Evaluation of the potassium channel tracer [18F]3F4AP in rhesus macaques

Demyelination causes slowed or failed neuronal conduction and is a driver of disability in multiple sclerosis and other neurological diseases. Currently, the gold standard for imaging demyelination is MRI, but despite its high spatial resolution and sensitivity to demyelinated lesions, it remains challenging to obtain specific and quantitative measures of molecular changes involved in demyelination. To understand the contribution of demyelination in different diseases and to assess the efficacy of myelin-repair therapies, it is critical to develop new in vivo imaging tools sensitive to changes induced by demyelination. Upon demyelination, axonal K⁺ channels, normally located underneath the myelin sheath, become exposed and increase in expression, causing impaired conduction. Here, we investigate the properties of the K⁺ channel PET tracer [¹⁸F]3F4AP in primates and its sensitivity to a focal brain injury that occurred three years prior to imaging. [¹⁸F]3F4AP exhibited favorable properties for brain imaging including high brain penetration, high metabolic stability, high plasma availability, high reproducibility, high specificity, and fast kinetics. [¹⁸F]3F4AP showed preferential binding in areas of low myelin content as well as in the previously injured area. Sensitivity of [¹⁸F]3F4AP for the focal brain injury was higher than [¹⁸F]FDG, [¹¹C]PiB, and [¹¹C]PBR28, and compared favorably to currently used MRI methods.     

Early-stage 11C-Flumazenil PET predicts day-14 selective neuronal loss in a rodent model of transient focal cerebral ischemia

Predicting tissue outcome early after stroke is an important goal. MRI >3 h accurately predicts infarction but is insensitive to selective neuronal loss (SNL). Previous studies suggest that chronic-stage ¹¹C-flumazenil PET (FMZ-PET) is a validated marker of SNL in rats, while early-stage FMZ-PET may predict infarction. Whether early FMZ-PET also predicts SNL is unknown. Following 45-min distal MCA occlusion, adult rats underwent FMZ-PET at 1 h and 48 h post-reperfusion to map distribution volume (V_T), which reflects GABA-_A receptor binding. NeuN immunohistochemistry was performed at Day 14. In each rat, V_T and %NeuN loss were determined in 44 ROIs spanning the hemisphere. NeuN revealed isolated SNL and cortical infarction in five and one rats, respectively. In the SNL subgroup, V_T-1 h was mildly reduced and only weakly predicted SNL, while V_T-48 h was significantly increased and predicted SNL both individually (p < 0.01, Kendall) and across the group (p < 0.001), i.e. the higher the V_T, the stronger the SNL. Similar correlations were found in the rat with infarction. Our findings suggest GABA-_A receptors are still present on injured neurons at the 48 h timepoint, and the increased 48 h V_T observed here is consistent with earlier rat studies showing early GABA-_A receptor upregulation. That FMZ binding at 48 h was predictive of SNL may have clinical implications.     

Positron emission tomography/magnetic resonance hybrid scanner imaging of cerebral blood flow using 15O-water positron emission tomography and arterial spin labeling magnetic resonance imaging in newborn piglets

Abnormality in cerebral blood flow (CBF) distribution can lead to hypoxic–ischemic cerebral damage in newborn infants. The aim of the study was to investigate minimally invasive approaches to measure CBF by comparing simultaneous ¹⁵O-water positron emission tomography (PET) and single TI pulsed arterial spin labeling (ASL) magnetic resonance imaging (MR) on a hybrid PET/MR in seven newborn piglets. Positron emission tomography was performed with IV injections of 20 MBq and 100 MBq ¹⁵O-water to confirm CBF reliability at low activity. Cerebral blood flow was quantified using a one-tissue-compartment-model using two input functions: an arterial input function (AIF) or an image-derived input function (IDIF). The mean global CBF (95% CI) PET-AIF, PET-IDIF, and ASL at baseline were 27 (23; 32), 34 (31; 37), and 27 (22; 32) mL/100 g per minute, respectively. At acetazolamide stimulus, PET-AIF, PET-IDIF, and ASL were 64 (55; 74), 76 (70; 83) and 79 (67; 92) mL/100 g per minute, respectively. At baseline, differences between PET-AIF, PET-IDIF, and ASL were 22% (P<0.0001) and −0.7% (P=0.9). At acetazolamide, differences between PET-AIF, PET-IDIF, and ASL were 19% (P=0.001) and 24% (P=0.0003). In conclusion, PET-IDIF overestimated CBF. Injected activity of 20 MBq ¹⁵O-water had acceptable concordance with 100 MBq, without compromising image quality. Single TI ASL was questionable for regional CBF measurements. Global ASL CBF and PET CBF were congruent during baseline but not during hyperperfusion.     

Cerebral metabolic rate of oxygen during transition from wakefulness to sleep measured with high temporal resolution OxFlow MRI with concurrent EEG

During slow-wave sleep, synaptic transmissions are reduced with a concomitant reduction in brain energy consumption. We used 3 Tesla MRI to noninvasively quantify changes in the cerebral metabolic rate of O₂ (CMRO₂) during wakefulness and sleep, leveraging the ‘OxFlow’ method, which provides venous O₂ saturation (SvO₂) along with cerebral blood flow (CBF). Twelve healthy subjects (31.3 ± 5.6 years, eight males) underwent 45–60 min of continuous scanning during wakefulness and sleep, yielding one image set every 3.4 s. Concurrent electroencephalography (EEG) data were available in eight subjects. Mean values of the metabolic parameters measured during wakefulness were stable, with coefficients of variation below 7% (average values: CMRO₂ = 118 ± 12 µmol O₂/min/100 g, SvO₂ = 67.0 ± 3.7% HbO₂, CBF = 50.6 ±4.3 ml/min/100 g). During sleep, on average, CMRO₂ decreased 21% (range: 14%–32%; average nadir = 98 ± 16 µmol O₂/min/100 g), while EEG slow-wave activity, expressed in terms of δ-power, increased commensurately. Following sleep onset, CMRO₂ was found to correlate negatively with relative δ-power (r = −0.6 to −0.8, P < 0.005), and positively with heart rate (r = 0.5 to 0.8, P < 0.0005). The data demonstrate that OxFlow MRI can noninvasively measure dynamic changes in cerebral metabolism associated with sleep, which should open new opportunities to study sleep physiology in health and disease.     

Examination of the effects of coordination and balance problems on gait in ataxic multiple sclerosis patients

Objectives:To investigate the effects of coordination and balance problems on gait and plantar pressure distribution in multiple sclerosis patients.Methods:This was an observational, cross-sectional study. It was conducted at Necmettin Erbakan University between March and December 2017. Twenty-four individuals with coordination problems, 36 individuals with balance problems and 32 healthy individuals were included in the study. The EDSS, Functional Reach Test, Dynamic Gait Index, baropodometry and stabilometry evaluations were performed.Results:There were significant differences between the groups (velocity p = 0.000, cadence p = 0.000, step width p = 0.018, step length p = 0.000, foot angle p = 0.000). Multiple comparisons demonstrated that the velocities and cadences of the coordination group were lower, while their step widths were found to be higher, compared to the balance group (p = 0.012, p = 0.004, p = 0.017, respectively). In static plantar pressure distribution, lateral forefoot pressure, lateral hindfoot pressure and medial hindfoot pressure were significantly different between the groups (p = 0.002, p = 0.000, respectively) Multiple comparisons showed that the pressure on the lateral part of the hindfoot in the coordination group was found to be significantly higher compared to the balance group (p = 0.002). According to the dynamic plantar pressure distribution, lateral forefoot, medial forefoot, lateral hindfoot and medial hindfoot pressures were significantly different between the groups (p < 0.05).Conclusion:Coordination and balance problems affect gait and plantar pressure distribution. The identification of these changes will help physiotherapists determine specific therapeutic targets.

Multiple sclerosis (MS) is an infectious disease of the central nervous system of unknown etiology. Typically, patients initially experience a relapse and remission course (RRMS). In many cases, secondary progressive MS (SPMS) is observed, causing the slow and insidious development of disability.1 One of the common symptoms of MS is ataxia. Ataxia, which is characterised by postural control, balance and coordination impairment that causes limitation in MS, is one of the most important causes of disability. Coordination problems are common due to problems in the cerebellum and its connections. Cerebellar pathology causes nystagmus, dysarthria and tremor with limb, trunk and gait ataxia depending on the lesion area. In about 80% of MS patients, different types of ataxia emerge as significant symptoms.2Ataxia is one of the most critical factors affecting gait. Gait ataxia emerges with balance and coordination problems or a combination of these. While previous studies have clearly displayed the effect of balance on gait, the effects of coordination problems on gait are not apparent.3-5 In a limited number of studies, the effect of coordination on gait was investigated, and conflicting results were found. Limb coordination,3 standing and balance control4,5 and locomotion6-8 were the subjects that the researchers emphasised frequently. Morton and Bastian reported that balance in patients with cerebellar ataxia caused an impairment in the spatiotemporal parameters of gait, but coordination did not affect the spatiotemporal parameters of gait.9,10 Winfried et al11 reported that coordination problems affect gait. This study aimed to investigate the effect of balance and coordination problems on gait and plantar pressure in MS patients and to compare its effects with balance problems.     

Deep-learning-based attenuation correction in dynamic [15O]H2O studies using PET/MRI in healthy volunteers

Quantitative [¹⁵O]H₂O positron emission tomography (PET) is the accepted reference method for regional cerebral blood flow (rCBF) quantification. To perform reliable quantitative [¹⁵O]H₂O-PET studies in PET/MRI scanners, MRI-based attenuation-correction (MRAC) is required. Our aim was to compare two MRAC methods (RESOLUTE and DeepUTE) based on ultrashort echo-time with computed tomography-based reference standard AC (CTAC) in dynamic and static [¹⁵O]H₂O-PET. We compared rCBF from quantitative perfusion maps and activity concentration distribution from static images between AC methods in 25 resting [¹⁵O]H₂O-PET scans from 14 healthy men at whole-brain, regions of interest and voxel-wise levels. Average whole-brain CBF was 39.9 ± 6.0, 39.0 ± 5.8 and 40.0 ± 5.6 ml/100 g/min for CTAC, RESOLUTE and DeepUTE corrected studies respectively. RESOLUTE underestimated whole-brain CBF by 2.1 ± 1.50% and rCBF in all regions of interest (range −2.4%– −1%) compared to CTAC. DeepUTE showed significant rCBF overestimation only in the occipital lobe (0.6 ± 1.1%). Both MRAC methods showed excellent correlation on rCBF and activity concentration with CTAC, with slopes of linear regression lines between 0.97 and 1.01 and R² over 0.99. In conclusion, RESOLUTE and DeepUTE provide AC information comparable to CTAC in dynamic [¹⁵O]H₂O-PET but RESOLUTE is associated with a small but systematic underestimation.     

Regional and depth-dependence of cortical blood-flow assessed with high-resolution Arterial Spin Labeling (ASL)

Methods for imaging of cerebral blood flow do not typically resolve the cortex and thus underestimate flow. However, recent work with high-resolution MRI has emphasized the regional and depth-dependent structural, functional and relaxation times variations within the cortex. Using high-resolution Arterial Spin Labeling (ASL) and T₁ mapping acquisitions, we sought to probe the effects of spatial resolution and tissue heterogeneity on cortical cerebral blood flow (CBF) measurements with ASL. We acquired high-resolution (1.6mm)³ whole brain ASL data in a cohort of 10 volunteers at 3T, along with T₁ and transit-time (ATT) mapping, followed by group cortical surface-based analysis using FreeSurfer of the different measured parameters. Fully resolved regional analysis showed higher than average mid-thickness CBF in primary motor areas (+15%,p<0.002), frontal regions (+17%,p<0.01) and auditory cortex, while occipital regions had lower average CBF (-20%,p<10⁻⁵). ASL signal was higher towards the pial surface but correction for the shorter T₁ near the white matter surface reverses this gradient, at least when using the low-resolution ATT map. Similar to structural measures, fully-resolved ASL CBF measures show significant differences across cortical regions. Depth-dependent variation of T₁ in the cortex complicates interpretation of depth-dependent ASL signal and may have implications for the accurate CBF quantification at lower resolutions.     

A local-neighborhood Lassen plot filter for creating occupancy and non-displaceable binding images

For radioligands without a reference region, the Lassen plot can be used to estimate receptor occupancy by an exogenous drug (ODrug). However, the Lassen plot is not well-suited for spatial variation in ODrug. To overcome this limitation, we introduce a Lassen plot filter, i.e. a Lassen plot applied to local neighborhoods in PET images. Image data were simulated with regional variation in VND, ODrug, both, or neither and analyzed using the change in binding potential (ΔBPND), the conventional Lassen plot, and the Lassen plot filter at the region of interest (ROI) and voxel level. All methods were also applied to a human [¹¹C]flumazenil occupancy study using PF-06372865. This combination of a non-selective radioligand and selective drug should lead to varying ODrugprovided the distribution of subtypes varies spatially. In contrast with ΔBPND and the conventional Lassen plot, ROI-level and voxel-level Lassen plot filter estimates remained unbiased in the presence of regional variation in VND or ODrug. In the [¹¹C]flumazenil data-set, ODrug was shown to vary regionally in accordance with the distribution of binding sites for [¹¹C]flumazenil and PF-06372865. We demonstrate that a local-neighborhood Lassen plot filter provides robust and unbiased estimates of ODrug and VND without the need for any user intervention.     

Cerebral blood flow measurements with 15O-water PET using a non-invasive machine-learning-derived arterial input function

Cerebral blood flow (CBF) can be measured with dynamic positron emission tomography (PET) of ¹⁵O-labeled water by using tracer kinetic modelling. However, for quantification of regional CBF, an arterial input function (AIF), obtained from arterial blood sampling, is required. In this work we evaluated a novel, non-invasive approach for input function prediction based on machine learning (MLIF), against AIF for CBF PET measurements in human subjects.Twenty-five subjects underwent two 10 min dynamic ¹⁵O-water brain PET scans with continuous arterial blood sampling, before (baseline) and following acetazolamide medication. Three different image-derived time-activity curves were automatically segmented from the carotid arteries and used as input into a Gaussian process-based AIF prediction model, considering both baseline and acetazolamide scans as training data. The MLIF approach was evaluated by comparing AIF and MLIF curves, as well as whole-brain grey matter CBF values estimated by kinetic modelling derived with either AIF or MLIF.The results showed that AIF and MLIF curves were similar and that corresponding CBF values were highly correlated and successfully differentiated before and after acetazolamide medication. In conclusion, our non-invasive MLIF method shows potential to replace the AIF obtained from blood sampling for CBF measurements using ¹⁵O-water PET and kinetic modelling.     

Association between craniovertebral junction abnormalities and syringomyelia in patients with chiari malformation type-1

Objectives:To assess the correlation between craniovertebral junction (CVJ) abnormalities and syringomyelia in patients with Chiari malformation type-1 (CM1).Methods:This was a retrospective study including patients with CM1. Identification of cases was done by searching a radiology database at a university hospital from 2012 to 2017. Patients were divided into 2 groups based on whether CVJ abnormalities were present (CVJ+) or absent (CVJ-). The patients’ demographic and clinical data were reviewed. All magnetic resonance imaging studies were examined by a certified neuroradiologist.Results:Sixty-four consecutive patients with CM1 were included. The mean age was 24±17 years; 59% were females. The CVJ+ group had more female patients (p = 0.012). The most frequent CVJ abnormality was platybasia (71%), followed by short clivus (44%) and cervical kyphosis (33%). The CVJ abnormalities were more in Syringomyelia cases (p = 0.045). However, the results were not significant when hydrocephalus cases were excluded.Conclusion:Among CM1 patients, CVJ abnormalities were found more in patients with syringomyelia. Future studies with larger sample size are required to further study the correlation between CVJ abnormalities and both syringomyelia and hydrocephalus in CM1 patients.

Chiari malformation type-1 (CM1) was first described in 1891 by Austrian pathologist Hans Chiari.1,2 The CM1 is defined as caudal displacement of the cerebellar tonsils below the foramen magnum by 5 mm or more.3,4 This definition is merely a radiological definition. In the literature, the degree of cerebellar tonsil displacement varies from 3 mm to 5 mm.4 CM1 affects approximately 1% of the population and may involve a spectrum of neurologic involvement.2 Syringomyelia is reported in 25% of CM1 cases and may cause irreversible damage to the spinal cord with subsequent neurological deficits.5The pathophysiology of syringomyelia development in patients with CM1 has been extensively studied.6-9 Majority of publications indicated a block to the cerebrospinal fluid (CSF) circulation at the level of the craniovertebral junction (CVJ).8,9 Subsequently, the cerebrospinal fluid (CSF) accumulates and forms syringomyelia.8,9 The source of the CSF forming the syringomyelia can be from the fourth ventricle, the subarachnoid space (SAS), or from an extracellular source.8,9 From the 1950s to the 1970s, syringomyelia was believed to result from a difference in CSF pressure between the fourth ventricle and the central canal of the spinal canal.7 Theories to explain this mechanism include James Gardner’s water-hammer theory, Bernard Williams’ cranio-spinal pressure dissociation theory, and Ball and Dayan’s theory of tonsillar obstruction to the CSF pathway.10-12 In the 1990s, Oldfield believed that the mechanism of the development of syringomyelia involved abnormal CSF flow at the level of the foramen magnum.6,7 The descent of the cerebellar tonsils with each cardiac cycle produces a pressure wave in the spinal SAS, and thereby compresses the spinal cord from the outside and propagates a syrinx.7,9Several intradural and extradural factors have been implicated in the pathophysiology of CM1. Among the intradural factors identified during surgery for CM1, the presence of an arachnoid membrane obstructing the foramen of Magendie (i.e., an arachnoid veil) was significantly more frequent in patients with an associated syringomyelia.6 Other studies have examined whether the degree of tonsillar descent below foramen magnum in the CM1 patients is a contributing factor to the development of syringomyelia; however, the impact of tonsillar descent is controversial.6,9,13 Some studies have reported that the rate of syringomyelia increases as the degree of tonsillar herniation increases.6,9 As a possible explanation for syringomyelia development, other studies14,15 have addressed crowding of the SAS at the foramen magnum caused by tonsillar decent. In a study by Doruk et al15, the measured cervicomedullary compression ratio, defined as the ratio of the area occupied by the cerebellar tonsils to the area of the foramen magnum, was significantly correlated with the development of syringomyelia. This ratio could reflect the severity of blockage of the SAS at the CVJ and further supports the previously described mechanisms of syringomyelia development.9Extradural abnormalities at the CVJ are associated with CM1.15 Such pathologies include a small posterior cranial fossa, platybasia, basilar invagination, and short clivus.3,6,8,9 Several studies have examined the presence of CVJ abnormities in CM1 patients with and without syringomyelia.13,16-21 However, the presence of associated syringomyelia within the context of CM1 with and without CVJ abnormalities was inadequately highlighted. For instance, in one study,13 syringomyelia existed in 64% of CM1 patients with a short clivus, compared to 36% of CM1 patients without a short clivus. In order to further understand the relationship between the presence of one or more CVJ abnormalities and syringomyelia in CM1, the current study was conducted. Such knowledge will likely enhance the understanding of CVJ relationship with CM1 and may aid in the management of syringomyelia in such patients.     

Subfascial drainage and clipping technique for treatment of cerebrospinal fluid leak following spinal surgery

Objectives:To investigate the treatment of iatrogenic cerebrospinal fluid (CSF) leak that develops after degenerative lumbar spinal surgery with a subfascial drainage and clipping (SDC) technique.Methods:This study retrospectively reviewed the medical records of 46 patients who developed iatrogenic CSF leak after surgery for lumbar degenerative spine disease from 2007 to 2019. Twenty-five patients were treated with the SDC procedure (SDC group), whereas 21 were not (control group). Outcomes were compared between the two groups.Results:CSF leakage ceased within 6–9 days (average 7.4±1) after the procedure in the SDC group. In the control group, CSF leakage was controlled with conservative measures in 14 patients, and in 7 patients, lumbar external drainage was performed. Among these 7, the CSF leak was controlled by lumbar external drainage in 3, and 4 required reoperation to repair the dural defect. No infection occurred in either group. Length of hospital stay was also shorter in SDC group (8.4±1 vs 10.0±1.3 days, p < 0.001).Conclusion:The SDC technique is effective for the treatment of iatrogenic CSF leak that develops after degenerative lumbar spinal surgery.

Iatrogenic cerebrospinal fluid (CSF) leaks are one of the most common surgical complications of spinal surgery. Incidental dural injury is common during spinal surgery, epidural injection, and myelography. Previous studies have reported incidence rates ranging between 1% and 17% for incidental durotomy during surgery,¹ and Gerardi et al² reported a 6.8% incidence of intraoperatively undiagnosed CSF leak. As many patients with this condition are asymptomatic, it is difficult to predict CSF leaks that are not diagnosed at the time of surgery. Patients with symptomatic CSF leaks may suffer intracranial hypotension-related vertigo, posture-related headache, photophobia, double vision, neck stiffness and dizziness.Patients who are not diagnosed at the time of surgery or undergo inadequate dural repair may develop a postoperative dural leakage or pseudomeningocele.³In 1983, Teplick and Haskin⁴ reported a pseudomeningocele incidence of 1.6% detected by computerised tomography imaging among 750 patients who underwent lumbar spinal surgery and remained free of dural leak. When they occur, cutaneous leakage usually develop between the first and seventh days after surgery.In spinal CSF leaks, oversuturing the incision and application of a pressure dressing may suffice in most cases. When these measures fail, bed rest in the semi-Fowler’s position is recommended. The main target of bed rest is to reduce the CSF hydrostatic pressure in the lumbar region. In 2 previous studies, Wang et al² systematically prescribed short-term (2.9 days) bed rest, and Camisa et al² prescribed bed rest for 3–5 days. In addition, acetazolamide,⁵ repair with blood patch, and closed lumbar subarachnoid CSF drainage can be used. Kitchel et al reported that closed subarachnoid CSF drainage is an effective technique for treatment of postoperative CSF leaks and can prevent a repeat surgical intervention.⁶ Despite this, the outcomes are not always favourable. When these measures fail, a second surgery for primary dural repair can be performed.Cain et al⁷ examined the biology of a dural CSF leak repair in a canine model. They reported that fibroblastic bridging started on the 6th day and dural defects were healed on the 10th day.We did not encounter any other study in the literature that described the subfascial drainage and clipping (SDC) technique that we perform to treat CSF leaks after degenerative lumbar spinal surgery and report our experience herein.     

Rater experience and the predictive validity of Psychopathy Checklist: Youth Version scores

We compared the predictive validity of Psychopathy Checklist: Youth Version (PCL:YV) scores assigned by a licensed clinician to scores assigned by a graduate student across a sample of 82 juvenile offenders. Although both raters completed in-depth training and practice scoring cases, the graduate student had no prior clinical experience. The raters showed a high level of agreement in their scoring for 11 reliability check cases (intraclass correlation coefficient, ICC_A,1 = .90 for PCL:YV Total score), but the scores assigned by the licensed clinician were better predictors of post-release recidivism (area under the curve, AUC = .77) than those assigned by the graduate student (AUC = .45). There was more variability in the scores assigned by the licensed clinician than those assigned by the graduate student, suggesting that more experienced clinicians’ willingness to assign both high and low scores may help explain rater differences in predictive validity.Key words: Clinical experience, Psychopathy Checklist, Psychopathy Checklist: Youth Version, risk assessment

Although meta-analytic findings suggest that there is only a minimal (d = 0.15) association between clinician experience and accuracy in many forms of mental health assessment (Spengler & Pilipis, 2015), a small, but growing, body of research suggests a more meaningful association between experience and accuracy in the context of risk assessment. Researchers have found that risk ratings from experienced psychiatrists were more predictive of future violence than those from psychiatric residents (Teo, Holley, Leary, & McNiel, 2012) and that risk measure scores assigned by master’s level clinical psychologists outperformed those assigned by treatment providers from other vocational backgrounds (de Vogel & de Ruiter, 2006). Another recent study found that Psychopathy Checklist–Revised (PCL–R; Hare, 2003) scores assigned to sexual offenders by field evaluators were better predictors of future misconduct in a sex offender civil commitment program than those assigned by graduate student raters (Boccaccini, Rufino, Jeon, & Murrie, 2017).The extent to which this handful of findings suggesting an association between experience and accuracy in risk assessment generalizes to the larger risk assessment literature is unclear, largely due to researchers overlooking the issue. Researchers often provide cursory information about rater training and education, but they rarely provide any detailed information about the clinical experience of their raters. Moreover, researchers rarely examine the extent to which risk assessment validity findings vary across individual raters, instead preferring to collapse scores across raters without examining the possibility of rater effects. Thus, the extent to which rater experience may have affected study outcomes within an individual study is almost always unclear, and the lack of detailed information from study authors makes it difficult to come to any conclusions about whether differences in rater experience may explain some of the variability in instrument validity findings across studies.Three recent studies examining Psychopathy Checklist ratings suggest that the standard procedure of collapsing across raters can sometimes mask potentially meaningful differences between raters. In one study, PCL–R scores from evaluators who had conducted 35 or more assessments were predictive of future violent offending (d = 0.66), while scores from evaluators who had conducted fewer evaluations were not (d = −0.24; Murrie, Boccaccini, Caperton, & Rufino, 2012). In the second study, researchers reported predictive validity findings separately for each rater who assigned Psychopathy Checklist: Screening Version (PCL:SV; Hart, Cox, & Hare, 1995) scores in the MacArthur Violence Risk Assessment study (Monahan et al., 2001). They found that Cohen’s d values for scores from individual raters ranged from less than 0.01 to more than 1.50 (Harris, Boccaccini, & Murrie, 2015). Although the researchers could not completely explain why scores from some evaluators were better predictors than others, there was some evidence of range restriction affecting prediction. Scores from evaluators who were willing to assign a broader range of scores across cases (i.e. larger standard deviation) were more predictive than those from evaluators who assigned consistently low scores across cases. This pattern of findings is consistent with the well-known attenuating effect of range restriction on validity coefficients, which leads to weaker effects when range is restricted (Bobko, Roth, & Bobko, 2001; Schmidt, Oh, & Le, 2006).Willingness to assign a broad range of scores also appeared to play a role in the third study that found differences in Psychopathy Checklist score predictive validity (Boccaccini et al., 2017). Researchers found that there was more variability in the PCL–R Total scores assigned to sexual offenders by doctoral level field evaluators (SD = 7.66) than by graduate student raters (SD = 5.35–5.54), even though the raters had scored the same offenders. Scores from the field evaluators were statistically significant predictors of subsequent convictions (area under the curve, AUC = .58 to .77), whereas those from the graduate student raters were not (AUC = .51 to .59).In the current study, we compare the predictive validity of Psychopathy Checklist: Youth Version (PCL:YV) scores assigned to juvenile offenders in Korea, by either a licensed psychologist (n = 43) or a graduate student rater with no prior clinical experience (n = 39). We report the association between PCL:YV scores and recidivism for the overall sample, and examine whether the size of the association between scores and recidivism depends on the rater who assigned the score. To be clear, we did not design this study specifically to examine the association between rater experience and PCL score validity. The study was designed as a prototypical recidivism study, employing multiple raters for efficiency – to allow for more evaluations during the study time frame – as opposed to a study of possible rater effects. The recent findings of rater differences in psychopathy measure predictive validity (Boccaccini et al., 2017; Harris et al., 2015; Murrie et al., 2012) prompted us to take a closer look at the possibility of a rater experience effect in our recidivism study, which happened to have used both a graduate student and licensed practitioner to score the PCL:YV.Predictive effects for PCL:YV tend to be in the AUC = .70 to .85 range for total scores (see Schmidt, Campbell, & Houlding, 2011; Stockdale, Olver, & Wong, 2010). If rater experience has no effect on the validity of PCL:YV scores, we would expect to see AUC values in this same range for both evaluators.     

Pediatric intracranial hypertension: Experience from 2 Tertiary Centers

Objectives:To review the experience of 2 tertiary centers in Saudi Arabia with intracranial hypertension (IH) in the pediatric population.Methods:We retrospectively reviewed and analyzed pediatric patients diagnosed with IH from June 2002 to May 2017 in 2 institutes.Results:We identified 53 patients (30 females and 23 males) with a mean age of 7 years at the time of presentation. Among them, 41 patients were younger than 12 years, and 12 were older. Obese and overweight patients constituted 27.00% (n = 14) of all cases, 8 (66.7%) of whom were older than 12 years. The most common presenting feature was papilledema followed by headache. Vitamin D deficiency, which constituted the most common associated condition, was identified in 12 (22.6%) patients. Acetazolamide was the treatment option in 98.11% of patients, and only 5.7% underwent surgical interventions. The length of follow-up ranged from 6 months to 8 years.Conclusion:Intracranial hypertension is rare in children and commonly seen in overweight females older than 12 years similar to adults. Patients younger than 12 years tend to develop secondary IH. More studies are needed to characterize the clinical presentation and guide the management plan.

Intracranial hypertension (IH) is rarely reported in children. It is characterized by increased intracranial pressure (ICP) without any evidence of underlying brain pathology, structural abnormalities, hydrocephalus, or any abnormal meningeal enhancement.1 The incidence of IH differs from region to region due to variations in the prevalence of obesity and other secondary causes. The annual incidence of IH in children is 0.9 per 100,000 in the United States,2 0.5 per 100,000 in Germany,3 0.6 per 100,000 in Nova Scotia and Prince Edward Island in Eastern Canada,4 and 1.2 per 100,000 in Croatia.5 A study carried out in Oman estimated the incidence of IH to be 1.9 per 100,000 in children below 15 years of age; with it being higher in female children.6 The present study aimed to review the clinical presentation, possible aetiological factors, diagnosis, management, and outcomes in children with IH in 2 tertiary institutes in Saudi Arabia.     

Bilateral transcranial direct current stimulation modulates activation-induced regional blood flow changes during voluntary movement

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that induces changes in cortical excitability: anodal stimulation increases while cathodal stimulation reduces excitability. Imaging studies performed after unilateral stimulation have shown conflicting results regarding the effects of tDCS on surrogate markers of neuronal activity. The aim of this study was to directly measure these effects on activation-induced changes in regional cerebral blood flow (ΔrCBF) using positron emission tomography (PET) during bilateral tDCS. Nine healthy subjects underwent repeated rCBF measurements with ¹⁵O-water and PET during a simple motor task while receiving tDCS or sham stimulation over the primary motor cortex (M1). Motor evoked potentials (MEPs) were also assessed before and after real and sham stimulation. During tDCS with active movement, ΔrCBF in M1 was significantly lower on the cathodal than the anodal side when compared with sham stimulation. This decrease in ΔrCBF was accompanied by a decrease in MEP amplitude on the cathodal side. No effect was observed on resting or activated rCBF relative to sham stimulation. We thus conclude that it is the interaction of cathodal tDCS with activation-induced ΔrCBF rather than the effect on resting or activated rCBF itself which constitutes the physiological imaging correlate of tDCS.     

The comorbidity of headaches in pediatric epilepsy patients: How common and what types?

Objectives:To estimate the prevalence and characteristics of headache in pediatric epileptic patients.Methods:This cross-sectional study was performed over 6 months period from January 2018 to June 2018 at King Abdullah Specialist Children Hospital, King Abdulaziz Medical City, Riyadh, Kingdom of Saudi Arabia using a structured questionnaire in pediatric patients with epilepsy.Results:There were 142 patients enrolled (males, 57.7%; average age, 10.7±3.1 years) with idiopathic epilepsy (n=115, 81%) or symptomatic epilepsy (n=27, 19%). Additionally, patients had focal epilepsy (n=102, 72%) or generalized epilepsy (n=40, 28%), and among them, 11 had absence epilepsy. Overall, 65 (45.7%) patients had headaches compared with 3/153 (2%) in the control group (p < 0.0001). Among the 65 patients with headaches, 29 (44.6%) had migraine-type, 12 (18.4%) had tension-type, and 24 (36.9%) had unclassified headache. There was no significant difference in age, gender, type of epilepsy syndrome, and antiepileptic used except in patients with or without headache. For migraine patients, there was a lower headache prevalence in the subgroup treated with valproic acid compared with other treatments.Conclusion:Headache, predominantly migraine, is a common problem in pediatric epileptic patients and choosing valproic acid when possible can be important in preventing migraine in these patients.

Epilepsy and headache are chronic paroxysmal disorders that affect adult and pediatric patients1 with episodic manifestations. Headache or (cephalalgia) is defined as a feeling of pain in the region of the head or neck. Primary headaches include migraines, tension-type headache, and cluster headache. Epileptic seizure is a brief episode of signs or symptoms caused by abnormal excessive synchronized neuronal activity.2 Epilepsy is defined as a condition where the patient has an enduring tendency to have recurrent unprovoked seizures.2 These two disorders coexist in some patients.3 There are few studies on the comorbidity of headaches in children with epilepsy.4-6 Other studies reported a significant association between migraine and epilepsy.1,7-9 Additionally, the genetic predisposition for both entities was reported in some forms of channelopathy,10 and others found more prevalence of migraine headache in specific diseases in pediatric like benign epilepsy with centrotemporal spikes and juvenile myoclonic epilepsy.11 Seizure-associated headache is common, with an incidence of 42–51% in adult epileptic patients.12 However, for pediatric patients, it is often neglected by parents and physicians because of other neurological manifestations of the seizure such as loss of consciousness and motor components,13 and approximately 36% of the parents were reported to be unaware that their children experienced headache.14 It is our experience that headache is a common problem in up to 50% of epilepsy patients but we do not know exactly the prevalence, in addition to what type of headache is most commonly found in epileptic pediatric patients. Because of few reports on this topic have conflicting results, the objective of this study was to evaluate the prevalence and characteristics of headache in children with epilepsy who were seen at one center in Saudi Arabia.     

Perfusion imaging-based tissue-level collaterals predict ischemic lesion net water uptake in patients with acute ischemic stroke and large vessel occlusion

Ischemic lesion Net Water Uptake (NWU) quantifies cerebral edema formation and likely correlates with the microvascular perfusion status of patients with acute ischemic stroke due to large vessel occlusion (AIS-LVO). We hypothesized that favorable tissue-level collaterals (TLC) predict less NWU and good functional outcomes. We performed a retrospective multicenter analysis of AIS-LVO patients who underwent thrombectomy triage. TLC were measured on cerebral perfusion studies using the hypoperfusion intensity ratio (HIR; volume ratio of brain tissue with [Tmax > 10 sec/Tmax > 6 sec]); favorable TLC were regarded as HIR ≤ 0.4. NWU was determined using a quantitative densitometry approach on follow-up CT. Primary outcome was NWU. Secondary outcome was a good functional outcome (modified Rankin Scale [mRS] 0–2).580 patients met inclusion criteria. Favorable TLC (β: 4.23, SE: 0.65; p < 0.001) predicted smaller NWU after treatment. Favorable TLC (OR: 2.35, [95% CI: 1.31–4.21]; p < 0.001), and decreased NWU (OR: 0.75, [95% CI: 0.70–0.79]; p < 0.001) predicted good functional outcome, while controlling for age, glucose, CTA collaterals, baseline NIHSS and good vessel reperfusion status.We conclude that favorable TLC predict less ischemic lesion NWU after treatment in AIS-LVO patients. Favorable TLC and decreased NWU were independent predictors of good functional outcome.     

Inflammatory bowel disease and restless leg syndrome

Objectives:Inflammatory bowel disease (IBD) has been associated with restless leg syndrome (RLS). This study aims to explore the prevalence, clinical predictors, and severity of RLS in IBD patients compared to controls.Methods:We conducted a case-control study between January and December of 2019 comparing IBD patients with controls. Assessment of RLS was performed using the previously validated diagnostic restless leg syndrome questionnaire (RLSQ). Logistic regression analyses were applied to investigate associations between patient demographics and clinical features and RLS diagnosis.Results:A total of 218 IBD patients and 211 healthy controls were incorporated after excluding 6 patients with positional discomfort and 4 patients with habitual foot tapping. The mean age was 30.2±11.7 and 64% were females. The prevalence of RLS was 16/218 (7.34%) and 17/211 (8.06%) among cases and controls, respectively. Based on the RLSQ severity score, 6/16 (37.5%), 4/16 (25%) and 1/16 (6.3%) of the IBD patients with RLS had mild, moderate and severe RLS; respectively. The odds of IBD were lower among patients with confirmed RLS (OR=0.90, 95% CI=0.44-1.84, p = 0.78). In the logistic regression analysis, only vitamin B12 deficiency (OR=10.20, 95% CI=1.40-74.10, p = 0.022) was associated with RLS diagnosis among IBD patients.Conclusion:No difference was found in the prevalence of RLS between IBD patients and non-IBD controls. Vitamin B12 deficiency was associated with RLS diagnosis among patients with IBD.

Inflammatory bowel disease (IBD) is a family of chronic inflammatory disorders that cause inflammation of the gastrointestinal tract. It comprises two main conditions: ulcerative colitis (UC) and Crohn’s disease (CD). Approximately 30% of IBD patients suffer from extra-intestinal manifestations (EIMs), which can involve the rheumatologic, musculo-cutaneous, and hepato-biliary systems.1,2 Anemia is a common manifestation of IBD that can be attributed to iron, folate (folic acid), or vitamin B12 deficiencies.3Patients with IBD may develop neurological symptoms as part of the disease itself or through secondary complications, such as anemia. Perhaps one of its most distressing neurological manifestations is restless leg syndrome (RLS), which is a movement disorder characterized by an uncomfortable sensation in the legs which engenders restlessness temporarily relieved by movement. This discomfort takes place most commonly during night and when resting, and often disturbs sleep.4 Iron deficiency anemia (IDA) has been strongly associated with RLS.5,6 The RLS can be primary, i.e., idiopathic, or secondary, and is believed to be caused by both genetic and environmental factors.7 The most common secondary causes of RLS include iron deficiency and kidney disease; other causes include cardiovascular disease, arterial hypertension, diabetes, liver cirrhosis, migraine, Parkinson’s disease, and pregnancy.7-9 In a previous study conducted in Saudi Arabia, the prevalence of RLS among IBD patients was estimated to be 21.5%, compared to 9.7% in controls.10 Another study reported a 10% prevalence rate of RLS in North America and Europe, which is much higher than the prevalence rate reported by studies from Asian countries (0.6-1.8%).9 In contrast to many findings in Asian countries, the prevalence of RLS has been reported to increase with age in Europe, North America, and Saudi Arabia,10,11 and women have a higher prevalence of RLS compared to men.11,12 Moreover, it has been suggested that patients with RLS have poorer health and quality of life.11 This study describes the prevalence, clinical predictors, and severity of RLS in IBD patients compared with healthy controls.     

Consanguinity in patients with mesial temporal lobe epilepsy due to hippocampal sclerosis in a Saudi population

Objectives:To investigate if there is an association between consanguinity and hippocampal sclerosis (HS) in the Saudi population.Methods:A retrospective case-control study was conducted by assessing the prevalence of consanguinity in patients with pathologically proven HS, who underwent epilepsy surgery at King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia, between January 2004 and December 2015. We reviewed the medical records to extract data, which included; age, gender, duration of epilepsy, history of febrile seizure, family history of epilepsy in a first or second-degree relative, and pathology reports.Results:A total of 120 patients, out of which 40 patients (65% male) having mesial temporal lobe epilepsy due to HS, and 80 controls (56% male) with cryptogenic epilepsy, were identified. Twenty-two patients (53.5%) in the HS group had a history of consanguinity. In the control group, 30 patients (37.5%) had a history of consanguinity. The odds ratio was 2.04 (95% confidence interval = 0.94 - 4.4, p = 0.052). A family history of epilepsy was found in 28% of the patients with HS and 32.5% cryptogenic epilepsy. Only 8 patients (19.5%) with HS reported a history of febrile seizure.Conclusion:Our retrospective case-control study suggests that consanguinity might increase the likelihood of developing HS.

Consanguineous marriage, in clinical genetics, is defined as a union between couples related as second cousins or closer.1 Saudi Arabian culture has a higher consanguinity rate than other Arab, Asian, and Western communities. Consanguinity is not known to increase the risk of idiopathic or cryptogenic epilepsy, based on recent studies from Saudi Arabia and UAE.2,3 However, there is a strong evidence that the marriage of first cousins is one of the main reasons for the increased prevalence of autosomal recessive diseases.4The association between consanguinity and epilepsy due to hippocampal sclerosis (HS), the most common pathology found in patients with intractable focal epilepsy, has not been adequately studied.5 A familial type of mesial temporal lobe epilepsy (FMTLE) has been described with homogeneous and heterogeneous clinical manifestations.6-8 Moreover, magnetic resonance imaging (MRI) of the brain of asymptomatic first-degree relatives of patients with confirmed FMTLE showed evidence of HS, which supports the genetic predisposition to FMTLE.9 Although, FMTLE is widely recognized as an autosomal dominant disease with incomplete penetrance, autosomal recessive or X-linked forms have also been reported. Still, they have not been confirmed by extensive studies.10In this study, we aimed to investigate the association between consanguinity and HS in a Saudi population. This study may help expand our knowledge of the underlying mechanisms of HS and may shed some light on a possible genetic substrate that contributes to the development of HS in this population.