Randomized Clinical Trial of High-Dose Rifampicin With or Without Levofloxacin Versus Standard of Care for Pediatric Tuberculous Meningitis: The TBM-KIDS Trial.

BACKGROUND: Pediatric tuberculous meningitis (TBM) commonly causes death or disability. In adults, high-dose rifampicin may reduce mortality. The role of fluoroquinolones remains unclear. There have been no antimicrobial treatment trials for pediatric TBM. METHODS: TBM-KIDS was a phase 2 open-label randomized trial among children with TBM in India and Malawi. Participants received isoniazid and pyrazinamide plus: (i) high-dose rifampicin (30 mg/kg) and ethambutol (R30HZE, arm 1); (ii) high-dose rifampicin and levofloxacin (R30HZL, arm 2); or (iii) standard-dose rifampicin and ethambutol (R15HZE, arm 3) for 8 weeks, followed by 10 months of standard treatment. Functional and neurocognitive outcomes were measured longitudinally using Modified Rankin Scale (MRS) and Mullen Scales of Early Learning (MSEL). RESULTS: Of 2487 children prescreened, 79 were screened and 37 enrolled. Median age was 72 months; 49%, 43%, and 8% had stage I, II, and III disease, respectively. Grade 3 or higher adverse events occurred in 58%, 55%, and 36% of children in arms 1, 2, and 3, with 1 death (arm 1) and 6 early treatment discontinuations (4 in arm 1, 1 each in arms 2 and 3). By week 8, all children recovered to MRS score of 0 or 1. Average MSEL scores were significantly better in arm 1 than arm 3 in fine motor, receptive language, and expressive language domains (P < .01). CONCLUSIONS: In a pediatric TBM trial, functional outcomes were excellent overall. The trend toward higher frequency of adverse events but better neurocognitive outcomes in children receiving high-dose rifampicin requires confirmation in a larger trial. CLINICAL TRIALS REGISTRATION: NCT02958709.

Mullen Scales of Early Learning Adaptation for Assessment of Indian Children and Application to Tuberculous Meningitis.

INTRODUCTION: Tuberculous meningitis (TBM) results in significant morbidity and mortality among children worldwide. Associated neurocognitive complications are common but not well characterized. The Mullen Scales of Early Learning (MSEL), a well-established measure for assessment of neurodevelopment, has not yet been adapted for use in India. This study's goal was to adapt the MSEL for local language and culture to assess neurocognition among children in India, and apply the adapted measure for assessment of children with TBM. METHODS: Administration of MSEL domains was culturally adapted. Robust translation procedures for instructions took place for three local languages: Marathi, Hindi and Tamil. Multilingual staff compared instructions against the original version for accuracy. The MSEL stimuli and instructions were reviewed by psychologists and pediatricians in India to identify items concerning for cultural bias. RESULTS: MSEL stimuli unfamiliar to children in this setting were identified and modified within Visual Reception, Fine-Motor, Receptive Language and Expressive Language Scales. Item category was maintained for adaptations of items visually or linguistically different from those observed in daily life. Adjusted items were administered to six typically developing children to determine modification utility. Two children diagnosed with confirmed TBM (ages 11 and 29 months) were evaluated with the adapted MSEL before receiving study medications. Skills were below age-expectation across visual reception, fine motor and expressive language domains. CONCLUSIONS: This is the first study to assess children with TBM using the MSEL adapted for use in India. Future studies in larger groups of Indian children are warranted to validate the adapted measure.

Recognition and management of adults with Turner syndrome: From the transition of adolescence through the senior years.

Turner syndrome is recognized now as a syndrome familiar not only to pediatricians and pediatric specialists, medical geneticists, adult endocrinologists, and cardiologists, but also increasingly to primary care providers, internal medicine specialists, obstetricians, and reproductive medicine specialists. In addition, the care of women with Turner syndrome may involve social services, and various educational and neuropsychologic therapies. This article focuses on the recognition and management of Turner syndrome from adolescents in transition, through adulthood, and into another transition as older women. It can be viewed as an interpretation of recent international guidelines, complementary to those recommendations, and in some instances, an update. An attempt was made to provide an international perspective. Finally, the women and families who live with Turner syndrome and who inspired several sections, are themselves part of the broad readership that may benefit from this review.

Limbic encephalitis and Post-Acute neuropsychology rehabilitation: A review and case examples.

Rehabilitation research on limbic encephalitis (LE), a rare disorder characterized by inflammation of the brain caused by autoimmunity or infection, has focused on acute rather than post-acute management of symptoms. The frequency of clinical relapse in encephalitis ranges from 12% to 35%. Commonly, individuals diagnosed with LE experience relapses or breakthrough seizures during their post-acute treatment. The treating neuropsychologist will often need to do family and staff education regarding the disorder, possible unusual pattern of recovery and discuss the risk of relapse. Additionally, staff may need help with behavior management and the potential need for a behavior management plan. This manuscript presents a review of these complex issues and reviews how these issues manifest in five individuals who were admitted to a post-acute brain injury rehabilitation program. Only one achieved significant functional gains, as measured by the Mayo Portland Adaptability Inventory(MPAI-4). Each had a low level of functioning on admission with low scores on the Orientation-Log (O-Log) and high scores on the MPAI-4. Relapse involving need for re-admission to an acute setting occurred in four cases and medication side effects (sedation) in three. As a whole, these cases highlight the complex and potentially unusual course of recovery in individuals with LE.

Younger Age at Onset Is Associated With Worse Long-term Behavioral Outcomes in Anti-NMDA Receptor Encephalitis.

BACKGROUND AND OBJECTIVES: Anti-NMDA receptor encephalitis (anti-NMDARE) is one of the most common causes of encephalitis. It typically presents in adolescence and young adulthood, but little is known about its potential long-term consequences across the lifespan. Adaptive behavior describes an individual's ability to respond and adapt to environmental demands and unanticipated changes in daily routines. In this study, we evaluate the relationship between features from clinical presentation, including age, and long-term adaptive behavior in participants with anti-NMDARE. METHODS: Cross-sectional informant-reported data were collected between 2017 and 2019 from 41 individuals/caregivers of individuals with anti-NMDARE treated at 3 major academic hospitals. Neurologic disability was assessed by record review using the modified Rankin Scale (mRS). Functional outcomes were assessed using the validated Adaptive Behavior Assessment System, Third Edition (ABAS-3). RESULTS: The mean age at the time of study enrollment was 23.4 years (SD 17.0 years), and the mean time from symptom onset to study enrollment was 4.0 years. Seventeen participants were aged <12 years at symptom onset, 19 participants were aged 12-30 years, and 5 participants were aged >30 years. Mean ABAS-3 scores at study enrollment for all participants were in the average range (mean general adaptive composite standard score 92.5, SD 18.7). Individuals aged <12 years at symptom onset had lower mean ABAS-3 scores and were in the below average range compared with those aged 12-30 years at symptom onset, whose mean scores were in the average range (87 vs 99, p < 0.05). Similar differences were seen in 3 of the individual subscales (functional academics, health and safety, and self-care). There were no significant differences in mRS scores between age groups (p > 0.05). DISCUSSION: Although anti-NMDARE is associated with an overall favorable outcome, younger age at onset associates with worse long-term adaptive behavior despite no differences in neurologic disability. These findings suggest that the disease may have distinct consequences on the early developing brain. Future studies should evaluate behavioral recovery and quality of life after anti-NMDARE and identify additional factors associated with differential recovery.

Return-to-driving following acquired brain injury: A neuropsychological perspective.

BACKGROUND: Return to driving after an acquired brain injury (ABI) has been positively associated with return to employment, maintenance of social relationships, and engagement in recreational and other community activities. Safe driving involves multiple cognitive abilities in a dynamic environment, and cognitive dysfunction resulting from ABI can negatively impact driving performance. OBJECTIVE: This manuscript examines the post-injury return-to-driving process, including performances on the in-office and on-road assessments, and the role of a rehabilitation neuropsychologist in helping patients resume driving. METHOD: In this study, 39 of 200 individuals (approximately 20%) treated at an outpatient neurorehabilitation facility, who performed satisfactorily on a pre-driving cognitive screening, completed a behind-the-wheel driving test. RESULTS: Of the 200 individuals, 34 (87%) passed the road test. Among the remaining five individuals who did not pass the road test, primary reasons for their failure included inability to follow or retain examiner directions primarily about lane position, speed, and vehicle control. The errors were attributable to cognitive difficulties with information processing, memory, attention regulation, and dual tasking.CONCLUSIONThe rehabilitation neuropsychologist contributed to the process by assessing cognition, facilitating self-awareness and error minimization, providing education about driving regulations and safety standards, and preparing for the road test and its outcomes.

Mild TBI in interdisciplinary neurorehabilitation: Treatment challenges and insights.

BACKROUND: Traumatic brain injury (TBI) has an estimated prevalence rate of 1.7 million occurrences a year in the United States with over 75% of traumatic brain injuries classified as 'mild.' The majority of individuals with mild traumatic brain injuries resume their daily functioning fairly quickly, and many fully within the first year. However, a minority of persons with mild TBI (mTBI), with estimates ranging between 1% and 20%, develop persistent cognitive, emotional, behavioral, and physical symptoms. Clinicians vary considerably in their clinical opinions regarding these individuals and there is no consensus on the treatment protocol for this population. OBJECTIVE: This manuscript presents four case studies of mild TBI with persistent symptoms treated by a transdisciplinary team in an outpatient neurorehabilitation setting based on community reintegration. Clinical challenges and insights involved in conceptualizing and effectively treating these individuals are discussed to facilitate future direction. METHODS: Four different mild TBI cases, each with persistent symptoms, but different injury mechanisms, dynamics, and factors affecting symptom persistence, expression, course, and outcome were included in the analysis of their treatment course and outcome. The treatment protocol included: brain injury education combined with supportive counseling for cultivation of positive expectancy effects, symptom-based, graded treatment involving most disciplines, frequent treatment team consultations, collaborations, and planning, and consistent team messages about post-injury recovery and expected return to community activities. Treatment outcomes were assessed with self and family reports, as well as the Mayo Portland Adaptability Inventory (MPAI-4) at admission and at discharge. RESULTS AND CONCLUSIONS: Each of the individuals made functional progress during rehabilitation, as evidenced by self and family reports and the MAPI-4. The cases posed various challenges to the treatment team, though a transdisciplinary team under the guidance of a rehabilitation physician and rehabilitation neuropsychologist was able to help patients navigate the path to their functional recovery. In addition to the specific treatment protocol, transdisciplinary team collaboration guided by rehabilitation neuropsychology contributed to treatment success.

Three case studies of nonparaneoplastic limbic encephalitis (NPLE) in young adult males: Onset, course, and recovery following rehabilitation services.

Limbic encephalitis (LE) is a rare neurological disorder characterized by inflammation of the brain caused by autoimmunity or infection. LE has been a difficult to define and diagnose disorder due to the insidious and nonspecific (e.g., irritability, low mood, short-term memory complaints) presentation of early symptoms, as well as inconsistent findings on neuroimaging, lumbar puncture serum analysis, and electroencephalogram. Seizures, memory problems, and psychiatric disturbance are among the earliest and most prominent clinical features. This manuscript describes three adolescent males who developed LE and became psychotic, needed inpatient care, were trialed on various psychotropic medications, and exhibited lingering cognitive and psychiatric issues, though generally had very positive recoveries and return to community activities. There was no history of psychiatric disturbance, developmental disorder, or learning difficulties in any of these three young men. Two of the three cases exhibited a long, insidious symptom onset. None of the adolescents benefitted from antipsychotic medications and did not begin to experience improvement and eventual recovery until intravenous immunoglobulin (IVIG) was added to their treatment regimen. Neuropsychological consultation and team education was helpful in each of these cases. Neuropsychological findings for each individual are presented.

Neurocognitive and functional impairment in adult and paediatric tuberculous meningitis.

In those who survive tuberculous meningitis (TBM), the long-term outcome is uncertain; individuals may suffer neurocognitive, functional and psychiatric impairment, which may significantly affect their ability to lead their lives as they did prior to their diagnosis of TBM. In children who survive, severe illness has occurred at a crucial timepoint in their development, which can lead to behavioural and cognitive delay. The extent and nature of this impairment is poorly understood, particularly in adults. This is in part due to a lack of observational studies in this area but also inconsistent inclusion of outcome measures which can quantify these deficits in clinical studies. This leads to a paucity of appropriate rehabilitative therapies available for these individuals and their caregivers, as well as burden at a socioeconomic level. In this review, we discuss what is known about neurocognitive impairment in TBM, draw on lessons learnt from other neurological infections and discuss currently available and emerging tools to evaluate function and cognition and their value in TBM. We make recommendations on which measures should be used at what timepoints to assess for impairment, with a view to optimising and standardising assessment of neurocognitive and functional impairment in TBM research.

Comparative Outcomes in Children and Adults With Anti- N-Methyl-D-Aspartate (anti-NMDA) Receptor Encephalitis.

This study compared neurologic disability and adaptive function in children and adults >1 year following anti- N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis diagnosis. Retrospective record review identified 12 patients with anti-NMDAR encephalitis. At last follow-up, all surviving patients had "good" modified Rankin Score (0-2). Four children, 6 adults, and their families participated in a telephone interview. Median duration since diagnosis was similar for children (2.42 years, interquartile range 2.12-3.32) and adults (3.55 years, interquartile range 2.08-5.50 years). 3/4 (75%) pediatric and 3/5 (60%) adult patients reported neuropsychiatric symptoms (fatigue, emotional lability, short-term memory deficits or concentration deficits). On the Adaptive Behavior Assessment System (ABAS-3), although overall adaptive function was intact for adults (general adaptive composite standard score: median 104.5, interquartile range 98.8-112.5), the median for children was below average (General Adaptive Composite Standard Score: median 82.0, interquartile range 79.0-89.0). Children with anti-NDMAR encephalitis may have long-term effects impacting daily life while adults regain normal function.

Neurobehavioral outcomes in autoimmune encephalitis.

This study evaluates long-term neurobehavioral function in patients with clinically diagnosed autoimmune encephalitis (AE) of various etiologies through retrospective chart review and a cross-sectional structured telephone interview. Of 77 patients meeting clinical diagnostic criteria for AE over a ten year period, 39/77 (51%) patients had known AE-associated antibodies, and 38/77 (49%) had no detected antibody. 9/77 (12%) died, and 26/77 (34%) had "poor" neurologic disability score (mRS 3-5) at the last documented follow-up. 44 participants enrolled in the telephone interview, of whom 38/44 (86%) endorsed ongoing difficulties with fatigue, emotional lability, short-term memory, and/or concentration. On standardized assessment of adaptive behavior (ABAS-3), 23/44 (52%) scored "below average" (general adaptive composite: mean 86.95, standard deviation 18.45). Of the participants with "good" neurologic disability outcome (mRS 0-2), 12/30 (40%) scored "below average" in adaptive behavior. In summary, patients with AE frequently have persistent impairments in neurologic disability, neurocognitive symptomatology, and adaptive behavior, which may not be adequately captured by routine neurologic assessments. Comprehensively elucidating these persistent neurobehavioral impairments and predicting which patients are at highest risk will allow for optimal care of patients and their families.

Three approaches to investigating functional compromise to the default mode network after traumatic axonal injury.

The default mode network (DMN) is a reliably elicited functional neural network with potential clinical implications. Its discriminant and prognostic utility following traumatic axonal injury (TAI) have not been previously investigated. The present study used three approaches to analyze DMN functional connectedness, including a whole-brain analysis [A1], network-specific analysis [A2], and between-node (edge) analysis [A3]. The purpose was to identify the utility of each method in distinguishing between healthy and brain-injured individuals, and determine whether observed differences have clinical significance. Resting-state fMRI was acquired from 25 patients with TAI and 17 healthy controls. Patients were scanned 6-11 months post-injury, and functional and neurocognitive outcomes were assessed the same day. Using all three approaches, TAI subjects revealed significantly weaker functional connectivity (FC) than controls, and binary logistic regressions demonstrated all three approaches have discriminant value. Clinical outcomes were not correlated with FC using any approach. Results suggest that compromise to the functional connectedness of the DMN after TAI can be identified using resting-state FC; however, the degree of functional compromise to this network, as measured in this study, may not have clinical implications in chronic TAI.