOTIVATION: Huntington's disease (HD) may evolve through gene deregulation. However, the impact of gene deregulation on the dynamics of genetic cooperativity in HD remains poorly understood. Here, we built a multi-layer network model of temporal dynamics of genetic cooperativity in the brain of HD knock-in mice (allelic series of Hdh mice). To enhance biological precision and gene prioritization, we integrated three complementary families of source networks, all inferred from the same RNA-seq time series data in Hdh mice, into weighted-edge networks where an edge recapitulates path-length variation across source-networks and age-points. RESULTS: Weighted edge networks identify two consecutive waves of tight genetic cooperativity enriched in deregulated genes (critical phases), pre-symptomatically in the cortex, implicating neurotransmission, and symptomatically in the striatum, implicating cell survival (e.g. Hipk4) intertwined with cell proliferation (e.g. Scn4b) and cellular senescence (e.g. Cdkn2a products) responses. Top striatal weighted edges are enriched in modulators of defective behavior in invertebrate models of HD pathogenesis, validating their relevance to neuronal dysfunction in vivo. Collectively, these findings reveal highly dynamic temporal features of genetic cooperativity in the brain of Hdh mice where a 2-step logic highlights the importance of cellular maintenance and senescence in the striatum of symptomatic mice, providing highly prioritized targets. AVAILABILITY AND IMPLEMENTATION: Weighted edge network analysis (WENA) data and source codes for performing spectral decomposition of the signal (SDS) and WENA analysis, both written using Python, are available at http://www.broca.inserm.fr/HD-WENA/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Learning clinical networks from medical records based on information estimates in mixed-type data.

The precise diagnostics of complex diseases require to integrate a large amount of information from heterogeneous clinical and biomedical data, whose direct and indirect interdependences are notoriously difficult to assess. To this end, we propose an efficient computational approach to simultaneously compute and assess the significance of multivariate information between any combination of mixed-type (continuous/categorical) variables. The method is then used to uncover direct, indirect and possibly causal relationships between mixed-type data from medical records, by extending a recent machine learning method to reconstruct graphical models beyond simple categorical datasets. The method is shown to outperform existing tools on benchmark mixed-type datasets, before being applied to analyze the medical records of eldery patients with cognitive disorders from La Pitié-Salpêtrière Hospital, Paris. The resulting clinical network visually captures the global interdependences in these medical records and some facets of clinical diagnosis practice, without specific hypothesis nor prior knowledge on any clinically relevant information. In particular, it provides some physiological insights linking the consequence of cerebrovascular accidents to the atrophy of important brain structures associated to cognitive impairment.

[Geriatric pathways and organisation in response to the needs of EDS]. / Organisation et filières gériatriques en réponse aux besoins des SAU.

The emergency department remains the main method of admission for older people to hospital. The management of old elderly in these departments is a complex subject. It's particularities and the specificities of the evaluation of their health contribute to the difficulties of the care teams. For the elderly, a visit to the emergency room is a significant medical event in the care process that can have repercussions on their functional decline. The promotion of a geriatric culture in emergency departments is essential and can be done in different ways, but collaboration between emergency physicians and geriatricians remains essential for successful care adapted to the specific characteristics of elderly patients.

[Confusional syndrome in the emergency room: from diagnosis to management]. / Le syndrome confusionnel, une urgence diagnostique et thérapeutique.

Delirium is an emergency and can have serious consequences. On the arrival at the emergency room of an elderly person, it should be systematically checked for confusional syndrome. If it is confirmed, a systematic and rapid etiological assessment carried out in the emergency room allows the identification of predisposing and precipitating factors. Therapeutic management is urgent, and includes treatment of the causes in the first instance.

[A pragmatic approach to iatrogenic risk in the emergency room]. / Approche pragmatique du risque iatrogène aux urgences.

The links between the emergency department (ED) and drug-related harm are close. In practice, it is necessary to ask systematically if an iatrogenic accident is possible and to evaluate a new prescription carefully so as not to create iatrogenia during the visit to the emergency department. Any situation in which a nurse takes charge of an emergency room must be subject to precautions. Simple measures should be put in place during any hospitalisation of an elderly person.

Multicenter phase III randomized trial comparing laparoscopy and laparotomy for colon cancer surgery in patients older than 75 years: the CELL study, a Fédération de Recherche en Chirurgie (FRENCH) trial.

BACKGROUND: Several multicenter randomized controlled trials comparing laparoscopy and conventional open surgery for colon cancer have demonstrated that laparoscopic approach achieved the same oncological results while improving significantly early postoperative outcomes. These trials included few elderly patients, with a median age not exceeding 71 years. However, colon cancer is a disease of the elderly. More than 65% of patients operated on for colon cancer belong to this age group, and this proportion may become more pronounced in the coming years. In current practice, laparoscopy is underused in this population. METHODS: The CELL (Colectomy for cancer in the Elderly by Laparoscopy or Laparotomy) trial is a multicenter, open-label randomized, 2-arm phase III superiority trial. Patients aged 75 years or older with uncomplicated colonic adenocarcinoma or endoscopically unresectable colonic polyp will be randomized to either colectomy by laparoscopy or laparotomy. The primary endpoint of the study is overall postoperative morbidity, defined as any complication classification occurring up to 30 days after surgery. The secondary endpoints are: 30-day and 90-day postoperative mortality, 30-day readmission rate, quality of surgical resection, health-related quality of life and evolution of geriatric assessment. A 35 to 20% overall postoperative morbidity rate reduction is expected for patients operated on by laparoscopy compared with those who underwent surgery by laparotomy. With a two-sided α risk of 5% and a power of 80% (ß = 0.20), 276 patients will be required in total. DISCUSSION: To date, no dedicated randomized controlled trial has been conducted to evaluate morbidity after colon cancer surgery by laparoscopy or laparotomy in the elderly and the benefits of laparoscopy is still debated in this context. Thus, a prospective multicenter randomized trial evaluating postoperative outcomes specifically in elderly patients operated on for colon cancer by laparoscopy or laparotomy with curative intent is warranted. If significant, such a study might change the current surgical practices and allow a significant improvement in the surgical management of this population, which will be the vast majority of patients treated for colon cancer in the coming years. TRIAL REGISTRATION: ClinicalTrials.gov NCT03033719 (January 27, 2017).

Simultaneous quantification of tau and α-synuclein in cerebrospinal fluid by high-resolution mass spectrometry for differentiation of Lewy Body Dementia from Alzheimer's Disease and controls.

Tau and α-synuclein are central in several neurodegenerative diseases, including Alzheimer Disease (AD), Dementia with Lewy Bodies (DLB) and Parkinson Disease (PD). New analytical methods for precise quantification of cerebrospinal fluid (CSF) levels of both tau and α-synuclein are required to differentiate between dementias or monitor therapeutic responses. Notably, levels of total α-synuclein reported by ELISA are inconsistent among studies, impacted by antibody specificity or lack of standardization. Here, we report on the development and validation of a sensitive and robust mass spectrometry-based assay for the simultaneous quantification of tau and α-synuclein in CSF. The optimized workflow avoided any affinity reagents, and involved the combination of two enzymes, Glu-C and trypsin for optimal sequence coverage of α-synuclein acidic C-terminus. Up to 7 α-synuclein peptides were quantified, including the C-terminal peptide (132-140), resulting in a sequence coverage of 54% in CSF. The lower limits of quantification (LLOQ) ranged from 0.1 ng mL-1 to 1 ng mL-1 depending on the peptide. Regarding CSF tau, 4 peptides common to all isoforms were monitored, and LLOQ ranged from 0.5 ng mL-1 to 0.75 ng mL-1. The multiplex method was successfully applied to CSF samples from AD and DLB patients, two clinically overlapping neurodegenerative diseases. CSF α-synuclein levels were significantly lower in DLB patients compared to AD and controls. Moreover, tau and α-synuclein concentrations showed opposite trends in AD and DLB patients, suggesting the benefit of combining the two biomarkers for differentiation of DLB from AD and controls.

[Differential diagnosis of strokes, the traps to avoid]. / Diagnostics différentiels d'AVC, les pièges à éviter.

Strokes are a significant issue in geriatric medicine as more than half occur in patients over the age of 75. However, not all the symptoms of a focal neurological deficit in the elderly are indicative of a stroke. There are a number of differential diagnoses and only a detailed examination of the patient can enable an accurate diagnosis to be established. However, in no case must this delay the urgent treatment of the patient suspected of having a stroke.

Study protocol on Alzheimer's disease and related disorders: focus on clinical and imaging predictive markers in co-existing lesions.

BACKGROUND: One of the crucial challenges for the future of therapeutic approaches to Alzheimer's disease (AD) is to target the main pathological processes responsible for disability and dependency. However, a progressive cognitive impairment occurring after the age of 70, the main population affected by dementia, is often related to mixed lesions of neurodegenerative and vascular origins. Whereas young patients are mostly affected by pure lesions, ageing favours the occurrence of co-lesions of AD, cerebrovascular disease (CVD) and Lewy body dementia (LBD). Most of clinical studies report on functional and clinical disabilities in patients with presumed pure pathologies. But, the weight of co-morbid processes involved in the transition from an independent functional status to disability in the elderly with co-lesions still remains to be elucidated. Neuropathological examination often performed at late stages cannot answer this question at mild or moderate stages of cognitive disorders. Brain MRI, Single Photon Emission Computed Tomography (SPECT) with DaTscan®, amyloid Positron Emission Tomography (PET) and CerebroSpinal Fluid (CSF) AD biomarkers routinely help in performing the diagnosis of underlying lesions. The combination of these measures seems to be of incremental value for the diagnosis of mixed profiles of AD, CVD and LBD. The aim is to determine the clinical, neuropsychological, neuroradiological and biological features the most predictive of cognitive, behavioral and functional impairment at 2 years in patients with co-existing lesions. METHODS: A multicentre and prospective cohort study with clinical, neuro-imaging and biological markers assessment will recruit 214 patients over 70 years old with a cognitive disorder of AD, cerebrovascular and Lewy body type or with coexisting lesions of two or three of these pathologies and fulfilling the diagnostic criteria for dementia at a mild to moderate stage. Patients will be followed every 6 months (clinical, neuropsychological and imaging examination and collection of cognitive, behavioural and functional impairment) for 24 months. DISCUSSION: This study aims at identifying the best combination of markers (clinical, neuropsychological, MRI, SPECT-DaTscan®, PET and CSF) to predict disability progression in elderly patients presenting coexisting patterns. TRIAL REGISTRATION: NCT02052947 .

[Dementia with Lewy bodies]. / Démence à corps de Lewy.

Dementia with lewy bodies. Dementia with Lewy bodies (DLB) is the second most frequent causes of dementia notably in the elderly. The clinical signs are extremly various and the diagnosis is rarely correctly made with an important deficit of sensitivity. Although practical attitudes are linked to the right diagnosis. In this work we will evocate the main caracteristics of DLB in order to facilitate its diagnosis in primary care and we will survey the principles of take care.

Démence à corps de lewy. La démence à corps de Lewy est la deuxième des maladies neurodégénératives en cause dans la survenue de troubles neurocognitifs majeurs, en particulier dans la population âgée. Sa présentation est très polymorphe, et le diagnostic reste souvent non fait alors que des implications pratiques dans sa prise en charge existent. Nous passerons en revue les caractéristiques de cette maladie pour qu'elle soit plus facilement évoquée en médecine générale, et nous évoquerons les grands principes de sa prise en charge.

[Restraint in geriatric care, pharmacological and non-pharmacological approaches]. / Contention en gériatrie, approches médicamenteuse et non médicamenteuse.

Restraint in geriatric care is not a trivial act. It must be regulated, performed in accordance with best practice guidelines and respect patients' fundamental rights. It requires initial evaluation as well as daily re-evaluation. An alternative must always be considered by the whole team, which should be mindful of its responsibility and its sense of ethics.

Exposure to psychotropics in the French older population living with dementia: a nationwide population-based study.

BACKGROUND: Little is known about the level of psychotropic chronic exposure in all patients living with dementia. The aim of the study was to quantify chronic psychotropic exposure in older adults with dementia compared with the general population of the same age. METHODS: This prospective cohort study was conducted in France between 2009 and 2011. Aged at least 65 years, 10,781,812 individuals (440,215 of them with dementia) either community based or nursing home residents were included. The numbers of single or combined prescriptions, per year for antipsychotics, antidepressants, anxiolytics, or hypnotics were measured. RESULTS: Of patients with dementia, 15.5% are exposed to antipsychotics compared with 2.2% of the age-matched population (relative risk [RR] = 6.44, 95% confidence interval [CI] [6.39-6.48]), 39.5% to antidepressants compared with 12.6% (RR = 4.10, 95% CI [.4.07-4.12]), and 39.6% to anxiolytics or hypnotics compared with 26.9% (RR = 1.74, 95% CI [1.72-1.75]). Among older adults with dementia, 13.8% simultaneously consumed at least three psychotropics. All class age of older patients with dementia is more exposed to all psychotropics except for long-acting benzodiazepines. During the study period, chronic anxiolytic/hypnotic and antipsychotic exposure slightly decreased in population with dementia while chronic exposure to antidepressant drugs tended to increase. CONCLUSION: This nationwide, population-based, drug-used study showed for the first time that older patients with dementia are chronically overexposed not only to antipsychotics but also to psychotropics.

Cross-validation of a Shortened Battery for the Assessment of Dysexecutive Disorders in Alzheimer Disease.

The frequency of executive disorders in mild-to-moderate Alzheimer disease (AD) has been demonstrated by the application of a comprehensive battery. The present study analyzed data from 2 recent multicenter studies based on the same executive battery. The objective was to derive a shortened battery by using the GREFEX population as a training dataset and by cross-validating the results in the REFLEX population. A total of 102 AD patients of the GREFEX study (MMSE=23.2±2.9) and 72 patients of the REFLEX study (MMSE=20.8±3.5) were included. Tests were selected and receiver operating characteristic curves were generated relative to the performance of 780 controls from the GREFEX study. Stepwise logistic regression identified 3 cognitive tests (Six Elements Task, categorical fluency and Trail Making Test B error) and behavioral disorders globally referred as global hypoactivity (P=0.0001, all). This shortened battery was as accurate as the entire GREFEX battery in diagnosing dysexecutive disorders in both training group and the validation group. Bootstrap procedure confirmed the stability of AUC. A shortened battery based on 3 cognitive tests and 3 behavioral domains provides a high diagnosis accuracy of executive disorders in mild-to-moderate AD.

Biomarkers of vascular dysfunction and cognitive decline in patients with Alzheimer's disease: no evidence for association in elderly subjects.

BACKGROUND: Several studies have suggested that vascular dysfunction plays an important role in Alzheimer's disease. AIMS: We hypothesized that significant differences might be observed in the levels of blood endothelial biomarkers across elderly population of subjects with dementia. METHODS: We analyzed, in a prospective monocentric study, three different endothelial biomarkers, endothelial microparticles (EMPs), endothelial progenitor cells (EPCs) and circulating endothelial cells (CECs) in 132 older patients who underwent a full evaluation of a memory complaint. RESULTS: There was no difference in specific EMP, EPC or CEC levels between demented or non-demented patients, nor considering cognitive decline. DISCUSSION: Blood endothelial biomarkers may be too sensitive and it is likely that the multimorbidity observed in our patients may lead to opposite and confounding effects on endothelial biomarkers levels. CONCLUSION: Unlike younger AD patients, our results suggest that endothelial biomarkers are not valuable for the diagnosis of dementia in elderly patients.

Multidimensional assessment of social cognition using non-immersive virtual reality in dementia with Lewy bodies and Alzheimer's disease: an exploratory study.

INTRODUCTION: Few studies have focused on social cognition in dementia with Lewy bodies (DLB), even though some brain structures being well known as underlying social cognitive processes are directly impacted in this disease. Furthermore, social cognition processes have been mostly studied independently using evaluations with poor ecological validity. We aimed at studying the ability of a new naturalistic and multidimensional social cognition task to reveal impairments in DLB patients. We chose to compare the profile of these patients with that of Alzheimer's disease (AD) patients, for which social cognition is better preserved. METHOD: Fifteen patients (DLB: n = 7; AD: n = 8) and 28 healthy controls underwent the REALSoCog task. They encountered several social situations (e.g. control versus transgressions) in a non-immersive virtual city environment allowing the assessment of moral cognition, cognitive and affective theory of mind (ToM), emotional empathy and behavioral intentions. RESULTS: The main results showed (i) a lower ability to detect transgressions in DLB patients, particularly conventional ones, whereas moral cognition seemed better preserved in AD patients; (ii) a cognitive ToM impairment in both DLB and AD patients, while affective ToM is impaired only in DLB patients; (iii) a decreased emotional empathy specifically observed in DLB patients; (iv) more inappropriate behavioral intentions, mainly in DLB patients, but also in some AD patients. CONCLUSIONS: This study suggests the feasibility and potential interest of the REALSoCog task in revealing social cognition deficits, particularly for DLB patients by showing different social patterns as compared to AD patients. These results offer interesting clinical perspectives to develop more naturalistic tasks in such populations and for clinical differential diagnosis. Limitations and future perspectives are discussed.

Cerebral Amyloid Angiopathy-Related Inflammation and Biopsy-Positive Primary Angiitis of the CNS: A Comparative Study.

BACKGROUND AND OBJECTIVES: Cerebral amyloid angiopathy-related inflammation (CAA-RI) and biopsy-positive primary angiitis of the CNS (BP-PACNS) have overlapping clinicoradiologic presentations. It is unknown whether clinical and radiologic features can differentiate CAA-RI from BP-PACNS and whether both diseases have different relapse rates. The objectives of this study were to compare clinicoradiologic presentations and relapse rates in patients with CAA-RI vs BP-PACNS. METHODS: Patients with CAA-RI and BP-PACNS were enrolled from 2 retrospective multicenter cohorts. Patients with CAA-RI were biopsy-positive or met probable clinicoradiologic criteria. Patients with BP-PACNS had histopathologic confirmation of CNS angiitis, with no secondary etiology. A neuroradiologist read brain MRIs, blinded to the diagnosis of CAA-RI or BP-PACNS. Clinicoradiologic features were compared using univariable logistic regression models. Relapse rates were compared using a univariable Fine-Gray subdistribution hazard model, with death as a competing risk. RESULTS: This study enrolled 104 patients with CAA-RI (mean age 73 years, 48% female sex) and 52 patients with BP-PACNS (mean age 45 years, 48% female sex). Patients with CAA-RI more often had white matter hyperintense lesions meeting the probable CAA-RI criteria (93% vs 51%, p < 0.001), acute subarachnoid hemorrhage (15% vs 2%, p = 0.02), cortical superficial siderosis (27% vs 4%, p < 0.001), ≥1 lobar microbleed (94% vs 26%, p < 0.001), past intracerebral hemorrhage (17% vs 4%, p = 0.04), ≥21 visible centrum semiovale perivascular spaces (34% vs 4%, p < 0.01), and leptomeningeal enhancement (70% vs 27%, p < 0.001). Patients with BP-PACNS more often had headaches (56% vs 31%, p < 0.01), motor deficits (56% vs 36%, p = 0.02), and nonischemic parenchymal gadolinium enhancement (82% vs 16%, p < 0.001). The prevalence of acute ischemic lesions was 18% in CAA-RI and 22% in BP-PACNS (p = 0.57). The features with the highest specificity for CAA-RI were acute subarachnoid hemorrhage (98%), cortical superficial siderosis (96%), past intracerebral hemorrhage (96%), and ≥21 visible centrum semiovale perivascular spaces (96%). The probable CAA-RI criteria had a 71% sensitivity (95% CI 44%-90%) and 91% specificity (95% CI 79%-98%) in differentiating biopsy-positive CAA-RI from BP-PACNS. The rate of relapse in the first 2 years after remission was lower in CAA-RI than in BP-PACNS (hazard ratio 0.46, 95% CI 0.22-0.96, p = 0.04). CONCLUSION: Clinicoradiologic features differed between patients with CAA-RI and those with BP-PACNS. Specific markers for CAA-RI were hemorrhagic signs of subarachnoid involvement, past intracerebral hemorrhage, ≥21 visible centrum semiovale perivascular spaces, and the probable CAA-RI criteria. A biopsy remains necessary for diagnosis in some cases of CAA-RI. The rate of relapse in the first 2 years after disease remission was lower in CAA-RI than in BP-PACNS.

[Cerebral amyloid angiopathy and atrial fibrillation: anticoagulant dilemma]. / Angiopathie amyloïde cérébrale et fibrillation atriale : le dilemme des anticoagulants.

Cerebral amyloid angiopathy and atrial fibrillation are two frequent comorbidities in older patients, leading to a therapeutic dilemma on the risk-benefit ratio of long-term anticoagulation. These patients both have a risk of cardioembolic complications due to atrial fibrillation, and a risk of cerebral haemorrhage from cerebral amyloid angiopathy. Since there is no therapeutic consensus, the best therapeutic strategy should be discussed during a multidisciplinary staff, based on four risk estimations: 1) the baseline risk of intracerebral haemorrhage without anticoagulation; 2) the risk of ischaemic stroke without anticoagulation; 3) the expected increase of intracerebral haemorrhage with anticoagulation; 4) the expected reduction in ischaemic stroke risk with anticoagulation. The risk of intracerebral haemorrhage varies according to the cerebral amyloid angiopathy phenotype. Patients with transient neurological episode or cortical superficial siderosis have the highest risk of intracerebral haemorrhage. Direct oral anticoagulant should be preferred to vitamin K antagonists, as the risk of intracerebral haemorrhage is lower with direct oral anticoagulants. If anticoagulation is introduced, a close clinical and radiological monitoring should be performed every 6-12 months minimum. If it has been decided not to anticoagulate, left atrial appendage occlusion should be proposed. In all situations, close blood pressure control is essential to reduce the risk of intracerebral haemorrhage.

[Pyoderma gangrenosum and hemopathies in older patients]. / Pyoderma gangrenosum et hémopathies chez la personne âgée.

Pyoderma gangrenosum (PG) belongs to neutrophilic dermatoses. PG can have different clinical presentations (ulcerated, bullous, pustular), is often painful, and preferentially affects the lower limbs. The diagnosis can be challenging, and a cutaneous biopsy is often necessary, which shows an aseptic cutaneous infiltrate of neutrophils. The association with inflammatory or hematologic conditions is frequent, especially in older patients. The hematologic diseases the most frequently associated with PG are myelodysplastic syndrome, followed by monoclonal gammopathy of undetermined significance. Because of the strong impact of its treatment, recognition of PG is crucial. The treatment is based on first-line corticosteroids and topical or systemic immunosuppressive drugs and most often leads to a favourable outcome. The management of an acute hematologic disease would further improve the prognosis of PG. The singularity of geriatric patients encourages to thoroughly balance the risks and benefits of the recommended drugs and to consider associated non-drug measures. Here, we propose a review of the scientific literature about the association between PG and hematologic diseases, with a special focus on older patients, accompanied by the report of two cases in geriatric ward.