Factors associated with treatment escalation among MS specialists and general neurologists: Results from an International cojoint study.

BACKGROUND: Previous studies in multiple sclerosis (MS) showed that therapeutic inertia (TI) affects 60-90% of neurologists and up to 25% of daily treatment decisions. The objective of this study was to determine the most common factors and attribute levels associated with decisions to treatment escalation in an international study in MS care. METHODS: 300 neurologists with MS expertise from 20 countries were invited to participate. Participants were presented with 12 pairs of simulated MS patient profiles described by 13 clinically relevant factors. We used disaggregated discrete choice experiments to estimate the weight of factors and attributes affecting physicians' decisions when considering treatment selection. Participants were asked to select the ideal candidate for treatment escalation from modest to higher-efficacy therapies. RESULTS: Overall, 229 neurologists completed the study (completion rate: 76.3%). The top 3 weighted factors associated with treatment escalation were: previous relapses (20%), baseline expanded disability status scale [EDSS] (18%), and MRI activity (13%). Patient demographics and desire for pregnancy had a modest influence (≤ 3%). We observed differences in the weight of factors associated with treatment escalation between MS specialists and non-MS specialists. CONCLUSIONS: Our results provide critical information on factors influencing neurologists' treatment decisions and should be applied to continuing medical education strategies.

Anodal transcranial direct current stimulation in chronic migraine and medication overuse headache: A pilot double-blind randomized sham-controlled trial.

OBJECTIVES: Little evidence is available on the role of transcranial direct current stimulation (tDCS) in patients affected by chronic migraine (CM) and medication overuse headache (MOH). We aim to investigate the effects of tDCS in patients with CM and MOH as well as its role on brain activity. METHODS: Twenty patients with CM and MOH were hospitalized for a 7-day detoxification treatment. Upon admission, patients were randomly assigned to anodal tDCS or sham stimulation delivered over the primary motor cortex contralateral to the prevalent migraine pain side every day for 5 days. Clinical data were recorded at baseline (T0), after 1 month (T2) and 6 months (T3). EEG recording was performed at T0, at the end of the tDCS/Sham treatment, and at T2. RESULTS: At T2 and T3, we found a significant reduction in monthly migraine days (p = 0.001), which were more pronounced in the tDCS group when compared to the sham group (p = 0.016). At T2, we found a significant increase of alpha rhythm in occipital leads, which was significantly higher in tDCS group when compared to sham group. CONCLUSIONS: tDCS showed adjuvant effects to detoxification in the management of patients with CM and MOH. The EEG recording showed a significant potentiation of alpha rhythm, which may represent a correlate of the underlying changes in cortico-thalamic connections. SIGNIFICANCE: This study suggests a possible role for tDCS in the treatment of CM and MOH. The observed clinical improvement is coupled with a potentiation of EEG alpha rhythm.

Correlation between HLA-DQB1*06:02 and narcolepsy with and without cataplexy: approving a safe and sensitive genetic test in four major ethnic groups. A systematic meta-analysis.

STUDY OBJECTIVES: we performed a meta-analysis to assess the usefulness of HLA testing for Narcolepsy diagnosis in four major ethnical groups: Asians, Afro-Americans, Amerindians and Caucasians. METHODS: PubMed, EMBASE, Web of Science, Scopus and Cochrane databases were searched for articles in English and French published before October 2017 on HLA class II alleles in Narcolepsy. We included case-control studies, cross-sectional and retrospective cohort studies with patients diagnosed following the International classifications of sleep disorders (1990-2012) and ethnically matched controls. Following PRISMA guidelines, two investigators independently extracted data according to the inclusion criteria listed in PROSPERO CRD42017058677. A third researcher was consulted for discrepancies. We extracted and pooled adjusted OR using random-effect models. We verified the strength of the association between HLA-DQB1*06:02 and the worldwide distribution of Narcolepsy type 1 (NT1) and type 2 (NT2); furthermore, we pooled the OR measuring the association between HLA-DQB1*06:02 and NT1, NT2 and hypersomniacs. RESULTS: We identified 511 titles. Of these, 12 case-control studies were included, for a total of 2077 NT1 patients, 235 NT2 patients, 161 hypersomniacs and 7802 controls. In the population-stratified analysis, HLA-DQB1*06:02 conferred an increased risk for NT1 (OR: 24.1, IC: 14.6-39.5, p < 0.001) and NT2 (OR: 3.9; IC: 2.2-6.8, p < 0.001). For NT1 the pooled estimated positive Likelihood Ratio (LR+) was 5.94 (IC: 3.71-9.51) and the negative Likelihood Ratio (LR-) was 0.23 (IC: 0.16-0.33); for NT2 LR+ was 3.35 (IC: 2.08-5.38) and LR- 0.72 (IC: 0.63-0.81). Moreover, for hypersomniacs LR+ was 1.436 (IC 0.668-3.089) and LR- 0.903 (IC 0.714-1.142). CONCLUSIONS: Our data support the preponderant role of HLA-DQB1*06:02 in susceptibility to NT1/NT2 across all ethnicities. HLA-DQB1*06:02 negativity should make clinicians cautious in excluding other diagnoses.

Transcription factors PRE3 and WOX11 are involved in the formation of new lateral roots from secondary growth taproot in A. thaliana.

The spatial deployment of lateral roots determines the ability of a plant to interact with the surrounding environment for nutrition and anchorage. This paper shows that besides the pericycle, the vascular cambium becomes active in Arabidopsis thaliana taproot at a later stage of development and is also able to form new lateral roots. To demonstrate the above, we implemented a two-step approach in which the first step leads to development of a secondary structure in A. thaliana taproot, and the second applies a mechanical stress on the vascular cambium to initiate formation of a new lateral root primordium. GUS staining showed PRE3, DR5 and WOX11 signals in the cambial zone of the root during new lateral root formation. An advanced level of wood formation, characterized by the presence of medullar rays, was achieved. Preliminary investigations suggest the involvement of auxin and two transcription factors (PRE3/ATBS1/bHLH135/TMO7 and WOX11) in the transition of some vascular cambium initials from a role as producers of xylem/phloem mother cells to founder cells of a new lateral root primordium.

SNCA 3'UTR genetic variants in patients with Parkinson's disease and REM sleep behavior disorder.

REM sleep behavior disorder (RBD) is an early marker of Parkinson's disease (PD); however, it is still unclear which patients with RBD will eventually develop PD. Single nucleotide polymorphisms (SNPs) in the 3'untranslated region (3'UTR) of alpha-synuclein (SNCA) have been associated with PD, but at present, no data is available about RBD. The 3'UTR hosts regulatory regions involved in gene expression control, such as microRNA binding sites. The aim of this study was to determine RBD specific genetic features associated to an increased risk of progression to PD, by sequencing of the SNCA-3'UTR in patients with "idiopathic" RBD (iRBD) and in patients with PD. We recruited 113 consecutive patients with a diagnosis of iRBD (56 patients) or PD (with or without RBD, 57 patients). Sequencing of SNCA-3'UTR was performed on genomic DNA extracted from peripheral blood samples. Bioinformatic analyses were carried out to predict the potential effect of the identified genetic variants on microRNA binding. We found three SNCA-3'UTR SNPs (rs356165, rs3857053, rs1045722) to be more frequent in PD patients than in iRBD patients (p = 0.014, 0.008, and 0.008, respectively). Four new or previously reported but not annotated specific genetic variants (KP876057, KP876056, NM_000345.3:c*860T>A, NM_000345.3:c*2320A>T) have been observed in the RBD population. The in silico approach highlighted that these variants could affect microRNA-mediated gene expression control. Our data show specific SNPs in the SNCA-3'UTR that may bear a risk for RBD to be associated with PD. Moreover, new genetic variants were identified in patients with iRBD.

Specific patterns of laryngeal electromyography during wakefulness are associated to sleep disordered breathing and nocturnal stridor in multiple system atrophy.

BACKGROUND: Nocturnal stridor and respiratory abnormalities are important features of multiple system atrophy (MSA) with relevance to patient survival, and they are detected and evaluated mainly through video-polysomnography (video-PSG). Diurnal laryngoscopy seems to yield abnormal findings only in the presence of significant vocal cord (VC) dysfunction. AIM: To assess whether specific electrophysiological patterns of diurnal EMG of VC muscles may indicate nocturnal stridor or respiratory dysfunctions in MSA patients. MATERIALS AND METHODS: Seventeen patients with probable MSA were examined. A full-night video-PSG to collect standard breathing parameters (apnea/hypopnea index, mean HbSAO2, oxygen desaturation index, total sleep time with HbSaO2 below 90%) was performed in all the patients. Laryngoscopy and EMG investigation of adductor (thyroarytenoid-TA) and abductor (posterior cricoarytenoid-PCA) muscles of the VCs were also performed. RESULTS: Both the laryngeal EMG abnormalities (based on MUAP analysis and kinesiologic EMG investigation of VC muscles) and the laryngoscopic alterations correlated with video-PSG respiratory abnormalities. Specific patterns of EMG findings were consistently found in MSA subjects with nocturnal stridor detected at PSG. In particular, the following EMG findings were related to the severity of breathing abnormalities and the presence of stridor on video-PSG: neurogenic pattern on MUAP analysis of the PCA, paradoxical activation of the TA during inspiration and tonic EMG activity of the TA during quiet breathing. CONCLUSIONS: Electromyographic/kinesiologic investigation of VC muscles during wakefulness provides additional information on the pathophysiology of the respiratory abnormalities in MSA patients that could be useful for guiding the choice of the best appropriate treatment and care.

Interspecific variation in functional traits of oak seedlings (Quercus ilex, Quercus trojana, Quercus virgiliana) grown under artificial drought and fire conditions.

To face summer drought and wildfire in Mediterranean-type ecosystems, plants adopt different strategies that involve considerable rearrangements of biomass allocation and physiological activity. This paper analyses morphological and physiological traits in seedlings of three oak species (Quercus ilex, Quercus trojana and Quercus virgiliana) co-occurring under natural conditions. The aim of this study was to evaluate species-specific characteristics and the response of these oak seedlings to drought stress and fire treatment. Seedlings were kept in a growth chamber that mimicked natural environmental conditions. All three species showed a good degree of tolerance to drought and fire treatments. Differences in specific biomass allocation patterns and physiological traits resulted in phenotypic differences between species. In Q. ilex, drought tolerance depended upon adjustment of the allocation pattern. Q. trojana seedlings undergoing mild to severe drought presented a higher photosystem II (PSII) efficiency than control seedlings. Moreover, Q. trojana showed a very large root system, which corresponded to higher soil area exploitation, and bigger leaf midrib vascular bundles than the other two species. Morphological and physiological performances indicated Q. trojana as the most tolerant to drought and fire. These characteristics contribute to a high recruitment potential of Q. trojana seedlings, which might be the reason for the dominance of this species under natural conditions. Drought increase as a result of climate change is expected to favour Q. trojana, leading to an increase in its spatial distribution.

Sleep continuity scale in Alzheimer's disease (SCADS): application in daily clinical practice in an Italian center for dementia.

Sleep disorders can occur in many neurodegenerative disorders; in a previous paper we constructed a scale investigating sleep discontinuity/fragmentation with the aim to obtain a rapidly and easily administered tool suitable for early identification and longitudinal monitoring of sleep disturbances in Alzheimer's disease (AD). We introduced this instrument in the daily clinical practice in a center for dementia; here we present the results of our experience. Two hundred and sixteen AD outpatients referred to the Alzheimer's Disease Assessment Unit at the IRCCS C. Mondino National Neurological Institute, Pavia, Italy, in the period October 2012 to March 2014 were administered the scale. The questionnaire global score was correlated with measures of cognitive, functional and behavioral impairment; a significant association was found with Mini-Mental State (p = 0.005), Activities of Daily Living (p = 0.01), Neuropsychiatric Inventory (p = 0.01) and Clinical Dementia Rating (p = 0.0005). The present data indicate that the previously validated questionnaire proves to be a suitable, rapid and easy to use tool in investigating sleep quality in AD in daily clinical practice. An early identification and longitudinal monitoring of sleep disturbances in AD may improve pharmacological and non-pharmacological interventions.

A sleep continuity scale in Alzheimer's disease: validation and relationship with cognitive and functional deterioration.

Considering that disrupted sleep may be detrimental to daytime performance in people with dementia, we set out to construct a questionnaire able to identify sleep patterns potentially associated with clinical and functional disease variables in this population. Two subsets of items indicative of patterns of unstable sleep and of disordered rapid eye movement sleep (REM) were selected. The first included items investigating sleep continuity, with low sleep continuity markers considered indicative of high arousability; the second included items investigating the frequency and quality of dreams and the frequency of clinically identifiable REM sleep behaviour disorder episodes. The questionnaire was administered to 140 outpatients with a diagnosis of mild-to-moderate Alzheimer's disease. The Mini-Mental State Examination (MMSE), Activities of Daily Living (ADL), Instrumental Activities of Daily Living, Neuropsychiatric Inventory and Clinical Dementia Rating (CDR) were administered to quantify cognitive, functional and behavioural impairment. A subscale comprising items investigating sleep discontinuity/fragmentation and showing high internal consistency was constructed and found to correlate significantly with variables considered indexes of cognitive and functional deterioration in AD (MMSE, ADL and CDR). Conversely, it did not prove possible to obtain a subscale of dysfunctional REM phenomena. The use of a rapidly and easily administered sleep scale, like the one we constructed, appears to be suitable for early identification and longitudinal monitoring of sleep disturbances in AD.

Environmental risk factors for REM sleep behavior disorder: a multicenter case-control study.

OBJECTIVE: Idiopathic REM sleep behavior disorder is a parasomnia characterized by dream enactment and is commonly a prediagnostic sign of parkinsonism and dementia. Since risk factors have not been defined, we initiated a multicenter case-control study to assess environmental and lifestyle risk factors for REM sleep behavior disorder. METHODS: Cases were patients with idiopathic REM sleep behavior disorder who were free of dementia and parkinsonism, recruited from 13 International REM Sleep Behavior Disorder Study Group centers. Controls were matched according to age and sex. Potential environmental and lifestyle risk factors were assessed via standardized questionnaire. Unconditional logistic regression adjusting for age, sex, and center was conducted to investigate the environmental factors. RESULTS: A total of 694 participants (347 patients, 347 controls) were recruited. Among cases, mean age was 67.7 ± 9.6 years and 81.0% were male. Cases were more likely to smoke (ever smokers = 64.0% vs 55.5%, adjusted odds ratio [OR] = 1.43, p = 0.028). Caffeine and alcohol use were not different between cases and controls. Cases were more likely to report previous head injury (19.3% vs 12.7%, OR = 1.59, p = 0.037). Cases had fewer years of formal schooling (11.1 ± 4.4 years vs 12.7 ± 4.3, p < 0.001), and were more likely to report having worked as farmers (19.7% vs 12.5% OR = 1.67, p = 0.022) with borderline increase in welding (17.8% vs 12.1%, OR = 1.53, p = 0.063). Previous occupational pesticide exposure was more prevalent in cases than controls (11.8% vs 6.1%, OR = 2.16, p = 0.008). CONCLUSIONS: Smoking, head injury, pesticide exposure, and farming are potential risk factors for idiopathic REM sleep behavior disorder.

Hallucinations and sleep-wake cycle in Alzheimer's disease: a questionnaire-based study in 218 patients.

The aim was to evaluate the relationship between hallucinations and the sleep-wake cycle in a sample of Alzheimer's disease (AD) patients in the early-moderate stage. Two hundred and eighteen AD patients (66 males, 152 females, mean age 74.3+/-6.85) were administered a sleep questionnaire in the presence of a care-giver. Twenty-six out of 218 (12%) reported the occurrence of hallucinations, mainly visual. In 18/28 (69%) hallucinations occurred when the patient was awake and in 8 (31%) hallucinations were reported to occur close to a specific phase of the sleep-wake cycle. Vivid dreams were reported in 25/218 (11%) and violent sleep-related and dream-related behaviours (probable REM behaviour episodes) in 22/218 (10%). Both REM phenomena were more frequent in AD hallucinators than in AD non-hallucinators (26.9% vs. 9.3%, and 26.9% vs. 7.8%, p<0.007). Our data indicate a lower incidence of hallucinations and presumable REM behaviour disorder (RBD) in AD, at least in the early-moderate phase, than that observed in synucleinopathies. However, the higher occurrence of vivid dreams and RBD in AD patients with hallucinations compared to those without hallucinations indicates a potential role of disordered REM sleep in influencing the occurrence of hallucinations in AD, similar to what has been observed in synucleinopathies.

Sleep disorders in Parkinson's disease: facts and new perspectives.

Awareness of the clinical and pathophysiological importance of sleep disorders in Parkinson's disease (PD) has been growing in recent years. Sleep disorders are now regarded as important among non-motor symptoms in PD and as a significant variable of PD-related quality of life. Furthermore, some sleep disorders, namely REM behaviour disorder (RBD), has been hypothesised to herald PD by years. Subjective reports of disrupted nocturnal sleep and daytime sleepiness appear to be supported by descriptions of several sleep alterations at nocturnal polysomnographic investigation and Multiple Sleep Latency Test findings. Sleep alterations in PD are to be viewed from the multifactorial perspective of a framework of reciprocally interacting factors: pathophysiology of the disease itself, sleep-related motor symptoms, dopaminergic treatments, ageing, depression, restless legs, periodic limb movements (PMLs) and sleep-disordered breathing. Ad hoc questionnaires and scales such as the Parkinson's Disease Sleep Scale and the Short and Practical (SCOPA) Sleep Scale are now available for the evaluation of disordered sleep in PD patients and have been proved to be useful for preliminary screening of sleep disorders in PD. However in a few cases a video-polysomnography (V-PSG) is needed in order to confirm a diagnosis of sleep disorder in PD, particularly in diagnosing RBD. As for treatment of sleep disorders, combined pharmacological and non-pharmacological protocols appear to be particularly suitable in their treatment in PD.

Non-convulsive status epilepticus and generalised tonic-clonic seizures persisting in old age in a patient with idiopathic generalised epilepsy: a long-term observation.

Persisting non-convulsive status epilepticus in a man with idiopathic generalised epilepsy is reported. After a first generalised tonic/clonic seizure on awakening one day at the age of 20, the patient experienced rare non-convulsive status epilepticus until the age of 73, when the frequency of the episodes increased, in spite of the initiation of treatment with antiepileptic drugs. No significant cognitive decline was documented when the patient was 83. The existence of such conditions in the context of idiopathic generalised epilepsy shows the problems of syndromic diagnosis and of age dependency of some epileptic phenomena over the course of life with potential bidirectional influences between epileptic manifestations and senile processes.

Rhythmic movements during sleep: a physiological and pathological profile.

Rhythmic movement disorder (RMD) consists of rhythmic movements (RMs) that occur on falling asleep or during sleep, can involve any part of the body and have a reported frequency ranging from 0.5 to 2 Hz. RMs have been reported to occur in a high proportion of normal children as a self-limiting phenomenon starting and remitting within early infancy. However, there have also been descriptions of forms of RMD occurring against a background of mental retardation or persisting beyond childhood, or having onset in adulthood. So, the occurrence of RMs can be regarded as both a physiological and a pathological phenomenon. The few polysomnographic studies conducted in this field have shown that, in some forms of RMD, RMs are highly linked to arousal fluctuations. However, the mechanisms that underlie the genesis of RMs and are capable of leading to both physiological and pathological patterns of RMs are not fully understood. Here we emphasise the possibility that the central motor pattern generator, recently hypothesised to play a role in the genesis of motor phenomena during sleep in the cases of parasomnia and epileptic seizures, might account for the occurrence of RMs in both physiological and pathological conditions.

Intracerebral recordings of minor motor events, paroxysmal arousals and major seizures in nocturnal frontal lobe epilepsy.

The clinical features of nocturnal frontal lobe epilepsy (NFLE) consist of a spectrum of paroxysmal motor manifestations ranging from minor motor events (MMEs) to paroxysmal arousals (PAs) and major seizures. During MMEs and PAs scalp EEG generally does not show definite ictal abnormalities. We describe the clinical and electrophysiological features of three patients affected by drug-resistant NFLE studied with intracerebral electrodes during a presurgical evaluation. The stereo-EEG (SEEG) investigation revealed that MMEs can be fragments of the major seizure and occur during a brief epileptic discharge or on the following arousal. PAs, in the same subject, do not show a definite stereotypy despite the morphological and topographic similarity of the epileptic discharges, thus indicating that other variables may influence the clinical features of PAs.

Hypnic headache: PSG evidence of both REM- and NREM-related attacks.

Hypnic headache (HH) occurs exclusively during sleep. Six attacks were recorded during nocturnal polysomnographic (PSG) monitoring of 10 HH patients. The PSG data obtained indicate that the attacks arose directly from sleep: four from non-REM and two from REM sleep. In no patient were the HH attacks found to show any close temporal relationship with sleep-related breathing abnormalities.

Sleep attacks in Parkinson's disease: a clinical and polysomnographic study.

The objective of the study was to evaluate daytime sleepiness, (the features of episodes of sudden sleep onset), i. e., so-called sleep attacks (SAs), in three male Parkinson's disease (PD) patients (mean age 66 years) on chronic therapy with ropirinole or pramipexole. A structured clinical interview, the Epworth Sleepiness Scale, and continuous 24-h ambulatory polysomnography were used to assess the features of SAs occurring in the patients in their normal home environments. The polysomnographic patterns characterizing SAs (sleep occurring against a background of wakefulness, and not preceded by a feeling of sleepiness or by other heralding symptoms) were analyzed. The results showed that SAs can be clearly documented through polysomnographic monitoring and really, but rarely, occur in PD. SAs seem to represent the extreme of the continuum of daytime sleepiness observed in PD patients.

Hallucinations and sleep-wake cycle in PD: a 24-hour continuous polysomnographic study.

Twenty-four-hour ambulatory polysomnography was performed in 20 patients with PD who were having visual hallucinations (12 men and 8 women, mean age 70 +/- 6 years). Visual hallucinations were clearly related to daytime NREM sleep or nocturnal REM sleep in 33% of the instances. The data reinforce the hypothesis that neural mechanisms implicated in generating sleep and, in particular, in dream imagery play a role in the occurrence of visual hallucinations in PD.