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Parents of children with ASD (N = 86; mean age 44.8 months; 67 boys) were randomized to either WHO Caregiver Skills Training (CST) delivered in public health settings in Italy or enhanced treatment-as-usual. Primary blinded outcomes were 3-months post-intervention change scores of autism severity and engagement during caregiver-child interaction. CST was highly acceptable to caregivers and feasibly delivered by trained local clinicians. Intention-to-treat analysis showed a large and significant effect on parent skills supporting joint engagement and a smaller significant effect on flow of interaction. Expected changes in child autism severity and joint engagement did not meet statistical significance. Analysis of secondary outcomes showed a significant effect on parenting stress, self-efficacy, and child gestures. Strategies to improve the effectiveness of CST are discussed., (© 2021. The Author(s).)

Lay Abstract: Across the globe, children with neurodevelopmental disorders, including autism, have limited access to care through public services. To improve access to care the World Health Organization developed a novel, open-access programme: the Caregiver Skills Training programme. The Caregiver Skills Training consists of nine group sessions and three individual home visits, focused on training the caregiver on how to use everyday play and home routines as opportunities for learning and development. We implemented Caregiver Skills Training in public child neuropsychiatry services in Italy and examined with questionnaires and focus groups how feasible it was to deliver the programme in public health settings and how acceptable and relevant it was for caregiver users. We found that the Caregiver Skills Training was largely considered acceptable and relevant for families and feasible to deliver. We discuss potential solutions to address the specific implementation challenges that were identified, such as strategies to improve training of interventionists and overcome barriers to caregiver participation.

Lennox-Gastaut syndrome (LGS) is characterized by interictal epileptiform discharges (IEDs) occurring during sleep. The aim of this study was to determine whether sleep influences not only the frequency of seizures and IEDs, but also the time-dependent evolution that may support the hypothesis of homeostatic influences on epileptic threshold. Video polysomnography data from our database were reviewed to identify adult LGS patients with at least seven hours of nocturnal recording. Thirteen patients were identified and a second polysomnography was available for nine. The number, duration and index of IEDs, relative to total sleep, sleep stages, and time during the night, were calculated. The majority of IEDs occurred during non-rapid eye movement sleep, mainly in stage 2 and slow-wave sleep. Adjusting for time spent in each sleep stage, we found 45 IEDs/hour in stage 1, 123/hour in stage 2, 106/hour in slow-wave sleep, and 26/hour in rapid eye movement sleep. The temporal distribution of IEDs showed a significant rise in the first three hours of sleep, followed by a progressive decrease at the end of the night (F=85.6; p<0.0001). Interictal epileptiform discharges occurrence in adult LGS is facilitated by non-rapid eye movement sleep with an evident effect of stage 2 and slow-wave sleep. The significant IED occurrence in the first part of the night and the subsequent decline suggests a link between epileptic threshold and homeostatic sleep mechanisms. The latter should be considered regarding choice of therapy.

Coffin-Lowry syndrome (CLS) is a rare neurodevelopmental condition caused by heterogeneous mutations in the RPS6KA3 gene on the X chromosome, leading to severe intellectual disability and dysmorphism in men, while women are carriers and only weakly affected. CLS is well known for stimulus-induced drop episodes; however, epilepsy is not commonly reported in this condition. We report on a CLS patient presenting with recurrent episodes of nonconvulsive status epilepticus (NCSE) with generalized epileptic activity, for which investigations did not find any other cause than the patient's genetic condition. This case underlines that the possibility of nonconvulsive epileptic seizures and status epilepticus should, therefore, be considered in those patients. The treatable diagnosis of NCSE may easily be overlooked, as symptoms can be unspecific.

Background: Vitamin D deficiency is prevalent in HIV-infected individuals and vitamin D supplementation is proposed according to standard care. This study aimed at characterizing the kinetics of 25(OH)D in a cohort of HIV-infected individuals of European ancestry to better define the influence of genetic and non-genetic factors on 25(OH)D levels. These data were used for the optimization of vitamin D supplementation in order to reach therapeutic targets., Methods: 1,397 25(OH)D plasma levels and relevant clinical information were collected in 664 participants during medical routine follow-up visits. They were genotyped for 7 SNPs in 4 genes known to be associated with 25(OH)D levels. 25(OH)D concentrations were analysed using a population pharmacokinetic approach. The percentage of individuals with 25(OH)D concentrations within the recommended range of 20-40 ng/ml during 12 months of follow-up and several dosage regimens were evaluated by simulation., Results: A one-compartment model with linear absorption and elimination was used to describe 25(OH)D pharmacokinetics, while integrating endogenous baseline plasma concentrations. Covariate analyses confirmed the effect of seasonality, body mass index, smoking habits, the analytical method, darunavir/ritonavir and the genetic variant in GC (rs2282679) on 25(OH)D concentrations. 11% of the inter-individual variability in 25(OH)D levels was explained by seasonality and other non-genetic covariates, and 1% by genetics. The optimal supplementation for severe vitamin D deficient patients was 300,000 IU two times per year., Conclusions: This analysis allowed identifying factors associated with 25(OH)D plasma levels in HIV-infected individuals. Improvement of dosage regimen and timing of vitamin D supplementation is proposed based on those results.

Purpose: To study the clinical outcome in hippocampal deep brain stimulation (DBS) for the treatment of patients with refractory mesial temporal lobe epilepsy (MTLE) according to the electrode location., Methods: Eight MTLE patients implanted in the hippocampus and stimulated with high-frequency DBS were included in this study. Five underwent invasive recordings with depth electrodes to localize ictal onset zone prior to chronic DBS. Position of the active contacts of the electrode was calculated on postoperative imaging. The distances to the ictal onset zone were measured as well as atlas-based hippocampus structures impacted by stimulation were identified. Both were correlated with seizure frequency reduction., Results: The distances between active electrode location and estimated ictal onset zone were 11±4.3 or 9.1±2.3mm for patients with a >50% or <50% reduction in seizure frequency. In patients (N=6) showing a >50% seizure frequency reduction, 100% had the active contacts located <3mm from the subiculum (p<0.05). The 2 non-responders patients were stimulated on contacts located >3mm to the subiculum., Conclusion: Decrease of epileptogenic activity induced by hippocampal DBS in refractory MTLE: (1) seems not directly associated with the vicinity of active electrode to the ictal focus determined by invasive recordings; (2) might be obtained through the neuromodulation of the subiculum., (Copyright © 2013 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

The objective of this study was to evaluate the efficiency and the effects of changes in parameters of chronic amygdala-hippocampal deep brain stimulation (AH-DBS) in mesial temporal lobe epilepsy (TLE). Eight pharmacoresistant patients, not candidates for ablative surgery, received chronic AH-DBS (130 Hz, follow-up 12-24 months): two patients with hippocampal sclerosis (HS) and six patients with non-lesional mesial TLE (NLES). The effects of stepwise increases in intensity (0-Off to 2 V) and stimulation configuration (quadripolar and bipolar), on seizure frequency and neuropsychological performance were studied. The two HS patients obtained a significant decrease (65-75%) in seizure frequency with high voltage bipolar DBS (≥1 V) or with quadripolar stimulation. Two out of six NLES patients became seizure-free, one of them without stimulation, suggesting a microlesional effect. Two NLES patients experienced reductions of seizure frequency (65-70%), whereas the remaining two showed no significant seizure reduction. Neuropsychological evaluations showed reversible memory impairments in two patients under strong stimulation only. AH-DBS showed long-term efficiency in most of the TLE patients. It is a valuable treatment option for patients who suffer from drug resistant epilepsy and who are not candidates for resective surgery. The effects of changes in the stimulation parameters suggest that a large zone of stimulation would be required in HS patients, while a limited zone of stimulation or even a microlesional effect could be sufficient in NLES patients, for whom the importance of the proximity of the electrode to the epileptogenic zone remains to be studied. Further studies are required to ascertain these latter observations., (Copyright © 2011 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Purpose: Lafora disease (LD) is an autosomal recessive form of progressive myoclonus epilepsy with onset in childhood or adolescence and with fatal outcome caused by mutations in two genes: EPM2A and NHLRC1. The aim of this study was to characterize the mutation spectrum in a cohort of unrelated patients with presumed LD., Methods: Sequencing of the two genes and search for large rearrangements was performed in 46 unrelated patients with suspected LD, 33 originating from France and the others from different countries. Patients were classified into two groups according to the clinical presentation., Results: Mutations of various types were found in EPM2A in 10 patients and in NHLRC1 in 4 patients. Mutations were found in 14 (93%) of 15 patients with classical clinical and electroencephalography (EEG) presentation of LD and in no patients with an atypical presentation. Ten mutations were novel, including the first substitution reported in a donor splice site of EPM2A, leading to the deletion of exon 2 at the RNA level. Four large deletions, including two deletions of exon 2 with different sizes and breakpoints, were found in EPM2A, corresponding to 20% of the alleles of this gene., Discussion: We described several novel mutations of EPM2A and NHLRC1 and brought additional data to the genetic epidemiology of LD. This study emphasized the high mutation rate in patients with classical LD as well as the high negativity rate of skin biopsy.

Cortical dysgenesis is increasingly recognised as a cause of epilepsy. We report a case with double cortex heterotopia and secondarily generalized seizures with a generalised spike wave pattern. During the course of the disease, the child developed electrical status epilepticus in slow wave sleep. From the first examination, sleep pattern revealed increased frequency and amplitude of spindle activity, more evident in anterior areas. The role of the thalamocortical pathway in increased sleep spindle activity is discussed with emphasis on the possible role of altered thalamocortical pathways in abnormal cortical migration. A strong suspicion of cortical dysgenesis may therefore be based on specific EEG sleep patterns.

Generic substitution of antiepileptic drugs (EAD) have limited use because epilepsy is a chronic disease, seizure recurrence has an important impact of the quality of life and the potential risk of accidents. EADs have a narrow therapeutic window, non negligible side effects and complex interactions. Bioavailability of generic EADs, tested in healthy men during a limited period of time must be within the 90% IC, in which means that serum levels can range from 80% to 125% of the original drug. A slight drop in serum level could increase the risk of seizure recurrence, as indicated by several publications. Although no formal studies regarding cost effectiveness and the rate of seizure recurrence is available yet, the prevailing consensus recommends not to replace an original antiepileptic drug by a generic, due to the harmful risk of seizure recurrence.

Mental disorders in patients having difficulties to treat their epilepsy are without a doubt more frequent than those presented by patients with controlled epilepsies or within a general population. These problems are especially affective disorders; clinical presentations of these troubles are often particular and difficult to classify through the current admitted classification guidelines. We speak generally about an interictal dysphoric disorder. The relationship between observed troubles in seizures is in some cases very particular: postictal depressions and psychosis are very peculiar disorders, self limited, difficult to detect and to treat. Some considerations are made about certain topics related to severe epilepsies: suicide, pseudo seizures and therapeutic attitude.

The Whiplash Associated Disorders (WAD) are mostly chronic cervical and cephalic pain syndromes. They are often associated with general disorders and with sensorial difficulties. The neurologist evaluates this trouble according to neurochemical and neurophysiological models, hypothesizing a "central hypersensitivity" after a localised peripheral lesion (such as cervical distortion). Other epistemological points of view are certainly legitimate, for example "biopsychosocial" models. From a therapeutic point of view, it seems worth while to try to prevent the development of WAD. When chronic pain is accompanied by difficult life situation, the solution is not simply medical but also social. Faced with a persistent WAD, the therapeutic attitude should be individualised and multidisciplinary, seeking the autonomy of the patient.

Cervicogenic headaches are a relatively new nosological entity. The diagnostic criteria are still under discussion. They are rare: the diagnostic is based on anamnestic and clinical considerations. Rx investigation is mandatory. The aetiology is multifactorial. In case of cervical trauma, the relationship with the primary peripheral lesion must be carefully discussed. The actual opinion from the neurophysiological point of view is based on the hypothesis of "central hypersensitivity". This progressive dysfunction is probably modulated by genetic characteristics: the mechanism is triggered by the initial peripheral nociceptive input. In chronic situations, psychosocial factors are important. The treatment must be considered individually. It is based on a pharmacological approach and, in selected cases, includes anaesthetic block.

Senology is going to be an independent branch, but resistances to the acknowledgement of the senologist as a devoted professional are still under way. Nevertheless, in the last 20 years an irreversible educational training was traced out. The senologist is not only the surgeon who operates on the breast: he is also a clinician, a researcher and a philosopher. Restricting the senologist's role to that of a knife-user is by far reductive, as this does not put in its true light his huge knowledge: senology is first of all a cultural item. Europe is going to set up independent Breast Units because this is the only way to offer excellent services, whose final result will be the reduction of mortality and the improvement of quality of life.

Purpose: The exact anatomic and neurophysiologic correlates of idiopathic generalized epilepsy (IGE) in humans are still not well understood, although the thalamus has frequently been invoked as the crucial structure in the generation of primary generalized seizures. The few in vivo magnetic resonance (MR)-based studies in IGE patients suggest an altered cortical/subcortical gray matter ratio, but with no evidence of structural alterations of the thalamus. In this study, we sought to determine the volumes of the other subcortical structures., Methods: The volumes of the caudate nucleus, putamen, pallidum as well as the thalamus were each determined in both hemispheres in 11 patients with various IGE syndromes, normalized for whole-brain volumes and then compared with 15 age-matched controls., Results: No differences were noted in thalamic volumes, confirming previous reports. However, smaller subcortical volumes were noted in the IGE patients (p < 0.009), mainly due to smaller putamen bilaterally (p < or = 0.015)., Conclusions: It is speculated that the presence of discrete frontal dysfunction, as noted in neuropsychological studies in IGE patients, indirectly supports our results because the putamen projects predominantly to the frontal cortex. Larger studies with more homogeneous patient populations are needed to determine the robustness of these findings and whether they are specific for particular IGE syndromes.

Functional outcome after stroke with severe disability (Barthel Index<60 points) was analyzed retrospectively in one hundred patients, including seventy-three with nonhemorrhagic stroke and twenty-seven with hemorrhagic stroke admitted to our neurorehabilitation center between 1986 and 2000. Neurological deficits and functional disabilities were assessed with the Barthel Index at admission to rehabilitation and after the rehabilitation program in survivors. The rehabilitation therapy was based on the Bobath concept. Patients were not discharged until neurological and functional stability had been reached. There was no difference for age, length of stay, Barthel Index scores at admission and discharged between the groups. Gain in the Barthel Index scores between admission and discharge (p=0.005) resulted from more efficiency in the group with hemorrhagic stroke. These patients appeared to exhibit better functional gain at discharge from rehabilitation than nonhemorrhagic patients. This observation points out that long-term outcome is also better for patients who experience hemorrhagic stroke.

Since the beginning of the 1990's, a dozen of new anti-epileptic drugs have been on the market or will be soon. This article reviews the daily clinical utilisation of new anti-epileptic drugs. It considers, without being complete, the current opinions and tendencies. The new anti-epileptic substances are generally as efficient as conventional medications. However, they are better tolerated and are more easily used in combination with conventional anti-epileptic drugs. Polytherapy is certainly the form of treatment, which is used in the most cases of resistant epilepsies. The surgical treatment can be used in only a very limited number of cases. The objective of treatment is the complete control of seizures, with minimum secondary effects. Though this objective is rarely reached, the NAE significantly improves the quality of life of patients suffering from severe epilepsy. The utilisation of NAE is not without risk. Increase in the frequency and severity of seizures may occur; we should remember that severe adverse effects appeared in the post-marketing period of the use of Vigabatrine and Felbamate. Therefore, we must remain vigilant in the clinical use of the anti-epileptic drugs.

Common distortion of the cervical spine without evidence of neurological or osteoligamentary damage is a frequent consequence of indirect head and neck trauma. The mechanism of the injury (called "whiplash", "coup de lapin", or "Schleudertrauma") does not imply direct trauma to the head or neck. In the acute phase, common distortion of the cervical spine requires treatment. Rapid management may avoid or considerably reduce the chronic pain syndrome with the characteristic chronic tension-like headache. The chronic pain and the numerous associated functional disorders are not well understood: certain factors favour central and peripheral dysfunction and others emphasize the importance of extra-trauma phenomena. In our opinion, extra-trauma phenomena would explain the invalidating nature of pain in a small number of patients. Management of these chronic patients requires a multidisciplinary approach aimed at helping the patient overcome the inconveniences of this condition.

We have presented two cases of chronic disabling exertional headaches following a minor head trauma. MRI studies of the cranio-cervical junction showed Chiari Type I malformation, without bony occipito-cervical dysplasia. Headaches after a mild trauma are a common finding. The exertional character of the headache can lead the clinician to his diagnosis in cases involving long-term complaints.

Objectives: The aim of this study was to identify the characteristics of post-traumatic headache after whiplash injury in order to obtain some indications as to the pathogenesis of this particularly frequent clinical entity., Methods: A retrospective study of 63 patients who had suffered whiplash injury and who had persistent chronic pain was conducted., Results: Forty-seven patients complained of headache and pain in the cervical spine and 16 of pain in the cervical spine alone. Among the patients with headache 74% complained of tension-like pain, while only about 10% had identifiable post-trauma migraine headache with or without aura. Current neurophysiological hypotheses of central dysfunction due to neurochemical disorders induced by the initial nociceptive stimuli, frequently found in the general population, would not explain the disabling characteristics observed in these patients with chronic pain., Conclusion: A multifactorial pathogenesis of post-traumatic chronic headache should be entertained, suggesting that not only trauma but also extra-trauma factors unrelated to whiplash would be involved.

This study of prevalence is based in a population of 34,577 people aged from 15 to 19 resident in the canton of Vaud (Switzerland) and on the Swiss Federal Disability Insurance files (AI, AVS, IV), a compulsory insurance for all young residents. The study had two aims: firstly, to evaluate the necessary number of institutional beds for people needing multidisciplinary management because of medical, social and educational problems related to severe epilepsy, secondly, to form an idea of the number of epileptic patients needing to be considered for surgical treatment of epilepsy. In fact, we collected only 12 cases requiring multidisciplinary institutional assessment and management due to refractory epilepsy associated with mild or moderate mental handicap. Clinicians dealing with epileptic patients believe that people for whom surgical treatment needs to be considered are rare: the study confirms this rarity. We found this indication to be clearly legitimate in only 7 patients (less than 10% of all epileptic patients).

This presentation summarises the opinions concerning chronic pain after mild cervical trauma without neurological and radiological findings. Clinicians are often surprised by the disabling character of the pain, despite the lack of severe lesions. The initial lesions lead in some cases to chronic headache having different features associated with cervical pain, but in our opinion this pain does not have a disabling nature. When the disabling character is present, we postulated that it is associated with other psychological, social and professional factors. In fact, the pathogenesis of this chronic disorder is multifactorial. Its treatment doesn't lead to healing but to better management of patient life with chronic pain.

Several and different solutions have been used for lung preservation but, at present, fluids and solutions are quite alike. In the last years extracellular type solutions have been progressively tested in experimental researches and have shown a better protection vs intracellular one. In this research we have studied the effect of a low-potassium solution normally used as plasma expander (Haemmaccel, HM) on isolated foetal human fibroblasts (WI-38). HM has been compared with Belzer solution (UWS) after 16 hrs incubation at 10 degrees C and low-potassium solutions with dextran 2% and 5% after 6 hrs and 16 hrs incubation at 10 degrees C. Wi-38 cells have been seeded at the density of 9x10(4)/cm2 onto plastic well plates. Cellular viability was measuring using the rate of protein synthesis through the incorporation of 3H leucine in growth medium during a 1 hr incubation at 37 degrees C. The results were expressed as nmol 3 H leu/mg of proteins/minute and presented as means +/- SD; the comparison has been performed by the one way variance analysis test. After 16 hrs incubation at 10 degrees C HM preserves WI-38 cells significantly better than UWS. Comparing HM with LPD 2% and 5% a significant difference both at 6 hrs and at 16 hrs was observed. Our preliminary in vitro results confirm that low-potassium solutions are less toxic on isolated lung cells than intracellular one. Polygelin contained in HM could be considered a suitable colloidal substance that determine a better preservation if compared with Low-Potassium Dextran solutions.

We present clinical date and follow up in a rehabilitation unit with a multidisciplinary team for twenty two old patients with severe cerebrovascular disease. The patients were fully examined in the "Service de neurologie de Lausanne". New cerebral vascular accidents occurred in three patients. The other patients improved in functional status evaluated by the Barthel-Index in spite of no significant changes in neurological and neuropsychological status.