Emotional, Behavioral, and Cognitive Symptom Associations With Community Participation in Chronic Traumatic Brain Injury.

OBJECTIVES: To determine the association between self-reported emotional and cognitive symptoms and participation outcomes in chronic traumatic brain injury (TBI) and to explore the relative contribution of self-reported versus performance-based cognition to participation outcomes. SETTING: Community. PARTICIPANTS: Community-dwelling adults ( n = 135) with a lifetime history of mild to severe TBI. DESIGN: Secondary analysis of a cross-sectional study on neurobehavioral symptoms in chronic TBI. MAIN MEASURES: Behavioral Assessment Screening Tool (BAST) (Negative Affect, Fatigue, Executive Dysfunction, Impulsivity, Substance Abuse subscales) measured self-reported neurobehavioral symptoms; Participation Assessment with Recombined Tools (Productivity, Social Relations, and Out and About) measured self-reported participation outcomes; and Brief Test of Adult Cognition by Telephone (BTACT) measured performance-based cognition (Episodic Memory and Executive Function summary scores) in a subsample ( n = 40). RESULTS: The BAST Executive Dysfunction was significantly associated with less frequent participation and had the strongest effect on participation in all participation domains. No other BAST subscales were associated with participation, after adjusting for all subscale scores and age, with the exception of BAST Impulsivity, which was associated with more frequent Social Relationships. Exploratory analysis in the sample including the BTACT revealed that, after accounting for subjective Executive Dysfunction using the BAST, performance-based Executive Function was associated with Productivity and Working Memory was associated with Social Relations, but neither was associated with being Out and About; the BAST Executive Dysfunction remained significant in all models even after including BTACT scores. CONCLUSIONS: Self-reported Executive Dysfunction contributed to participation outcomes after mild to severe TBI in community-dwelling adults, whereas self-reported emotional and fatigue symptoms did not. Performance-based cognition measures may capture different variability in participation after injury.

Tandem detergent-extraction and immunoprecipitation of proteinopathy: Scalable enrichment of ALS-associated TDP-43 aggregates.

Transactive response DNA-binding protein of 43 kDa (TDP-43) is a highly conserved, ubiquitously expressed nucleic acid-binding protein that regulates DNA/RNA metabolism. Genetics and neuropathology studies have linked TDP-43 to several neuromuscular and neurological disorders including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Under pathological conditions, TDP-43 mislocalizes to the cytoplasm where it forms insoluble, hyper-phosphorylated aggregates during disease progression. Here, we optimized a scalable in vitro immuno-purification strategy referred to as tandem detergent-extraction and immunoprecipitation of proteinopathy (TDiP) to isolate TDP-43 aggregates that recapitulate those identified in postmortem ALS tissue. Moreover, we demonstrate that these purified aggregates can be utilized in biochemical, proteomics, and live-cell assays. This platform offers a rapid, accessible, and streamlined approach to study ALS disease mechanisms, while overcoming many limitations that have hampered TDP-43 disease modeling and therapeutic drug discovery efforts.

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.

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.

The role of rehabilitation psychology in stroke care described through case examples.

BACKGROUND: A stroke event, sometimes referred to as a cerebrovascular accident (CVA), is a sudden and often traumatic life event that results in life-changing consequences with which affected people must cope. There are nearly 800,000 instances of stroke annually in the U.S. (American Heart Association, 2018). Stroke is the leading cause of disability in adults, and more than one-third of people who survive a stroke will have severe disability in the U.S. (Mayo, 2005). Between 35% and 75% of stroke survivors will have significant cognitive impairment (Tatemichi et al., 1994; Nys et al., 2007). An estimated one-third of people suffer depression after stroke (Hackett et al., 2005), about one-fourth experience significant anxiety (Barker-Collo, 2007), and about one-fifth suffer from insomnia (Leppavuoria et al., 2002). These and other stroke-related psychological issues negatively influence rehabilitation and outcomes through a variety of mechanisms. For example, post-stroke depression has been shown to be related to more negative functional consequences (Kneebone et al., 2000; Matsuzaki et al., 2015). Psychological disturbances may affect rehabilitation outcomes through a reduction in adherence to home exercise programs, reduced energy level, increased fatigue, reduced frustration tolerance, and potentially less motivation and hope about the future. OBJECTIVES: This manuscript aims to identify and describe the role of rehabilitation psychology in treating these common post-stroke complaints and, ultimately, optimizing post-stroke outcomes via two case examples. METHODOLOGY: This manuscript describes two cases of individuals in post-acute rehabilitation who had psychological issues which were negatively affecting outcomes. CONCLUSION: Given the abrupt and significant life-changing nature of stroke, it is often necessary to manage a diverse array of psychological issues that often cannot be simply managed via psychotropic medications. Moreover, an understanding of the patients' emotional adjustment and issues can help them maximize their rehabilitation, recovery, and community integration. For the cases discussed, psychology consultations were central in helping optimize their rehabilitation and functional 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.

Structure of an anti-PEG antibody reveals an open ring that captures highly flexible PEG polymers.

Polyethylene glycol (PEG) is a polymer routinely used to modify biologics and nanoparticles to prolong blood circulation and reduce immunogenicity of the underlying therapeutic. However, several PEGylated therapeutics induce the development of anti-PEG antibodies (APA), leading to reduced efficacy and increased adverse events. Given the highly flexible structure of PEG, how APA specifically bind PEG remains poorly understood. Here, we report a crystal structure illustrating the structural properties and conformation of the APA 6-3 Fab bound to the backbone of PEG. The structure reveals an open ring-like sub-structure in the Fab paratope, whereby PEG backbone is captured and then stabilized via Van der Waals interactions along the interior and exterior of the ring paratope surface. Our finding illustrates a strategy by which antibodies can bind highly flexible repeated structures that lack fixed conformations, such as polymers. This also substantially advances our understanding of the humoral immune response generated against PEG.

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.

Megalencephaly-capillary malformation polymicrogyria: A review and complex pediatric case report.

Megalencephaly-Capillary Malformation Polymicrogyria (M-CAP) is a rare genetic disorder characterized by a spectrum of anomalies including macrocephaly and neurovascular malformations. Although developmental delays have been identified, research is devoid of neuropsychological data. This case report presents the neuropsychological profile of a 7-year-old, identified with M-CAP. Neuropsychological evaluation was completed subsequent to medical diagnosis. Reports from both parents and teachers included cognitive regression; specifically in the recall of learned material, reading, and information sequencing. Direct testing revealed a WISC-IV GAI at <1st percentile, a diverse range of scores across the battery, and a splinter skill strength of average to above on visual memory tests. Performance included below grade level reading and writing, reduced adaptive functioning, and reported executive dysfunction. Her strong visual memory skills were recommended as a medium to enhance learning. Neurocognitive deficits revealed diverse, multisystem and multifocal impairments. The neuropsychological evaluation also showed significant decline from the previous evaluation and prompted a neurologic consult and corrective surgical procedure.

Test of memory malingering with children: The utility of Trial 1 and TOMMe10 as screeners of test validity.

There is a growing body of research suggesting that the shorter versions of the Test of Memory Malingering (TOMM) may provide an accurate assessment of effort in children. During neuropsychological evaluations, some circumstances result in only one completed trial of the TOMM or partial completion of a trial. Research suggests that a cut-score of 40 or 41 on Trial1 is highly predictive of passing the TOMM overall. In the current study, 194 school-age children with academic and/or behavioral problems were used to compare the accuracy of TOMM1 and TOMMe10 (errors on the first 10 items of TOMM1) in predicting passing/failing of TOMM2. For the children in this sample, a score of < 40 items correct (≥ 10 errors) on TOMM1 was highly accurate in predicting a passing performance on the TOMM2 (sensitivity = .80, specificity = .91) with a Negative Predictive Value = .98 at the malingering base rate of 7% (TOMM2 failure in our sample). A score of 2 errors (8 items correct) on the TOMMe10 was slightly less sensitive than that of the TOMM1 (specificity = .96, sensitivity = .53) but with a similar Negative Predictive Value (.96). Consistent with the research from adult populations, TOMM1 and TOMMe10 appear to be quite accurate in predicting performance on the standard administration of the TOMM and may be useful screeners. However, compared to that found in adult samples, slight differences in suggested cutoffs for TOMM1 and TOMMe10 may be warranted for children.

Anti-N-Methyl-D-Aspartate Receptor Encephalitis: A Review and Neuropsychological Case Study.

OBJECTIVE: Anti-N-Methyl-d-Aspartate Receptor (NMDAR) Encephalitis is an autoimmune-mediated encephalitis, which may be associated with a tumor, which occurs when antibodies bind central NMDA receptors. Although typically diagnosed in women, approximately 20% of cases have been males. Due to the challenges with identification, imaging, and diverse symptom presentation, this syndrome is often misdiagnosed. Accurate diagnosis may provide an opportunity for introduction of disease-modifying therapies, which may alter disease trajectory. Moreover, neuropsychology has yet to fully clarify the pattern of impairments expected with this disorder. METHODS: This manuscript reviews a single case study of a 42-year-old male diagnosed with NMDAR encephalitis. Neuropsychological evaluation was completed subsequent to diagnosis, treatment, and rehabilitation. Ongoing patient complaints, approximately six months post diagnosis, included reduced sustained attention, poor word retrieval, and daily forgetfulness. Adaptive skills were improved following rehabilitation. RESULTS: Direct testing revealed mildly impaired sustained attention, processing speed, oral word fluency, and executive functioning. All other cognitive domains were within estimated premorbid range, low average to average. CONCLUSIONS: Neuropsychological deficits were consistent with mild frontal brain dysfunction and continued recovery. This case illustrates the need for medical and psychological practitioners to understand NMDAR encephalitis, its symptom presentation, and related neuropsychological impact; particularly with the potential for misdiagnosis.

Rehabilitation Outcomes: Ischemic versus Hemorrhagic Strokes.

Background. Ischemic and hemorrhagic strokes have different pathophysiologies and possibly different long-term cerebral and functional implications. Hemorrhagic strokes expose the brain to irritating effects of blood and ischemic strokes reflect localized or diffuse cerebral vascular pathology. Methods. Participants were individuals who suffered either an ischemic (n = 172) or hemorrhagic stroke (n = 112) within the past six months and were involved in a postacute neurorehabilitation program. Participants completed three months of postacute neurorehabilitation and the Mayo Portland Adaptability Inventory-4 (MPAI-4) at admission and discharge. Admission MPAI-4 scores and level of functioning were comparable. Results. Group ANOVA comparisons show no significant group differences at admission or discharge or difference in change scores. Both groups showed considerably reduced levels of productivity/employment after discharge as compared to preinjury levels. Conclusions. Though the pathophysiology of these types of strokes is different, both ultimately result in ischemic injuries, possibly accounting for lack of findings of differences between groups. In the present study, participants in both groups experienced similar functional levels across all three MPAI-4 domains both at admission and discharge. Limitations of this study include a highly educated sample and few outcome measures.

Prenatal and perinatal anesthesia and the long-term cognitive sequelae: a review.

Many children have cognitive weaknesses or impairments of uncertain etiology. A variety of gestational and early-life variables contribute to normative neurocognitive development with countless events potentially hindering successful neural development. Recent research suggests that anesthesia has the potential to negatively affect fetal brain development both prenatally and perinatally. Some of the anesthesiology research suggests that under certain circumstances, children may have a heightened risk for attention-deficit hyperactivity disorder, learning disorders, and perhaps other issues. Though there are no prospective studies evaluating neurocognitive function in children after neonatal exposure to anesthetics, there are several retrospective reviews that demonstrate temporary neurological sequelae after prolonged anesthetic exposure in young children and larger studies identifying long-term neurodevelopmental impairment after neonatal surgery and anesthesia. Studies also suggest a heightened vulnerability likely during the first trimester, particularly when neurons are undergoing rapid development. Specifically, heightened vulnerability to cerebral dysfunction tends to be associated with exposure to multiple anesthetic agents, longer duration of exposure, and multiple episodes of exposure to anesthetic agents.

Gestational Diabetes: Long-Term Central Nervous System Developmental and Cognitive Sequelae.

Gestational diabetes is a common complication of pregnancy and occurs in approximately 7% of all pregnancies. It has been associated with an increased rate of congenital anomalies including disturbances of intrauterine growth, delayed brain maturity, and neurobehavioral abnormalities in the offspring. The resulting maternal and fetal metabolic dysfunction leads to diminished iron stores (which can affect red blood cell [RBC] production and subsequent organogenesis), a metabolism-placental perfusion mismatch, increased FFA, increased lactic acidosis, and potential hypoxia. Though most newborns born in the context of gestational diabetes are not significantly affected by it, empirical research suggests gestational diabetes has been associated with lower general intelligence, language impairments, attention weaknesses, impulsivity, and behavioral problems. In extreme cases, it may essentially function as a gestational brain insult. Children who are exposed to poorly controlled gestational diabetes may benefit from some form of tracking or follow-up assessments. Additionally, clinicians evaluating children with developmental learning or cognitive dysfunction may want to seek appropriate gestational diabetes-related information from the parents. A greater understanding of this significant gestational risk may help foster improved prenatal diabetes management and may help reduce the neurodevelopmental effects of gestational diabetes.

Spectrum of Mathematical Weaknesses: Related Neuropsychological Correlates.

Math disorders have been recognized for as long as language disorders yet have received far less research. Mathematics is a complex construct and its development may be dependent on multiple cognitive abilities. Several studies have shown that short-term memory, working memory, visuospatial skills, processing speed, and various language skills relate to and may facilitate math development and performance. The hypotheses explored in this research were that children who performed worse on math achievement than on Full-Scale IQ would exhibit weaknesses in executive functions, memory, and visuoperceptual skills. Participants included 436 children (27% girls, 73% boys; age range = 5-17 years, M(age) = 9.45 years) who were referred for neuropsychological evaluations due to academic and/or behavioral problems. This article specifically focuses on the spectrum of math weakness rather than clinical disability, which has yet to be investigated in the literature. Results suggest that children with relative weakness to impairments in math were significantly more likely to have cognitive weaknesses to impairments on neuropsychological variables, as compared with children without math weaknesses. Specifically, the math-weak children exhibit a weakness to impairment on measures involving attention, language, visuoperceptual skills, memory, reading, and spelling. Overall, our results suggest that math development is multifaceted.

Advances and issues in the diagnostic differential of malingering versus brain injury.

The past decade has seen numerous advancements in the assessment of malingered brain injury, though the current diagnostic system offers only guidelines in which malingering should be suspected. This article presents an overview of advances in the clinical and neuropsychological assessment of malingering, issues in diagnostic differential, neuropsychological test methods, and special issues presented by the medical-legal context, and other factors which may affect presentations. Cautions and recommendations for practice are presented.

Performance and specificity rates in the Test of Memory Malingering: an investigation into pediatric clinical populations.

Symptom validity tests are becoming standard as an effort measure during pediatric neuropsychological assessment. An important component of symptom validity test use is understanding limitations of these measures and how select clinical groups may have difficulty with them. Research has begun to clarify the limits of the Test of Memory Malingering (TOMM) with diverse childhood diagnoses. This study compared TOMM scores of children (N = 86) classified with common childhood disorders. Findings suggest that a substantial proportion of children performed below the recommended cutoff score of 45 on Trial 2 and attained varied specificity rates. This included children with conduct disorders (85%), affective disorders (92%), traumatic brain injury (83%), attention-deficit hyperactivity disorder (93%), learning disabilities (100%), and pervasive developmental disorder (88%). The group with the most children scoring below the cutoff was children with intellectual disabilities (76%). This finding is consistent with some of the adult research suggesting that very limited cognitive ability may compromise TOMM performance. Caution may be necessary when drawing conclusions about test-taking effort based on the recommended TOMM cutoff scores when evaluating children with disabilities.

The influence of effort on neuropsychological performance in children: is performance on the TOMM indicative of neuropsychological ability?

The Test of Memory Malingering (TOMM) is a measure of effort that has traditionally been utilized with adults but is being increasingly used with children, though it is not yet entirely clear what suboptimal TOMM performance means in terms of neuropsychological test scores. The purpose of this study was to investigate whether performance on the TOMM can be used as a predictive marker for neuropsychological performance in children. Participants (N = 75) completed the TOMM, Wechsler Intelligence Scale for Children-Fourth Edition, Wisconsin Card-Sorting Test (WCST), Children's Memory Test, and Delis-Kaplan Executive Function System Trails. Results revealed significant correlations between age, education level, IQ, and many of the neuropsychological measures administered, indicating that as children's TOMM scores increase, so do their cognitive performances. Children were subsequently divided into two groups: optimal effort and suboptimal effort, based on their TOMM Trial 2 scores. Results suggest significant differences in IQ performance and WCST Failure to Maintain Set; however, there were no differences in regard to any other neuropsychological measures administered. It was also found that a larger proportion of the younger children (aged 6 to 10 years old) scored below the TOMM cutoff compared with older children. This study illustrates that although correlations exist, suboptimal effort on the TOMM may not predict poorer performance on a neuropsychological evaluation in children as has been reported in other studies.

Neuropsychological profiles and subsequent diagnoses of children with early life insults: do caregiver reports suggest deficits?

Many types of early life events can cause cerebral dysfunction; however, not all children have medical records or neurologic imaging documenting brain injuries. Rather, many neuropsychologists base their findings on caregiver reports describing possible early brain insults. Neuropsychological studies suggest that brief perinatal cyanosis and/or childhood neglect may negatively affect cognitive functioning. Should the mere suggestion of these events from caregiver reports be enough to suggest deficits? This study examines four groups of children: those with (1) reported nuchal cord compression with brief cyanosis, (2) reported childhood neglect, (3) reported history of both, and (4) reported history of none. It was hypothesized that based on the literature of these populations, children who present at an evaluation with the report of these insults would also present cognitive deficits. Results revealed no significant difference in intellect, memory, or academic abilities. A significant difference was shown between groups during the Wisconsin Card-Sorting Test Failure to Maintain Set, as groups with a history of neglect had lower scores. A history of childhood neglect also suggested an increased risk for subsequent emotional/behavioral diagnoses. These findings suggest that although the profiles range between low-average and average, reports of early life insults can flag potential deficits in a child's neuropsychological profile.

Cognitive impairment and memory loss associated with histoplasmosis: a case study.

Histoplasmosis is a rare disease caused by inhalation of the fungus Histoplasma capsulatum. It can spread via cerebral circulation to the central nervous system as a manifestation of a disseminated infection; particularly in patients with immune suppression, which can result in isolated ring-enhancing lesions and inflammation in the brain. Of the reported disseminated histoplasmosis cases (approximately 1 in 2000 per year), only 5-20% have evidence of central nervous system involvement. This paper reviews a single case study of a 57-year-old female diagnosed with disseminated CNS histoplasmosis. Patient's complaints included reduced short-term memory, word-finding problems, and difficulty organizing, making decisions, getting lost while driving, recalling names, retaining information while reading, and slowed processing speed. There was also a history of mild depression and anxiety. Direct testing revealed deficits in multiple cognitive domains including complex attention, processing speed, semantic fluency, visual scanning, motor speed, set-shifting, naming, nonverbal memory, and verbal memory. Neuropsychological deficits suggest cortical and subcortical brain dysfunction, including anterior, temporal, and mesial-temporal regions. This case illustrates the need for neuropsychologists to understand histoplasmosis, the related pathophysiology, and the neuropsychological impact; particularly with the potential for delayed progression.