Clinicopathologic correlations in 172 cases of rapid eye movement sleep behavior disorder with or without a coexisting neurologic disorder

ObjectiveTo determine the pathologic substrates in patients with rapid eye movement (REM) sleep behavior disorder (RBD) with or without a coexisting neurologic disorder.MethodsThe clinical and neuropathologic findings were analyzed on all autopsied cases from one of the collaborating sites in North America and Europe, were evaluated from January 1990 to March 2012, and were diagnosed with polysomnogram (PSG)-proven or probable RBD with or without a coexisting neurologic disorder. The clinical and neuropathologic diagnoses were based on published criteria.Results172 cases were identified, of whom 143 (83%) were men. The mean ± SD age of onset in years for the core features were as follows – RBD, 62 ± 14 (range, 20–93), cognitive impairment (n = 147); 69 ± 10 (range, 22–90), parkinsonism (n = 151); 68 ± 9 (range, 20–92), and autonomic dysfunction (n = 42); 62 ± 12 (range, 23–81). Death age was 75 ± 9 years (range, 24–96). Eighty-two (48%) had RBD confirmed by PSG, 64 (37%) had a classic history of recurrent dream enactment behavior, and 26 (15%) screened positive for RBD by questionnaire. RBD preceded the onset of cognitive impairment, parkinsonism, or autonomic dysfunction in 87 (51%) patients by 10 ± 12 (range, 1–61) years. The primary clinical diagnoses among those with a coexisting neurologic disorder were dementia with Lewy bodies (n = 97), Parkinson’s disease with or without mild cognitive impairment or dementia (n = 32), multiple system atrophy (MSA) (n = 19), Alzheimer’s disease (AD)(n = 9) and other various disorders including secondary narcolepsy (n = 2) and neurodegeneration with brain iron accumulation-type 1 (NBAI-1) (n = 1). The neuropathologic diagnoses were Lewy body disease (LBD)(n = 77, including 1 case with a duplication in the gene encoding α-synuclein), combined LBD and AD (n = 59), MSA (n = 19), AD (n = 6), progressive supranulear palsy (PSP) (n = 2), other mixed neurodegenerative pathologies (n = 6), NBIA-1/LBD/tauopathy (n = 1), and hypothalamic structural lesions (n = 2). Among the neurodegenerative disorders associated with RBD (n = 170), 160 (94%) were synucleinopathies. The RBD-synucleinopathy association was particularly high when RBD preceded the onset of other neurodegenerative syndrome features.ConclusionsIn this large series of PSG-confirmed and probable RBD cases that underwent autopsy, the strong association of RBD with the synucleinopathies was further substantiated and a wider spectrum of disorders which can underlie RBD now are more apparent.     

An antibody to the GM1/GalNAc-GD1a complex correlates with development of pure motor Guillain–Barré syndrome with reversible conduction failure

Antibodies to a ganglioside complex consisting of GM1 and GalNAc-GD1a (GM1/GalNAc-GD1a) are found in sera from patients with Guillain–Barré syndrome (GBS). To elucidate the clinical significance of anti-GM1/GalNAc-GD1a antibodies in GBS, clinical features of 58 GBS patients with IgG anti-GM1/GalNAc-GD1a antibodies confirmed by enzyme-linked immunosorbent assay and thin layer chromatography immunostaining were analyzed. Compared to GBS patients without anti-GM1/GalNAc-GD1a antibodies, anti-GM1/GalNAc-GD1a-positive patients more frequently had a preceding respiratory infection (n = 38, 66%, p < 0.01) and were characterized by infrequency of cranial nerve deficits (n = 9, 16%, p < 0.01) and sensory disturbances (n = 26, 45%, p < 0.01). Of the 28 anti-GM1/GalNAc-GD1a-positive patients for whom electrophysiological data were available, 14 had conduction blocks (CBs) at intermediate segments of motor nerves, which were not followed by evident remyelination. Eight of 10 bedridden cases were able to walk independently within one month after the nadir. These results show that the presence of anti-GM1/GalNAc-GD1a antibodies correlated with pure motor GBS characterized by antecedent respiratory infection, fewer cranial nerve deficits, and CBs at intermediate sites of motor nerves. The CB may be generated through alteration of the regulatory function of sodium channels in the nodal axolemma.     

Efficacy and ethics of artificial nutrition in patients with neurologic impairments in home care

Outcomes, particularly survival, for home-care patients with neurologic impairments who receive artificial nutrition, such as home parenteral nutrition (HPN) or percutaneous endoscopic gastrostomy (PEG) feeding, remain unclear. The efficacy of tube feeding for life prolongation in elderly patients remains controversial. The aim of this study was to assess the survival of elderly patients with neurologic impairments after the start of HPN or PEG. We retrospectively evaluated 80 patients with neurologic impairments who had received home care before they died. They were divided into three groups according to feeding method: oral-intake group (n = 23), HPN group (n = 21) and PEG group (n = 36). The factors considered were: age; survival period after commencement of home care; swallowing function; serum albumin concentration; level of activities of daily living (ADL); and behavioral, cognitive and communication functions. Survival periods of the patients in the PEG (736 ± 765 days) and HPN (725 ± 616 days) groups were twice that of the self-feeding oral-intake group (399 ± 257 days) despite lower serum albumin concentration (for PEG patients), reduced swallowing function and cognitive function, and poorer levels of ADL at the start of home care. Almost all patients were incapable of deciding whether they should receive artificial nutrition due to dementia or poor comprehension. Physicians should provide clinical evidence to families before commencing PEG feeding or HPN and support their decisions to maintain the dignity of the patient.     

Prevalence of sleep-disordered breathing in Japanese medical students based on type-3 out-of-center sleep test

BackgroundSleep-disordered breathing (SDB), especially obstructive sleep apnea disorder (OSA), is thought to mainly affect men over the age of 40. Following findings that Asian people are more likely to experience severe OSA, regardless of obesity, we investigated the prevalence of SDB and OSA in a larger sample and in more younger age groups than those described in previous reports.MethodsBetween 2011 and 2016, 487 medical students (358 males, mean age 24.8 ± 1.9 years; 129 females: mean age 23.8 ± 1.6 years) underwent an out-of-center sleep test using a type-3 portable monitor. The results were analyzed visually.ResultsThe mean ± standard deviation of the respiratory event index (REI: events/hour of monitoring) was 5.4 ± 6.7 (6.7 ± 7.5 in male participants, 2.6 ± 2.1 in female participants). There were 170 participants (36.6%) with an REI ≥ 5, including 158 male participants (46.9%) and 12 female participants (9.1%). SDB or undefined OSA with low REI (15 > REI ≥ 5) was observed in 141 participants (30.4%), defined OSA with moderate REI (30 > REI ≥ 15) in 19 participants (4.1%), and defined OSA with high REI (REI ≥ 30) in 10 participants (2.2%). Among the male students, 129 had low REI (38.3%), 19 had moderate REI (5.6%), and 10 had high REI (3.0%). All female participants with OSA events (9.4%) had a low REI.ConclusionsThe prevalence of OSA in Japanese young adults, especially males under 30 years old, is similar or even higher than that in older age groups described previously. Thus, an aggressive sleep study for SDB might be necessary for the younger generation in the Asian population.     

Validation de la batterie rapide de dénomination (BARD) chez 382 témoins et 1004 patients d’une consultation mémoire

IntroductionThe Rapid BAttery of Denomination (BARD) is a short 10-item naming test derived from the 60-item Boston Naming Test. It is easily performed in less than 15 seconds by normal controls independently of age, gender and education (Croisile, 2005, Croisile, 2007, Croisile, 2008). Our aim was to evaluate the BARD in various conditions seen in a memory clinic.Patients and methodsThe BARD was used in 382 normal subjects (165 men and 217 women, aged from 20 to 97 years) and 1004 patients attending a memory clinic. Three groups of 505 patients with Alzheimer's disease (AD) were compared: mild patients (n = 402), moderate patients (n = 84) and moderately severe patients (n = 19). The BARD was also used in 499 patients with a Mini Mental Status (MMSE) ≥ 20: 173 patients with amnestic Mild Cognitive Impairment (aMCI), 56 patients with frontotemporal dementia (FTD), 41 patients with Lewy Body dementia (LBD), 36 patients with nonfluent primary progressive aphasia (NFPPA), 27 patients with semantic dementia (SD), 16 patients with posterior cortical atrophy (PCA), 150 patients with anxiety or depression (ADD).ResultsThe performance of the patients was not affected by age, gender or education. aMCI had a score of 9.97 ± 0.18, ADD a score of 9.97 ± 0.2. A mild anomia was observed in three groups: mild AD (9.78 ± 0.5), FTD (9.79 ± 0.65) et LBD (9.98 ± 0.16). A more pronounced anomia was present in moderate AD (9.10 ± 1.06), moderately severe AD (8.05 ± 1.27), PCA (8.12 ± 3.28) and NFPPA (8.44 ± 1.61). The anomia was severe in SD (5.85 ± 2.46). The 10 items were perfectly named by 98 % of ADD, 96.53 % of aMCI, 82.09 % of mild AD, 87.5 % of FTD patients, 97.56 % of LBD patients, 68.75 % of PCA patients, but only 45.24 % moderate AD, 5.26 % of moderately severe AD, 27.78 % of NFPPA, and 3.7 % of SD. In the patients with MMS ≥ 20, Anova showed that the BARD scores of the ADD, aMCI, mild AD, FTD and LBD groups were significantly greater than the BARD scores of NFPPA, SD and PCA. PCA and NFPPA groups did not differ for BARD scores whereas they were significantly better than SD. A ROC curve comparing the 822 mild anomic patients (AD, FTD, LBD, aMCI, ADD) with the 79 more anomic patients (NFPPA, SD, PCA) showed that for a BARD score of 10, sensitivity was 72.2 %, specificity was 89.2 %, and 87.7 % of the patients were correctly classified.ConclusionThe BARD is a quick and useful tool for identifying naming disorders in a memory clinic. In patients with MMSE ≥ 20, making one error at the BARD is highly abnormal and significantly characteristic of cognitive disorders: the more frequent the errors are, the more probable is the presence of a visual agnosia (PCA), an aphasia (NFPPA), or a semantic disorder (SD).     

Clinical and electrophysiological features of Guillain–Barré syndrome in Iran

We evaluated the clinical and electrophysiological characteristics of 121 consecutive patients admitted with Guillain–Barré syndrome (GBS) to a tertiary referral hospital in Tehran, Iran, from 1997 to 2007. The mean age of patients was 38.9 (standard deviation 19.7) years. The predominant subtype of GBS was the demyelinating form. Miller Fisher syndrome was present in 3.3% of patients. There was no significant seasonal clustering among the three subtypes, but axonal variants tend to occur in summer. In contrast with other subtypes, the majority of patients with acute motor-sensory axonal neuropathy (AMSAN) were female (72.3%). AMSAN patients also had significantly longer hospitalization time (p = 0.002) and intensive care unit (ICU) admission (p = 0.017), while none of the acute motor axonal neuropathy patients needed ICU admission. Involvement of cranial nerves and symmetry of signs were significantly detected in the demyelinating variant (p = 0.021 and p = 0.040, respectively). The overall mortality was 3.3%.     

Mazindol in narcolepsy and idiopathic and symptomatic hypersomnia refractory to stimulants: A long-term chart review

ObjectiveMazindol is a tricyclic, anorectic, non-amphetamine stimulant used in narcolepsy and obesity since 1970. This study aimed to evaluate the long-term benefit/risk ratio in drug-resistant hypersomniacs and cataplexy sufferers.MethodsBy retrospective analysis of the patients’ files in the hospitals of Paris-Salpêtrière (n = 91), Montpellier (n = 40) and Lyon (n = 8), the benefit (Epworth Sleepiness Score (ESS), cataplexy frequency, authorization renewal) and tolerance (side-effects, vital signs, electrocardiogram and cardiac echography) of mazindol were assessed.ResultsThe 139 patients (45% men) aged 36 ± 15 years (range: 9–74) suffered narcolepsy (n = 94, 66% with cataplexy), idiopathic (n = 37) and symptomatic hypersomnia (n = 8) refractory to modafinil, methylphenidate and sodium oxybate. Under mazindol (3.4 ± 1.3 mg/day, 1–6 mg) for an average of 30 months, the ESS decreased from 17.7 ± 3.5 to 12.8 ± 5.1, with an average fall of −4.6 ± 4.7 (p < 0.0001) and the frequency of cataplexy fell from 4.6 ± 3.1 to 2 ± 2.8 episodes per week. The cataplexy was eliminated in 14.5% of patients, improved in 27.5%, and unchanged in 29% (missing data in 29%). The treatment was maintained long term in 83 (60%) patients, and stopped because of a lack of efficacy (22%) and/or secondary effects (9%). There was no pulmonary hypertension in the 45 patients who underwent a cardiac echography. The most common adverse effects were dry mouth (13%), palpitations (10%, including one with ventricular hyperexcitability), anorexia (6%), nervousness (6%) and headaches (6%).ConclusionMazindol has a long-term, favorable benefit/risk ratio in 60% of drug-resistant hypersomniacs, including a clear benefit on cataplexy.     

The demyelination neurophysiological criteria can be misleading in Campylobacter jejuni-related Guillain–Barré syndrome

ObjectiveThe exclusive association of Campylobacter jejuni infection with the axonal variant of Guillain–Barré syndrome (GBS) is debatable. The current study aims to elucidate the GBS subtypes of patients with an antecedent C. jejuni infection.MethodsNerve conduction study results of 73 patients with GBS were reviewed. Patients were defined as having a recent C. jejuni infection when there was a positive stool culture or serological evidence of C. jejuni in the presence of preceding diarrhea.ResultsA total of 23 patients had evidence of a recent C. jejuni infection. At the early stage, patients were classified as AMAN (n = 9; 39%), AIDP (n = 3; 13%) or equivocal (n = 9) using existing electrophysiological criteria. Prolonged distal latencies and conduction slowing that were seen in 11 patients rapidly normalized within 3 weeks in seven, whereas four had minor abnormalities throughout the course. Subsequently, all patients showed either acute motor axonal neuropathy pattern or reversible conduction failure.ConclusionSerial neurophysiology suggests that C. jejuni infections are exclusive to axonal GBS.SignificanceOur findings suggest that AMAN can demonstrate the full complement of demyelinating features at the early stages of disease.     

Anticeramide antibody and butyrylcholinesterase in peripheral neuropathies

Ceramide is a glycosphingolipid, a component of nerve and non neuronal cell membrane and plays a role in maintaining the integrity of neuronal tissue. Butyrylcholinesterase (BChE) is a multifunctional enzyme, its involvement in neurodegenerative diseases has been well established. Anticeramide antibody (Ab-Cer) and enzyme BChE have been implicated in peripheral neuropathies. The present study investigates whether there is an association between Ab-Cer and BChE activities and peripheral neuropathies. Patients included: human immunodeficiency virus associated peripheral neuropathy (HIV-PN, n = 39), paucibacillary leprosy (PB-L, n = 36), multibacillary leprosy (MB-L, n = 52), diabetic neuropathy (DN, n = 22), demyelinating sensory motor polyneuropathy (DSMN, n = 13) and chronic inflammatory demyelinating polyneuropathy (CIDP, n = 10). Plasma Ab-Cer was measured by indirect enzyme linked immune assay (ELISA) and BChE activity in plasma was measured by colorimetric method. Ab-Cer levels were significantly elevated in MB-L and DN as compared to healthy subjects (HS). BChE levels were significantly higher in MB-L and DN as well as in HIV and HIV-PN. There is no significant difference in either Ab-Cer or BChE levels in DSMN and CIDP. Elevated plasma Ab-Cer and BChE levels may be considered significant in the pathogenesis of neuropathies. The variation in concurrent involvement of both the molecules in the neuropathies of the study, suggest their unique involvement in neurodegenerative pathways.     

New-onset status epilepticus and cluster seizures in the elderly

We evaluated the frequency, therapeutic response and predictors of status epilepticus (SE) and cluster seizures among elderly people. Patients over 60 years old with epilepsy (n = 201; age, 68.0 ± 7.5 years) were prospectively recruited. Among them, 64 patients (32%) who presented with new-onset cluster attacks and/or SE formed the study group. All underwent evaluation with electroencephalography (EEG) and CT scans. The mean duration of SE and cluster seizures at admission was 14.9 ± 53.7 hours. Cluster seizures were observed in 53 (26.4%) and SE in 34 (17%) elderly patients with seizures (n = 201). The types of SE were: generalized convulsive (23 patients), epilepsia partialis continua (eight patients), non-convulsive (two patients) and myoclonic (one patient). The types of epilepsy syndrome included were: acute symptomatic (37 patients; 57.8%), cryptogenic (15 patients; 23.4%) and remote symptomatic (12 patients; 18.8%). Interictal EEG was abnormal in 79.7% of patients with critical presentation compared to 53.3% of patients without critical presentation. Epileptiform activity was observed in 46.9% of patients with SE and/or cluster seizures compared to 27.0% without SE and/or cluster seizures (p = 0.001). The neuroimaging differences between the two groups were the absence of white-matter changes on CT scan in those with, compared to those without, SE and/or cluster seizures (28.1% compared to 41.6%, p = 0.06). The risk factors for SE and/or cluster seizures were: acute symptomatic seizures, simple partial seizures, a higher number of seizures, lower Glasgow coma scale (GCS) score and an absence of white-matter changes on CT scan. After multivariate analysis, lower GCS score (p = 0.01; odds ratio [OR] = 0.82) and a higher number of seizures (p = 0.03; OR = 1.03) significantly predicted the occurrence of SE and/or cluster seizures. Seizures were controlled with two antiepileptic drugs in 70.6%. To conclude, SE and/or cluster seizures are common (32%) among elderly patients with epilepsy. Early and aggressive treatment is effective in the majority.     

Depression and anxiety among high-risk obstetric inpatients

ObjectiveTo assess the following among women hospitalized antenatally due to high-risk pregnancies: (1) rates of depression symptoms and anxiety symptoms, (2) changes in depression symptoms and anxiety symptoms and, (3) rates of mental health treatment.MethodsSixty-two participants hospitalized for high-risk obstetrical complications completed the Edinburgh Postnatal Depression Scale (EPDS), Generalized Anxiety Disorder 7-item scale (GAD-7) and Short-Form 12 weekly until delivery or discharge, and once postpartum.ResultsAverage length of total hospital stay was 8.3±7.6days for women who completed an initial admission survey (n= 62) and 16.3±8.9 (n= 34), 25.4±10.2 (n= 17) and 35±10.9 days (n= 9) for those who completed 2, 3 and 4 surveys, respectively. EPDS was ≥ 10 in 27% (n= 17) and GAD-7 was ≥ 10 in 13% (n= 8) of participants at initial survey. Mean anxiety (4.2±6.5 vs. 5.2±5.1, p= .011) and depression (4.4±5.6 vs. 6.9±4.8, p= .011) scores were lower postpartum compared to initial survey. Past mental health diagnosis predicted depression symptoms [odds ratio (OR)=4.54; 95% confidence interval (CI) 1.91–7.17] and anxiety symptoms (OR=5.95; 95% CI 3.04–8.86) at initial survey; however, 21% (n= 10) with no diagnostic history had EPDS ≥ 10. Five percent (n= 3) received mental health treatment during pregnancy.ConclusionHospitalized high-risk obstetrical patients may commonly experience depression symptoms and/or anxiety symptoms and not receive treatment. A history of mental health treatment or diagnosis was associated with depression symptoms or anxiety symptoms in pregnancy. Of women with an EPDS ≥ 10, > 50% did not report a past mental health diagnosis.     

Surgical treatment of ossification of the ligamentum flavum associated with dural ossification in the thoracic spine

Between January 2006 and December 2009, dural ossification (DO) was found intraoperatively in 26 of 98 patients with thoracic spinal stenosis due to ossification of the ligamentum flavum (OLF). MRI showed single-level (n = 2), two-level (n = 8) and multilevel (n = 16) areas of low signal intensity in the ligamentum flavum of the thoracic spine. Of the 68 ossified segments in the study population, 11 (16.2%) were located in the upper thoracic spine (T1–T4), nine (13.2%) were located in the midthoracic spine (T5–T8), and 48 (70.6%) were located in the lower thoracic spine (T9–L1). All patients underwent en bloc resection of the areas affected by OLF and DO. All patients underwent posterior decompression; we did not use instrumented fusion to restore the stability of the involved segments after decompression for any patient. The dural defect was not repaired. The neurological status had improved at follow up (22–66 months; mean, 46.7 months) from a preoperative mean Japanese Orthopaedic Association score of 5.46 ± 1.73 points to 8.92 ± 1.38 points at the last follow up (t = 13.87, p < 0.05). The mean values for preoperative and postoperative kyphosis of the involved vertebrae were 6.6 ± 1.5° and 8.2 ± 1.4°, respectively; the mean increase in kyphosis was only 1.7 ± 1.4°. Thus, the surgical techniques discussed in this paper for treatment of OLF associated with DO in the thoracic spine, are effective.     

Anti-JCV antibody serostatus and longitudinal evaluation in a Portuguese Multiple Sclerosis population

Multiple Sclerosis (MS) treatment with natalizumab is associated with Progressive Multifocal Leukoencephalopathy (PML). The risk of PML being related to the anti-JCV antibody index is well established, but there is less known about seroconversion rates in natalizumab-treated patients and longitudinal variation in the anti-JCV antibody index. Our objective was to assess anti-JCV antibody prevalence in an MS population and to evaluate the evolution of the anti-JCV antibody index in natalizumab-treated patients. To assess anti-JCV antibody prevalence, we included all patients who had the anti-JCV antibody test in our consultation, regardless of the treatment. To evaluate the evolution of the anti-JCV antibody index and seroconversion, only natalizumab-treated patients with at least two samples were selected. Demographic characteristics were evaluated. From a total of 371 patients included, 68.19% (n = 253) were seropositive for anti-JCV antibodies (JCV+). There was a significant difference in anti-JCV antibody seropositivity concerning gender (male 76.27% vs. female 64.43%, p = 0.023), but not age. To evaluate seroconversion, 85 patients who were initially seronegative (JCV−) were selected. The annual rate of seroconversion in the first two years was stable, but after that there was a significant increase with treatment duration (ρ = 0.90, p = 0.037): in the first year it was 5.88% (n = 5/85); in the second, 5.71% (n = 4/70); in the third, 6.82% (n = 3/44); in the fourth, 10.34% (n = 3/29); and in the fifth, 15.0% (n = 3/20). The mean index variability was higher in patients who experienced seroconversion (1.16 ± 0.97), followed by JCV+ patients (0.44 ± 0.48), compared to JCV− patients (0.08 ± 0.05). In conclusion, anti-JCV antibody prevalence in our population is comparable to other reported cohorts. The seroconversion rate increased with treatment duration. We found a high fluctuation in the antibody index in JCV+ patients.     

Common CYP7A1 promoter polymorphism associated with risk of neuromyelitis optica

Neuromyelitis optica (NMO) is a severe idiopathic inflammatory disease of the central nervous system primarily affecting the optic nerves and spinal cord. In this study, we generated genome-wide SNP data from NMO patients and normal controls (53 cases and 240 controls), and followed up on the association signals with samples from a larger number of inflammatory demyelinating diseases, including NMO (n = 93), multiple sclerosis (MS, n = 71), idiopathic recurrent transverse myelitis (IRTM, n = 57), and normal controls (n = 240). Statistical analyses revealed that a common promoter SNP in CYP7A1 has a protective/gene dose-dependent effect on the risk of NMO (P = 0.0004). A stronger association between the variables and subsequently, a higher protective effect (lower OR) on the risk of NMO were observed among patients carrying the “G/G” genotype of rs3808607 than those with the “T/G” genotype (OR = 0.38/P = 0.01 vs. OR = 0.12/P = 0.0004, respectively). The associations which were only observed in patients with NMO suggest that there are differences in the genetic etiology of the inflammatory demyelinating diseases (NMO, classical MS, and IRTM).     

Effect of exercise training on skeletal muscle cytokine expression in the elderly

Aging is associated with increased circulating pro-inflammatory and lower anti-inflammatory cytokines. Exercise training, in addition to improving muscle function, reduces these circulating pro-inflammatory cytokines. Yet, few studies have evaluated changes in the expression of cytokines within skeletal muscle after exercise training. The aim of the current study was to examine the expression of cytokines both at rest and following a bout of isokinetic exercise performed before and after 12 weeks of resistance exercise training in young (n = 8, 20.3 ± 0.8 yr) and elderly men (n = 8, 66.9 ± 1.6 yr). Protein expression of various cytokines was determined in muscle homogenates. The expression of MCP-1, IL-8 and IL-6 (which are traditionally classified as ‘pro-inflammatory’) increased substantially after acute exercise. By contrast, the expression of the anti-inflammatory cytokines IL-4, IL-10 and IL-13 increased only slightly (or not at all) after acute exercise. These responses were not significantly different between young and elderly men, either before or after 12 weeks of exercise training. However, compared with the young men, the expression of pro-inflammatory cytokines 2 h post exercise tended to be greater in the elderly men prior to training. Training attenuated this difference. These data suggest that the inflammatory response to unaccustomed exercise increases with age. Furthermore, regular exercise training may help to normalize this inflammatory response, which could have important implications for muscle regeneration and adaptation in the elderly.     

Hypercholesterolemia magnitude increases sympathetic modulation and coagulation in LDLr knockout mice

We investigated the effects of low lipoprotein receptor deficiency in cholesterol blood concentrations, blood pressure, hemostatic factors, and the autonomic nervous system in three groups: control mice fed standard diet (CO, n = 9), lipoprotein receptor-deficient mice (LDLr^-/-, n = 9) fed standard diet (LDLr-S) or hypercholesterolemic diet (LDLr-H, n = 8). Frequency domain analysis of heart rate and blood pressure variability was performed with an autoregressive algorithm. The spectral components were expressed in absolute (s² or mm Hg²) and normalized units. Spontaneous baroreflex sensitivity (BRS) was estimated by alpha index, defined as square root ratio between low frequency power in blood pressure variability and heart rate variability. LDLr/- mice presented a significant increase in the cholesterol blood concentration (mean ± SD; mg/dl; LDLr-S = 202.01 ± 34.38 and LDLr-H = 530.7 ± 75.17) compared to CO (79.2 ± 13.6), p = 0.001. The receptor deletion was associated with a heart rate variability reduction (p = 0.013). The BRS was reduced (p < 0.05) in LDLr-S and LDL-H (mean ± SD: 0.96 ± 0.39 and 0.59 ± 0.34, respectively) compared to CO (4.02 ± 1.92). Moreover, hypercholesterolemic diet significantly increased the cardiac sympathetic modulation (0V pattern of symbolic analysis: mean ± SD, CO = 8.04 ± 4.53; LDLr-S = 16.49 ± 4.52 and LDLr-H = 21.80 ± 8.24, p = 0.006). The 0V pattern was statically correlated to coagulation factor VII (r = 0.555, p = 0.0208). In LDLr-H, the concentration (interquartile range) of plasmatic fibrinogen and hemostatic factors VII (2.8–3.3) and XII (1.1–1.3) were increased compared to CO (0.9–1.1and 0.9–1.0, respectively) and LDLr-S (0.7–1.0 and 0.8–0.9, respectively) (p < 0.004 for FVII and p < 0.006 for FXII). Taken together, the results indicate that plasmatic cholesterol magnitude is determinant to increase the coagulation and the sympathetic modulation.     

Acute behavioral crises in psychiatric inpatients with autism spectrum disorder (ASD): Recognition of concomitant medical or non-ASD psychiatric conditions predicts enhanced improvement

During adolescence, some individuals with autism spectrum disorder (ASD) engage in severe challenging behaviors, such as aggression, self-injury, disruption, agitation and tantrums. We aimed to assess risk factors associated with very acute behavioral crises in adolescents with ASD admitted to a dedicated neurobehavioral unit. We included retrospectively in 2008 and 2009 29 adolescents and young adults with ASD hospitalized for severe challenging behaviors and proposed a guideline (Perisse et al., 2010) that we applied prospectively for 29 patients recruited for the same indications between 2010 and 2012. In total, 58 patients were admitted (n = 70 hospitalizations, mean age = 15.66 (±4.07) years, 76% male). We systematically collected data describing socio-demographic characteristics, clinical variables (severity, presence of language, cognitive level), comorbid organic conditions, etiologic diagnosis of the episode, and treatments. We explored predictors of Global Assessment Functioning Scale (GAFS) score and duration of hospitalization at discharge. All but 2 patients exhibited severe autistic symptoms and intellectual disability (ID), and two-thirds had no functional verbal language. During the inpatient stay (mean = 84.3 (±94.9) days), patients doubled on average their GAFS scores (mean = 17.66 (±9.05) at admission vs. mean = 31.4 (±9.48) at discharge). Most common etiologies for acute behavioral crises were organic causes [n = 20 (28%), including epilepsy: n = 10 (14%) and painful medical conditions: n = 10 (14%)], environmental causes [n = 17 (25%) including lack of treatment: n = 11 (16%) and adjustment disorder: n = 6 (9%)], and non-ASD psychiatric condition [n = 33 (48%) including catatonia: n = 5 (7%), major depressive episode: n = 6 (9%), bipolar disorder: n = 4 (6%), schizophrenia: n = 6 (9%), other/unknown diagnosis: n = 12 (17%)]. We found no influence of age, gender, socio-economic status, migration, level of ID, or history of seizure on improvement of GAFS score at discharge. Severity of autism at admission was the only negative predictor (p < .001). Painful medical conditions (p = .04), non-ASD psychiatric diagnoses (p = .001), prior usage of specialized ASD care programs (p = .004), functional language (p = .007), as well as a higher number of challenging behaviors upon admission (p = .001) were associated with higher GAFS scores at discharge. Clinical severity at admission, based on the number of challenging behaviors (r = .35, p = .003) and GAFS score (r = −.32, p = .008) was correlated with a longer inpatient stay. Longer hospitalization was however correlated (r = .27, p = .03) with higher GAFS score at discharge even after adjustment for confounding factors. Challenging behaviors among adolescents with ASD may stem from diverse risk factors, including environmental problems, comorbid acute psychiatric conditions, or somatic illness such as epilepsy or acute pain. The management of these behavioral challenges requires a unified, multidisciplinary approach.     

Tumor necrosis factor-α impairs the recovery of synaptic transmission from hypoxia in rat hippocampal slices

Cerebral ischaemia is a common occurrence in a range of pathological conditions, including stroke and traumatic brain injury. Two of the components in ischaemia are tissue hypoxia and the release of pro-inflammatory agents such as TNF-α. The role of TNF-α in an ischaemic/hypoxic episode is still controversial, although deleterious effects of pro-inflammatory cytokines in the area of injury are well documented. One of the prime adaptive mechanisms in response to hypoxia is the cellular activation of adenosine 1 receptors (A1Rs), which inhibits excitatory synaptic transmission. In the present study we have examined the effect of TNF-α application on synaptic transmission during hypoxic exposure and re-oxygenation using extracellular recordings in the CA1 region of the rat hippocampal slice. Hypoxia caused a reversible depression of the field EPSP (29.6 ± 9.7% of control, n = 5), which was adenosine A₁ receptor-dependent (85.7 ± 4.3%, in the presence of DPCPX (200 nM), the adenosine A₁ receptor antagonist). DPCPX inhibited the maintenance of long-term potentiation obtained 30 min post hypoxia (143.8 ± 8.2% versus 96.4 ± 10.6% respectively, 1 h post tetanus; n = 5; p < 0.005). In TNF-α (150 pM) treated slices hypoxic depression was similar to controls but a reduction in fEPSP slope was observed during re-oxygenation (66.8 ± 1.4%, n = 5). This effect was reversed by pre-treatment with SB 203580 (1 µM), a p38 MAP kinase inhibitor (91.8 ± 6.9%, n = 5). These results demonstrate a novel p38 MAPK dependent role for TNF-α in attenuating synaptic transmission after a hypoxic episode.     

Accuracy and safety of targeting using intraoperative “O-arm” during placement of deep brain stimulation electrodes without electrophysiological recordings

The aim of our study was to investigate the accuracy of targeting using intraoperative “O-arm” during deep brain stimulation (DBS) surgery. Intraoperative O-arm (Medtronic, Minneapolis, MN, USA) images were obtained to confirm the accuracy of placement. The difference between intended and actual target coordinates was calculated based on intraoperative images and postoperative CT scan. Euclidian vector error was obtained to estimate the directional error. Correlation of targeting error with the pneumocephalus and the deviation from the planned trajectory was also estimated. Twenty eight DBS leads (globus pallidus internus [GPi], n = 13; subthalamic nucleus [STN], n = 9; ventralis intermedius nucleus [VIM], n = 6) were implanted in 20 patients using the stereotactic Leksell frame (Elekta AB, Stockholm, Sweden) under general anesthesia over a period of 1 year. The mean age was 63.6 ± standard error of the mean (SEM) 15.7 years and 60% of patients were males. The mean absolute difference (+SEM) between intended and actual target in x, y and z coordinates based on intraoperative CT scan was 0.65 ± 0.09 (p = 0.84), 0.58 ± 0.08 (p = 0.98), 1.13 ± 0.10 (p = 0.08), respectively, and postoperative (1 month) CT scan was 0.82 ± 0.15 (p = 0.89), 0.55 ± 0.11 (p = 0.97), and 1.58 ± 0.29 (p = 0.08), respectively. The Euclidean vector error was 1.59 ± 0.10 and 2.16 ± 0.26 based on intraoperative and postoperative images, respectively. There was no statistically significant targeting error based on fusion of intraoperative CT images to either preoperative CT scan or MRI as registration series, the presence of pneumocephalus, deviation from planned trajectory or the anatomical target (STN versus VIM versus GPi) (p > 0.05). Superficial skin infection was encountered in a single patient in this study. The mean total operating room time was 193.5 ± 74.6 minutes. None of the patients required revision in our study. DBS leads can be implanted safely and accurately using intraoperative O-arm with a frame based targeting system and can be used in selected patients.