[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.

[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.

[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.

Prodromal characteristics of dementia with Lewy bodies: baseline results of the MEMENTO memory clinics nationwide cohort.

BACKGROUND: Isolated subjective cognitive impairment (SCI) and mild cognitive impairment (MCI) are the prodromal phases of dementia with Lewy bodies (DLB). MEMENTO is a nationwide study of patients with SCI and MCI with clinic, neuropsychology, biology, and brain imaging data. We aimed to compare SCI and MCI patients with symptoms of prodromal DLB to others in this study at baseline. METHODS: Participants of the French MEMENTO cohort study were recruited for either SCI or MCI. Among them, 892 were included in the Lewy sub-study, designed to search specifically for symptoms of DLB. Probable prodromal DLB diagnosis (pro-DLB group) was done using a two-criteria cutoff score among the four core clinical features of DLB. This Pro-DLB group was compared to two other groups at baseline: one without any core symptoms (NS group) and the one with one core symptom (1S group). A comprehensive cognitive battery, questionnaires on behavior, neurovegetative and neurosensory symptoms, brain 3D volumetric MRI, CSF, FDG PET, and amyloid PET were done. RESULTS: The pro-DLB group comprised 148 patients (16.6%). This group showed more multidomain (59.8%) MCI with slower processing speed and a higher proportion of patients with depression, anxiety, apathy, constipation, rhinorrhea, sicca syndrome, and photophobia, compared to the NS group. The pro-DLB group had isolated lower P-Tau in the CSF (not significant after adjustments for confounders) and on brain MRI widening of sulci including fronto-insular, occipital, and olfactory sulci (FDR corrected), when compared to the NS group. Evolution to dementia was not different between the three groups over a median follow-up of 2.6 years. CONCLUSIONS: Patients with symptoms of prodromal DLB are cognitively slower, with more behavioral disorders, autonomic symptoms, and photophobia. The occipital, fronto-insular, and olfactory bulb involvement on brain MRI was consistent with symptoms and known neuropathology. The next step will be to study the clinical, biological, and imaging evolution of these patients. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01926249.

Lack of Association Between Perioperative Medication and Postoperative Delirium in Hip Fracture Patients in an Orthogeriatric Care Pathway.

OBJECTIVES: Units for perioperative geriatric care are playing a growing role in the care of older patients after hip fracture surgery. Postoperative delirium is one of the most common complications after hip fracture, but no study has assessed the impact of therapeutics received during a dedicated orthogeriatric care pathway on its incidence. Our main objective was to assess the association between drugs used in emergency, operating, and recovery departments and postoperative delirium during the acute stay. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: All patients ≥70 years old admitted for hip fracture to the emergency department and hospitalized in our unit for perioperative geriatric care after hip fracture surgery under general anesthesia between July 2009 and December 2019 in an academic hospital in Paris. METHODS: Demographic, clinical, and biological data and all medications administered pre-, peri-, and postoperatively were prospectively collected by 3 geriatricians. Postoperative delirium in the unit for perioperative geriatric care was assessed by using the confusion assessment method scale. Logistic regression analysis was used to assess variables independently associated with postoperative delirium. RESULTS: A total of 490 patients were included [mean (SD) age 87 (6) years]; 215 (44%) had postoperative delirium. The occurrence was not associated with therapeutics administered during the dedicated orthogeriatric care pathway. Probability of postoperative delirium was associated with advanced age [>90 years, odds ratio (OR) 2.03, 95% confidence interval (CI) 1.07-3.89], dementia (OR 3.51, 95% CI 2.14--5.82), depression (OR 1.85, 95% CI 1.14-3.01), and preoperative use of beta-blockers (OR 1.75, 95% CI 1.10-2.79). CONCLUSIONS AND IMPLICATIONS: No emergency or anesthetic drugs were significantly associated with postoperative delirium. Further studies are needed to demonstrate a possible causal link between preoperative use of beta-blockers and postoperative delirium.

[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.

[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.

[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.

Fecal impaction is associated with postoperative urinary retention after hip fracture surgery.

BACKGROUND: Postoperative urinary retention (POUR) is a common hip fracture (HF) complication. Although fecal impaction (FI) is one of the oft-cited causes of POUR in clinical practice, evidence regarding this association is scarce. OBJECTIVE: The aim of this study was to determine whether FI was associated with POUR after HF surgery in older patients. METHODS: All patients consecutively admitted after a HF surgery in a geriatric perioperative unit were included in this cross-sectional study. FI was systematically assessed by a digital rectal exam at admission and according to clinical suspicion during the hospital stay. The dependent variable was POUR, systematically screened according to the department protocol and defined as a bladder volume>400ml requiring catheterization. The association between FI and POUR was assessed by multivariable analysis. RESULTS: A total of 256 patients were included (mean [SD] age 86 [6] years), (76% women): 108 (42%) presented FI and 63 (25%) POUR. The frequency of FI was higher with than without POUR (73% vs. 32%, P<0.001). On multivariable analysis, after adjusting for age, sex, Cumulative Illness Rating Scale score and anticholinergic load, FI was the only factor independently associated with POUR (odds ratio 4.78) [95% confidence interval 2.44-9.71], P<0.001. CONCLUSIONS: FI was the only independent factor associated with POUR after HF surgery in older adults. Further studies are needed to optimize perioperative geriatric care including FI and POUR assessment and management.

FOXO3 targets are reprogrammed as Huntington's disease neural cells and striatal neurons face senescence with p16INK4a increase.

Neurodegenerative diseases (ND) have been linked to the critical process in aging-cellular senescence. However, the temporal dynamics of cellular senescence in ND conditions is unresolved. Here, we show senescence features develop in human Huntington's disease (HD) neural stem cells (NSCs) and medium spiny neurons (MSNs), including the increase of p16INK4a , a key inducer of cellular senescence. We found that HD NSCs reprogram the transcriptional targets of FOXO3, a major cell survival factor able to repress cell senescence, antagonizing p16INK4a expression via the FOXO3 repression of the transcriptional modulator ETS2. Additionally, p16INK4a promotes cellular senescence features in human HD NSCs and MSNs. These findings suggest that cellular senescence may develop during neuronal differentiation in HD and that the FOXO3-ETS2-p16INK4a axis may be part of molecular responses aimed at mitigating this phenomenon. Our studies identify neuronal differentiation with accelerated aging of neural progenitors and neurons as an alteration that could be linked to NDs.

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.

Procalcitonin and C-Reactive Protein for Bacterial Infection Diagnosis in Elderly Patients After Traumatic Orthopedic Surgery.

BACKGROUND: Biomarkers prove valuable for diagnosing postoperative bacterial infection, but data in elderly patients are scarce. Here we analyze how procalcitonin and C-reactive protein (CRP) perform for bacterial infection diagnosis after traumatic orthopedic surgery in elderly patients. METHODS: We included all patients admitted to our perioperative geriatrics unit after traumatic orthopedic surgery. Patients on antibiotics, presenting preoperative bacterial infection, or without procalcitonin measurement were excluded. Clinical and biological data were collected prospectively. Medical charts were reviewed by three experts blinded to biomarker results to assess bacterial infection diagnosis. Areas under the curve and 90%-specificity thresholds were analyzed for baseline procalcitonin and CRP levels and relative variations. RESULTS: Analysis included 229 patients (median age 86 years, hip fracture 83%), of which 40 had bacterial infection (pneumonia [n = 23], urinary tract infection [n = 8]; median delay to onset: 2 days post-admission). For bacterial infection diagnosis, the computed areas under the curve were not significantly different (procalcitonin-baseline 0.64 [95% confidence interval: 0.57-0.70]; procalcitonin-relative variation 0.65 [0.59-0.71]; CRP-baseline 0.68 [0.61-0.74]; CRP-relative variation 0.70 [0.64-0.76]). The 90%-specificity thresholds were 0.75 µg/L for procalcitonin-baseline, +62% for procalcitonin-variation, 222 mg/L for CRP-baseline, +111% for CRP-variation. CONCLUSIONS: Diagnostic performances of procalcitonin and CRP were not significantly different. Baseline levels and relative variations of these biomarkers showed little diagnostic value after traumatic orthopedic surgery in elderly patients.

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.

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.

[Lewy body dementia: therapeutic propositions according to evidence based medicine and practice]. / Maladie à corps de Lewy avec troubles neurocognitifs majeurs : le traitement selon la médecine basée sur les preuves et en pratique.

Lewy body dementia (LBD) may present with two clinical forms: dementia with Lewy bodies (DLB) and Parkinson's disease with dementia. LBD is characterized by a profound deficiency of acetylcholine and a deficiency of dopamine. The cholinergic deficit is implicated in major attention disorders and fluctuations. Acetylcholinesterase inhibitors (donepezil or rivastigmine) were studied in several double-blind placebo-controlled studies. The meta-analyzes show a moderate benefit on the cognitive level and on some psychiatric manifestations including hallucinations. A disabling parkinsonian syndrome can be treated with L-dopa as in Parkinson's disease. However, the results are often limited because the increase in doses is restricted by cognitive and psychobehavioral disorders. Hallucinations may require antipsychotic treatment and the best documented drug is clozapine. Some other antipsychotics were assessed but in few therapeutic trials, and appear less efficacious, and with bad tolerance. Finally, the last of LBD cardinal disorders, REM sleep behavior disorders can be improved by melatonin. Other manifestations of LBD are troublesome. Some therapeutic trials with modafinil were proposed to improve diurnal hypersomnia. Anxiety and depression are often difficult to be treated. For antidepressant drugs, the first choice seems to be selective serotonin receptor inhibitors. Treatment for orthostatic hypotension, constipation, and swallowing dysfunction has also been more or less documented. In each case, non-drug management is considered (cognitive stimulation, physiotherapy, speech therapy, etc.). Finally, a therapeutic strategy is suggested, based on the medical and clinical experience. This strategy underlines the importance to improve cholinergic deficit and sleep disturbances. It also stresses the importance of a careful revision of all drugs administered to the patients with a peculiar attention to the anticholinergic treatment.

Contribution of geriatric model to the management of an epileptic seizure or epilepsy.

Epileptic seizures and epilepsy appear frequent in the elderly. The diagnosis is often more difficult and therapeutic decisions are often debated. In this context, the implementation of a rigorous analysis and reasoning to correctly determine the various components at the origin of the epileptic seizure is fundamental. Some data are in favor of a decrease of the epileptogenic threshold with advancing age. But, this is in no way sufficient to account for the occurrence of a seizure. It is necessary to add to aging factor a chronic pathology responsible for brain lesions (micro or macroscopic: stroke, Alzheimer's disease, brain tumors...) and/or acute aggression (trauma, central nervous system infection, metabolic or toxic disorders...) to trigger a seizure. It is notable that an association of some mild brain lesions and a weak metabolic disturbance could trigger a seizure. In these cases, the probability of trigger a new seizure with another mild precipitant factor appears very high. This analysis is necessary and particularly useful in these multi-pathological patients. It also makes it easier to decide whether to start antiepileptic treatment. In case of a triggering factor such as hyponatremia, for example, in the absence of associated underlying lesions, it seems legitimate not to start treatment at the first epileptic seizure. On the other hand, if hyponatremia (often less deep than in the previous case) is associated with sequel of stroke or Alzheimer's disease, it seems reasonable to start treatment quickly.