Hypoxie-ischémie cérébrale néonatale : rôle de la voie de JNK et implication de l'autophagie dans la mort neuronale

Résumé : Malgré les immenses progrès réalisés depuis plusieurs années en médecine obstétricale ainsi qu'en réanimation néonatale et en recherche expérimentale, l'asphyxie périnatale, une situation de manque d'oxygène autour du moment de la naissance, reste une cause majeure de mortalité et de morbidité neurologique à long terme chez l'enfant (retard mental, paralysie cérébrale, épilepsie, problèmes d'apprentissages) sans toutefois de traitement pharmacologique réel. La nécessité de développer de nouvelles stratégies thérapeutiques pour les complications de l'asphyxie périnatale est donc aujourd'hui encore essentielle. Le but général de ce travail est l'identification de nouvelles cibles thérapeutiques impliquées dans des mécanismes moléculaires pathologiques induits par l'hypoxie-ischémie (HI) dans le cerveau immature. Pour cela, le modèle d'asphyxie périnatale (proche du terme) le plus reconnu chez le rongeur a été développé (modèle de Rice et Vannucci). Il consiste en la ligature permanente d'une artère carotide commune (ischémie) chez le raton de 7 jours combinée à une période d'hypoxie à 8% d'oxygène. Il permet ainsi d'étudier les lésions de type hypoxique-ischémique dans différentes régions cérébrales dont le cortex, l'hippocampe, le striatum et le thalamus. La première partie de ce travail a abordé le rôle de deux voies de MAPK, JNK et p38, après HI néonatale chez le raton à l'aide de peptides inhibiteurs. Tout d'abord, nous avons démontré que D-JNKI1, un peptide inhibiteur de la voie de JNK présentant de fortes propriétés neuroprotectrices dans des modèles d'ischémie cérébrale adulte ainsi que chez le jeune raton, peut intervenir sur différentes voies de mort dont l'activation des calpaïnes (marqueur de la nécrose précoce), l'activation de la caspase-3 (marqueur de l'apoptose) et l'expression de LC3-II (marqueur de macroautophagie). Malgré ces effets positifs le traitement au D-JNKI1 ne modifie pas l'étendue de la lésion cérébrale. L'action limitée de D-JNKI1 peut s'expliquer par une implication modérée des JNKs (faiblement activées et principalement l'isotype JNK3) après HI néonatale sévère. Au contraire, l'inhibition de la voie de nNOS/p38 par le peptide DTAT-GESV permet une augmentation de 20% du volume du tissu sain à court et long terme. Le second projet a étudié les effets de l'HI néonatale sur l'autophagie neuronale. En effet, l'autophagie est un processus catabolique essentiel au bien-être de la cellule. Le type principal d'autophagie (« macroautophagie » , que nous appellerons par la suite « autophagie ») consiste en la séquestration d'éléments à dégrader (protéines ou organelles déficients) dans un compartiment spécialisé, l'autophagosome, qui fusionne avec un lysosome pour former un autolysosome où le contenu est dégradé par les hydrolases lysosomales. Depuis peu, l'excès ou la dérégulation de l'autoptiagie a pu être impliqué dans la mort cellulaire en certaines conditions de stress. Ce travail démontre que l'HI néonatale chez le raton active fortement le flux autophagique, c'est-à-dire augmente la formation des autophagosomes et des autolysosomes, dans les neurones en souffrance. De plus, la relation entre l'autophagie et l'apoptose varie selon la région cérébrale. En effet, alors que dans le cortex les neurones en voie de mort présentent des caractéristiques mixtes apoptotiques et autophagiques, ceux du CA3 sont essentiellement autophagiques et ceux du CA1 sont principalement apoptotiques. L'induction de l'autophagie après HI néonatale semble donc participer à la mort neuronale soit par l'enclenchement de l'apoptose soit comme mécanisme de mort en soi. Afin de comprendre la relation pouvant exister entre autophagie et apoptase un troisième projet a été réalisé sur des cultures primaires de neurones corticaux exposés à un stimulus apoptotique classique, la staurosporine (STS). Nous avons démontré que l'apoptose induite par la STS était précédée et accompagnée par une forte activation du flux autophagique neuronal. L'inhibition de l'autophagie de manière pharmacologique (3-MA) ou plus spécifiquement par ARNs d'interférence dirigés contre deux protéines autophagiques importantes (Atg7 et Atg5) a permis de mettre en évidence des rôles multiples de l'autophagie dans la mort neuronale. En effet, l'autophagie prend non seulement part à une voie de mort parallèle à l'apoptose pouvant être impliquée dans l'activation des calpaïnes, mais est également partiellement responsable de l'induction des voies apoptotiques (activation de la caspase-3 et translocation nucléaire d'AIF). En conclusion, ce travail a montré que l'inhibition de JNK par D-JNKI1 n'est pas un outil neuroprotecteur efficace pour diminuer la mort neuronale provoquée par l'asphyxie périnatalé sévère, et met en lumière deux autres voies thérapeutiques beaucoup plus prometteuses, l'inhibition de nNOS/p38 ou de l'autophagie. ABSTRACT : Despite enormous progress over the last«decades in obstetrical and neonatal medicine and experimental research, perinatal asphyxia, a situation of lack of oxygen around the time of the birth, remains a major cause of mortality and long term neurological morbidity in children (mental retardation, cerebral palsy, epilepsy, learning difficulties) without any effective treatment. It is therefore essential to develop new therapeutic strategies for the complications of perinatal asphyxia. The overall aim of this work was to identify new therapeutic targets involved in pathological molecular mechanisms induced by hypoxia-ischemia (HI) in the immature brain. For this purpose, the most relevant model of perinatal asphyxia (near term) in rodents has been developed (model of Rice and Vannucci). It consists in the permanent ligation of one common carotid artery (ischemia) in the 7-day-old rat combined with a period of hypoxia at 8% oxygen. This model allows the study of the hypoxic-ischemic lesion in different brain regions including the cortex, hippocampus, striatum and thalamus. The first part of this work addressed the role of two MAPK pathways (JNK and p38) after rat neonatal HI using inhibitory peptides. First, we demonstrated that D-JNKI1, a JNK peptide inhibitor presenting strong neuroprotective properties in models of cerebral ischemia in adult and young rats, could affect different cell death mechanisms including the activation of calpain (a marker of necrosis) and caspase-3 (a marker of apoptosis), and the expression of LC3-II (a marker of macroautophagy). Despite these positive effects, D-JNKI1 did not modify the extent of brain damage. The limited action of D-JNKI1 can be explained by the fact that JNKs were only moderately involved (weakly activated and principally the JNK3 isotype) after severe neonatal HI. In contrast, inhibition of nNOS/p38 by the peptide D-TAT-GESV increased the surviving tissue volume by around 20% at short and long term. The second project investigated the effects of neonatal HI on neuronal autophagy. Indeed, autophagy is a catabolic process essential to the well-being of the cell. The principal type of autophagy ("macroautophagy", that we shall henceforth call "autophagy") involves the sequestration of elements to be degraded (deficient proteins or organelles) in a specialized compartment, the autophagosome, which fuses with a lysosome to form an autolysosome where the content is degraded by lysosomal hydrolases. Recently, an excess or deregulation of autophagy has been implicated in cell death in some stress conditions. The present study demonstrated that rat neonatal HI highly enhanced autophagic flux, i.e. increased autophagosome and autolysosome formation, in stressed neurons. Moreover, the relationship between autophagy and apoptosis varies according to the brain region. Indeed, whereas dying neurons in the cortex exhibited mixed features of apoptosis and autophagy, those in CA3 were primarily autophagíc and those in CA1 were mainly apoptotic. The induction of autophagy after neonatal HI seems to participate in neuronal death either by triggering apoptosis or as a death mechanism per se. To understand the relationships that may exist between autophagy and apoptosis, a third project has been conducted using primary cortical neuronal cultures exposed to a classical apoptotic stimulus, staurosporine (STS). We demonstrated that STS-induced apoptosis was preceded and accompanied by a strong activation of neuronal autophagic flux. Inhibition of autophagy pharmacologically (3-MA) or more specifically by RNA interference directed against two important autophagic proteins (Atg7 and AtgS) showed multiple roles of autophagy in neuronal death. Indeed, autophagy was not only involved in a death pathway parallel to apoptosis possibly involved in the activation of calpains, but was also partially responsible for the induction of apoptotic pathways (caspase-3 activation and AIF nuclear translocation). In conclusion, this study showed that JNK inhibition by D-JNKI1 is not an effective neuroprotective tool for decreasing neuronal death following severe perinatal asphyxia, but highlighted two more promising therapeutic approaches, inhibition of the nNOSlp38 pathway or of autophagy.

Ammonia toxicity to the brain.

Hyperammonemia can be caused by various acquired or inherited disorders such as urea cycle defects. The brain is much more susceptible to the deleterious effects of ammonium in childhood than in adulthood. Hyperammonemia provokes irreversible damage to the developing central nervous system: cortical atrophy, ventricular enlargement and demyelination lead to cognitive impairment, seizures and cerebral palsy. The mechanisms leading to these severe brain lesions are still not well understood, but recent studies show that ammonium exposure alters several amino acid pathways and neurotransmitter systems, cerebral energy metabolism, nitric oxide synthesis, oxidative stress and signal transduction pathways. All in all, at the cellular level, these are associated with alterations in neuronal differentiation and patterns of cell death. Recent advances in imaging techniques are increasing our understanding of these processes through detailed in vivo longitudinal analysis of neurobiochemical changes associated with hyperammonemia. Further, several potential neuroprotective strategies have been put forward recently, including the use of NMDA receptor antagonists, nitric oxide inhibitors, creatine, acetyl-L-carnitine, CNTF or inhibitors of MAPKs and glutamine synthetase. Magnetic resonance imaging and spectroscopy will ultimately be a powerful tool to measure the effects of these neuroprotective approaches.

Intraoperative angiography reloaded: a new hybrid operating theater for combined endovascular and surgical treatment of cerebral arteriovenous malformations: a pilot study on 25 patients.

BACKGROUND: Multimodality treatment suites for patients with cerebral arteriovenous malformations (AVM) have recently become available. This study was designed to evaluate feasibility, safety and impact on treatment of a new intraoperative flat-panel (FP) based integrated surgical and imaging suite for combined endovascular and surgical treatment of cerebral AVM. METHODS: Twenty-five patients with AVMs to treat with combined endovascular and surgical interventions were prospectively enrolled in this consecutive case series. The hybrid suite allows combined endovascular and surgical approaches with intraoperative scanner-like imaging (XperCT®) and intraoperative 3D rotational angiography (3D-RA). The impact of intraoperative multimodal imaging on feasibility, workflow of combined interventions, surgery, and unexpected imaging findings were analyzed. RESULTS: Twenty-five patients (mean age 38 ± 18.6 year) with a median Spetzler-Martin grade 2 AVM (range 1-4) underwent combined endovascular and surgical procedures. Sixteen patients presented with a ruptured AVM and nine with an unruptured AVM. In 16 % (n = 4) of cases, intraoperative imaging visualized AVM remnants ≤3 mm and allowed for completion of the resections in the same sessions. Complete resection was confirmed in all n = 16 patients who had follow-up angiography one year after surgery so far. All diagnostic and therapeutical steps, including angiographic control, were performed without having to move the patients CONCLUSION: The hybrid neurointerventional suite was shown to be a safe and useful setup which allowed for unconstrained combined microsurgical and neuroradiological workflow. It reduces the need for extraoperative angiographic controls and subsequent potential surgical revisions a second time, as small AVM remnants can be detected with high security.

Serum procalcitonin as a marker of post-cardiac arrest syndrome and long-term neurological recovery, but not of early-onset infections, in comatose post-anoxic patients treated with therapeutic hypothermia.

OBJECTIVE: To examine the relationship of early serum procalcitonin (PCT) levels with the severity of post-cardiac arrest syndrome (PCAS), long-term neurological recovery and the risk of early-onset infections in patients with coma after cardiac arrest (CA) treated with therapeutic hypothermia (TH). METHODS: A prospective cohort of adult comatose CA patients treated with TH (33°C, for 24h) admitted to the medical/surgical intensive care unit, Lausanne University Hospital, was studied. Serum PCT was measured early after CA, at two time-points (days 1 and 2). The SOFA score was used to quantify the severity of PCAS. Diagnosis of early-onset infections (within the first 7 days of ICU stay) was made after review of clinical, radiological and microbiological data. Neurological recovery at 3 months was assessed with Cerebral Performance Categories (CPC), and was dichotomized as favorable (CPC 1-2) vs. unfavorable (CPC 3-5). RESULTS: From December 2009 to April 2012, 100 patients (median age 64 [interquartile range 55-73] years, median time from collapse to ROSC 20 [11-30]min) were studied. Peak PCT correlated with SOFA score at day 1 (Spearman's R=0.44, p<0.0001) and was associated with neurological recovery at 3 months (peak PCT 1.08 [0.35-4.45]ng/ml in patients with CPC 1-2 vs. 3.07 [0.89-9.99] ng/ml in those with CPC 3-5, p=0.01). Peak PCT did not differ significantly between patients with early-onset vs. no infections (2.14 [0.49-6.74] vs. 1.53 [0.46-5.38]ng/ml, p=0.49). CONCLUSIONS: Early elevations of serum PCT levels correlate with the severity of PCAS and are associated with worse neurological recovery after CA and TH. In contrast, elevated serum PCT did not correlate with early-onset infections in this setting.

Influence of chronic hyperglycemia on cerebral microvascular remodeling: an in vivo study using perfusion computed tomography in acute ischemic stroke patients.

BACKGROUND AND PURPOSE: To investigate the effect of chronic hyperglycemia on cerebral microvascular remodeling using perfusion computed tomography. METHODS: We retrospectively identified 26 patients from our registry of 2453 patients who underwent a perfusion computed tomographic study and had their hemoglobin A1c (HbA1c) measured. These 26 patients were divided into 2 groups: those with HbA1c>6.5% (n=15) and those with HbA1c≤6.5% (n=11). Perfusion computed tomographic studies were processed using a delay-corrected, deconvolution-based software. Perfusion computed tomographic values were compared between the 2 patient groups, including mean transit time, which relates to the cerebral capillary architecture and length. RESULTS: Mean transit time values in the nonischemic cerebral hemisphere were significantly longer in the patients with HbA1c>6.5% (P=0.033), especially in the white matter (P=0.005). Significant correlation (R=0.469; P=0.016) between mean transit time and HbA1c level was observed. CONCLUSIONS: Our results from a small sample suggest that chronic hyperglycemia may be associated with cerebral microvascular remodeling in humans. Additional prospective studies with larger sample size are required to confirm this observation.

Brain lactate metabolism in humans with subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Lactate is central for the regulation of brain metabolism and is an alternative substrate to glucose after injury. Brain lactate metabolism in patients with subarachnoid hemorrhage has not been fully elucidated. METHODS: Thirty-one subarachnoid hemorrhage patients monitored with cerebral microdialysis (CMD) and brain oxygen (PbtO(2)) were studied. Samples with elevated CMD lactate (>4 mmol/L) were matched to PbtO(2) and CMD pyruvate and categorized as hypoxic (PbtO(2) <20 mm Hg) versus nonhypoxic and hyperglycolytic (CMD pyruvate >119 μmol/L) versus nonhyperglycolytic. RESULTS: Median per patient samples with elevated CMD lactate was 54% (interquartile range, 11%-80%). Lactate elevations were more often attributable to cerebral hyperglycolysis (78%; interquartile range, 5%-98%) than brain hypoxia (11%; interquartile range, 4%-75%). Mortality was associated with increased percentage of samples with elevated lactate and brain hypoxia (28% [interquartile range 9%-95%] in nonsurvivors versus 9% [interquartile range 3%-17%] in survivors; P=0.02) and lower percentage of elevated lactate and cerebral hyperglycolysis (13% [interquartile range, 1%-87%] versus 88% [interquartile range, 27%-99%]; P=0.07). Cerebral hyperglycolytic lactate production predicted good 6-month outcome (odds ratio for modified Rankin Scale score, 0-3 1.49; CI, 1.08-2.05; P=0.016), whereas increased lactate with brain hypoxia was associated with a reduced likelihood of good outcome (OR, 0.78; CI, 0.59-1.03; P=0.08). CONCLUSIONS: Brain lactate is frequently elevated in subarachnoid hemorrhage patients, predominantly because of hyperglycolysis rather than hypoxia. A pattern of increased cerebral hyperglycolytic lactate was associated with good long-term recovery. Our data suggest that lactate may be used as an aerobic substrate by the injured human brain.

Cerebral vasculitis complicating postoperative meningitis: the role of steroids revisited.

Meningitis due to Streptococcus pneumoniae is a rare complication of trans-sphenoidal surgery. We present the case of a patient who developed pneumococcal meningitis with associated bacteraemia after elective endoscopic trans-sphenoidal resection of a pituitary macro-adenoma. After initial treatment with ceftriaxone and dexamethasone, the patient made a good recovery and dexamethasone was discontinued. Two days later the patient's condition deteriorated rapidly, presenting focal and diffuse neurological deficits. Cerebral MRI revealed widespread punctate ischaemic-type lesions affecting both anterior and posterior vascular territories bilaterally and involving features consistent with cerebral vasculitis. Antibiotic treatment was broadened to include meropenem and dexamethasone was restarted, but the patient remained in a comatose state and died 14 days later. Steroid treatment may play a dual role in this poorly characterised infectious complication of trans-sphenoidal pituitary surgery. This possibility is discussed and the options for prophylaxis are reviewed.

Impact of tight glycemic control on cerebral glucose metabolism after severe brain injury: a microdialysis study.

OBJECTIVES: To analyze the effect of tight glycemic control with the use of intensive insulin therapy on cerebral glucose metabolism in patients with severe brain injury. DESIGN: Retrospective analysis of a prospective observational cohort. SETTING: University hospital neurologic intensive care unit. PATIENTS: Twenty patients (median age 59 yrs) monitored with cerebral microdialysis as part of their clinical care. INTERVENTIONS: Intensive insulin therapy (systemic glucose target: 4.4-6.7 mmol/L [80-120 mg/dL]). MEASUREMENTS AND MAIN RESULTS: Brain tissue markers of glucose metabolism (cerebral microdialysis glucose and lactate/pyruvate ratio) and systemic glucose were collected hourly. Systemic glucose levels were categorized as within the target "tight" (4.4-6.7 mmol/L [80-120 mg/dL]) vs. "intermediate" (6.8-10.0 mmol/L [121-180 mg/dL]) range. Brain energy crisis was defined as a cerebral microdialysis glucose <0.7 mmol/L with a lactate/pyruvate ratio >40. We analyzed 2131 cerebral microdialysis samples: tight systemic glucose levels were associated with a greater prevalence of low cerebral microdialysis glucose (65% vs. 36%, p < 0.01) and brain energy crisis (25% vs.17%, p < 0.01) than intermediate levels. Using multivariable analysis, and adjusting for intracranial pressure and cerebral perfusion pressure, systemic glucose concentration (adjusted odds ratio 1.23, 95% confidence interval [CI] 1.10-1.37, for each 1 mmol/L decrease, p < 0.001) and insulin dose (adjusted odds ratio 1.10, 95% CI 1.04-1.17, for each 1 U/hr increase, p = 0.02) independently predicted brain energy crisis. Cerebral microdialysis glucose was lower in nonsurvivors than in survivors (0.46 +/- 0.23 vs. 1.04 +/- 0.56 mmol/L, p < 0.05). Brain energy crisis was associated with increased mortality at hospital discharge (adjusted odds ratio 7.36, 95% CI 1.37-39.51, p = 0.02). CONCLUSIONS: In patients with severe brain injury, tight systemic glucose control is associated with reduced cerebral extracellular glucose availability and increased prevalence of brain energy crisis, which in turn correlates with increased mortality. Intensive insulin therapy may impair cerebral glucose metabolism after severe brain injury.

Outcome at two years of age in a Swiss national cohort of extremely preterm infants born between 2000 and 2008.

BACKGROUND: While survival rates of extremely preterm infants have improved over the last decades, the incidence of neurodevelopmental disability (ND) in survivors remains high. Representative current data on the severity of disability and of risk factors associated with poor outcome in this growing population are necessary for clinical guidance and parent counselling. METHODS: Prospective longitudinal multicentre cohort study of preterm infants born in Switzerland between 24(0/7) and 27(6/7) weeks gestational age during 2000-2008. Mortality, adverse outcome (death or severe ND) at two years, and predictors for poor outcome were analysed using multilevel multivariate logistic regression. Neurodevelopment was assessed using Bayley Scales of Infant Development II. Cerebral palsy was graded after the Gross Motor Function Classification System. RESULTS: Of 1266 live born infants, 422 (33%) died. Follow-up information was available for 684 (81%) survivors: 440 (64%) showed favourable outcome, 166 (24%) moderate ND, and 78 (11%) severe ND. At birth, lower gestational age, intrauterine growth restriction and absence of antenatal corticosteroids were associated with mortality and adverse outcome (p < 0.001). At 36(0/7) weeks postmenstrual age, bronchopulmonary dysplasia, major brain injury and retinopathy of prematurity were the main predictors for adverse outcome (p < 0.05). Survival without moderate or severe ND increased from 27% to 39% during the observation period (p = 0.02). CONCLUSIONS: In this recent Swiss national cohort study of extremely preterm infants, neonatal mortality was determined by gestational age, birth weight, and antenatal corticosteroids while neurodevelopmental outcome was determined by the major neonatal morbidities. We observed an increase of survival without moderate or severe disability.

Official positions of the International Society for Clinical Densitometry (ISCD) on DXA evaluation in children and adolescents.

Dual-energy X-ray absorptiometry (DXA) is the most widely used technical instrument for evaluating bone mineral content (BMC) and density (BMD) in patients of all ages. However, its use in pediatric patients, during growth and development, poses a much more complex problem in terms of both the technical aspects and the interpretation of the results. For the adults population, there is a well-defined term of reference: the peak value of BMD attained by young healthy subjects at the end of skeletal growth. During childhood and adolescence, the comparison can be made only with healthy subjects of the same age, sex and ethnicity, but the situation is compounded by the wide individual variation in the process of skeletal growth (pubertal development, hormone action, body size and bone size). The International Society for Clinical Densitometry (ISCD) organized a Pediatric Position Development Conference to discuss the specific problems of bone densitometry in growing subjects (9-19 years of age) and to provide essential recommendations for its clinical use.

Being Small for Gestational Age: Does it Matter for the Neurodevelopment of Premature Infants? A Cohort Study.

BACKGROUND: Whether being small for gestational age (SGA) increases the risk of adverse neurodevelopmental outcome in premature infants remains controversial. OBJECTIVE: to study the impact of SGA (birthweight < percentile 10) on cognition, behavior, neurodevelopmental impairment and use of therapy at 5 years old. METHODS: This population-based prospective cohort included infants born before 32 weeks of gestation. Cognition was evaluated with the K-ABC, and behavior with the Strengths and Difficulties Questionnaire (SDQ). Primary outcomes were cognitive and behavioral scores, as well as neurodevelopmental impairment (cognitive score < 2SD, hearing loss, blindness, or cerebral palsy). The need of therapy, an indirect indicator of neurodevelopmental impairment, was a secondary outcome. Linear and logistic regression models were used to analyze the association of SGA with neurodevelopment. RESULTS: 342/515 (76%) premature infants were assessed. SGA was significantly associated with hyperactivity scores of the SDQ (coefficient 0.81, p < 0.04), but not with cognitive scores, neurodevelopmental impairment or the need of therapy. Gestational age, socio-economic status, and major brain lesions were associated with cognitive outcome in the univariate and multivariate model, whereas asphyxia, sepsis and bronchopulmonary dysplasia were associated in the univariate model only. Severe impairment was associated with fetal tobacco exposition, asphyxia, gestational age and major brain lesions. Different neonatal factors were associated with the use of single or multiple therapies: children with one therapy were more likely to have suffered birth asphyxia or necrotizing enterocolitis, whereas the need for several therapies was predicted by major brain lesions. DISCUSSION: In this large cohort of premature infants, assessed at 5 years old with a complete panel of tests, SGA was associated with hyperactive behavior, but not with cognition, neurodevelopmental impairment or use of therapy. Birthweight <10th percentile alone does not appear to be an independent risk factor of neurodevelopmental adverse outcome in preterm children.

Visual signs and symptoms in patients with the visual variant of Alzheimer disease.

BACKGROUND: Prominent visual symptoms can present in the visual variant of Alzheimer's disease (VVAD). Ophthalmologists have a significant role to play in the early diagnosis of VVAD. METHODS: We retrospectively reviewed the files of ten consecutive patients diagnosed with VVAD. All patients had a full neuro-ophthalmologic examination, a formal neurological and neuro-psychological testing, and cerebral MRI to confirm diagnosis. In addition, functional neuroimaging was obtained in seven patients. RESULTS: The common primary symptom at presentation with all patients was difficulty with near vision (reading difficulty n = 8, "visual blur" in near vision n = 2), and difficulty writing (n = 3). Following assessment, impaired reading and writing skills were evident in 9/10 and 8/10 patients respectively. Median distance visual acuity was 20/25 and at near the median visual acuity was J6. Partial homonymous visual field defect was detected in 80 % (8/10) of the patients. Color vision was impaired in all patients when tested with Ishihara pseudoisochromatic plates, but simple color naming was normal in 8/9 tested patients. Simultanagnosia was present in 8/10 patients. Vision dysfunction corresponded with cerebral MRI findings where parieto-occipital cortical atrophy was observed in all patients. PET scan (5 patients) or SPECT (2 patients) revealed parieto-occipital dysfunction (hypometabolism or hypoperfusion) in all 7 tested patients CONCLUSIONS: Visual difficulties are prominent in VVAD. Dyslexia, incomplete homonymous hemianopia, preserved color identification with abnormal color vision on Ishihara, and simultanagnosia were all symptoms observed frequently in this patient series. Ophthalmologists should be aware of the possibility of neurodegenerative disorders such as VVAD in patients with unexplained visual complaints, in particular reading difficulties.

Devenir et prise en charge des enfants grands prématurés [Neurodevelopmental outcome of very premature infants].

Very preterm infants are at risk of neurodevelopmental impairments, which may affect motor development, intelligence and behavior. Neurodevelopmental follow-up is offered to these children who represent 1% of Swiss births, and may show abnormal motor tone, which sometimes resolves spontaneously or evolves in cerebral palsy. Standardized tests explore intellectual functioning and may allow the diagnosis of specific learning impediments. Finally, behavior is assessed with standardized questionnaires which can reveal hyperactivity with or without attention deficit, impaired social relations, psychiatric troubles or autism, all more frequent amongst preterm children.

Neuroenergetic Response to Prolonged Cerebral Glucose Depletion after Severe Brain Injury and the Role of Lactate.

Lactate may represent a supplemental fuel for the brain. We examined cerebral lactate metabolism during prolonged brain glucose depletion (GD) in acute brain injury (ABI) patients monitored with cerebral microdialysis (CMD). Sixty episodes of GD (defined as spontaneous decreases of CMD glucose from normal to low [<1.0 mmol/L] for at least 2 h) were identified among 26 patients. During GD, we found a significant increase of CMD lactate (from 4±2.3 to 5.4±2.9 mmol/L), pyruvate (126.9±65.1 to 172.3±74.1 μmol/L), and lactate/pyruvate ratio (LPR; 27±6 to 35±9; all, p<0.005), while brain oxygen and blood lactate remained normal. Dynamics of lactate and glucose supply during GD were further studied by analyzing the relationships between blood and CMD samples. There was a strong correlation between blood and brain lactate when LPR was normal (r=0.56; p<0.0001), while an inverse correlation (r=-0.11; p=0.04) was observed at elevated LPR >25. The correlation between blood and brain glucose also decreased from r=0.62 to r=0.45. These findings in ABI patients suggest increased cerebral lactate delivery in the absence of brain hypoxia when glucose availability is limited and support the concept that lactate acts as alternative fuel.

Brain structure in asymptomatic FMR1 premutation carriers at risk for fragile X-associated tremor/ataxia syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset movement disorder affecting FMR1 premutation carriers, is associated with cerebral and cerebellar lesions. The aim of this study was to test whether computational anatomy can detect similar patterns in asymptomatic FMR1 premutation carriers (mean age 46.7 years) with qualitatively normal -appearing grey and white matter on brain MRI. We used a multimodal imaging protocol to characterize brain anatomy by automated assessment of gray matter volume and white matter properties. Structural changes in the hippocampus and in the cerebellar motor network with decreased gray matter volume in lobule VI and white matter alterations of the corresponding afferent projections through the middle cerebellar peduncles are demonstrated. Diffuse subcortical white matter changes in both hemispheres, without corresponding gray matter alterations, are only identified through age × group interactions. We interpret the hippocampal fimbria and cerebellar changes as early alterations with a possible neurodevelopmental origin. In contrast, progression of the diffuse cerebral hemispheric white matter changes suggests a neurodegenerative process, leading to late-onset lesions, which may mark the imminent onset of FXTAS.