Meckel-Gruber syndrome together with Dandy-Walker malformation: an atypical case report of a 2nd recurrence in a consanguine marriage.

Meckel-Gruber syndrome is a lethal disorder characterized by occipital encephalocele, polycystic kidneys, and polydactyly. In most cases, it is identified and terminated antenatally. In this report, the authors present a case of Meckel-Gruber syndrome together with Dandy-Walker malformation. A pregnant woman referred at the 28th week of gestation with an abnormal ultrasound scan showing posterior encephalocele and bilaterally enlarged kidneys. Further imaging also indicated communication between the 4th ventricle and posterior cerebellar cerebrospinal fluid space, after which the fetus was diagnosed with Meckel-Gruber syndrome and Dandy-Walker malformation. Pregnancy termination was refused by the parents and the offspring was prematurely born to be the 2nd recurrence of Meckel-Gruber syndrome in this consanguine family. Remarkably, at the 3 different pregnancies, ultrasound was inconclusive before the 7th month of gestation. Though up to date Meckel-Gruber syndrome is ultimately lethal, the lifespan of affected newborns varied greatly. We suggest developing a severity classification to estimate life expectancy in unterminated cases.

Complex Craniosynostosis in Pitt-Hopkins Syndrome: Case Report in Twins.

INTRODUCTION: Pitt-Hopkins syndrome (PTHS) is a rare genetic syndrome associated with neurodevelopmental disorders and craniofacial dysmorphisms caused by variations in the TCF4 transition factor. The aim of this article was to report the case of two twin infants diagnosed with PTHS, confirmed by the identification of a heterozygous pathogenic variant in the TCF4 gene through DNA extracted from a buccal swab. CASE PRESENTATION: Both infants presented with craniofacial asymmetry with a metopic crest and cranial deformity. During the diagnostic investigation, computed tomography with three-dimensional reconstruction of the skull showed premature fusion of the left coronal and metopic sutures in both twins. They underwent craniofacial reconstruction at the 9th month of age using a combination of techniques. The postoperative outcomes were satisfactory in both cases. CONCLUSION: To the best of our knowledge, this is the first case report to describe the occurrence of complex craniosynostosis (CCS) in children with PTHS. Further studies are needed to determine whether the co-occurrence of PTHS and CCS described here indicates an association or is explained by chance.

Parent and Provider Differences in Ratings of Mental Health and Neurodevelopmental Concerns in Children with Neurologic Disorders.

Children with neurologic disorders face increased risks for mental health and neurodevelopmental conditions, with information often limited to parent report. To better understand mental health and neurodevelopmental needs in this population, a retrospective chart review of a convenience sample of children with neurologic disorders referred for a neuropsychological evaluation was conducted in the present study to explore interrater agreement between care team members (referring providers, parents, pediatric neuropsychologist). Qualitative and quantitative data were collected from the evaluation reports of 129 youth (9:0-17:11 years old; 51.2% of female sex) with neurologic disorders (i.e., 38.0% traumatic brain injury, 27.1% epilepsy, 14.7% premature birth, 7.8% pediatric cancer, 3.9% prenatal substance exposure, and 14.7% other) who completed an evaluation in 2019. Over half the youth were flagged for unmet neurodevelopmental and mental health concerns and analyses revealed low interrater agreement for mental health concerns (κ = .324), better agreement for neurodevelopmental concerns (κ = .511), and low sensitivity of referring providers (Se = .326) and parents (Se = .366). One-way analyses of variance uncovered important factors (e.g., symptom severity, adaptive skills) that may account for missed concerns. Findings guide recommendations to strengthen methods for understanding mental health and/or neurodevelopmental concerns in children with neurologic disorders.

Psychometric properties of light touch-pressure somatosensory measures in adults with neurological disorders: A systematic review.

OBJECTIVES: To critically appraise the psychometric properties of light touch-pressure somatosensory assessments to provide guidance for tool selection for research or clinical purposes. DATA SOURCES: MEDLINE, CINAHL, and PsycInfo were searched for research indexed from January 1990-November 2022. English language and human subject filters were applied. "Somatosensation", "psychometric property", and "nervous system-based health condition" search terms were combined. Grey literature and manual searches were conducted to ensure thoroughness. REVIEW METHODS: The reliability, construct validity, and/or measurement error of light touch-pressure assessments was reviewed in adult populations with neurological disorders. Reviewers individually extracted and managed data including patient demographics, assessment characteristics, statistical methods, and psychometric properties. Methodological quality of results was evaluated using an adapted version of the COnsensus-based Standards for the selection of health Measurement INstruments checklist. RESULTS: Thirty-three of 1938 articles were included for review. Fifteen light touch-pressure assessments demonstrated good or excellent reliability. Further, five of those 15 assessments achieved adequate validity and one of the 15 assessments achieved adequate measurement error. Over 80% of the summarized study ratings were determined to be of low or very low quality. CONCLUSION: We recommend using electrical perceptual tests, the Semmes-Weinstein Monofilaments, the Graded and Redefined Assessment of Strength, Sensibility, and Prehension, and the Moving Touch Pressure Test given that they demonstrated good to excellent results in three psychometric properties. No other assessment achieved adequate ratings in more than two psychometric properties. This review highlights a fundamental need to develop sensory assessments that are reliable, valid, and sensitive to change.

Vagal Nerve Stimulation: A Bibliometric Analysis of Current Research Trends.

BACKGROUND: Vagal nerve stimulation (VNS) has become established as an effective tool for the management of various neurologic disorders. Consequently, a growing number of VNS studies have been published over the past four decades. This study presents a bibliometric analysis investigating the current trends in VNS literature. MATERIALS AND METHODS: Using the Web of Science collection data base, a search was performed to identify literature that discussed applications of VNS from 2000 to 2021. Analysis and visualization of the included literature were completed with VOSviewer. RESULTS: A total of 2895 publications were identified. The number of articles published in this area has increased over the past two decades, with the most citations (7098) occurring in 2021 and the most publications (270) in 2020. The h-index, i-10, and i-100 were 97, 994, and 91, respectively, with 17.0 citations per publication on average. The highest-producing country and institution of VNS literature were the United States and the University of Texas, respectively. The most productive journal was Epilepsia. Epilepsy was the predominant focus of VNS research, with the keyword "epilepsy" having the greatest total link strength (749) in the keyword analysis. The keyword analysis also revealed two major avenues of VNS research: 1) the mechanisms by which VNS modulates neural circuitry, and 2) therapeutic applications of VNS in a variety of diseases beyond neurology. It also showed a significant prevalence of noninvasive VNS research. Although epilepsy research appears more linked to implanted VNS, headache and depression specialists were more closely associated with noninvasive VNS. CONCLUSION: VNS may serve as a promising intervention for rehabilitation beyond neurologic applications, with an expanding base of literature over the past two decades. Although epilepsy researchers have produced most current literature, other fields have begun to explore VNS as a potential treatment, likely owing to the rise of noninvasive forms of VNS.

Role of the functional head impulse test in evaluating vestibulo-ocular reflex abnormalities in individuals with Parkinson's disease.

PURPOSE: To assess vestibular-ocular reflex (VOR) function in patients with Parkinson's disease (PD) using a new method called functional head impulse test (fHIT). STUDY DESIGN: Case-control study. SETTING: Tertiary medical center. PARTICIPANTS: Twenty individuals with PD were recruited for PD group, and twenty healthy individuals for the control group. Ages of both groups ranged from 47 to 76 years. MAIN OUTCOME MEASURES: According to the modified Hoehn-Yahr score, PD group was classified as an early stage with a range of 1-2.5 and a mid-late stage with a range of 3-5. Percentage of correct answers (%CA) was calculated using fHIT for lateral, anterior and posterior semicircular canal (SCC) planes. RESULTS: PD group had statistically lower fHIT %CA in the right lateral, left lateral, and left posterior SCC planes compared to control group (p < .05). There was no statistical difference between two PD severity groups and functional VOR abnormality. CONCLUSION: It was concluded that the functional VOR in the right lateral and left lateral and left posterior SCC plane was affected in individuals with PD. Our results show that impaired VOR and reduced dynamic visual acuity should be considered in individuals with PD for vestibular rehabilitation exercises.

Acute Ultrasonographic Changes in Lower Extremity Muscle Structure after Motor Complete Spinal Cord Injury.

Background: There is a lack of studies examining ultrasonographic muscle changes in patients with acute spinal cord injury (SCI). Methods: We recruited adults with motor complete acute SCI and performed longitudinal ultrasound measurements. The primary outcome measures were rectus femoris and medial gastrocnemius thickness and echo intensity. Results: This study recruited 20 patients, with a mean time to the first ultrasound measurement of 17.2 ± 2.14 days, with the second measurement done 4 weeks after the first measurement. We found that there was a mean decrease in the rectus femoris muscle thickness of 18.7% (P = 0.027), as well as a mean increase in the rectus femoris echo intensity of 13.0 a.u. (P = 0.009), although no significant differences were found for the medial gastrocnemius. Conclusion: This study demonstrates decreased thickness and increased echo intensity in the rectus femoris but not in the medial gastrocnemius in patients with motor complete SCI.

Outcomes of children and adolescents 1 year after being seen in a multidisciplinary psychogenic nonepileptic seizures clinic.

OBJECTIVE: Psychogenic nonepileptic seizures (PNES) are paroxysmal events that may involve altered subjective experience and change in motor activity with a psychological cause. The aim of this work is to describe a population of pediatric patients with PNES and identify factors predictive of 12-month outcomes. METHODS: We conducted a prospective observational study of children and adolescents referred to the multidisciplinary Nationwide Children's Hospital PNES clinic between November 2017 and July 2019. Information was collected from patients during clinic visits and semistructured follow-up phone calls. Descriptive statistics and Fisher exact test were used for analysis. RESULTS: Of the 139 consecutive patients referred to the PNES clinic, 104 were seen in clinic and 63 answered 12-month follow-up calls. Patients with comorbid epilepsy had increased rates of participation at 12-month follow-up (p = .04). Complete remission was achieved by 32% (20/63) of patients at 12 months. Combined PNES remission and improvement was 89% (56/63) at 12 months. Patients and families who were linked with counseling at 1 month were more likely to achieve remission at 12 months (p = .005). Less than half (44%, 28/63) of patients reached at 12 months had their events documented on video-electroencephalogram (EEG) at diagnosis; however, those who did were not more likely to be accepting of the diagnosis at 12 months (p = 1.0), be linked with counseling at 12 months (p = .59), or be event-free at 12 months (p = .79). SIGNIFICANCE: Remission occurred in one third of patients by 12 months; however, improvement in events was seen in 89%. Connection to counseling by 1 month was associated with increased remission rates at 12 months. Capturing events on video-EEG was not associated with increased acceptance or event freedom at 12 months. Diagnosis should be followed by strong encouragement to connect with counseling quickly to achieve a goal of increasing 12-month PNES remission rates.

Virtual visits for chronic neurologic disorders during COVID-19 pandemic.

BACKGROUND: COVID-19 pandemic has boosted telemedicine in medical clinical practice. Experiences in the management of chronic neurological disorders are limited and scattered. The aim of the study was to evaluate feasibility and efficacy of virtual visit for chronic neurological disorders during COVID-19 pandemic. METHODS: All patients scheduled for a visit during the lockdown period were contacted. The patients fell into four categories: (1) long-term follow-up, the patient was re-scheduled; (2) visit was necessary, teleconsultation was accepted; (3) problem was solved by phone call; and (4) visit was necessary and teleconsultation was not feasible, then visit was maintained. Google Meet was used. During the virtual visit, neurological examination was performed, and demographic and clinical characteristics were recorded. RESULTS: At the end of May 2020, 184 virtual visits for 178 patients were performed for the following diseases: myasthenia gravis (47 patients), multiple sclerosis (79), epilepsy (12), headache (6), and parkinsonism (34). The patients were 70 males and 108 females with a mean age of 53.5 years (range 13-90). During virtual visit, we were able to obtain a satisfactory neurological examination. CONCLUSIONS: We demonstrated feasibility and effectiveness of virtual visit in the management of a large group of patients with common chronic neurological disorders.

The Psychiatric Comorbidities of Migraine in Children and Adolescents.

PURPOSE OF REVIEW: Understanding comorbidities in migraine is important because it can help us understand disease pathophysiology while also aiding the development of more effective treatment strategies. Additionally, it can provide greater awareness about appropriate diagnosis, the need for additional disease screening, and the natural history of migraine. Psychiatric comorbidities have been independently studied in both adults and children with migraine because their presentations can be distinct, and the physiology in these two groups can be different. RECENT FINDINGS: While symptoms of anxiety and depression seem to be comorbid with migraine in children, clinically significant disease does not appear to be, though the clarity of these data is limited by overlap between migraine symptomatology and that assessed by many screening tools. Functional neurologic disorders like psychogenic non-epileptic episodes (PNEE) and other functional movement disorders are not common but can be comorbid with migraine in this population and tend to improve with migraine treatment. The number of adverse childhood experiences (ACEs) a child is exposed to seems to be near-linearly associated with risk of migraine, but not with tension-type headache (TTH). The findings from these studies underscore the importance of utilizing appropriate screening methodologies for identifying psychiatric disorders in children with migraine. Additionally, the role of the insula, the hypothalamic-pituitary-adrenal axis, the serotonergic system, and the instability of hyperactivated neural networks may underlie the pathophysiology of both migraine and its psychiatric comorbidities.

Measurement and Correction of Stooped Posture during Gait Using Wearable Sensors in Patients with Parkinsonism: A Preliminary Study.

Stooped posture, which is usually aggravated during walking, is one of the typical postural deformities in patients with parkinsonism. However, the degree of stooped posture is difficult to quantitatively measure during walking. Furthermore, continuous feedback on posture is also difficult to provide. The purpose of this study is to measure the degree of stooped posture during gait and to investigate whether vibration feedback from sensor modules can improve a patient's posture. Parkinsonian patients with stooped posture were recruited for this study. Two wearable sensors with three-axis accelerometers were attached, one at the upper neck and the other just below the C7 spinous process of the patients. After being calibrated in the most upright posture, the sensors continuously recorded the sagittal angles at 20 Hz and averaged the data at every second during a 6 min walk test. In the control session, the patients walked with the sensors as usual. In the vibration session, sensory feedback was provided through vibrations from the neck sensor module when the sagittal angle exceeded a programmable threshold value. Data were collected and analyzed successfully in a total of 10 patients. The neck flexion and back flexion were slightly aggravated during gait, although the average change was <10° in most patients in both measurement sessions. Therefore, it was difficult to evaluate the effect of sensory feedback through vibration. However, some patients showed immediate response to the feedback and corrected their posture during gait. In conclusion, this preliminary study suggests that stooped posture could be quantitatively measured during gait by using wearable sensors in patients with parkinsonism. Sensory feedback through vibration from sensor modules may help in correcting posture during gait in selected patients.

Hospital admission for neurologic disorders among 5-year survivors of noncentral nervous system tumors in childhood: A cohort study within the Adult Life after Childhood Cancer in Scandinavia study.

Large, comprehensive studies of the risk for neurologic disorders among long-term survivors of noncentral nervous system (CNS) childhood cancers are lacking. Thus, the aim of our study was to assess the lifetime risk of Nordic non-CNS childhood cancer survivors for neurologic disorders. We identified 15,967 5-year survivors of non-CNS childhood cancer diagnosed in Denmark, Iceland, Finland and Sweden in 1943-2008, and 151,118 matched population comparison subjects. In-patient discharge diagnoses of neurologic disorders were used to calculate relative risks (RRs) and absolute excess risks (AERs). A neurologic disorder was diagnosed in 755 of the survivors while 370 were expected, yielding a RR of 2.0 (95% confidence interval (CI) 1.9-2.2). The highest risks were found among survivors of neuroblastoma (4.1; 95% CI 3.2-5.3) and leukemia (2.8; 95% CI 2.4-3.2). The AER decreased from 331 (278-383) excess neurologic disorders per 100,000 person-years 5-9 years after diagnosis to 82 (46-118) ≥ 20 years after diagnosis. Epilepsy was the most common diagnosis (n = 229, 1.4% of all survivors), and significantly increased risks were seen among survivors of eight out of 12 types of childhood cancer. Survivors of neuroblastoma had remarkably high risks (RR ≥ 10) for hospitalization for paralytic syndromes and hydrocephalus, while survivors of leukemia had additional high risks for dementia and encephalopathy. In conclusion, survivors of non-CNS childhood cancer are at high risk for neurologic disorders, especially within the first decade after diagnosis. Therefore, intensive follow-up to identify those who require close management is needed.

Impaired Action Control in Patients With Functional Movement Disorders.

OBJECTIVE: Despite being a major cause of neurological disability, the neural mechanisms of functional movement disorders (FMDs) remain poorly understood. Recent studies suggest that FMD is linked to dysfunctional motor and prefrontal regions that could lead to motor and cognitive impairments. The aim of this study was to investigate different components of action control in FMD by using choice-reaction, stop-signal, and Simon tasks. METHODS: Thirty patients with an FMD were prospectively recruited from the University of Louisville Movement Disorders Clinic and compared with 53 healthy control subjects, recruited from the Vanderbilt University Medical Center Movement Disorders Clinic. FMD motor symptom severity was rated with the Simplified Functional Movement Disorder Rating Scale (S-FMDRS). By using a computer and handheld response grips, participants completed three action-control tasks (choice-reaction task, stop-signal task, and Simon task) that tested action initiation, action cancelation, and interference control over actions. Action-control measures were compared between groups with analyses of variance. RESULTS: Patients with FMD were less proficient in suppressing incorrect response impulses on the Simon task and were slower to stop on the stop-signal task compared with healthy control subjects. No significant correlation with neuropsychological measurements, S-FMDRS scores, and action-control measurements was observed. CONCLUSIONS: These results suggest that two forms of inhibitory control, selective impulse inhibition and global action cancelation, are impaired in patients with FMD, independent of slowing on go reaction times. Improved understanding of action control in FMD may help in the development of new diagnostic and therapeutic strategies.

Current application of cannabidiol (CBD) in the management and treatment of neurological disorders.

Cannabidiol (CBD), which is nonintoxicating pharmacologically relevant constituents of Cannabis, demonstrates several beneficial effects. It has been found to have antioxidative, anti-inflammatory, and neuroprotective effects. As the medicinal use of CBD is gaining popularity for treatment of various disorders, the recent flare-up of largely unproven and unregulated cannabis-based preparations on medical therapeutics may have its greatest impact in the field of neurology. Currently, as lot of clinical trials are underway, CBD demonstrates remarkable potential to become a supplemental therapy in various neurological conditions. It has shown promise in the treatment of neurological disorders such as anxiety, chronic pain, trigeminal neuralgia, epilepsy, and essential tremors as well as psychiatric disorders. While recent FDA-approved prescription drugs have demonstrated safety, efficacy, and consistency enough for regulatory approval in spasticity in multiple sclerosis (MS) and in Dravet and Lennox-Gastaut Syndromes (LGS), many therapeutic challenges still remain. In the current review, the authors have shed light on the application of CBD in the management and treatment of various neurological disorders.

Derivation of a clinical decision instrument to identify patients with status epilepticus who require emergent brain CT.

BACKGROUND: Studies have shown the value of CT brain imaging in adults with first-time seizures, but there are no recommendations regarding emergent brain CTs in persons with an established seizure disorders. Our study aimed to derive a clinical decision instrument (CDI) to determine which patients with status epilepticus (SE) require emergent brain imaging. METHODS: This was a retrospective chart review of patients who presented to our emergency department with SE between 2010 and 2018. Patients with first-time seizures were excluded. A priori, we defined high risk criteria for emergent imaging as well as positive findings on brain CT. High risk criteria included known malignancy, trauma, and immunosuppression. Positive CT scans included findings such as intracranial hemorrhage (ICH) and mass. RESULTS: We identified 214 patients who met inclusion criteria Of the 181 patients without high risk criteria, 3% had positive CT scans. Of the 33 patients with high risk criteria, 10% had positive CT scans. The sensitivity, specificity, PPV, and NPV for our initial CDI were 38%, 85%, 9%, and 97%. Adding the criterion of prior ICH would have lowered our miss rate to 0.6%. Modifying our CDI to 1) History of ICH, 2) Malignancy, 3) Immunosuppression, and 4) Trauma would result in a CDI with sensitivity, specificity, PPV, and NPV of 87.5%, 87.4%, 21.2%, and 99.5%. CONCLUSIONS: By using four criteria to identify high risk patients, we can defer CT scanning in the vast majority of patients with SE and known seizure disorders. This CDI should be prospectively validated before adoption.

A Systematic Review of Total Knee Arthroplasty in Neurologic Conditions: Survivorship, Complications, and Surgical Considerations.

BACKGROUND: Patients with neurologic disorders present a unique set of challenges for knee surgeons because of contractures, muscle weakness, spasticity, and ligament instability. The primary purpose of this review was to report the outcomes of total knee arthroplasty (TKA) in these patients, including survivorship, complications, and surgical considerations. METHODS: We performed a systematic review of articles using PubMed, Cochrane Central, EMBASE, and Google Scholar. All studies reporting outcomes of TKA in patients with Parkinson disease, multiple sclerosis, poliomyelitis, Charcot joint, spina bifida, stroke, and cerebral palsy were included. RESULTS: In total 38 studies were included: 22 studies (461 patients) reported patient-reported outcome measures and 24 studies (510 patients) reported survivorship. All 38 studies reported complication rates. TKA resulted in an improvement in functional outcome in all series. Complication rate was higher in patients with neurologic conditions. Of studies reporting survivorship, mean follow-up ranged from 1 to 12 years with survivorship from 66% to 100%. All levels of implant constraint were reported without consensus. Limited rehabilitative data exist. CONCLUSION: TKA in patients with neurologic disorders improves symptoms and function but carries significant risk. This review helps surgeons preoperatively counsel their patients in an informed manner. Careful planning, perioperative care, and appropriate implant selection may mitigate risk of complication.

Updates on the Risk of Neuropsychiatric and Gastrointestinal Comorbidities in Rosacea and Its Possible Relationship with the Gut-Brain-Skin Axis.

Rosacea is a common chronic cutaneous inflammatory disorder. Recently, patients with rosacea were identified as having a higher risk of developing various comorbidities such as cardiovascular disease, psychiatric disorders, neurologic disorders, and gastrointestinal disorders. However, the risks of some comorbidities in patients with rosacea are somewhat contradictory, depending upon the study design. Moreover, pathomechanisms associated with the comorbidities of patients with rosacea remain poorly elucidated. The purpose of this review was to provide the most up-to-date evidence on the risks of neuropsychiatric and gastrointestinal comorbidities in patients with rosacea. Moreover, the molecular pathomechanisms associated with neuropsychiatric and gastrointestinal comorbidities in patients with rosacea were evaluated based on recent studies. This review was also intended to focus more on the role of the gut-brain-skin axis in the association of neuropsychiatric and gastrointestinal comorbidities in rosacea.

Focus on the Role of NLRP3 Inflammasome in Diseases.

Inflammation is a protective reaction activated in response to detrimental stimuli, such as dead cells, irritants or pathogens, by the evolutionarily conserved immune system and is regulated by the host. The inflammasomes are recognized as innate immune system sensors and receptors that manage the activation of caspase-1 and stimulate inflammation response. They have been associated with several inflammatory disorders. The NLRP3 inflammasome is the most well characterized. It is so called because NLRP3 belongs to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs). Recent evidence has greatly improved our understanding of the mechanisms by which the NLRP3 inflammasome is activated. Additionally, increasing data in animal models, supported by human studies, strongly implicate the involvement of the inflammasome in the initiation or progression of disorders with a high impact on public health, such as metabolic pathologies (obesity, type 2 diabetes, atherosclerosis), cardiovascular diseases (ischemic and non-ischemic heart disease), inflammatory issues (liver diseases, inflammatory bowel diseases, gut microbiome, rheumatoid arthritis) and neurologic disorders (Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis and other neurological disorders), compared to other molecular platforms. This review will provide a focus on the available knowledge about the NLRP3 inflammasome role in these pathologies and describe the balance between the activation of the harmful and beneficial inflammasome so that new therapies can be created for patients with these diseases.

Biochemistry and structural studies of kynurenine 3-monooxygenase reveal allosteric inhibition by Ro 61-8048.

The human kynurenine 3-monooxygenase (hKMO) is a potential therapeutic target for neurodegenerative and neurologic disorders. Inhibition of KMO by Ro 61-8048, a potent, selective, and the most widely used inhibitor of KMO, was shown effective in various models of neurodegenerative or neurologic disorders. However, the molecular basis of hKMO inhibition by Ro 61-8048 is not clearly understood. Here, we report biochemistry studies on hKMO and crystal structures of an hKMO homolog, pfKMO from Pseudomonas fluorescens, in complex with the substrate l-kynurenine and Ro 61-8048. We found that the C-terminal ∼110 aa are essential for the enzymatic activity of hKMO and the homologous C-terminal region of pfKMO folds into a distinct, all-α-helical domain, which associates with the N-terminal catalytic domain to form a unique tunnel in proximity to the substrate-binding pocket. The tunnel binds the Ro 61-8048 molecule, which fills most of the tunnel, and Ro 61-8048 is hydrogen bonded with several completely conserved residues, including an essential catalytic residue. Modification of Ro 61-8048 and biochemical studies of the modified Ro 61-8048 derivatives suggested that Ro 61-8048 inhibits the enzyme in an allosteric manner by affecting the conformation of the essential catalytic residue and by blocking entry of the substrate or product release. The unique binding sites distinguish Ro 61-8048 as a noncompetitive and highly selective inhibitor from other competitive inhibitors, which should facilitate further optimization of Ro 61-8048 and the development of new inhibitory drugs to hKMO.-Gao, J., Yao, L., Xia, T., Liao, X., Zhu, D., Xiang, Y. Biochemistry and structural studies of kynurenine 3-monooxygenase reveal allosteric inhibition by Ro 61-8048.

Acute endovascular reperfusion treatment in patients with ischaemic stroke and large-vessel occlusion (Denmark 2011-2017).

BACKGROUND AND PURPOSE: Acute endovascular reperfusion treatment (aERT) of stroke patients with large-vessel occlusions is efficacious and safe according to several clinical trials. Data on outcome and safety of aERT in daily clinical routine are warranted and, in this study, we present national data from Denmark during 2011-2017. METHODS: National data for Denmark from 2011 to 2017 on all aERT procedures in patients with acute ischaemic stroke and computed tomography angiography/magnetic resonance angiography-verified large-vessel occlusion were derived from the Danish Stroke Registry, a national clinical quality registry to which reporting is mandatory for all hospitals treating stroke patients. Outcome (modified Rankin Scale score) after 3 months, including time of death, was assessed prospectively based on clinical examination or the Danish Civil Registration System. RESULTS: During the 7 years of observation, a total of 1720 patients were treated with aERT. The annual number of procedures increased from 128 in 2011 to 409 in 2017. The median age was 70 years, 58% were males and median National Institutes of Health Stroke Scale score at baseline was 16. Median time from symptom onset to groin puncture was 238 min with a decreasing trend during the years. Successful recanalization was reported in 1306 (76%) patients. At 3-month follow-up, an modified Rankin Scale score of 0-2 was reported in 46% of patients, whereas 14% of patients had died. CONCLUSION: Routine data on aERT in acute ischaemic stroke in Denmark from 2011 to 2017 suggest that the procedure is safe and efficacious.