The prevalence of seizures in children with developmental delay

Objectives:To study the prevalence of seizures in children with GDD and identify the characteristics of such patients; to examine the association of GDD with epilepsy and to determine the effect of certain risk factors on this association.Methods:A retrospective cross-sectional study conducted at the pediatric neurology and developmental assessment clinic at King Fahad specialist hospital (KFSH), Saudi Arabia. All data were collected by reviewing the electronic medical records of 200 pediatric patients who presented with global developmental delay from February 2016 to April 2018.Results:The sample includes 200 children (113 males, 87 females) aged zero to 12 years. The largest group of participants came from the Dammam region, representing 27.5% of the sample. The prevalence of epilepsy in GDD patients was 56%; the epilepsy and non-epilepsy groups differed significantly in age. The most common type of seizure was generalized onset motor, which were observed in 37.5% of the sample. Problems during labor occurred in 15% of the sample; consanguineous marriage occurred in 61.6% of the participants. Neither of these factors differed significantly in the epilepsy and non-epilepsy groups. Advanced paternal age did differ significantly in the two groups (p=0.003).Conclusion:The prevalence of epilepsy is high in children with GDD, and of the factors studied here, the most significant variables affecting this correlation are the type of seizure and advanced paternal age.

Global developmental delay (GDD) is a general term used when children under the age of five years’ experience significant delays in 2 or more developmental domains (daily living activities, motor skills, speech/language, cognitive abilities, and social/emotional skills). The precise prevalence of GDD is unknown, but it is estimated to be 1%-3%.¹ Several studies have proposed an association between GDD and epilepsy.^1-3 Seizures are common; 4-10% of children experience at least one episode of seizures. Abnormal excessive or synchronous neuronal activity in the brain cause seizure and result in transient signs and/or symptoms.⁴ According to the International League Against Epilepsy (ILAE) patient can be diagnosed with epilepsy if the probability of further seizures after first unprovoked seizure similar to the general recurrence risk of at least 60% after 2 unprovoked seizures, occurring over the next 10 years.⁵ About 30% of children with epilepsy have behavioral or cognitive impairments.⁶ Epilepsy has been associated with neurocognitive impairment in children, and it can adversely impact school performance and long-term psychosocial prospects.^7,8 The impact of epilepsy on GDD can be explained by the effect of seizures on developing brain structures and functions and on repeated brain volume reduction (especially white matter tissue, which is seen in patients with childhood-onset temporal lobe epilepsy). Brain reduction is also associated with poor cognitive skills.^9-11 However, cognitive impairments in general often go undiagnosed; therefore, children with epilepsy should be periodically screened for GDD to enable early intervention and to maximize these patients’ chances for academic, professional, and social success.^2,3,6,7,9Little research has been carried out aiming to address the etiological factors of GDD in children attending a tertiary care hospital. This study was the only one study was done in Saudi Arabia in 2019 that focused on the prevalence of epilepsy in pediatric patients with developmental delay in Saudi Arabia, as it found that 56% of Saudi children with GDD have epilepsy. The same study showed that multiple variables were found to be related to GDD including consanguineous marriage (57%), and low birth weight (22%). Causes identified includes neuroradiology abnormalities in 58% of GDD children, 45% had abnormal EEG, genetic defects in 40%, and lastly metabolic disorders in one quarter of the participants.¹The aim of the present study is to examine the prevalence of epilepsy in children who visited a development clinic and the demographic characteristics of these patients. It will also examine the effects of other factors such as type of seizures, problems during pregnancy or labor, and advanced maternal or paternal age.     

Prescribing practices in the treatment of depression among psychiatrists in Oman

Objectives:To examine the prescribing patterns of antidepressants among a sample of psychiatrists working in Oman and to compare these practices to the current evidence for prescribing specific antidepressant in particular clinical situations.Methods:This retrospective cross sectional study. Massachusetts General Hospital Psychopharmacology Questionnaire, a 10-item questionnaire listing factors that might have influenced the choice of antidepressant medication, was sent to 83 psychiatrists working in governmental health sectors in Oman. The study was done from March to July 2019.Results:A total number of 78 psychiatrists responded to the questionnaire. Of these, 44 of the psychiatrists (56.4%) believed that one type of antidepressant is more efficacious than others, while 74 psychiatrists (94.9%) indicated that selective serotonin reuptake inhibitors (SSRIs) were their first-line treatment preference. Mirtazapine was chosen as the most likely antidepressant to cause weight gain by two-thirds of the participants. For the treatment of anxious depression and depression with melancholic feature, SSRIs were the first choice of treatment for 64.1% and 7% of respondents, respectively. For depression with atypical features, 42.3% indicated that a monoamine oxidase inhibitor would be their first option.Conclusion:There is a discrepancy between the current antidepressant prescribing practices in Oman and empirical antidepressant-prescribing evidence, and this finding is consistent with previous studies.

Depression is a serious and a major public health problem around the world. According to the World Health Organization (WHO), depression is the fourth leading cause of disability worldwide and it is projected that by 2030 to be the leading cause of disease burden,¹ There are different modalities to treat depression including self-help, exercise, psychotherapy and counseling, however antidepressants remain the mainstay of treatment for moderate to severe depressive symptoms. Most antidepressants alleviate depression by affecting the neurotransmitters levels, mainly the monoamines (norepinephrine, serotonin, and dopamine). The first antidepressants used were monoamine oxidase inhibitors (MAOIs), followed by tricyclic antidepressants (TCAs), such as amitriptyline and imipramine. These two groups of drugs were widely used until the introduction of fluoxetine as the first selective serotonin reuptake inhibitors (SSRI) in 1978.² Recently, different types of antidepressant appeared in the markets including venlafaxine and duloxetine which are work on reuptake of both serotonin and norepinephrine neurotransmitters so called (SNRIs) and the atypical antidepressant such as bupropion and mirtazapine.³Generally, antidepressants are all equally effective in treating depression despite the difference in mechanism of action.³ The NICE guidelines recommend that SSRIs should be used as a first-line pharmacological treatment for treating depression, for no reason other than better tolerability to side effects. It is well known that TCA are associated with various side effects ranging from troublesome anticholinergic side effects to the more serious arrythmia and cardiovascular side effects. The MAOIs, are well-known for their interaction with certain foods and increase risk for hypertensive crisis. However, despite being equally effective, among the same group of SSRIs specific drugs are preferred in certain clinical situations and in particular depressive subtypes. In addition, specific antidepressant agents within the same class are associated with increased risk of certain side effects. For example, previous studies have shown that paroxetine is associated with weight gain and higher incidence of sexual dysfunction, and sertraline is more associated with diarrhea comparing to other SSRIs.⁴As a general rule, and with increased numbers of antidepressant available in the markets, psychiatrists prefer to select antidepressants that are more tolerable and have a reduced risk of harm following overdose. However, there are multiple other factors that influence the decision making. These can be divided into patient-specific factors, such as patient preference, patient age, comorbid medical illness, and drug-specific factors, such as cost, tolerability, safety following overdose.⁵Few studies have been conducted to examine antidepressant prescribing practices. We only identified 5 studies which focused exclusively on psychiatrists: Olfson and Klerman, 1993; Olfson et al., 1998, Moore et al., 2002, Baboolal, 2002, Petersen et al., 2002.^6-10 The first 2 studies did not examine prescribing practices of a specific antidepressant agents. The third study, conducted in Trinidad by Moore et al⁸ found that the TCAs, mainly amitriptyline, were the most prescribed antidepressants among outpatients in psychiatric clinics in Trinidad and that fluoxetine was the only SSRI prescribed in these clinics. The other 2 studies by Baboolal, 2002, and Peterson et al., 2002, were more focused on individualized drugs. The study by Baboolal surveyed 31 psychiatrists in Trinidad and Tobago using a self-administered, extensive questionnaire and Peterson et al, 2002, surveyed 450 psychiatrists in Massachusetts, USA.^9,10 In both studies, psychiatrists were asked about their prescribing practices and the results were compared with empirical evidence from the scientific literature. The findings of both studies were significant and highlighted a discrepancy between the empirical evidence and clinical practices and suggested that other factors influence clinicians and their medication choices in the treatment of depression.^10,11This study aims to examine the prescribing patterns of antidepressants among a sample of psychiatrists working in Oman and to compare these practices to the current evidence for prescribing specific antidepressant in a particular situations.     

Public Awareness of Ischemic Stroke in Medina city,Kingdom of Saudi Arabia

Objectives:To assess social awareness of ischemic stroke amongst Saudi citizens in Medina city.Methods:In a cross-sectional study conducted between February and September 2019, we used a validated questionnaire to conduct face-to-face interviews and collect data, at 4 shopping malls and 5 supermarkets in Medina city, KSA.Results:Five hundred and nineteen participants completed the questionnaire. Of the respondents, 57.4% correctly defined stroke, 42.6% correctly chose ≥2 stroke signs and made ≤one mistake, 23.1% knew of blood clot-dissolving drugs, 32.8% correctly identified ≥ 4 risk factors with ≤ one mistake, 85.93% knew that going to the Emergency Room (ER) was the correct action, and 35.84% identified ≥ 3 post-discharge requirements, with ≤one mistake. Most participants (65.77%) cited internet and social media as information sources. In the univariate comparison, older age (p<0.001) and family history of stroke (p=0.001) better predicted stroke knowledge. In a multivariate logistic regression, the only predictor for stroke recognition was the educational level. The gender and family history were predictors for stroke signs knowledge. Educational level and the family history of stroke were predictors for risk factors knowledge respectively.Conclusion:We observed a significant stroke knowledge deficit in our Saudi cohort, thus there is a need to increase public awareness about stroke risk factors, warning signs and emphasizing prevention approaches.

Ischemic stroke is caused by an interrupted blood supply to the brain, due to either a thrombotic or embolic event. This event cuts off oxygen and nutrients, causing damage to brain tissue.¹ Stroke is the second most common cause of death after heart disease, and the leading cause of approximately 11.3% of total deaths worldwide.² In 2010, its global prevalence was 33 million.³ In the Middle East region, it is forecasted that stroke mortality will approximately double by 2030.⁴ In the Kingdom of Saudi Arabia (KSA), the stroke prevalence is 29 individuals per 100,000 per annum,⁵ and is a major social and economic medical problem afflicting that country.⁶Stroke results in physical, psychological and social functional impairments, ending in long term disability and mortality.⁷ Several risk factors have been identified as the most common causes of stroke in Saudi Arabia;⁸ they include hypertension, dyslipidemia, obesity, and diabetes mellitus are major risk factors for stroke and might be considered as critical factors for primary and secondary prevention of stroke. Importantly, 80% of stroke cases can be prevented with proper risk factor knowledge;⁹ such actions can lead to early hospitalization and improved stroke prognoses and survival rates,³ thus social awareness is key to preventing stroke and/or improving outcomes.In the KSA, stroke ranks second in the top ten causes of death.¹⁰ In a 2017 study in Riyadh city, researchers measured knowledge and attitudes to stroke. The authors determined stroke information sources and assessed their reliability, and found inadequate knowledge on stroke symptoms and causes.¹¹Lack of awareness about stroke was found to be a major cause of the high incidence of stroke in the Middle East, as awareness about risks can help in the primary prevention of the disease.¹² This study therefore assessed awareness levels of ischemic stroke, including risk factors, warning signs and therapeutic options in Saudi citizens in Medina City.     

Identification of posterior visual pathway lesions and MRI burden in people with Multiple Sclerosis

Objectives:This review systematically identifies posterior visual pathway lesions and MRI burden in people with multiple sclerosis (MS).Methods:The articles were searched through Web of Science, Medline, and Embase databases on January 2020, for English language articles from 2000 to 2019.Results:This review presents summary measures if related to MRI assessment to an overall measure of MS and visual pathway lesions. A total of 44 articles fulfilled all inclusion criteria, covering the period 2000-2019. Different atypical outcomes reveal a low risk for subsequent clinically predefined MS development, specifically in the presence of normal brain MRI. Several impairments related to quality of life have been identified as a result of the effect of retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer.Conclusion:The afferent visual system in MS offers unique accessibility and structure-related functions with further understanding offered by electrophysiology, considering vision as a useful framework for examining new multiple sclerosis therapies.

Multiple sclerosis (MS) is an unidentifiable disease of the central nervous system (CNS) that interrupts the flow of information throughout the brain and between the brain and the spinal cord. It is classified by both axonal degeneration and inflammation. Visual deficits are regular, and optic neuritis (ON) is the earlier indication in approximately 20% of the patients experiencing MS. Multiple lesions are not experienced by optic neuritis patients as it is often determined among two-third of the patients.^1,2 The ON influences patients with MS during their disease course at some point. Differentiation of acute episodes is essential for treatment selection and additional patient management with respect to MS-related optic neuritis.³ Intereye difference thresholds might be beneficial to develop the occurrence of symptomatic and asymptomatic ON lesions in MS and can be beneficial in the diagnostic procedure.⁴ The visual system is highly vulnerable to MS associated damage. Visual disturbances are recurrent and cause extreme disability, but imaging has remained challenging because of technical limitations with respect to the visual pathway posterior to the optic chiasm as compared to the optic radiation (OR).⁵ The visual pathway is typically involved in MS, even in its preliminary stages such as in its clinical episodes of ON. Long-term structural damage throughout the retina and OR induced a single history of ON, which recommend both anterograde and retrograde neuroaxonal degeneration.⁶The most recurrent affected white matter pathway is represented from the afferent visual pathway in MS and neuromyelitis optics spectrum disorders. Non-overt brain tissue or microstructural and pathological procedure quantification can be revealed through diffusion tensor imaging (DTI). The reconstruction of major white matter fiber tracts can be facilitated through DTI, which allow the evaluation of damage-dysfunction and structure-function associations.⁷Optic neuritis was recently proposed as in vivo models in order to examine the pathophysiology of tissue damage and repair in MS with the visual pathways, and clinical manifestation that are agreeable to examine with different visual functional and imaging, and structural techniques.⁸ OR lesions cause retrograde transneuronal degeneration, which might play an essential role in progressive retinal nerve fiber layer loss. Additionally, it has been observed that the disease-associated neurodegenerative modifications in the retina instigate much earlier as compared to the clinical diagnosis of MS.⁹An important region of disease activity in MS is the visual pathway. Optic neuritis is an onset symptom, and almost 50% of MS patients have an occurrence of ON in their lifetime.¹⁰ Sub-clinical ON was also pre-defined and well-established, regardless of any effect of overt attacks.¹¹ However, there is lack of evidence regarding the level of MS-associated impairments in the optic tracts with the development of ON continuation after preliminary decussation.¹² Further information should be provided regarding the role of the visual platforms in MS visual dysfunction. Such information will allow studying optic tracts, which extend from the optic chiasm to the lateral geniculate nucleus, considering the rarity of focal lesion in the optic tract.¹³Previous studies have found that neurodegeneration and neuroinflammation could drive to an interaction of several aspects of the visual pathway such as retinal nerve axonal degeneration, intraretinal inflammation, pathological changes in the optic tract, retinal neurodegeneration, the visual cortex, and the optic radiation.^14-19 However, sensitive and vision-specific outcome measures were scarcely reported in MS clinical trials. The identification of low-contrast letter acuity (LCLA) is considered as a dominant actor to measure visual drawbacks in MS. It is related particularly with quality of life measures, offering evidence on clinical importance and with the structural integrity of the retina for performing optical coherence tomography.²⁰These factors led to collect information about visual drawbacks in ON and MS. The rapid availability facilitates the development of the visual platform, an advantageous model system to support inflammatory and neurodegenerative mechanisms in the Central Nervous System (CNS) for examining novel agents for detecting and repairing MS, considering further advancement of structural information and electrophysiological measures.^21-23 The relationship between visual dysfunction and MRI is not fully understood, but impairments assessed within white-matter optic tracts have indicated higher associations between spinal cord, corpus callosum, behavioral dysfunction, and corticospinal tract.^24-26This review systematically identifies the posterior visual pathway lesions and the MRI burden in people with MS. We systematically reviewed visual lesions, MRI burden, visual pathways, and MS via randomized controlled trials. This review further presents the role of MRI in identifying posterior visual pathway lesions in MS patients and offers mechanisms that assist to understand the importance of a model vision for assessing consequences in the field of therapy     

Assessment of the stroke-specific quality-of-life scale in KFHU,Khobar: A prospective cross-sectional study

Objectives:To assess the overall and domain-specific quality of life (QOL) in post-stroke patients using the stroke-specific quality of life (SS-QOL) scale and to identify variables that may affect the QOL after stroke.Methods:A prospective cross-sectional study, included 80 stroke patients, was conducted in the Neurology department at King Fahad Hospital of the University (KFHU), Khobar, Saudi Arabia, from December 2019 to February 2020. Stroke patients were interviewed using the Arabic version of the SS-QOL questionnaire and modified Rankin scale (mRS).Results:The overall quality of life in the surveyed participants was at the level of 3.72 points, which is above the average recognized in the middle of the scale that ranges from 1 to 5. The overall quality of life was not significantly correlated with sex, age, type of stroke, recurrence of stroke, and time since stroke (p>0.05). Hypertension and atrial fibrillation were the only comorbidities that were determined to be significantly associated with the overall quality of life at the level of (3.53), and (2.97) respectively (p<0.05). There was a statistically significant correlation between the mRS score and the overall quality of life (p<0.05).Conclusion:Performing a comprehensive assessment of the overall QOL in post-stroke patients will result in better health outcomes, particularly in terms of quality of functioning in psycho-social aspects.

Stroke is a disease that is known by its focal neurologic deficit.¹ It occurs when there is a disruption of the blood flow to the brain either by a clot, causing ischemic stroke or by a rupture of the blood vessels, causing hemorrhagic stroke.² It is experienced by approximately 15 million people worldwide and it is considered to be the second cause of mortality. Among these people, 5 million die and another 5 million live with lifelong disability, which creates a major economic and social burden. The number of cases of stroke in Saudi Arabia is increasing and becoming a debilitating reason for death and disability. Research on the incidence and prevalence of stroke in Saudi Arabia is still lacking. There is only one study conducted in Saudi Arabia in the last 10 years, which states that stroke’s prevalence is 29 per 100,000 each year.^2,3Stroke affects the quality of life (QOL) of patients owing to its related cognitive, physical and functional consequences, such as restrictions in mobility, language impairment and depression.^4,5 Although stroke causes extensive functional impairment, the objective methods of evaluation usually fail to assess the subjective impact of these impairments.⁶ The Health-related QOL (HR-QOL) is a term used to evaluate a person’s wellbeing including physical, psychological, functional, and social aspects.⁷ There are various instruments to assess HR-QOL, most of which are based on subjective self-administered questionnaires. Among these instruments is the stroke-specific QOL (SS-QOL) scale, which was established as a multi-dimensional tool for various effects in post-stroke patients.⁸Up to date, there have been 4 studies conducted in Saudi Arabia on the assessment of QOL in post-stroke patients.^9-12 Two of them were conducted in Jeddah; in these studies, the researchers studied QOL among stroke patients using the HR-QOL scale.^9,10 The other 2 studies were conducted in Al Khobar; the first study studied the psychometric properties of an Arabic version of the fatigue severity scale (FSS),¹¹ while the second study measured QOL using SS-QOL and compared its variables such as socio-demographic factors, type of stroke, time passed since the stroke, affected body side, and the living status of stroke patients.¹² However, QOL in post-stroke patients evaluated using SS-QOL has not been studied yet in terms of other variables such as recurrence of stroke, degree of physical disability, comorbidities, and risk factors. Therefore, the aim of this study is to assess the overall and domain-specific QOL in post-stroke patients using the SS-QOL scale and to identify variables that may affect the quality of life after stroke. The quality of life in post-stroke patients has a statistically significant relationship with the type of stroke, duration since the last event, patient demographics, comorbidities, and degree of physical disability.     

Prevalence of depression and anxiety among adult patients with multiple sclerosis at Riyadh City,Saudi Arabia

Objectives:To determine the prevalence of depression and anxiety in adult multiple sclerosis patients attending tertiary facilities in Riyadh, Saudi Arabia.Methods:This is a cross-sectional study conducted among MS patients in Riyadh City, Saudi Arabia. A self-administered questionnaire was distributed among MS patients at Prince Sultan Military Medical City in Riyadh, Saudi Arabia between April 2020 and January 2021. The questionnaire consisted of socio-demographic characteristics and the Hospital Anxiety and Depression Scale (HADS). Univariate using Chi-square test and multivariate regression analysis had been performed to determine the factors associated with anxiety and depression among MS patients.Results:A total of 328 MS patients took part in the study. The most prevalent age group was 36–45 years old (38.4%), with over 70% of the participants being females. Anxiety and depression were shown to be prevalent in MS patients at 42.9 percent and 58.8 percent, respectively. According to statistical tests, being less educated and having partial to severe disability was linked to an increased rate of anxiety and depression, whereas being female was more prone to anxiety symptoms but not depression.Conclusion:Depression was more frequent than anxiety. As a result, while assessing psychiatric diseases in the study group, depression/anxiety may be expected to be more frequent amongst those of greater disability.

Multiple sclerosis (MS) is a central nervous system demyelinating disease caused by an immunological response. Depression and anxiety are more common in patients with multiple sclerosis (PWMS) than in the general population, ^1-4 which is a well-known phenomenon. However, we believe that these illnesses are under-recognized in PWMS because several MS symptoms overlap with depression and anxiety, making detection more difficult. Fatigue, sleeplessness, anorexia, memory loss, and concentration problems are all common symptoms of depression, MS, or both. ^5,6 Furthermore, the symptoms of MS might mislead self-report rating scales designed to detect depression and anxiety, resulting in false positives or negatives. ^5,6 Moreover, depression in PWMS can impair their quality of life (QOL), medication adherence, and compliance, worsening their prognosis. ^7-9 Suicidal thoughts and attempts are also common. ^10-13 The hospital Anxiety and Depression Scale is a one-of-a-kind measure for detecting anxiety and depression while taking into account both disorders’ possible confounders, and it has been validated for use in PWMS. ⁶ Depression is a significant mood illness that affects many people. It creates severe symptoms that impact how you feel, think, and handle day-to-day tasks like working, sleeping, and eating. ¹⁴ In PWMS, the lifetime prevalence of depression in up to 50%, ³ compared to 10.8% in the general population. ¹⁵ The cause of depressive disorders in people with MS is unknown. However, it is assumed to be complex, with psychological, social, and neurological aspects - as well as immunologic and genetic factors - all having a part. ¹⁶ Furthermore, depression can have a severe impact on these patients’ health by raising the severity of their symptoms and reducing their compliance with therapy and follow-up, both of which have an impact on their medical costs. ⁹ In addition to a decreased quality of life (QOL), cognitive impairment, and an increased risk of suicide, especially when anxiety is present. ^7,10,11 Furthermore, PWMS have a 10-year lower life expectancy than the general population of the same age. ² Patients, caregivers, and care providers should not underestimate the impact of sadness and anxiety on PWMS. Improved identification, diagnosis, and treatment in medical offices, where people with mood disorders are frequently seen for the first time, can assist to improve these negative outcomes. ¹⁷ Unfortunately, despite convincing evidence of its high incidence, greater influence on prognosis, and quality of life, depression and anxiety are still underdiagnosed and undertreated. ¹³ The goal of this study is to find out how common depression and anxiety are among adult patients with multiple sclerosis in Riyadh, Saudi Arabia. We’ll also see if there’s a link between Hospital Anxiety and Depression Scale (HADS) score and patients’ demographical, socio-educational, and MS-related characteristics, as well as MS duration, Immunomodulatory type, and EDSS scores.     

How Postdoctoral Research in Paul Greengard's Laboratory Shaped My Scientific Career,Although I Never Did Another Phosphorylation Assay

In this short review, I describe from personal experience how every step in the career of any scientist, no matter how disjointed and pragmatic each might seem at the time, will almost inevitably meld together, to help us all tackle novel projects. My postdoctoral research in Paul Greengard''s laboratory, where I investigated neurotransmitter-mediated phosphorylation of Synapsin I, was instrumental in my career progression, and Paul''s support was instrumental in my ability to make a leap into independent research.

When the Society for Neuroscience was soliciting articles for its new journal, I was a postdoctoral fellow in Paul Greengard''s laboratory, completing studies of neurotransmitter regulation of synapsin I phosphorylation. When Paul informed me that he been invited to contribute a paper, we knew it would be risky thing to volunteer one''s precious data because this was an untested journal. But it came at a good time because I was about to leave the laboratory and had data that complemented my recently accepted paper demonstrating phosphorylation of the presynaptic protein Synapsin I (which we called Protein I at the time) by a neurotransmitter (Dolphin and Greengard, 1981b). So I was very happy to publish in the initial volume of the Journal of Neuroscience, which was to be the first of my 17 papers so far in the journal. The data published in 1981 extended my work on serotonin-mediated phosphorylation and also demonstrated phosphorylation by another class of neuromodulator, acting at adenosine receptors (Dolphin and Greengard, 1981a). It was such a pleasure for me to reread that paper, as it brought back many memories of life in the Greengard laboratory, together with colleagues and friends, including Pietro De Camilli, Angus Nairn, Wieland Huttner, Clive Palfrey, Eric Nestler, Suzanne Lohmann, Ulrich Walter, Howard Schulman, Mary Kennedy, and many others.My interest in intracellular signaling pathways activated by neurotransmitters began when I was an undergraduate student in Biochemistry; I wrote a dissertation on cyclic AMP in prokaryotes and eukaryotes, and then conducted an undergraduate research project examining glycine as a neurotransmitter, using spinal cord synaptosomes as an experimental preparation. This interest propelled me toward Parkinson''s disease research as a graduate student in the laboratory of the neurologist David Marsden at the Institute of Psychiatry in London, where I examined the importance of dopaminergic and noradrenergic pathways in animal models of Parkinson''s disease. I then wrote to Paul Greengard, asking to do postdoctoral research under his mentorship, because I knew I needed more basic training in cell signaling pathways, since my PhD environment had been very focused on translational and clinical research. I could not think of anywhere better than Paul''s laboratory because of his seminal work on cyclic nucleotide signaling pathways (Beam and Greengard, 1976). He said his laboratory was full, but agreed to take me in a year''s time, subject to interview. Fortunately, I had also obtained a UK Medical Research Council French exchange fellowship to work in the laboratory of Joel Bockaert, at College de France in Paris, where I studied the coupling between β-adrenergic receptors and adenylate cyclase. This valuable experience cemented my desire to continue research in this area and work with Paul Greengard. Thus it was that Paul, on a visit to Paris, invited me to be interviewed in his hotel room. I was on my guard when I knocked on the door, and a voice called out to come in. As I entered, I could see nothing but a large bed, but I soon located Paul lying flat on the floor beyond; he explained it was because of his chronic back problem. I perched on the bed, and tried to answer his searching scientific questions. I later realized that Paul lay on the floor at every opportunity, often in our laboratory meetings and indeed during other interviews (Nestler, 2019).When I arrived in Paul''s laboratory then at Yale, in the summer of 1978, the protein Synapsin I had recently been identified as a major presynaptic phosphoprotein (Ueda and Greengard, 1977). It was then called “Protein 1” because it stood out as the main polypeptide in synaptosomes that was phosphorylated in both a cAMP- and a Ca²⁺-dependent manner (Sieghart et al., 1979). However, no neurotransmitters had yet been found to influence the phosphorylation of Synapsin I, and to identify such a pathway seemed to be the holy grail at the time. Paul''s world view of multiple signaling cascades terminating in the phosphorylation of many different target proteins, that would underlie long-term synaptic events, was often at odds with the then prevailing view of ion channel biologists, that neurotransmission was mediated by fast neurotransmitters acting on ion channels, a process in which there was no need to consider neurochemical mechanisms. Eric Kandel (from an electrophysiological standpoint), and Paul, from the basis of biochemical pathways, were both key to the acceptance of the view that a multitude of biochemical pathways must play a role in longer term events. Indeed, Paul was collaborating with Eric Kandel''s laboratory at that time to elucidate whether a phosphorylation cascade mediated the effects of serotonin (5-HT) in Aplysia, and many of us in the laboratory were very influenced by these elegant studies, combining, as they did, electrophysiology and biochemical approaches (Castellucci et al., 1980, 1982).Paul suggested that my project should be to examine whether neurotransmitters could change the state of phosphorylation of Synapsin I in the brain, but he left it entirely to me what tissue I should use for my study. There were ∼25 postdocs and students in his laboratory at the time, and so I had a lot of help and advice, although Paul was the opposite of a micro-manager. Influenced both by the work of Eric Kandel and that of my previous mentor Joel Bockaert (Enjalbert et al., 1978), I decided that serotonin would be a good neurotransmitter to study. Taking inspiration from the work of George Aghajanian, also a professor in the Pharmacology Department at Yale, whose studies had revealed the effects of serotonin on many types of neuron (Aghajanian et al., 1990), I chose to examine the tiny facial nucleus in the brainstem, since Aghajanian had extensively examined the electrophysiological properties of this nucleus, as well as its ultrastructure (Aghajanian and McCall, 1980). His work indicated the facial nucleus had no interneurons, and therefore I thought it might lead to a more homogeneous phosphorylation response than many other brain areas. Indeed, serotonin did result in an increase in phosphorylation of Synapsin I in this preparation, but I initially found that the effects were small and very variable (Fig. 1, left). This was disappointing, and I remember blaming myself for being a cack-handed experimenter.Open in a separate windowFigure 1.Phosphorylation of Synapsin I by actions at serotonin and adenosine receptors. Stimulation of Synapsin I (then called Protein I) phosphorylation with serotonin in the presence and absence of IBMX (left) (from Dolphin and Greengard, 1981b, our Fig. 2) or 2-choloroadenosine (right) (from Dolphin and Greengard, 1981a, our Fig. 4). The “back phosphorylation” method was used, in which ³²P-ATP together with catalytic subunit of protein kinase A were used to phosphorylate residual nonphosphorylated sites on Synapsin I.A breakthrough came indirectly through family tragedy; my father died in 1979, and I returned to England for the funeral. Fortuitously, I also decided to investigate potential future positions in the UK, and visited Leslie Iversen''s Medical Research Council unit in Cambridge. While there, I showed my underwhelming phosphorylation data to John Dowling, who was on sabbatical in the unit at the time, working on dopamine-sensitive adenylate cyclase activity in the retina (Watling et al., 1979). I asked his advice and remember clearly that he suggested adding a low concentration of a phosphodiesterase inhibitor to the slices to potentiate the cAMP response to serotonin. On my return, I duly added isobutyl-methyl-xanthine (IBMX) to the facial nucleus slices, and the responses became much more robust (Dolphin and Greengard, 1981b) (Fig. 1, left). Similarly, Eric Nestler also found that dopamine and depolarization increased the phosphorylation of Synapsin I in superior cervical ganglion neurons (Nestler and Greengard, 1980).Something I could not understand in my data was that the serotonin-mediated phosphorylation of Synapsin I was Ca²⁺-dependent, whereas the phosphorylation mediated by stimulation of an adenosine receptor was not. This was the main topic of my follow-up paper in the first volume of Journal of Neuroscience (Dolphin and Greengard, 1981a) (Fig. 1, right). Everyone in the laboratory remembers that writing papers with Paul was exhausting, as we considered multiple versions of every sentence, and these were written and rewritten in pencil with many erasures. But I can still hear his voice in every phrase of this Journal of Neuroscience paper, and it remains a pleasure to reread each well-considered argument, for which I take absolutely no credit.In the Discussion, many possibilities are suggested to explain the surprising Ca²⁺ dependence of the serotonin-stimulated phosphorylation, and these points remain relevant, even now. For example, we point out that, in Aplysia neurons, serotonin stimulated a presynaptic adenylate cyclase, and this increased the influx of Ca²⁺ (Shimahara and Tauc, 1977; Klein and Kandel, 1978). We suggested that both processes might contribute to presynaptic Synapsin I phosphorylation. I also wonder now if we were seeing a combined effect of 5HT3 receptor activation, allowing Ca²⁺ entry, and subsequent Ca²⁺-calmodulin (CaM) kinase-dependent phosphorylation of Synapsin I, as well as activation of presynaptic serotonergic GPCRs that directly stimulated adenylate cyclase. Of course, the existence of 5HT3 receptors, which are Ca²⁺-permeable ion channels, and the many subtypes of G-protein-coupled 5-HT receptors was unknown at the time (Raymond et al., 2001).My study of neurotransmitter-dependent phosphorylation of Synapsin I was cut short because of family problems that called me back to the UK. But work on Synapsin I simultaneously involved many others in Paul''s laboratory, so research on its subcellular localization and function continued apace. For example, Wieland Huttner and Mary Kennedy both contributed to unraveling the process of Ca²⁺-dependent phosphorylation of Synapsin I (Huttner et al., 1981; Kennedy and Greengard, 1981). Indeed, cAMP-dependent protein kinase and CaM kinase both phosphorylated the same site on Synapsin I, and CaM kinase also phosphorylated additional sites (Huttner et al., 1981). Pietro De Camilli showed in elegant immuno-electron microscopic studies that Synapsin I was a cytoplasmic protein that was associated with synaptic vesicles (De Camilli et al., 1983). To date, there are over 2000 studies involving Synapsin I listed in PubMed, identifying its roles in synaptic function and pathology. These include many from Paul''s own laboratory, continuing throughout his career (Hilfiker et al., 2005; Venton et al., 2006).When I returned to UK, I had the good fortune to obtain a staff position at the Medical Research Council''s National Institute of Medical Research (NIMR) at Mill Hill in London. This was an institution that Paul knew well, since he had spent a postdoctoral period in Wilhelm Feldberg''s department at NIMR in the 1950s, recording from sympathetic nerve fibers. I find it fascinating that Paul was already interested in phosphorylation even then (Greengard and Straub, 1959a, 1959b). My post came about entirely through Paul''s suggestion and generosity: he wrote to Arnold Burgen, then the Director of the Institute, whom he must have known from his work on cholinergic transmission. Suddenly and miraculously, I was offered a job, during a period when Margaret Thatcher was Prime Minister, the UK was in a deep recession, and academic positions were few and far between.Before arriving, I knew very little about NIMR, and was thrilled to be appointed into the same Division of Neurophysiology and Neuropharmacology, which had previously housed the Yale triumvirate of Paul Greengard, Murdoch Ritchie, and Bill Douglas, and which currently contained an eclectic and exciting mix of groups studying pain, hearing, epilepsy, and hippocampal LTP. Wilhelm Feldberg also still had a laboratory there, and used to call me Delphine. I was, however, supernumerary, and given a small cupboard to work in, and an even smaller research consumables budget. In that environment, since I had become intrigued by presynaptic events, I decided to examine neurotransmitter release, and its modulation by activation of presynaptic receptors, including those activated by adenosine agonists, building on my knowledge of the very robust response of Synapsin I phosphorylation (Dolphin, 1983; Dolphin and Archer, 1983). I also rapidly developed an enjoyable collaboration with Tim Bliss and members of his group, including Mick Errington, working with them to measure field potentials and examine glutamate release from the dentate gyrus during the induction of LTP (Dolphin et al., 1982).Studying the regulation of neurotransmitter release naturally led me to further questions about regulation of the Ca²⁺ influx that triggers this release, but this was not something I could directly address at NIMR. Although it did not feel like it at the time, it was fortuitous that the rules for obtaining tenure changed while I was there, meaning that to apply for tenure I would have to reapply for my position and then remain untenured for another 5 years. Many of the affected staff started to look for university posts, and I was offered a lectureship at St. George''s Hospital Medical School, in the Department of Pharmacology. The interview went well, apart from being asked if I intended to have children, and I moved there in 1983, hoping again to pivot my research in a new direction. At that time, the Department was almost entirely populated by electrophysiologists, including the Head of Department, John Kelly, together with Vincenzo Crunelli, Mark Meyer, and Tom Bolton.In this environment, it would be feasible for me to study voltage-gated calcium channels and their modulation by neurotransmitters, and how this related to neurotransmitter release. Ironically, while I was at Yale, Richard Tsien was on the faculty in the Physiology department, doing beautiful work on cardiac electrophysiology, leading up to an understanding of how cAMP modulates cardiac calcium channels, and the existence of additional calcium channels in neurons (Bean et al., 1984; Nowycky et al., 1985). However, my main memory of Dick Tsien at the time was that he adjudicated on my Yale postdoctoral fellowship application. When I started investigating calcium channels, I very belatedly wished I had concentrated better during Physiology seminars at Yale, to take advantage of their wealth of knowledge. Nevertheless, through the enormous generosity particularly of John Kelly at St. George''s, I was able to learn how to record calcium currents in DRG neurons, which had already been established as a model to study presynaptic events (Dunlap and Fischbach, 1978). Together with my first postdoctoral research assistant and great friend, Rod Scott, we started to apply the same techniques to examine the mechanism of modulation of action potentials and calcium currents in these neurons by neurotransmitters, where we showed inhibition, particularly by activation of GABA-B and adenosine receptors (Dolphin et al., 1986).Tools were initially lacking to study the role of G proteins in the modulation of calcium channels and neurotransmitter release, but this changed for me when I visited Pietro De Camilli in Milan and attended the Fifth International Conference on Cyclic Nucleotides and Protein Phosphorylation, in July 1983. There I heard about the use of pertussis toxin to distinguish between different GTP binding protein mechanisms. Although it was not yet available commercially, I managed to locate a local source of pertussis toxin (entailing rather scary visits to the UK government Center for Applied Microbiology & Research at Porton Down, where research on dangerous toxins and pathogens was conducted). Using both pertussis toxin and nonhydrolyzable guanine nucleotide analogs (including photoactivatable forms, made by John Wootton and David Trentham at NIMR), we then investigated the involvement of pertussis toxin-sensitive G proteins in the modulation of both glutamate release (Dolphin and Prestwich, 1985) and calcium currents (Dolphin et al., 1986; Scott and Dolphin, 1986; Dolphin et al., 1988).One of the next big scientific questions was to examine the same modulatory processes using the calcium channel subunits that were being cloned at that time by several groups (Tanabe et al., 1987; Ellis et al., 1988; De Jongh et al., 1990; Mori et al., 1991; Starr et al., 1991; Williams et al., 1992). In 1989, I was asked to apply for the Chair of Pharmacology at the Royal Free Hospital School of Medicine in London, and there I reoriented our efforts to examine the role of specific calcium channel subunits in the modulation of native and cloned calcium currents by G proteins. In our work, we concentrated initially on the role of the calcium channel β subunits (Berrow et al., 1995). We then uncovered an essential role for the N-terminus of Ca_V2 calcium channels in their G-protein modulation (Page et al., 1998; Canti et al., 1999), and we demonstrated the importance of calcium channel β subunits in the G-protein modulation of Ca_V2.2 channels (Meir et al., 2000; Leroy et al., 2005), and also in PI3 kinase-mediated calcium channel modulation (Viard et al., 2004).At that time, very little work had been done on the role of the intriguing α₂δ subunits of calcium channels, whose topology and function were initially unclear (Brickley et al., 1995; Gurnett et al., 1996). We started working on these proteins through another fortunate encounter. When the Royal Free School of Medicine was merged with University College London (UCL), I was asked to move to the UCL Gower Street campus in 1997, primarily to free up my space for Professor Geoff Burnstock, who had relinquished his role as Head of Department of Anatomy at UCL. There, I had the good fortune to collaborate with Michele Rees in the Pediatrics Department, on the molecular basis for the Ducky mouse mutation, that causes absence epilepsy and ataxia. The mutation turned out to be in a calcium channel auxiliary subunit gene, Cacna2d2, encoding α₂δ−2 (Barclay et al., 2001). This work fortuitously led us on to an extended series of studies on the biochemistry, physiology, and pharmacology of the α₂δ subunit family, about which little was then known. These investigations allowed me to combine my interests in biochemistry, from my undergraduate years, with all the many other techniques we have embraced, including electrophysiology. Among our findings were that the von Willebrand factor domain of α₂δ subunits is essential for their ability to augment calcium currents (Canti et al., 2005; Hoppa et al., 2012; Dahimene et al., 2018), that α₂δ proteins are anchored to the plasma membrane via a glycosyl-phosphatidyl inositol linkage rather by a transmembrane domain (Davies et al., 2010), that the α₂δ subunits increase trafficking of calcium channels to the cell surface (Cassidy et al., 2014), and that proteolytic cleavage of α₂δ into α₂ and δ is an essential molecular switch for the augmentation of calcium currents and transmitter release (Kadurin et al., 2016; Ferron et al., 2018).Other studies, including work from our own laboratory, found that α₂δ−1 mRNA and protein are strongly upregulated in DRG neurons in rodent models of neuropathic pain (Luo et al., 2001; Newton et al., 2001; Bauer et al., 2009). Furthermore, α₂δ−1 is the main receptor for the antiepileptic drug gabapentin, which is also of therapeutic benefit in neuropathic pain (Gee et al., 1996). We contributed to showing that their binding to α₂δ−1 is essential for the action of gabapentinoids to alleviate neuropathic pain (Field et al., 2006). Since α₂δ proteins are auxiliary subunits, the molecular mechanism of action of these drugs in neuropathic pain was not immediately obvious, until we showed that gabapentinoids reduced calcium currents chronically, but not acutely, through an inhibitory effect on α₂δ trafficking, both in vitro (Hendrich et al., 2008; Tran-Van-Minh and Dolphin, 2010) and in vivo (Bauer et al., 2009). We then found, by making a functional extracellularly tagged version of Ca_V2.2, that as a consequence, gabapentin also reduced the trafficking and cell surface expression of the channel itself (Cassidy et al., 2014). A knock-in mouse containing this tagged Ca_V2.2 is now allowing us to identify that α₂δ−1 KO also reduces the cell surface localization of Ca_V2.2 in DRGs and their presynaptic terminals in vivo (Nieto-Rostro et al., 2018).The molecular mechanisms involved in the development and maintenance of neuropathic pain are the subject of research of many groups (for review, see Sexton et al., 2018; Alsaloum et al., 2020; Halievski et al., 2020). As a result of orienting our research toward the involvement of calcium channels in neuropathic pain, I encountered another unexpected advantage of moving to UCL. We have been able to benefit enormously from the knowledge and advice of the many experts in pain who work there, including John Wood, Tony Dickenson, and Maria Fitzgerald. It is remarkable that, during my time at UCL, threads from my past have been picked up and helped to shape my work. Indeed, we have collaborated extensively with Tony Dickenson, who was one of the other nontenured staff scientists who left NIMR at the same time as me, and who then obtained a lectureship directly at UCL (Bauer et al., 2009; Patel et al., 2013). Similarly, in an extension of the Greengard family, we had a valuable collaboration with Tim Ryan, who has also worked extensively with Paul Greengard''s laboratory, particularly on the role of Synapsins in vesicular release (Ryan et al., 1996; Chi et al., 2003). With Tim, we studied the role of α₂δ proteins in presynaptic Ca²⁺ entry and vesicular release (Hoppa et al., 2012), and this led us on to further examining the role of proteolytic cleavage of α₂δ in these processes (Kadurin et al., 2016; Ferron et al., 2018).I was honored to speak at Paul''s 80th birthday celebration, and then also to attend his 90th birthday symposium, both held at Rockefeller University, where I was very happy to meet up with so many previous colleagues (Fig. 2). At the latter meeting, I also had the privilege of being able to tell Paul of my election to the Royal Society, and to thank him for his support; and I could see his real pleasure in this news. Although I have never worked directly on Synapsins since leaving Paul''s laboratory, from these and other meetings, I have of course retained a keen interest in Paul''s wide-ranging research, maintained until his death at age 93 in 2019. His work unraveling the enormous complexity of the many pathways involving neuronal protein phosphorylation, and their physiological and pathologic roles (Hilfiker et al., 1999; Svenningsson et al., 2004; Brichta and Greengard, 2014), contributed to his being awarded the Nobel Prize in 2000, together with Arvid Carlsson and Eric Kandel.Open in a separate windowFigure 2.Eric Nestler, Paul Greengard, Annette Dolphin; December 11, 2015 at Paul''s 90th birthday celebration.For younger scientists, I have only a few messages. Like me, I hope you will find that all your scientific studies and experience will be of benefit in the long run, even if you change fields, and all your scientific mentors, colleagues, and friends will remain important throughout your career; but the value of chance, casual conversations, and fortuitous meetings cannot be overstated. Treasure them all.     

Pediatric age,posterior fossa meningioma

Meningiomas are benign, slow-growing tumors originating from arachnoid gap cells. They constitute 15%-20% of all intracranial tumors in adults and 04%-4% in the pediatric age group. Meningiomas in the posterior fossa in the pediatric period do not initially come to mind. In the case presented here, there was a cystic meningioma showing heterogenous contrast and obstructive hydrocephaly was observed associated with 4th ventricle pressure. the tumor was totally removed, then the ventriculo peritoneal shunt was applied.

Meningiomas are benign, slow-growing tumors originating from arachnoid gap cells. They constitute 15%-20% of all intracranial tumors in adults and 0.4%-4% in the pediatric age group.¹ In both adult and pediatric cases, they are often seen in a convexity and parasagittal area where there is dense arachnoid granulation tissue and arachnoidal villi, and posterior fossa localization are uncommon in both patient groups.² They are seen secondary to neurofibromatosis 2 in 20%-40% of cases.^1-4 Clinical findings show differences according to tumor size and localization. Findings may develop associated with hydrocephaly in posterior fossa tumors. The case is here presented of a meningioma with posterior fossa localization, which is rarely seen in the pediatric age group.     

Prevalence and associated factors of alexithymia among medical students: A cross-sectional study from Saudi Arabia

Objectives:To assess the prevalence of alexithymia and its associated factors among medical students at King Saud University (KSU), Riyadh, Kingdom of Saudi Arabia.Methods:A cross-sectional study was conducted at KSU, including 420 medical students from all years of medical college (i.e., first to the fifth year), by using an electronic questionnaire distributed during August 2021. The questionnaire consisted of sociodemographic-related questions and the 20-item Toronto alexithymia scale (a validated scale in the literature).Results:The prevalence of alexithymia among the participants was found to be 26.9%. A statistically significant association between alexithymia and gender (p=0.013) was found. A diagnosis with any psychiatric condition (p=0.026), history of abuse during childhood (p=0.006), and lack of physical activity were associated with alexithymia.Conclusion:The prevalence of alexithymia among medical students at KSU was significantly higher than general population in literatures. It was indicated in the results that being female, having a psychiatric condition or history of childhood abuse, and lack of physical activity were all associated with alexithymia. We recommend increasing awareness of and screening for alexithymia and its associated factors among medical students.

As described in the literature, alexithymia is a multi-facet construct with difficulty in recognizing, describing, and distinguishing between emotions and bodily tensions related to emotional excitement and having difficulty expressing feelings for others. ¹ The common signs of this construct include (a) trouble recognizing emotions and feelings, (b) difficulty recognizing vibes of passionate excitement, and (c) limitation in imagination and dreaming. ² The prevalence of alexithymia has been found in most previous studies to be approximately 10% among the general population. ^2-6 However, the literature regarding gender association with alexithymia is conflicting. The prevalence of alexithymia was higher in males than in females in some studies. ^2,7,8 However, the results were contrary in other studies, ^1,3,9 and no significant differences were found in some. ^4,10 Compared to the general population, the prevalence of alexithymia in medical students has been found to be higher. ^1,11 Alexithymia is associated with several mental health conditions. For instance, it is associated with anxiety and depression, ^1,12 eating disorders, ^13-15 and addiction. ¹⁶ Of note, mental disorders could lead to emotional suppressiveness and reduced communication skills, ^5,13 which could cause the inability to recognize having a problem. ¹¹ Alexithymia has also been associated with other factors. For instance, alexithymia is associated with childhood trauma. ¹⁷ The prevalence of alexithymia also appears to be affected by lifestyle, cultural beliefs, and socioeconomic status. ⁷ Single or isolated individuals, those who lack family support, and populations with low socioeconomic status all have a higher risk of developing alexithymia. ^11,13 Face-to-face relationships and social, linguistic, and neuroscience exploration have been suggested in previous studies as possible treatments by which alexithymia might be improved. ^2,16 Despite the significance of alexithymia, there are few studies regarding its prevalence and associated factors in Saudi Arabia. Therefore, we examined the prevalence of alexithymia among medical students and its related factors in this study. For this, we used a questionnaire and the 20-item Toronto alexithymia scale (TAS-20 scale). There are 3 factors (e.g., identifying the feeling, communicating feelings, and externally oriented thinking) and 20 stable and correlated items in the TAS-20 scale. ¹⁸      

Linguistic Structure and Meaning Organize Neural Oscillations into a Content-Specific Hierarchy

Neural oscillations track linguistic information during speech comprehension (Ding et al., 2016; Keitel et al., 2018), and are known to be modulated by acoustic landmarks and speech intelligibility (Doelling et al., 2014; Zoefel and VanRullen, 2015). However, studies investigating linguistic tracking have either relied on non-naturalistic isochronous stimuli or failed to fully control for prosody. Therefore, it is still unclear whether low-frequency activity tracks linguistic structure during natural speech, where linguistic structure does not follow such a palpable temporal pattern. Here, we measured electroencephalography (EEG) and manipulated the presence of semantic and syntactic information apart from the timescale of their occurrence, while carefully controlling for the acoustic-prosodic and lexical-semantic information in the signal. EEG was recorded while 29 adult native speakers (22 women, 7 men) listened to naturally spoken Dutch sentences, jabberwocky controls with morphemes and sentential prosody, word lists with lexical content but no phrase structure, and backward acoustically matched controls. Mutual information (MI) analysis revealed sensitivity to linguistic content: MI was highest for sentences at the phrasal (0.8–1.1 Hz) and lexical (1.9–2.8 Hz) timescales, suggesting that the delta-band is modulated by lexically driven combinatorial processing beyond prosody, and that linguistic content (i.e., structure and meaning) organizes neural oscillations beyond the timescale and rhythmicity of the stimulus. This pattern is consistent with neurophysiologically inspired models of language comprehension (Martin, 2016, 2020; Martin and Doumas, 2017) where oscillations encode endogenously generated linguistic content over and above exogenous or stimulus-driven timing and rhythm information.SIGNIFICANCE STATEMENT Biological systems like the brain encode their environment not only by reacting in a series of stimulus-driven responses, but by combining stimulus-driven information with endogenous, internally generated, inferential knowledge and meaning. Understanding language from speech is the human benchmark for this. Much research focuses on the purely stimulus-driven response, but here, we focus on the goal of language behavior: conveying structure and meaning. To that end, we use naturalistic stimuli that contrast acoustic-prosodic and lexical-semantic information to show that, during spoken language comprehension, oscillatory modulations reflect computations related to inferring structure and meaning from the acoustic signal. Our experiment provides the first evidence to date that compositional structure and meaning organize the oscillatory response, above and beyond prosodic and lexical controls.     

Characteristics of the patients who admitted to the emergency department with seizures and the factors affecting the frequency of admission

Objectives:To determine the features of patients applying to the emergency department (ED) with seizures and the factors affecting the frequency of admission.Methods:This study was designed as a retrospective, cross-sectional study. The demographic and clinical characteristics, admission frequencies, diagnostic tests (laboratory and imaging methods) of the patients who were older than 18 years old and admitted to the ED between January 1, 2014 and January 1, 2017 with seizures were analyzed.Results:The study included 867 patients with seizures. A comparison of the number of admissions by gender revealed a statistical significance (p=0.007). The number of admissions and the number of seizures until the time of admission were compared and found a statistical significance (p=0.002). In the logistic regression analysis of the factors affecting the frequency of admissions, seizure character [OR: 4.404 (%95 CI:1.761-11.015), p=0.002], comorbidity [OR: 2.021 (%95 CI:1.407-2.904), p<0.001], hospitalization [OR:1.893 (%95 CI: 1.259-2.847), p=0.002], concomitant injury [OR: 2.013 (%95 CI: 1.016-3.988), p=0.045], drug use (p<0.001), and possible etiology cerebrovascular disease (CVD) [OR: 2.763 (%95 CI: 1.327-5.752), p=0.007] were risk factors for frequent admission of patients applying to ED with seizures.Conclusion:Seizure character (first and known seizure), comorbidity status, hospitalization, concomitant injury, anti-epileptic drugs use, and possible etiology CVD are risk factors affecting the frequency of admission with seizure.

Patients who apply to the emergency department (ED) with seizures are in the group of patients that need to be evaluated quickly and accurately, which are challenging and open to errors. In the management of these patients in the ED, patient characteristics should be determined well. Although the patients’ complaints about having seizures are frequently seen in the ED, they vary widely in terms of frequency, severity, and prognostic significance.^1,2 Seizure constitutes 1% of annual emergency admissions in the USA.³ It has been reported that 28% of patients with epilepsy admit to EDs for treatment purposes every year.⁴ Examination of the reasons for admission, proper treatment, and orientation of patients who apply with a seizure complaint are factors that will reduce the re-admissions. The overall risk of recurrence after a first generalized tonic– clonic seizure is approximately 30% at 5 years. If the seizure is idiopathic, only 17% had a recurrence at 20 months.⁵ The first two years risk of recurrence rate in patients ranges from 21-45%.⁶ For this reason, knowing the reasons for the re-admission of patients and measures for this will also reduce the workload in EDs. Admissions show a broad spectrum from benign febrile seizures to status epilepticus (SE). Convulsive seizures occur in 0.53% to 7.6% of patients applying to ED.^1,7 While 40-45% of patients presenting with seizure have no identified cause, seizures induced by metabolic or toxicological reason have a lower chance of becoming epilepsy (lower than 3%).^8-9 This study was conducted to determine the frequency of seizure patients in the ED patient population and possible seizure etiologies, seizure type (focal, generalized, etc.), admission seizure type (first single seizure, known seizure-remote, active seizure, SE), characteristics of diagnostic activities (laboratory and imaging tools), anti-epileptics used, patient termination methods (discharge from the ED, hospitalization). There are not many studies revealing the frequency and reasons for admission of patients who applied to EDs with a complaint of seizures. Thus, the factors affecting the frequency of admission of patients will be determined with this study.     

Low versus standard dose intravenous alteplase in the treatment of acute ischemic stroke in Egyptian patients

Objectives:To assess low dose altepase outcome and safety in comparison with a standard-dose regimen for acute ischemic stroke treatment in Egyptian patients.Materials:An observational prospective cohort non-randomized single blinded study was carried out during the period from November 2017 to December 2018. Eighty Egyptian acute ischemic stroke patients, all eligible for intravenous alteplase, were subdivided into 2 groups (40 patients in each group). Patients were thrombolysed at a dose of 0.6 mg/kg in the first group and 0.9 mg/kg in the second group. Both groups were compared in regard to safety and outcome. Safety was expressed by the rate of symptomatic intracranial hemorrhage (SICH) and 3 months mortality, while outcome was expressed by favorable outcomes at three months (modified Rankin Scale [mRS] of 0 to 2).Results:In the first group, 69.2% (n=27) achieved favorable outcomes at 90 days compared with 64.1% (n=25) in the second group (p=0.631). Ninety-day mortality was 5% (n=2) in the first group versus 2.5% (n=1) in the second group (p=0.556). Symptomatic intracranial hemorrhage was noted in 3 patients in the second group and zero patients in the first group (p=0.077).Conclusion:Low-dose alteplase could be a practical alternative for Egyptian populations with acute ischemic stroke especially in 3 to 4.5 hours window.

Cerebrovascular stroke is the second death and the seventh disability leading cause worldwide.¹ Tissue-type plasminogen activator (tPA) alteplase was the first medication approved by the Food and Drug Administration (FDA) for the acute ischemic stroke (AIS) treatment on June 1996, within 3 hours of stroke onset with a recommended dose of 0.9 mg/kg (maximum 90mg).² In 2008, the safety of using alteplase within 3 to 4.5 hours of stroke onset was approved by the Safe Implementation of Treatments in Stroke International Stroke Thrombolysis Registry (SITS -ISTR)³ and the European Cooperative Acute Stroke Study (ECASS III).⁴ However, thrombolytic therapy use has not been widely adopted, especially in developing countries. The restricted time window (3 to 4.5 hours), intracerebral hemorrhage (ICH) risk and the drug high cost are major obstacles preventing its broad application.⁵ Coagulation and fibrinolysis responses differ among different races, which increase symptomatic intracerebral hemorrhage (SICH) risk with standard-dose alteplase⁶ in Asian populations, many Asian neurologists considered alteplase low dose to be a better alternative for ischemic stroke treatment. Many studies had been conducted in order to prove the efficacy and safety of Alteplase low dose.^7-9 One of these studies was the Japan Alteplase Clinical Trial (J-ACT) conducted by Yamaguchi et al¹⁰ According to this study, using a 0.6 mg/kg dose of intravenous recombinant tissue plasminogen activator (rtPA) in Japanese patients was safe and effective. Despite the relatively stroke high rate among Egyptian populations, 963/100,000 inhabitants, only less than 1% of stroke patients receive intravenous thrombolysis. A major reason for this is the drug cost.^11,12 Low-dose regimens (0.6 mg/kg) use will lower the economic burden of thrombolytic therapy in the community and will greatly promote the implementation of this therapy in Egypt. Our study aim was to assess the outcome and safety of alteplase low dose in comparison to the standard-dose regimen in AIS treatment in Egypt.     

Prevalence and biopsychosocial factors associated with treatment adherence among people with epilepsy in a tertiary care hospital in Riyadh,Saudi Arabia

Objectives:To identify the magnitude of treatment adherence among people with epilepsy (PWE) and the impact of sociodemographic, medical and psychosocial factors on treatment adherence.Methods:A quantitative cross-sectional observational study was performed based on data collected from adult patients attending the epilepsy clinic, King Saud University Medical City, Riyadh, Saudi Arabia. Patients completed paper-based questionnaires including a sociodemographic, cultural, psychiatric history and medical history sections. In addition to that we evaluated treatment adherence by visual-analogue scale (VAS), depressive symptoms by PHQ-9, anxiety symptoms by GAD7, physical symptoms by PHQ-15, attachment style by ECR16 and cognitive impairment by MOCA.Results:A total of 207 patients participated, with a mean age of 34 years;.53.6% were female. The mean patient-reported adherence to their treatment regimen was 81.6%±18.4%. Univariate analysis revealed statistically significant negative associations between depression, anxiety and physical symptoms and treatment adherence. However, multiple linear regression analysis only showed physical symptoms to be a significant predictor for epilepsy medication adherence.Conclusion:Somatic (physical) complaints could be important predictors of treatment adherence in (PWE). This study is one of the first to suggest the importance of targeting physical symptoms in screening and intervention approaches to improve Antiepileptic drugs (AEDs) adherence.

Epilepsy is one of the most common chronic serious neurological diseases and affects approximately 50 million people of all ages worldwide. ¹ The estimated median prevalence of epilepsy in Arab countries is 2.3/1,000 (varying from 0.9–6.5/1,000), which is just within the range found in Europe, North America, Australia, and Asia. ² In Saudi Arabia, the prevalence of active epilepsy is 6.54/1000 population. ³ According to global and local studies, most cases of epilepsy are idiopathic, though it may be caused by cerebrovascular accidents, head trauma, cerebral palsy and CNS infection. ^1,4 The overall mortality rate for (PWE) is increased by two- to threefold compared with the general population. ^1,5,6 In addition, there are high rates of psychological conditions such as depression and anxiety among (PWE). ^7-10 Patients with mood disorders are more likely to be nonadherent with regard to medication. ^8,11–13 The World Health Organization defines medication adherence as the extent to which a patient’s behavior, in terms of taking medications, following a diet, and/or executing lifestyle changes, corresponds with agreed recommendations from a health care provider. ¹⁴ Anti-epileptic drugs (AEDs) are the main therapy for epilepsy to prevent seizures. ¹⁵ Indeed, up to 70% of children and adults with epilepsy can be successfully treated with AEDs. ¹ However, the prevalence of significant medication nonadherence in epilepsy has been reported to vary between 26% and 79%. ¹⁶ A cross-sectional study performed locally in Riyadh, Saudi Arabia, at King Fahad Hospital found that 48.7% of patients were nonadherent regarding anti-epileptic medication. In this study, adherence was assessed by asking patients whether they ever missed or stopped their medications, with the most common factor for nonadherence being forgetfulness. ¹⁷ In another local study performed among adolescents with epilepsy conducted cross-sectionally at Riyadh National Hospital in Saudi Arabia, 38.3% were antiepileptic drugs nonadherent, and the most important factors affecting adherence to prescribed medication were the age of the mother, number of family members, number of administered drugs and seizure frequency. ¹⁸ In general, the risk of subsequent seizures among nonadherent patients may increase by 21%. ¹⁹ Nonadherence is also associated with an increased likelihood of hospitalization and emergency room admission and with an over threefold increased risk of mortality compared to adherence. ^20,21 Depression, stress and anxiety are all associated with reduced antiepileptic drug adherence. ^{8,11–13,22–24} Additionally, the results of another study showed that depression measured by another scale (NDDI-E) correlated with an increased risk of AED nonadherence, which led to the same result. ²⁵ Conversely, perceived social support correlated positively with adherence. ²³ In another study, however, neither depression nor family support were associated with adherence. ²⁶ Nevertheless, these studies did not discuss the correlation between attachment style and cognitive function with treatment adherence in patients with epilepsy (PWE). However, multiple studies conducted on other diseases showed an association between attachment style especially avoidance, and reduced adherence to medical treatments. ^27–29 A study at King Khalid University Hospital in Saudi Arabia has addressed the psychosocial predictors of treatment adherence in another neurological disorder, multiple sclerosis, and found that 79.47% of patients were adherent to treatment, with the most significant factor associated with nonadherence being cultural beliefs. ³⁰ To date, there is a lack of research about the psychosocial aspects of epilepsy in Arab countries. ³¹ In fact, none of the local studies we found mentioned psychosocial predictors related to adherence among patients with epilepsy. Hence, this cross-sectional study aims to identify psychosocial predictors, specifically depression symptoms, anxiety symptoms, cognitive impairment, attachment style and cultural beliefs, for treatment adherence among (PWE). Addressing psychosocial problems may help to optimize care for these patients. ³² Overall, identifying barriers to AED adherence is imperative to help practitioners who are developing appropriate strategies to improve adherence rates. ^20,24      

Efficacy of repetitive paravertebral block combined with medication in the treatment of zoster-related pain with different courses

Objectives:To compare the clinical outcomes of repetitive paravertebral block (PVB) combining oral medication in the treatment of zoster-related pain (ZP) with different courses.Methods:Sixty-seven patients with ZP were divided into 3 groups based on their course of herpes zoster (HZ). Group I: 24 patients with acute herpetic neuralgia (within one month of disease onset); group II: 22 patients with subacute herpetic neuralgia (disease onset from 1 to 3 months); group III: 21 patients with postherpetic neuralgia (more than 3 months since disease onset). All patients received ultrasound-guided repetitive PVB with oral gabapentin and tramadol sustained-release tablets. The VAS and QS scores and the incidences of hematoma, dizziness, nausea, and drowsiness were compared at 1 day, 3 months, and 6 months after treatment.Results:Pain intensity and sleep quality of the 3 groups improved to varying degrees after treatment. The best efficacy was achieved in the acute group, followed by the subacute group, and the poorest efficacy was observed in the chronic group.Conclusion:The efficacy of ultrasound-guided repetitive PVB with oral medication varied with the courses of HZ. The shorter the time since onset, the better the efficacy. This combined treatment showed better efficacy in patients at the acute and subacute stages and significantly improved their pain and sleep quality, while demonstrating limited pain relief in chronic patients.

Herpes zoster (HZ) is usually caused by reactivated varicella-zoster virus dormant in the sensory ganglia of the nervous system. Impairment of T cell-mediated immunity caused by stress, aging, or immunosuppression usually leads to high susceptibility to herpes zoster.^1-3 Zoster-related pain (ZP) refers to neuralgia during the course of or after recovery from herpes zoster. The ZP is divided into 3 types based on the course of disease, namely, acute herpetic neuralgia (AHN) (within 1 month of disease onset), subacute herpetic neuralgia (SHN) (within 3 months of disease onset) and postherpetic neuralgia (PHN) (3 months or more after disease onset).⁴ The pathophysiology of ZP is little known, and 2 potential mechanisms are more widely accepted. One is the sensitization mechanism, in which inflammatory mediators (e.g., substance P, histamine, and cytokines) lower the stimulus threshold of a nociceptor; the other is deafferentation, in which swelling caused by inflammation compresses the sensory ganglia in the intervertebral column, leading to ischemia and damage to nerve tissues. At present, the major treatments for ZP include medication and microinvasive intervention. Nerve block treatment is a widely used microinvasive technique for herpes zoster, offering an easy operation with few complications. A large number of reports have shown that nerve block treatment can achieve good clinical outcomes for ZP.^5-9 Paravertebral nerve block (PVB) is the easiest and fastest anesthetic method to inject local anesthetics into the space near the vertebrae to block the spinal nerves as they emerge from the intervertebral foramen. PVB and epidural anesthesia offer a similar pain-relieving effect, although PVB incurs fewer side effects.¹⁰ It has been reported that PVB can temporarily relieve refractory PHN.¹¹ However, according to some case reports, transcatheter repetitive PVB can achieve long-term pain relief.¹² The present study investigates the efficacy of repetitive PVB combined with oral medication in the treatment of ZP with different courses to provide a scientific basis for clinical treatment.     

Patterns and outcomes of stroke thrombolysis in a large tertiary care hospital in Riyadh,Saudi Arabia

Objectives:To present the experience on stroke thrombolysis of a tertiary care center in Riyadh, KSA.Methods:Cross-sectional, observational study of patients thrombolyzed between January 2012 and December 2018.Results:Thrombolysis was performed in 148 patients (mean age: 58.2±14.5 years), 94 (63.5%) of them were men. The median onset-to-door time was 81 minutes, and 25% of the patients arrived within 1 hour. The median National Institute of Health Stroke Scale score upon admission was 13. Hypertension (68.9%), diabetes (56.1%), and dyslipidemia (40.5%) were the most common risk factors for stroke. The most common mechanism of stroke was cardioembolism (43.2%), which was associated with a more severe presentation (p=0.031). Intravenous thrombolysis alone was given to 98 patients (66.2%); the rest received intravenous tissue plasminogen activator plus endovascular therapy or endovascular therapy alone. The median door-to-needle (DTN) time was 70.5 min, with a significant improvement from 2012 (111.6 minutes) to 2018 (69.9 minutes) (p<0.001). Among the patients, 53 (35.8%) showed a good outcome (with a modified Rankin score of 0–2) whereas 14 (9.5%) died. Symptomatic intracranial hemorrhage (sICH) was seen in 8.1%. All vascular risk factors were more common in patients aged >60 years, except smoking, which was more common in the younger age group (p=0.007).Conclusion:In our cohort, the utilization of thrombolysis and the DTN time improved over time. One-thirds of the patients received endovascular treatment. Moreover, the frequency of the vascular risk factors was high. Compared with the published findings, our results showed that cardioembolic strokes were the most frequent and had severe presentation and were likely the cause of the slight increase in mortality and sICH.

Acute ischemic stroke remains a major cause of morbidity and mortality worldwide. Intravenous (IV) thrombolysis is the standard of care in eligible stroke patients since 1995 after the publication of the National Institute of Neurological Disorders and Stroke (NINDS) recombinant tissue plasminogen activator [alteplase] (rtPA) trial.¹ In appropriately selected patients with acute ischemic stroke and large vessel occlusion (LVO), mechanical thrombectomy (MT) significantly improved the patients’ functional independence without increasing the mortality rate or hemorrhagic complications.² Despite the proven efficacy and relative safety of IV thrombolysis and MT, they remain underutilized. In our center, thrombolysis was utilized in 8.6% of all ischemic strokes between February 2016 and July 2018 and in 29% of patients who arrived within the therapeutic window.³ Although acute stroke care has significantly improved in Saudi Arabia in the past decade, it remains far from being optimal. In a recent survey, nearly half of the Saudi emergency physicians considered the role of rtPA in stroke as controversial, whereas 37% presume that the efficacy of rtPA remains unproven.⁴ A recent survey showed that among the neurologists in Saudi Arabia, 21.3% had never used rtPA in acute stroke, 82.4% believed that the delayed presentation to a hospital was the most important barrier to the use of intravenous rtPA, and 50% considered that the unclear time of onset was the barrier to the use of thrombolysis.⁵ Another survey showed that among the neurology residents in Saudi Arabia, 79% reported lack of good knowledge about IV thrombolysis and 53.1% expressed lack of confidence in using IV thrombolysis.⁶ The use of IV thrombolysis and MT has gained momentum in Saudi Arabia, but the published literature on the patterns and outcomes of thrombolysis remains scant. Recently, results from the Safe Implementation of Treatment in Stroke (SITS)-Middle East and North African (MENA) registry for IV thrombolysis were published,⁷ and a report from Dubai described the use and outcomes of thrombolysis in 176 patients.⁸A stroke unit was formally established in our tertiary care center in 2012, although thrombolysis treatment was already offered prior to that. Here, we report our experience on thrombolysis in acute ischemic stroke from January 2012 to December 2018. We presume that this report is the first of its kind in Saudi Arabia.     

Patterns and prognosis of Ventriculoperitoneal shunt malfunction among pediatrics in Saudi Arabia

Objectives:To examine the predictors of pediatric ventriculoperitoneal (VP) shunt malfunction in a university hospital.Methods:A retrospective cohort was conducted. Patients under 18 years old who underwent VP shunt revision at least once between 2016 and 2019 were included. Data were stratified based on age, gender, diagnosis, type of valve, valve position, cause of revision, and part revised.Results:A total of 45 patients (64% males and 36% females) were included in this study. Eighty-two revision surgeries were identified. The most common revised part was the entire shunt system. The most common type of valve which required revision was the low-pressure valve (15.5%). Since a p-value of less than 0.05 was considered significant, no significant differences among the 4 groups for different points.Conclusions:Younger age at initial VP shunt insertion is associated with a higher rate of shunt malfunction. Valve mechanical failures followed by infections are the most common causes for the first 3 revisions. A prospective multi-center study to confirm the current findings is recommended.

Ventriculoperitoneal (VP) shunt insertion is one of the most common procedures in pediatric neurosurgery for treating hydrocephalus.1 Among pediatric age group hydrocephalus is considered a common, surgically correctable condition in which there is an increase in the volume cerebrospinal fluid (CSF), leading to cerebral ventricles dilatation, thinning of the cerebral mantle, and elevation of intracranial pressure.2 Patients with VP shunts represent more than 30,000 hospital admissions per year.2 Although VP shunting has decreased the morbidity and mortality of hydrocephalus, it is still associated with multiple complications, many of which require surgical revision.1–4 Recent studies have reported the rate of complications following VP shunting to be between 30% and 50%.3–6 Shunt malfunctions causes can be categorized into infectious, mechanical, or functional.2–4 Shunt failure definition is revision or replacement of the original shunt between 30-days and 1-year.2 Mechanical failure can happen at the proximal end, valve, or distal end, and it includes obstruction, disconnection, fracture, distal end migration, or inflammation. Functional failure happens when there is overdrainage or underdrainage of cerebrospinal fluid while the whole shunt system is properly functioning. Infection happens when the patients demonstrate clinical findings and positive fluid sampling results.3 The most common complication necessitating revision are obstruction, infection, and displacement.2,3,6,7 Shunt failure is most common within the first 2 years postoperatively.3 Many important predictors of VP shunt failure have been reported in the literature, including etiologies of the hydrocephalus, prematurity, and age at the initial placement of the shunt.1,8,9 Clinical factors that may increase the risk of shunt revision include time from the first surgery, surgical procedure duration, prior treatments, number of surgeons, surgical expertise, surgical technique, anatomic site of the shunt, and diagnosis.1,7–10 Proximal catheter tip location is another predictor, as tip positions in the Foramen of Monro, lateral ventricles, or the third ventricle all were associated with lower rates of surgical revision.11 Other predictors of shunt failure were reported to be poor catheter placement and use of a non-programmable valve.12Previous studies have emphasized the need to identify children at risk, and for prospective cohorts to to investigate the relationship of risk factors and incidence of shunt revisions.1,9,10 Risk factors for VP shunt complications vary across institutions and populations, and a very limited number of studies addressing VP shunt malfunction have been conducted in Saudi Arabia, and only one in the last 10 years was published.13The goal of this study was to determine patterns and predictors of pediatric VP shunt malfunction, causes of the hydrocephalus and VP shunt revision and type of valve malfunction and define the best preventive measures. This knowledge will contribute to lowering the incidence of shunt malfunction, decreasing the number of surgeries, and increasing complication-free intervals between surgeries in hydrocephalic pediatric patients.