Formal Neurocognitive Testing Research Articles

Dural Arteriovenous Fistulas: Baseline Cognitive Changes and Changes following Treatment: A Prospective Longitudinal Study.

Dural arteriovenous fistulas (DAVFs) exhibit varied clinical manifestations, and high-grade cases are associated with both a risk of hemorrhage and (in certain cases) dementia. Less known, however, is the association between DAVF and more subtle cognitive changes, which might not be clinically apparent without formal neurocognitive testing. This study prospectively assesses baseline cognitive changes in patients with unruptured DAVFs and looks at the effects of treatment on any such changes. A longitudinal prospective study was conducted to formally evaluate the neurocognitive status of patients with unruptured DAVFs undergoing embolization. Pre- and posttreatment assessments included neurologic examinations and cognitive tests (Repeatable Battery for the Assessment of Neuropsychological Status and Trail-Making Test [TMT]). A total of 23 patients were treated, with 78% demonstrating cortical venous reflux at baseline. At baseline, 50% of patients demonstrated cognitive impairment in at least 1 cognitive domain, and this was significantly associated with cortical venous reflux (P < .05). Following treatment, significant improvements were observed in several cognitive domains. The mean change in Immediate Memory was an increase of 10.5 points (95% CI, 6.2-14.8, P < .001). Visuospatial/Constructional abilities showed a mean increase of 3.8 points (95% CI, 1.1-6.5, P = .008), while Language improved by a mean of 4.2 points (95% CI, 0.9-7.5, P = .015). Attention scores increased by a mean of 6.1 points (95% CI, 2.7-9.5, P < .001). Delayed Memory demonstrated a mean improvement of 7.4 points (95% CI, 3.5-11.3, P < .001), and the Total Repeatable Battery for the Assessment of Neuropsychological Status Score increased by a mean of 8.6 points (95% CI, 5.0-12.2, P < .001). For the TMT, the mean change in TMT-A was a decrease of 9.2 seconds (95% CI, 5.6-12.8, P < .001), indicating faster completion times. TMT-B scores decreased by a mean of 12.7 seconds (95% CI, 8.4-17.0, P < .001). The TMT B-A difference decreased by a mean of 3.5 seconds (95% CI, 0.5-6.5, P = .023), and the TMT B/A ratio showed a mean decrease of 0.18 (95% CI, 0.10-0.26, P = .002). Overall, among the patients with baseline cognitive impairment, 70% showed significant cognitive improvement following endovascular treatment, particularly in memory domains. In our study, 50% of patients with DAVFs had cognitive impairment when assessed with formal neurocognitive testing, with a significant link to cortical venous reflux. This cognitive impairment improved in 70% of those patients following treatment. These findings expand our understanding of how DAVF affects the brain, highlighting cognitive impairment as a critical factor. Consequently, the treatment of DAVFs should perhaps not only focus on hemorrhagic risk but also consider cognitive outcomes as a potential indicator for intervention.

Pilot Study of Longitudinal Geriatric Assessment and Neurocognitive Evaluation in CAR T-Cell Therapy for Older Patients with Relapsed Refractory, Large B-Cell Lymphoma

Introduction: Chimeric antigen receptor T-cell (CAR T) therapy is increasingly utilized for older patients with relapsed refractory, large b-cell lymphoma (LBCL) with promising efficacy. However, the feasibility of conducting serial geriatric assessments with appropriate management has not been examined in this vulnerable population of patients. Moreover, the short-term and long-term impact of CAR T-cell therapy on the older patient's overall physical and neurocognitive functioning remains unknown. Methods: In this prospective pilot study (NCT04300998), we enrolled older patients with LBCL receiving commercial CAR T and conducted serial geriatric assessments (GA), formal neurocognitive testing in domains sensitive to cancer therapy side effects including attention, memory, and executive functions, and quality-of-life surveys prior to and following CAR T treatment at 3, 6, and 12 months among patients who remained in remission. CAR T manufacturing, treatment, and follow-ups followed national and institutional guidelines. Cytokine release syndrome (CRS) and Immune effector cell-associated neurologic syndromes (ICANS) were graded according to the ASTCT criteria. Standard statistical analysis was performed for CAR T treatment outcomes. GA impairment in each domain (binary outcome) was tabulated as percentages. For neurocognitive testing, means across timepoints were estimated for each test score using a linear mixed model predicting the score by timepoint. A random intercept was included to account for multiple assessments per patient. Results: Between April 2020 to March 2022, 18 patients were enrolled. The median age was 69.8 years (range 63.7 to 85.0) and 8 of 18 patients, 44%, were female. Eight patients received Axicabtagene ciloleucel while 6 and 4 patients received Tisagenlecleucel and Lisocabtagene maraleucel, respectively. Fourteen out of 18 patients, 78% (95% confidence interval [CI] 52 - 94), completed all required GA visits (baseline and all follow-up timepoints while in remission), meeting the prespecified feasibility endpoint of 75%. Geriatric vulnerabilities detected by GA were highly prevalent at the baseline including functional impairment by instrumental activities of daily living (44%), mobility impairment (24%), multimorbidity (61%), polypharmacy (44%), poor psychosocial support (39%), and depression (28%). Moreover, on a panel of 7 neurocognitive tests, 52.9% of patients had at least one and 29.4% had 2 or more impairments at baseline. With a median follow-up of 24 months (95% 23 - not reached), the 2-year overall and progression-free survival was 70% (95% CI 51 - 96) and 42% (95% CI 24 - 74), respectively. Ten patients had relapsed/progressed and among them 5 had died. Thirteen patients, 72%, experienced CRS with the majority grade 1-2 and only 2 patients (11%) had grade 3 CRS. Four patients, 22%, experienced ICANS (three grade 1 and one grade 2). The most common high-grade toxicities within 100 days of CAR T treatment were infections (n=4); cardiac complications (n=2); and thrombotic complications (n=2). There was no treatment-related death. Finally, longitudinal GA post-CAR T revealed the stability of geriatric impairment overtime among patients remaining in remission (Figure 1 left). Moreover, detailed neurocognitive testing revealed global stability of cognitive performance with improvements in 3 cognitive tests overtime, HVLT, ZBTA, and ZBF (Figure 1 right HVLT test). These findings support the notion among patients who achieve remission. Conclusions: In this prospective pilot study, we showed that longitudinal GA was feasible to perform in older, vulnerable lymphoma patients receiving CAR T therapy. Despite advanced age and high prevalence of baseline geriatric and cognitive deficits, CAR T treatment was well tolerated without excessive or unexpected toxicities. Stable GA deficits and improvement in some areas of cognitive performance were observed descriptively among patients in ongoing remission, supporting that CAR T treatment in older patients is safe without detrimental, long-term cognitive and functional impacts. Although the small sample size and incomplete data limited study interpretation and generalization, GA and geriatric management may provide valuable, actionable information to optimize older lymphoma patients for CAR T-cell therapy.

Formal neurocognitive function and anti-N-methyl-D-aspartate receptor antibodies in paediatric lupus

ObjectiveSLE is a chronic multisystem autoimmune inflammatory disease impacting a number of organs, including the central nervous system (CNS). The pathophysiology of CNS lupus is multifactorial, making diagnosis problematic. Neurocognitive...

Cerebral microvascular and microstructural integrity is regionally altered in patients with systemic lupus erythematosus

BackgroundTo measure regional brain microvascular and microstructural changes in childhood-onset SLE (cSLE) using diffusion-weighted imaging (DWI) at multiple b values and investigate relationships of those measures with neurocognitive function and disease activity.MethodsIn this cross-sectional, case-control study, vascular volume fraction, effective diffusion, parenchymal diffusion, and blood flow parameters were regionally compared in cSLE patients and matched healthy controls. These markers of microvascular and microstructural integrity were derived by diffusion-weighted brain MRI and intravoxel incoherent motion (IVIM) modeling. Formal neurocognitive testing was completed focused on the domains of attention, visuoconstructional ability, working memory, and psychomotor speed. Test scores and measures of disease severity were regressed against regional microvascular integrity parameters among cSLE patients.ResultsFormal cognitive testing confirmed normal cognitive ability among all cSLE patients included in the analysis (n = 11). Nevertheless, reduction in blood volume fraction coincided with increased effective diffusion and flow parameters in cSLE patients vs. controls in posterior brain regions including the cuneus and precuneus. Regional microvascular measures correlated (|r| = 0.54–0.66) with neuropsychiatric scores and disease activity among cSLE patients.ConclusionsThere is imaging evidence, using IVIM, of degraded microvascular integrity in cSLE patients with normal cognitive ability. The observed regional changes correspond with posterior vascular border zones. These outcomes appear consistent with regional gray matter volume loss previously observed in cSLE patients with overt neurocognitive deficits, supporting the notion that adverse vascular changes precede loss of cognitive ability in cSLE. Longitudinal studies are needed to confirm the findings of this initial study.

366. Severe Neurologic Impairment Persists Despite Potent ART in HIV Encephalopathy

BackgroundApproximately 4–8% of the 1.1 million HIV patients in the United States have or will be diagnosed with HIV encephalopathy or HIV associated dementia (HAD). There are no published studies of the long-term outcomes of HAD treated with potent antiretroviral therapy (ART). We hypothesize that more than 60% of individuals diagnosed with HAD will have persistent neurocognitive impairment despite the successful use of potent ART and fewer than 20% will be employed.MethodsThis is a cross-sectional prospective and retrospective study of outcomes in individuals previously diagnosed with HAD. We identified all individuals with the diagnosis of dementia and HIV at the UC Infectious Diseases Center (IDC). For those who matched the 1993 CDC HAD definition, we collected medical, neurocognitive, and functional information. We attempted to contact all individuals alive and still in the IDC practice (N = 26) to perform a validated battery of neuropsychological tests. We excluded individuals with HIV-associated neurocognitive disease that developed after treatment with ART.ResultsWe confirmed 39 diagnoses of HAD out of 137 records reviewed. The median CD4 count at the time of diagnosis of HAD was 47 cells/mm3 with a median viral load of 211,475 copies/mL. The median length of follow-up after diagnosis of HAD was 72 months (range 1–166 months). Potent ART was prescribed to all individuals, with 67.5% reaching consistent undetectable viral loads (< 200 copies/mL, occasional blips allowed). Persistent neurologic deficits were noted in 32.5%, while 60% had persistent cognitive deficits. Psychiatric disturbances were present in 72.5%. Only 2.5% reported any employment. To date, 28% have died. Ten participants have undergone formal neurocognitive testing to date (N = 26 available). The median overall summary score (total Z score) was -1.17 (range 0.08, -1.95) and median global deficit (GDS) score was 1.48 (range 0, 2.92).ConclusionHIV-associated dementia results in substantial morbidity and mortality despite potent antiretroviral therapy. Prospective neurocognitive assessment documents significant impairments in most individuals. HIV-associated dementia will require additional strategies to mitigate the profound impact on the quality of life and longevity.Disclosures All authors: No reported disclosures.

Formal Neurocognitive Testing in 60 Patients with Congenital Hyperinsulinism

Background: Congenital hyperinsulinism (CHI) is hallmarked by persistent hypoketotic hypoglycemia in infancy. In the majority of all patients, CHI is caused by mutations in the KATP channel genes ABCC8 and KCNJ11, but other genes in the insulin-regulatory pathway have also been described. Repeated episodes of hypoglycemia include an increased risk of seizures and intellectual disability. So far, controlled psychometric studies on cognitive, motor, speech, and social-emotional outcome of CHI patients are missing. Until now, neurodevelopmental long-term outcome in CHI patients has only been measured by questionnaires, self-, parental-, or caregiver-administered instruments. Methods: This is a prospective study of 60 patients (median age 3.3 years, range 3 months to 57 years): 48 with a diffuse, 9 with a focal, and 3 with an atypical histology. Neurodevelopmental outcome was assessed using standardized psychological tests and questionnaires. Results: 28 of 60 patients showed developmental delay (46.7%). 9 of 57 patients had cognitive deficits (15.8%), 7 of 26 patients had speech problems (26.9%), and 17 of 44 patients had motor problems (38.6%). In 5 of 53 patients, social-emotional problems were reported. Outcome and the underlying genetic defect were not correlated. Conclusions: Motor problems seem to be prominent in CHI patients. Despite a high incidence of developmental delay, a permanent cognitive defect was only detectable in 9 of 58 patients.

Neurocognitive Performance After Cerebral Revascularization in Adult Moyamoya Disease.

Cerebral revascularization using EC-IC bypass is widely used to treat moyamoya disease, but the effects of surgery on cognition are unknown. We compared performance on formal neurocognitive testing in adults with moyamoya disease before and after undergoing direct EC-IC bypass. We performed a structured battery of 13 neurocognitive tests on 84 adults with moyamoya disease before and 6 months after EC-IC bypass. The results were analyzed using reliable change indices for each test, to minimize test-retest variability and practice effects. Twelve patients (14%) showed significant decline postoperatively, 9 patients (11%) improved, and 63 patients (75%) were unchanged. Similar results were obtained when the analysis was confined to those who underwent unilateral (33) or bilateral (51) revascularization. The majority of patients showed neither significant decline nor improvement in neurocognitive performance after EC-IC bypass surgery. Uncomplicated EC-IC bypass seems not to be a risk factor for cognitive decline in this patient population.

Altered Blood-Brain Barrier Permeability in Patients With Systemic Lupus Erythematosus: A Novel Imaging Approach.

To evaluate a safe, noninvasive magnetic resonance imaging (MRI) method to measure regional blood-brain barrier integrity and investigate its relationship with neurocognitive function and regional gray matter volume in juvenile-onset systemic lupus erythematosus (SLE). In this cross-sectional, case-control study, capillary permeability was measured as a marker of blood-brain barrier integrity in juvenile SLE patients and matched healthy controls, using a combination of arterial spin labeling and diffusion-weighted brain MRI. Regional gray matter volume was measured by voxel-based morphometry. Correlation analysis was done to investigate the relationship between regional capillary permeability and regional gray matter volume. Formal neurocognitive testing was completed (measuring attention, visuoconstructional ability, working memory, and psychomotor speed), and scores were regressed against regional blood-brain barrier integrity among juvenile SLE patients. Formal cognitive testing confirmed normal cognitive ability in all juvenile SLE subjects (n = 11) included in the analysis. Regional capillary permeability was negatively associated (P = 0.026) with neurocognitive performance concerning psychomotor speed in the juvenile SLE cohort. Compared with controls (n = 11), juvenile SLE patients had significantly greater capillary permeability involving Brodmann's areas 19, 28, 36, and 37 and caudate structures (P < 0.05 for all). There is imaging evidence of increased regional capillary permeability in juvenile SLE patients with normal cognitive performance using a novel noninvasive MRI technique. These blood-brain barrier outcomes appear consistent with functional neuronal network alterations and gray matter volume loss previously observed in juvenile SLE patients with overt neurocognitive deficits, supporting the notion that blood-brain barrier integrity loss precedes the loss of cognitive ability in juvenile SLE. Longitudinal studies are needed to confirm the findings of this pilot study.

Cognitive Performance Scores for the Pediatric Automated Neuropsychological Assessment Metrics in Childhood-Onset Systemic Lupus Erythematosus.

To develop and initially validate a global cognitive performance score (CPS) for the Pediatric Automated Neuropsychological Assessment Metrics (PedANAM) to serve as a screening tool of cognition in childhood lupus. Patients (n = 166) completed the 9 subtests of the PedANAM battery, each of which provides 3 principal performance parameters (accuracy, mean reaction time for correct responses, and throughput). Cognitive ability was measured by formal neurocognitive testing or estimated by the Pediatric Perceived Cognitive Function Questionnaire-43 to determine the presence or absence of neurocognitive dysfunction (NCD). A subset of the data was used to develop 4 candidate PedANAM-CPS indices with supervised or unsupervised statistical approaches: PedANAM-CPSUWA , i.e., unweighted averages of the accuracy scores of all PedANAM subtests; PedANAM-CPSPCA , i.e., accuracy scores of all PedANAM subtests weighted through principal components analysis; PedANAM-CPSlogit , i.e., algorithm derived from logistic models to estimate NCD status based on the accuracy scores of all of the PedANAM subtests; and PedANAM-CPSmultiscore , i.e., algorithm derived from logistic models to estimate NCD status based on select PedANAM performance parameters. PedANAM-CPS candidates were validated using the remaining data. PedANAM-CPS indices were moderately correlated with each other (|r| > 0.65). All of the PedANAM-CPS indices discriminated children by NCD status across data sets (P < 0.036). The PedANAM-CPSmultiscore had the highest area under the receiver operating characteristic curve (AUC) across all data sets for identifying NCD status (AUC >0.74), followed by the PedANAM-CPSlogit , the PedANAM-CPSPCA , and the PedANAM-CPSUWA , respectively. Based on preliminary validation and considering ease of use, the PedANAM-CPSmultiscore and the PedANAM-CPSPCA appear to be best suited as global measures of PedANAM performance.

Blood-based candidate biomarkers of the presence of neuropsychiatric systemic lupus erythematosus in children

ObjectiveTo examine select brain-reactive proteins for their usefulness to serve as blood-based biomarkers in the screening for neurocognitive deficits in childhood-onset systemic lupus erythematosus (cSLE-NCD).MethodsPatients withcSLE (n=40) were studied longitudinally...

Value of Questionnaire‐Based Screening as a Proxy for Neurocognitive Testing in Childhood‐Onset Systemic Lupus Erythematosus

To investigate the utility of questionnaire-based assessment of cognitive function and behavioral/emotional symptoms to screen for neurocognitive dysfunction in childhood-onset systemic lupus erythematosus (cSLE). Forty children with cSLE and 24 healthy controls ages 10–16 years were enrolled. Formal neurocognitive testing (FNCT) was done to determine cognitive performance in 4 key areas that appear to be sensitive to the adverse effects of cSLE: attention, working memory, psychomotor speed, and visuoconstructional ability. Paper and pencil questionnaires sampling cognitive functioning and behavioral/emotional symptoms were also completed: the Subjective Awareness of Neuropsychological Deficits for Children (SAND-C) questionnaire by patients, and the Child Behavioral Checklist and the Behavior Rating Inventory of Executive Function (BRIEF) by parents. Domain and summary scores of the BRIEF and SAND-C correlated modestly with participants' performance on FNCT. Questionnaire ratings did not discriminate subjects with different levels of cognitive ability as measured by FNCT. Contrary to some reports in adults with SLE, self-administered questionnaires of cognitive functioning and parent ratings of executive functioning do not appear well suited to replace FNCT in screening for neurocognitive impairment of children and adolescents with cSLE. However, they may provide information that is complementary to FNCT and therefore play a useful role in clinical followup.

Academic outcomes in childhood-onset systemic lupus erythematosus.

To explore academic outcomes in childhood-onset systemic lupus erythematosus (cSLE) and their relationship to variables such as demographic and socioeconomic status, neurocognitive functioning, behavioral/emotional adjustment, and cSLE disease status. Forty pairs of children diagnosed with cSLE and healthy best friend controls were rated by parents on a standardized scale of school competence. Information about participants' demographic and socioeconomic status was obtained, along with measures of cSLE disease activity and damage. All of the participants received formal neurocognitive testing and were also rated on standardized scales of behavioral/emotional adjustment and executive functioning. Compared to healthy controls, school competence was rated as lower in the cSLE group, although the groups did not differ significantly on indices of cognitive, behavioral, emotional, or executive functioning. School competence ratings were correlated with reading and mathematics achievement test scores in both groups, and with ratings of mental self-regulation in the cSLE group. School competence ratings were correlated with measures of cSLE disease activity and treatment intensity. cSLE is associated with inferior parent-rated academic outcomes compared to those noted in demographically-matched peers, despite similar neurocognitive function. The adverse academic outcomes that distinguish children with cSLE from their demographically-matched peers appear to be mediated by SLE disease activity and treatment.

Brief Screening for Executive Dysfunction in Schizophrenia in a Rehabilitation Hospital

Few tools assessing neurocognitive dysfunction in schizophrenia are able to measure integrated executive functions in the context of the problem-solving demands of a patient's everyday world. The authors evaluated the BRIEF-A (Behavior Rating Inventory of Executive Function-Adult version) Informant Report in 112 inpatients with chronic schizophrenia in a rehabilitation hospital. Factor analysis yielded a three-factor solution (Emotional Regulation, Problem-Solving, Orderliness). The BRIEF-A is psychometrically robust in this population and, in the absence of patient participation, provides an estimate of executive functions in a population that may otherwise be beyond the reach of formal neurocognitive testing.

Silent Cerebral Infarcts in Children With Sickle Cell Anemia

Source: Debaun MR, Sarnaik SA, Rodeghier MJ, et al. Associated risk factors for silent cerebral infarcts in sickle cell anemia: low baseline hemoglobin and relative high systolic blood pressure. Blood. Epub 2011 Nov 17; doi: 10.1182/blood-2011-05-349621Investigators from 29 clinical sites in the United States conducted the Silent Cerebral Infarct Transfusion (SIT) Trial to assess the risk factors for silent cerebral infarcts (SCI). In this cross-sectional study, children with sickle cell anemia (SCA) between the ages of 5 and 15 years with no history of overt stroke or seizures were evaluated with magnetic resonance imaging (MRI) of the brain to screen for SCI. SCI was radiographically defined as MRI signal abnormality measuring at least 3 mm on the T-2 weighted images judged by two of three neuroradiologists on a central review committee. SCI was determined to be truly silent by a central neurology committee’s review of the local neurologist’s examination and the patient’s MRI findings. Clinical history and baseline laboratory values were examined to determine potential risk factors for SCI.Study data were analyzed on 814 participants; the mean age of enrolled children was 9.1 years and 50.7% were male. SCIs were diagnosed in 30.8% (n=251) of study patients. In a multivariable logistic regression analysis, lower baseline hemoglobin concentration (P<.001), higher baseline systolic blood pressure (SBP) (P=.013), and male gender (P=.026) were all associated with a significantly increased risk of a SCI. The odds ratio for SCIs for patients with a hemoglobin less than 7.6 g/dl or SBP greater than 112 mm/Hg were 2.12 and 1.73, respectively. Those individuals who had both a hemoglobin less than 7.6 and SBP greater than 104 had the highest odds of a SCI. In addition, 83% (5 of 6) of patients who carried a diagnosis of hypertension had a higher rate of SCIs than the other study participants (P=.012).The investigators conclude that lower hemoglobin concentration and higher SBP are risk factors for SCI in children with SCA. Further research is needed to determine if interventions targeting these risk factors, such as hydroxyurea, blood transfusion therapy, or antihypertensive medications, can be effective in preventing SCIs.Dr Villella has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Although previous investigators have also identified SCIs in approximately one third of patients with SCA, this study is the first to identify a lower baseline hemoglobin and higher SBP as risk factors for SCI in a large multicenter setting.1–3 SCIs may be silent, but they are not benign. SCIs in children with SCA are associated with an increased risk of overt stroke as well as progressive SCIs.4 Additionally, SCIs are associated with poorer cognitive function and school performance as compared to children with SCA without SCIs as well as sibling controls.5–6 Even more concerning is the finding that cognitive function appears to worsen over time in children with SCA and SCIs.7 As children mature and develop into young adults, they may be silently losing IQ points. Indeed, a recent study showed that asymptomatic adults with SCA have significantly lower performance IQs as compared to matched controls.8These findings have important implications for all pediatric practitioners. Many children do not live in close proximity to a sickle cell center and therefore the responsibility of providing health maintenance for these children can fall onto the shoulders of the primary care giver. The American Academy of Pediatrics recommends that all children with SCA receive a thorough assessment of school attendance and performance with consideration for formal neurocognitive testing.9 MRI of the brain should also be considered for children struggling in school, although this remains controversial since a proven intervention to prevent or limit SCIs is lacking. Neurocognitive testing, however, can be extremely helpful in identifying cognitive deficiencies and helping the family and school to optimize the child’s learning environment.There is strong evidence that SCIs in children with SCA are common and associated with significant morbidity. Studies evaluating potential interventions are desperately needed. By identifying risk factors for SCI in this study, the investigators have uncovered potential therapeutic targets which may respond to interventions to decrease the proportion of sickle cells and thereby increase cerebral blood flow, such as hydroxyurea and chronic blood transfusion therapy, or decrease blood pressure through the use of antihypertensive medications. Thankfully, the investigators of the SIT trial are addressing this as well. Patients enrolled into SIT are randomized to receive chronic blood transfusion therapy or standard observation. Follow-up imaging and neurocognitive testing is then performed to ascertain whether chronic blood transfusion therapy can prevent progression of SCIs and stabilize cognitive function. We anxiously await the results.

Performances on the CogState and standard neuropsychological batteries among HIV patients without dementia.

HIV-associated neurocognitive disorders remain prevalent but challenging to diagnose particularly among non-demented individuals. To determine whether a brief computerized battery correlates with formal neurocognitive testing, we identified 46 HIV-infected persons who had undergone both formal neurocognitive testing and a brief computerized battery. Simple detection tests correlated best with formal neuropsychological testing. By multivariable regression model, 53% of the variance in the composite Global Deficit Score was accounted for by elements from the brief computerized tool (P < 0.01). These data confirm previous correlation data with the computerized battery. Using the five significant parameters from the regression model in a Receiver Operating Characteristic curve, 90% of persons were accurately classified as being cognitively impaired or not. The test battery requires additional evaluation, specifically for identifying persons with mild impairment, a state upon which interventions may be effective.

Is the diagnosis at hand?

In August, 2008, a 49-year-old west African woman presented to us with a 1-month history of blurred vision, dizziness, and falls. A friend had noticed increasing confusion and unusual behaviour, and found her collapsed at home. She was diagnosed with HIV-1 infection in August, 2007, when the patient presented with fungal nail infection. At diagnosis, HIV VL was 1 967 745 copies per mL with a CD4-cell count of 22 per μL (3·8%) and Pneumocystis jirovecii prophylaxis and combination antiretroviral therapy (cART) were started. Within 12 weeks, VL became undetectable (<40 copies per mL) with a CD4-cell count of 585 per μL (14·6%). During initial clinic attendances, she was quiet and slightly withdrawn, which we attributed to her personality. In April, 2008, she developed HIV viraemia attributed to poor cART concordance. Genotypically confi rmed drug resistance prompted cART switch. On examination, she was apyrexial and normotensive. She was disoriented in time, person, and place. She showed subcortical slowing, perseveration, and marked working memory impairment without focal neurological defi cit. Fundoscopy was normal. Investigations showed: HIV VL 12 062 copies per mL; CD4-cell count 502 per μL (16·1%); normal C-reactive protein concentration, white cell count, and lactate dehydrogenase. Treponema serology and cryptococcal antigen were negative. Brain MRI (fi gure A) showed extensive, multifocal signal abnormalities. Crowding of the cerebellar tonsils at the foramen magnum precluded lumbar puncture. The diff erential diagnoses were: viral encephalitis; acute disseminated encephalomyelitis; diff usely infi ltrative neoplasia; or immune reconstitution infl ammatory syndrome (IRIS) of pre-existing progressive multifocal leucoencephalopathy, toxo plasmosis, or HIV-associated neurocognitive disorder (HAND). She was treated empirically for herpes encephalitis and cerebral toxoplasmosis; montelukast was administered for possible IRIS. cART was continued. To avoid masking of lymphoma, steroids were withheld. On day 10, she was less disoriented, but repeat MRI showed progression of disease. A brain biopsy sample taken on day 24 showed perivascular large CD20-positive B cells (fi gure B) with 25% proliferation fraction, but Epstein-Barr virus (EBV) encoded RNA negative on in-situ hybridisation. There was also marked peri vascular and parenchymal T-cell infi ltration (pre dominantly CD8-positive) and microgliosis (CD68-positive). Tissue immunocytochemistry was negative for all viruses including EBV and HIVp24. She con tinued to improve without steroids, and repeat MRI (day 34) showed improvement (fi gure C). Given the clinical evolution and histopathology, a diagnosis of an IRIS driving HAND was made instead of B-cell lymphoma. She was discharged attaining full independence. When seen in November, 2009, she was fully interactive and spontaneously initiated appro priate conversation. HAND is a prevalent cause of morbidity in patients with HIV infection. Patients present with subcortical impairment manifested by slowed motor speed and decreased atten tion. Diagnosis is by exclusion and risk factors include low nadir CD4-cell count, apolipoprotein E4 carriage, and age. IRIS occurs in about a third of patients after cART initiation and probably represents immune hyperactivation towards foreign or self antigen. Diagnostic criteria include: worsening infl ammatory symptoms unexplained by new or previous infection, disease, or drug toxicity; temporal relation with cART; and ≥1 log fall in HIV VL. IRIS is asso ciated with severe immunosuppres sion. Histopatho logical studies of brain-IRIS emphasise CD8-positive T-cell lympho cytosis (CD4expressing T cells absent/rare) and CD68-positive microgliosis. Despite limited evidence, cortico steroids, non-steroidal anti-infl ammatory drugs, and monte lukast have been tried. In retrospect, our patient prob ably had features of HAND at HIV diagnosis. cART triggered IRIS, un masking HAND and precipitating cART non-con cordance. We propose that patients presenting with ad vanced HIV infection at diagnosis have formal neuro cognitive testing (±brain MRI) to assess for subclinical HAND.

Impairment of Cognitive Function Reported by Patients Suffering from Carcinoid Syndrome

Carcinoid syndrome (CS) is characterized by symptoms of diarrhea, flushing, bronchospasm, and valvular heart disease. It has been our impression that patients with CS also exhibit features of cognitive impairment. The purpose of this pilot study was to evaluate if symptoms of cognitive impairment were reported by patients with CS. Patients with proven CS completed a 38-question multiple-ability self-report questionnaire (MASQ) to assess symptoms in five cognitive domains: language skills, attention/concentration (A/C), visual-perceptual function, visual memory, and verbal memory. Patients subsequently underwent neurocognitive assessment using a battery of six standardized tests. Results of the MASQ and the cognitive test were compared to published results for healthy individuals. Twenty-one patients with CS were studied. MASQ symptom scores were higher than published norms in all five cognitive domains. Patients reported greatest difficulty with verbal memory (mean +/- SD = 2.74 +/- 0.5), followed by A/C (2.41 +/- 0.65), language (2.31 +/- 0.55), visual memory (2.30 +/- 0.65), and visual-perceptual function (2.17 +/- 0.59). In contrast, neurocognitive tests for verbal memory immediate recall, visual memory, language, and executive function were within the normal range. CS patients, however, scored lower than expected in tests of verbal memory delayed recall and visual-perceptual function. Patients with CS report high levels of symptoms of impairment in all cognitive domains; however, on formal neurocognitive testing, patients scored lower than expected only in tests of verbal memory delayed recall and visual-perceptual function. These findings appear to confirm our clinical impression that cognitive impairment may be an additional feature of CS. Further studies are needed to confirm and elucidate the cause of this cognitive impairment.

Use of a Computer Based Neurocognitive Software Program in Asymptomatic Neurologically Intact Adults with Sickle Cell Disease.

Abstract 1524Poster Board I-547Incidence of stroke in sickle cell disease (SCD) is approximately 11% under the age of 20, and 24% of patients have had a stroke by age 45. In children with SCD, 24% with no history of stroke are found to have neurocognitive deficits and silent infarcts. At least 20% of adults with SCD and no history of stroke also have an abnormal MRI, and up to 63% have either an abnormal MRI or neurocognitive dysfunction. However, formal neurocognitive testing can be difficult to obtain, especially in adults, as it is costly, time-consuming, and requires specialized expertise. An office-based screening tool would therefore be beneficial in this population. CNS Vital Signs™ (CNS-VS) is a computer-based software program designed to evaluate neurocognitive deficits based on traditional neuropsychological testing. The test reports an overall score referred to as the neurocognitive index (NCI), as well as scores based on seven domains: verbal memory, visual memory, finger tapping, symbol digit coding, Stroop test, shifting attention, and continuous performance test. The domains reflect areas of memory, psychomotor speed, reaction time, cognitive flexibility and complex attention. We conducted a pilot study in neurologically intact adults with SCD (HbSS or Sβ0 thalassemia) using CNS-VS as an office-based computer-administered tool for possible screening of patients with SCD for subtle neurocognitive impairment. SCD subjects were recruited from the Duke adult sickle cell clinic. Age, sex, and race matched controls were recruited by word of mouth. Each subject also underwent screening tests for severe depression and cognitive limitations using the mini mental status exam (MMSE) and the depression dejection score (DDS) from the Profile of Moods Survey. Patients also completed a perceived stress survey. Subjects with SCD were excluded if they had a recent hospitalization for pain within three weeks prior to enrollment, history of stroke or TIA, DDS score >40, or MMSE score <20. Controls were excluded with the same DDS/MMSE scores, history of stroke or TIA, or history of sickle trait. Thirty subjects were enrolled in this pilot study, 24 patients with SCD and 6 controls. Seventeen patients were male, 13 female, and 23 of 24 patients had HbSS. Twenty-seven subjects were right hand dominant and 3 left hand dominant, and all subjects were of African-American descent. Mean age for the controls was 43.54 yrs ± 4.24, and for the SCD group 34 yrs ± 2. The mean years of education (including primary) was 15 years for both SCD patients and controls. Mean baseline Hb and Hct values among SCD patients were 8.11 ± 0.29 g/dL and 23.97 ± 0.92 and 13.48 ±1.15 g/dL and 40.60 ± 3.11 for controls. Scores on the MMSE, DDS, and perceived stress survey were not statistically different between the controls and SCD patients. Using CNS-VS, no difference was found in scores in areas of memory, reaction time, cognitive flexibility, and complex attention between SCD patients and controls. However, psychomotor standard and percentile scores were statistically different (p=0.02) between SCD patients and controls. The symbol digit coding domain also showed statistical significance (p=0.001) between the groups for both standard and percentile scores. In SCD patients, Hb was significantly correlated with NCI standard and percentile scores (p < 0.0001). Reticulocyte count, lactate dehydrogenase level, total bilirubin, and creatinine level did not show any correlation with NCI scores. Symbol digit coding appeared to be the most sensitive of the tests, although psychomotor performance also differed significantly compared to controls. Decreased cognitive and psychomotor performance can reflect either localized or diffuse brain damage. The impact of medications, mild depression, and pain may also explain differences between the groups. Therefore, we believe that CNS Vital Signs™ is a promising screening tool for subtle neurocognitive deficits in asymptomatic neurologically intact adults with SCD. Our findings need to be validated in a larger cohort, along with correlation of scores with MRI results and expansion of testing to include patients with other variants of SCD. DisclosuresNo relevant conflicts of interest to declare.

Neurocognitive function in patients with small cell lung cancer

The use of prophylactic cranial irradiation (PCI) in patients with small cell lung cancer (SCLC) has been tempered by fears of detrimental effects on cognitive function. Neuropsychologic testing was prospectively conducted before and after PCI to evaluate its effects on cognitive function in patients with SCLC. Ninety-six patients who completely or partially responded to initial therapy underwent formal neurocognitive testing before PCI. Three patients who had central nervous system metastasis were excluded. Of the remaining patients, 69 received PCI (mean dose, 25 grays [Gy] in 10 fractions). Repeat testing was performed on 37 patients (median follow-up, 23 months; range, 6-120 months). Baseline impairment was defined as > or =1.5 standard deviations below the normative mean. Before undergoing PCI, 47% of patients had evidence of impaired cognitive function. After PCI, univariate analysis revealed significant transient declines in executive function (pre-PCI mean, 15.6 +/- 11.5; post-PCI, 27.1 +/- 17.6 [P = .008]) and language (pre-PCI mean, 33.8 +/- 9.9; post-PCI, 31.0 +/- 9.0 [P = .049]) at early timepoints. Controlling for noncentral nervous system disease progression the deficit in executive function was no longer significant. Moreover, these deficits were not sustained, and significant improvements in language and motor coordination were recorded. On multivariate analysis, no significant differences before and after PCI were found. Neurocognitive testing demonstrated that a substantial portion of patients with SCLC had impaired brain functioning at baseline. Persistent declines in cognitive function were not observed after cranial irradiation. These data do not favor the omission of PCI on the basis of fears of neurotoxic effects.

Invited commentary

Invited commentary