An initial MRI picture of limbic encephalitis in subacute sclerosing panencephalitis.

BACKGROUND: Subacute sclerosing panencephalitis (SSPE) is a rare and severe long-term complication of measles. Hallmarks of this entity include progressive cognitive decline, myoclonia, a generalized periodic pattern on EEG and deep white matter abnormalities on MRI. However, imaging can be normal in early stages. AIM: We report herein the case of a previously healthy 13-years-old girl with an unusual radiological presentation. RESULTS: She presented with unilateral myoclonia, cognitive decline with memory impairment and a first brain MRI with swelling of both hippocampi mimicking limbic encephalitis. Measles antibodies were positive in CSF and the EEG showed slow periodic complexes. CONCLUSION: This unusual radiological presentation has never been described in SSPE. Relationship between virus and limbic system are discussed.

Clinical neurophysiological assessment of sepsis-associated brain dysfunction: a systematic review.

IntroductionSeveral studies have reported the presence of electroencephalography (EEG) abnormalities or altered evoked potentials (EPs) during sepsis. However, the role of these tests in the diagnosis and prognostic assessment of sepsis-associated encephalopathy remains unclear.MethodsWe performed a systematic search for studies evaluating EEG and/or EPs in adult (¿18 years) patients with sepsis-associated encephalopathy. The following outcomes were extracted: a) incidence of EEG/EP abnormalities; b) diagnosis of sepsis-associated delirium or encephalopathy with EEG/EP; c) outcome.ResultsAmong 1976 citations, 17 articles met the inclusion criteria. The incidence of EEG abnormalities during sepsis ranged from 12% to 100% for background abnormality and 6% to 12% for presence of triphasic waves. Two studies found that epileptiform discharges and electrographic seizures were more common in critically ill patients with than without sepsis. In one study, EEG background abnormalities were related to the presence and the severity of encephalopathy. Background slowing or suppression and the presence of triphasic waves were also associated with higher mortality. A few studies demonstrated that quantitative EEG analysis and EP could show significant differences in patients with sepsis compared to controls but their association with encephalopathy and outcome was not evaluated.ConclusionsAbnormalities in EEG and EPs are present in the majority of septic patients. There is some evidence to support EEG use in the detection and prognostication of sepsis-associated encephalopathy, but further clinical investigation is needed to confirm this suggestion.

Sudden death and cocaine abuse

We read with great interest the results of the study by Lucena et al.(1) and present the following comments related to the paper. Lucena et al. presented a series of 21-cocaine-related sudden deaths (SD) showing two main structural abnormalities, cardiac hypertrophy and atherosclerotic coronary disease. Both abnormalities have been previously considered as a consequence of a chronic cocaine abuse, but could also be related to others cardiovascular risk factors, as admitted by Lucena et al.

Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets.

Fibroblast growth factor 23 (FGF23) is a circulating factor secreted by osteocytes that is essential for phosphate homeostasis. In kidney proximal tubular cells FGF23 inhibits phosphate reabsorption and leads to decreased synthesis and enhanced catabolism of 1,25-dihydroxyvitamin D3 (1,25[OH]2 D3 ). Excess levels of FGF23 cause renal phosphate wasting and suppression of circulating 1,25(OH)2 D3 levels and are associated with several hereditary hypophosphatemic disorders with skeletal abnormalities, including X-linked hypophosphatemic rickets (XLH) and autosomal recessive hypophosphatemic rickets (ARHR). Currently, therapeutic approaches to these diseases are limited to treatment with activated vitamin D analogues and phosphate supplementation, often merely resulting in partial correction of the skeletal aberrations. In this study, we evaluate the use of FGFR inhibitors for the treatment of FGF23-mediated hypophosphatemic disorders using NVP-BGJ398, a novel selective, pan-specific FGFR inhibitor currently in Phase I clinical trials for cancer therapy. In two different hypophosphatemic mouse models, Hyp and Dmp1-null mice, resembling the human diseases XLH and ARHR, we find that pharmacological inhibition of FGFRs efficiently abrogates aberrant FGF23 signaling and normalizes the hypophosphatemic and hypocalcemic conditions of these mice. Correspondingly, long-term FGFR inhibition in Hyp mice leads to enhanced bone growth, increased mineralization, and reorganization of the disturbed growth plate structure. We therefore propose NVP-BGJ398 treatment as a novel approach for the therapy of FGF23-mediated hypophosphatemic diseases.

Ictal cerebral positron emission tomography (PET) in focal status epilepticus.

The diagnosis of focal status epilepticus (SE) can be challenging, particularly when clinical manifestations leave doubts about its nature, and electroencephalography (EEG) is not conclusive. This work addresses the utility of ictal (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) in focal SE, which was performed in eight patients in whom SE was finally diagnosed. Clinical, MRI and EEG data were reviewed. (18)F-FDG-PET proved useful: (1) to establish the diagnosis of focal SE, when clinical elements were equivocal or the EEG did not show clear-cut epileptiform abnormalities; (2) to delineate the epileptogenic area in view of possible resective surgery; and (3) when clinical features, MRI and EEG were incongruent regarding the origin of SE. We suggest that ictal (18)F-FDG-PET may represent a valuable diagnostic tool in selected patients with focal SE or frequent focal seizures.

Cardiomyopathie de tako-tsubo: une entité clinique rare et méconnue [Tako-tsubo cardiomyopathy: a rare and badly known clinical entity]

Tako-tsubo cardiomyopathy or "transient left ventricular (LV) apical ballooning" clinically presents like acute myocardial infarction without angiographic stenosis on coronary angiogram and a transient (reversible) LV apical ballooning. We discuss here about a 56-year-old woman complains of first constrictive chest pain with ST elevation in leads V2-V6 and minimal enzymatic release. Coronary angiogram demonstrates vessels without stenosis and the left ventriculogram an extensive LV apical wall motion abnormalities. LV dysfunction will only be transient since 24 hours after admission echographic images demonstrate quite complete recovery of LV systolic function. The pain disappears 12 hours after admission and the creatine kinase level normalize after 48 hours.

Silencing mutant ataxin-3 rescues motor deficits and neuropathology in machado-joseph disease transgenic mice.

Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly-inherited neurodegenerative disorder caused by the over-repetition of a CAG codon in the MJD1 gene. This expansion translates into a polyglutamine tract that confers a toxic gain-of-function to the mutant protein - ataxin-3, leading to neurodegeneration in specific brain regions, with particular severity in the cerebellum. No treatment able to modify the disease progression is available. However, gene silencing by RNA interference has shown promising results. Therefore, in this study we investigated whether lentiviral-mediated allele-specific silencing of the mutant ataxin-3 gene, after disease onset, would rescue the motor behavior deficits and neuropathological features in a severely impaired transgenic mouse model of MJD. For this purpose, we injected lentiviral vectors encoding allele-specific silencing-sequences (shAtx3) into the cerebellum of diseased transgenic mice expressing the targeted C-variant of mutant ataxin-3 present in 70% of MJD patients. This variation permits to discriminate between the wild-type and mutant forms, maintaining the normal function of the wild-type allele and silencing only the mutant form. Quantitative analysis of rotarod performance, footprint and activity patterns revealed significant and robust alleviation of gait, balance (average 3-fold increase of rotarod test time), locomotor and exploratory activity impairments in shAtx3-injected mice, as compared to control ones injected with shGFP. An important improvement of neuropathology was also observed, regarding the number of intranuclear inclusions, calbindin and DARPP-32 immunoreactivity, fluorojade B and Golgi staining and molecular and granular layers thickness. These data demonstrate for the first time the efficacy of gene silencing in blocking the MJD-associated motor-behavior and neuropathological abnormalities after the onset of the disease, supporting the use of this strategy for therapy of MJD.

The expansion of 300 CTG repeats in myotonic dystrophy transgenic mice does not induce sensory or motor neuropathy.

Although many studies have been carried out to verify the involvement of the peripheral nervous system (PNS) in dystrophia myotonica (DM1) patients, the results remain controversial. The generation of DM1 transgenic mice displaying the human DM1 phenotype provides a useful tool to investigate the type and incidence of structural abnormalities in the PNS. In the present study, the morphological and morphometric analysis of semi-thin sections of sciatic and sural nerves, lumbar dorsal root ganglia (DRG) and lumbar spinal cords revealed that in DM1 transgenic mice carrying 300 CTG repeats, there is no change in the number and diameter of myelinated axons compared to wild type. Only a non-significant reduction in the percentage of thin myelinated axons was detected in electron micrographs of ultra-thin sciatic nerve sections. Analysis of the number of neurons did not reveal a loss in number of either sensory neurons in the lumbar DRG or motor neurons in the lumbar spinal cord in these DM1 mice. Furthermore, in hind limb muscle sections, stained with a neurofilament antibody and alpha-bungarotoxin, the intramuscular axon arborization appeared normal in DM1 mice and undistinguishable from that in wild-type mice. Moreover, in DM1 mice, there was no irregularity in the structure or an increase in the endplate area. Also statistical analysis did not show an increase in endplate density or in the concentration of acetylcholine receptors. Altogether, these results suggest that 300 CTG repeats are not sufficient to induce axonopathy, demyelination or neuronopathies in this transgenic mouse model.

Alpha rhythm and hypofrontality in schizophrenia

OBJECTIVE: To reveal the EEG correlates of resting hypofrontality in schizophrenia (SZ). METHOD: We analyzed the whole-head EEG topography in 14 patients compared to 14 matched controls by applying a new parameterization of the multichannel EEG. We used a combination of power measures tuned for regional surface mapping with power measures that allow evaluation of global effects. RESULTS: The SZ-related EEG abnormalities include i) a global decrease in absolute EEG power robustly manifested in the alpha and beta frequency bands, and ii) a relative increase in the alpha power over the prefrontal brain regions against its reduction over the posterior regions. In the alpha band both effects are linked to the SZ symptoms measured with Positive and Negative Symptom Scales and to chronicity. CONCLUSION: As alpha activity is related to regional deactivation, our findings support the concept of hypofrontality in SZ and expose the alpha rhythm as a sensitive indicator of it.

Clustering of cardiovascular risk factors mimicking the human metabolic syndrome X in eNOS null mice.

AIMS/HYPOTHESIS: The metabolic syndrome comprises a clustering of cardiovascular risk factors but the underlying mechanism is not known. Mice with targeted disruption of endothelial nitric oxide synthase (eNOS) are hypertensive and insulin resistant. We wondered, whether eNOS deficiency in mice is associated with a phenotype mimicking the human metabolic syndrome. METHODS AND RESULTS: In addition to arterial pressure and insulin sensitivity (euglycaemic hyperinsulinaemic clamp), we measured the plasma concentration of leptin, insulin, cholesterol, triglycerides, free fatty acids, fibrinogen and uric acid in 10 to 12 week old eNOS-/- and wild type mice. We also assessed glucose tolerance under basal conditions and following a metabolic stress with a high fat diet. As expected eNOS-/- mice were hypertensive and insulin resistant, as evidenced by fasting hyperinsulinaemia and a roughly 30 percent lower steady state glucose infusion rate during the clamp. eNOS-/- mice had a 1.5 to 2-fold elevation of the cholesterol, triglyceride and free fatty acid plasma concentration. Even though body weight was comparable, the leptin plasma level was 30% higher in eNOS-/- than in wild type mice. Finally, uric acid and fibrinogen were elevated in the eNOS-/- mice. Whereas under basal conditions, glucose tolerance was comparable in knock out and control mice, on a high fat diet, knock out mice became significantly more glucose intolerant than control mice. CONCLUSIONS: A single gene defect, eNOS deficiency, causes a clustering of cardiovascular risk factors in young mice. We speculate that defective nitric oxide synthesis could trigger many of the abnormalities making up the metabolic syndrome in humans.

Postpacing abnormal repolarization in catecholaminergic polymorphic ventricular tachycardia associated with a mutation in the cardiac ryanodine receptor gene.

BACKGROUND Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmogenic disease for which electrophysiological studies (EPS) have shown to be of limited value.OBJECTIVE This study presents a CPVT family in which marked postpacing repolarization abnormalities during EPS were the only consistent phenotypic manifestation of ryanodine receptor (RyR2) mutation carriers.METHODS The study was prompted by the observation of transient marked QT prolongation preceding initiation of ventricular fibrillation during atrial fibrillation in a boy with a family history of sudden cardiac death (SCD). Family members underwent exercise and pharmacologic electrocardiographic testing with epinephrine, adenosine, and flecainide. Noninvasive clinical test results were normal in 10 patients evaluated, except for both epinephrine- and exercise-induced ventricular arrhythmias in 1. EPS included bursts of ventricular pacing and programmed ventricular extrastimulation reproducing short-long sequences. Genetic screening involved direct sequencing of genes involved in long QT syndrome as well as RyR2.RESULTS Six patients demonstrated a marked increase in QT interval only in the first beat after cessation of ventricular pacing and/or extrastimulation. All 6 patients were found to have a heterozygous missense mutation (M4109R) in RyR2. Two of them, presenting with aborted SCD, also had a second missense mutation (I406T- RyR2). Four family members without RyR2 mutations did not display prominent postpacing QT changes.CONCLUSION M4109R- RyR2 is associated with a high incidence of SCD. The contribution of I406T to the clinical phenotype is unclear. In contrast to exercise testing, marked postpacing repolarization changes in a single beat accurately predicted carriers of M4109R- RyR2 in this family.

Retinal Dystrophy In The Oculo-auricular Syndrome Due to HMX1 Mutation.

Purpose: To report on the clinical and electrophysiological findings in a patient with oculo-auricular syndrome due to HMX1 mutation, with a follow-up of 12 years. Background: Oculo-auricular syndrome (MIM: 612109) is a rare developmental recessive condition affecting the eye and external ear that results from a mutation in the HMX1 gene. Previously described ocular abnormalities include bilateral microcornea, posterior synechiae, cataract, chorioretinal colobomas and rod-cone dystrophy. Methods: Retrospective chart review of an affected boy followed over a period of 12 years who had serial complete ophthalmologic examinations, fundus photographs, Goldmann perimetry and full-field electroretinograms (ERG). Results: Initial ERG tracings revealed generalized rod more than cone dysfunction. Thereafter, a rapid deterioration in rod and cone function was detected on follow up ERGs. Conclusion: The retinal degeneration in the recessively inherited oculo-auricular syndrome is a progressive rod-cone dystrophy. Visual prognosis is guarded considering the progressive nature of the retinal dystrophy in early infancy.