Literature review and protocol for a prospective multicentre cohort study on multimodal prediction of seizure recurrence after unprovoked first seizure.

INTRODUCTION: Epilepsy is a common neurological disorder characterised by recurrent seizures. Almost half of patients who have an unprovoked first seizure (UFS) have additional seizures and develop epilepsy. No current predictive models exist to determine who has a higher risk of recurrence to guide treatment. Emerging evidence suggests alterations in cognition, mood and brain connectivity exist in the population with UFS. Baseline evaluations of these factors following a UFS will enable the development of the first multimodal biomarker-based predictive model of seizure recurrence in adults with UFS. METHODS AND ANALYSIS: 200 patients and 75 matched healthy controls (aged 18-65) from the Kingston and Halifax First Seizure Clinics will undergo neuropsychological assessments, structural and functional MRI, and electroencephalography. Seizure recurrence will be assessed prospectively. Regular follow-ups will occur at 3, 6, 9 and 12 months to monitor recurrence. Comparisons will be made between patients with UFS and healthy control groups, as well as between patients with and without seizure recurrence at follow-up. A multimodal machine-learning model will be trained to predict seizure recurrence at 12 months. ETHICS AND DISSEMINATION: This study was approved by the Health Sciences and Affiliated Teaching Hospitals Research Ethics Board at Queen's University (DMED-2681-22) and the Nova Scotia Research Ethics Board (1028519). It is supported by the Canadian Institutes of Health Research (PJT-183906). Findings will be presented at national and international conferences, published in peer-reviewed journals and presented to the public via patient support organisation newsletters and talks. TRIAL REGISTRATION NUMBER: NCT05724719.

Cognitive dysfunction at epilepsy onset as a marker for seizure recurrence.

BACKGROUND: Cognitive dysfunction has been correlated with seizure control in chronic epilepsy and in newly diagnosed epilepsy, which potentially makes it a good marker for predicting disease course and seizure control. However, there is a lack of prospective studies examining the role of cognitive dysfunction in predicting seizure recurrence at the earliest stages of the disease, such as following the first unprovoked seizure (UFS) or new onset epilepsy (NOE). METHODS: Thirty three adult participants (FS=18, NOE=15) from the Halifax First Seizure Clinic (HFSC) completed a cognitive screening assessment at baseline (typically 3 months following diagnosis); seizure-recurrence was evaluated one year after the initial HFSC visit. RESULTS: Cognitive impairment, defined as at least one z-score in the impaired range (≤-1.5) relative to published test norms, was documented in 76% of the patients with seizure recurrence at follow-up and in 55% without seizure recurrence. Speed/executive functions and Memory were the most frequently affected domains, with impaired performance noted in 35% and 29% of the entire sample, respectively. Although the seizure recurrence vs. non-recurrence groups did not differ significantly on likelihood of impairment in any specific cognitive domains, a regression model of seizure recurrence that included years of education, baseline mood and anxiety scores, normal vs. abnormal baseline MRI, and impaired (vs. unimpaired) function in six cognitive domains was significant overall (Χ2 (10) = 24.04, p =.007*, R2N =.77). The regression model was no longer significant with the cognitive variables removed. CONCLUSIONS: Subtle cognitive dysfunction, especially in the domains of executive functions and memory are prevalent in individuals at the earliest stages of epilepsy. In addition to abnormal MRI and EEG findings at baseline, which are far less prevalent in FS and NOE, cognitive factors show promise in helping predict seizure recurrence in these populations.

Resting state functional connectivity in SLE patients and association with cognitive impairment and blood-brain barrier permeability.

OBJECTIVE: Extensive blood-brain barrier (BBB) leakage has been linked to cognitive impairment in SLE. This study aimed to examine the associations of brain functional connectivity (FC) with cognitive impairment and BBB dysfunction among patients with SLE. METHODS: Cognitive function was assessed by neuropsychological testing (n = 77). Resting-state FC (rsFC) between brain regions, measured by functional MRI (n = 78), assessed coordinated neural activation in 131 regions across five canonical brain networks. BBB permeability was measured by dynamic contrast-enhanced MRI (n = 61). Differences in rsFC were compared between SLE patients with cognitive impairment (SLE-CI) and those with normal cognition (SLE-NC), between SLE patients with and without extensive BBB leakage, and with healthy controls. RESULTS: A whole-brain rsFC comparison found significant differences in intra-network and inter-network FC in SLE-CI vs SLE-NC patients. The affected connections showed a reduced negative rsFC in SLE-CI compared with SLE-NC and healthy controls. Similarly, a reduced number of brain-wide connections was found in SLE-CI patients compared with SLE-NC (P = 0.030) and healthy controls (P = 0.006). Specific brain regions had a lower total number of brain-wide connections in association with extensive BBB leakage (P = 0.011). Causal mediation analysis revealed that 64% of the association between BBB leakage and cognitive impairment in SLE patients was mediated by alterations in FC. CONCLUSION: SLE patients with cognitive impairment had abnormalities in brain rsFC which accounted for most of the association between extensive BBB leakage and cognitive impairment.

Role of autoantibodies and blood-brain barrier leakage in cognitive impairment in systemic lupus erythematosus.

OBJECTIVE: Cognitive impairment is common in patients with SLE but the cause is unknown. The current cross-sectional study examined the association between select SLE-related autoantibodies, other serological biomarkers and extensive blood-brain barrier (BBB) leakage in patients with SLE with and without cognitive impairment. In addition, we determined whether the relationship between SLE autoantibodies, other biomarkers and cognitive impairment differed depending on the presence or absence of concurrent extensive BBB leakage. METHODS: Consecutive patients with SLE, recruited from a single academic medical centre, underwent formal neuropsychological testing for assessment of cognitive function. On the same day, BBB permeability was determined using dynamic contrast-enhanced MRI scanning. SLE autoantibodies and other serological biomarkers were measured. Regression modelling was used to determine the association between cognitive impairment, extensive BBB leakage and autoantibodies/biomarkers. RESULTS: There were 102 patients with SLE; 90% were female and 88% were Caucasian, with a mean±SD age of 48.9±13.8 years. The mean±SD SLE disease duration was 14.8±11.0 years. Impairment in one or more cognitive tests was present in 47 of 101 (47%) patients and included deficits in information processing speed (9%), attention span (21%), new learning (8%), delayed recall (15%) and executive abilities (21%). Extensive BBB leakage was present in 20 of 79 (25%) patients and was associated with cognitive impairment (15 of 20 (75%) vs 24 of 59 (41%); p=0.01) and shorter disease duration (median (IQR): 7 (8-24 years) vs 15 (2-16 years); p=0.02). No serological parameters were associated with extensive BBB leakage and there was no statistically significant association between cognitive impairment and circulating autoantibodies even after adjusting for BBB leakage. CONCLUSIONS: Extensive BBB leakage alone was associated with cognitive impairment. These findings suggest that BBB leakage is an important contributor to cognitive impairment, regardless of circulating SLE-related autoantibodies.

Blood-brain barrier leakage in systemic lupus erythematosus is associated with gray matter loss and cognitive impairment.

OBJECTIVES: To examine the association between blood-brain barrier (BBB) integrity, brain volume and cognitive dysfunction in adult patients with systemic lupus erythematosus (SLE). METHODS: A total of 65 ambulatory patients with SLE and 9 healthy controls underwent dynamic contrast-enhanced MRI scanning, for quantitative assessment of BBB permeability. Volumetric data were extracted using the VolBrain pipeline. Global cognitive function was evaluated using a screening battery consisting of tasks falling into five broad cognitive domains, and was compared between patients with normal versus extensive BBB leakage. RESULTS: Patients with SLE had significantly higher levels of BBB leakage compared with controls (p=0.04). Extensive BBB leakage (affecting over >9% of brain volume) was identified only in patients with SLE (16/65; 24.6%), who also had smaller right and left cerebral grey matter volumes compared with controls (p=0.04). Extensive BBB leakage was associated with lower global cognitive scores (p=0.02), and with the presence of impairment on one or more cognitive tasks (p=0.01). CONCLUSION: Our findings provide evidence for a link between extensive BBB leakage and changes in both brain structure and cognitive function in patients with SLE. Future studies should investigate the mechanisms underlying BBB-mediated cognitive impairment, validate the diagnostic utility of BBB imaging, and determine the potential of targeting the BBB as a therapeutic strategy in patients with SLE.

A prospective pilot study of cognitive impairment and mood in adults with first seizure, new-onset epilepsy, and newly diagnosed epilepsy at time of initial seizure presentation.

INTRODUCTION: This is an observational prospective cohort study of cognition and mood in individuals presenting to a tertiary neurology clinic with first unprovoked seizure (FS), new-onset epilepsy (NOE), and newly diagnosed epilepsy (NDE). Our aim was to understand the cognitive profile of these three diagnostic groups at the time of first presentation. Follow-up was obtained to evaluate any association between cognition at presentation and subsequent clinical course. METHODS: Forty-three participants (age: 18-60 years) were recruited with FS (n = 17), NOE (n = 16), and NDE (n = 10). Clinical details, neuropsychological testing, and screening for mood disorders were obtained at the time of presentation to clinic. Seizure recurrence was evaluated at clinic follow-up at least 6-12 months following the initial presentation. RESULTS: In all groups, general intelligence (intelligence quotient [IQ]) was consistent with population norms, but more than half of participants (55.8%) were impaired in at least one cognitive domain. The most commonly impaired domain in all diagnostic groups was visuospatial and visuoconstruction suggesting that it may be a sensitive marker of early cognitive impairment. Those with epilepsy (NOE and NDE) at initial presentation were more likely to be impaired than those with FS, particularly on tests of attention, working memory, and processing speed. Seven participants with FS converted to NOE (FSNOE) at follow-up. They were more likely to be impaired on tests of memory than those with FS who did not convert to NOE. On mood screening, 21% of participants scored moderate or severe for depressive symptoms, and 25.6% of participants scored moderate or severe for anxiety symptoms. DISCUSSION: Cognitive impairment and mood changes are common at first seizure presentation and mirror the pattern seen in chronic epilepsy. This cooccurrence of symptomatology at disease onset prior to prolonged antiepilepsy drug exposure suggests a shared underlying disease mechanism and carries important clinical implications for effective diagnosis and management of epilepsy. Furthermore, early cognitive testing may become a clinical biomarker and enable the prediction of an individual's clinical course.

Divergence between functional magnetic resonance imaging and clinical indicators of language dominance in preoperative language mapping.

Accurate determination of hemispheric language dominance prior to epilepsy surgery is critically important to minimize cognitive morbidity. Functional MRI (fMRI) is a noninvasive method that is highly concordant with other clinical indicators of language laterality, and is now commonly used to confirm language dominance. However, there is also a high frequency of divergence between fMRI findings and other clinical indices that complicate determination of dominance and surgical decision-making in individual patients. Despite this, divergent cases are rarely published or discussed. This article provides three illustrative examples to demonstrate common scenarios where fMRI may produce conflicting or otherwise difficult-to-interpret findings. We will also discuss potential reasons for divergence and propose a flow-chart to aid clinical decision making in such situations.

Visual memory and psychotic symptoms in youth.

BACKGROUND: Psychotic symptoms are common during childhood and adolescence and may indicate transdiagnostic risk of future psychiatric disorders. Lower visual memory ability has been suggested as a potential indicator of future risk of mental illness. The relationship between visual memory and clinician-confirmed definite psychotic symptoms in youth has not yet been explored. METHODS: We examined visual memory and psychotic symptoms among 205 participants aged 7-27 years in a cohort enriched for parental mood and psychotic disorders. We assessed visual memory using the Rey Complex Figure Test (RCFT) and psychotic symptoms using validated semi-structured interview measures. We tested the relationship between visual memory and psychotic symptoms using mixed-effects logistic regression. RESULTS: After accounting for age, sex, and family clustering, we found that psychotic symptoms were significantly associated with lower visual memory (OR = 1.80, 95% CI 1.06-3.06, p = 0.030). This result was unchanged after accounting for general cognitive ability. CONCLUSION: Lower visual memory performance is associated with psychotic symptoms among youth, regardless of general cognitive ability. This finding may inform future targeted early interventions.

Visual memory in offspring of parents with mental illness.

Severe mental illness (SMI) refers to impairing and frequently chronic disorders that are difficult to treat. Lower cognitive performance early in life may be a manifestation of risk for SMI. Visual memory has been highlighted as a potential cognitive predictor of future risk of developing bipolar disorder and schizophrenia. We examined visual memory in 214 participants (mean age = 12.62, SD = 4.49) using the Rey Complex Figure Test (RCFT). Our sample included 37 offspring with no parental history of mental illness, 103 offspring with parental history of non-severe mental illness (NSMI), and 74 offspring with parental history of SMI. We tested the effects of family history of mental illness on visual memory using mixed-effects linear regression. After accounting for age, sex, and family clustering, we found that as severity of parental mental illness increases, offspring visual memory performance decreases significantly (b = -3.58, 95% CI -6.79 to -0.37, p = 0.029). We found that severity of parental mental illness predicts visual memory ability. This finding may help identify youth most at risk of developing mental illness and thus inform future interventions.

Visual and Auditory fMRI Paradigms for Presurgical Language Mapping: Convergent Validity and Relationship to Individual Variables.

Functional MRI (fMRI) has emerged as a safe alternative to invasive procedures for determining hemispheric language dominance prior to neurosurgery. Despite this, there are currently no standardized fMRI protocols that have been explored in healthy controls to determine the influence of individual patient variables on the results, which poses challenges in clinical interpretation of ambiguous findings in patient populations. In addition, most fMRI protocols are not suitable for individuals with visual or intellectual disabilities (IQ<70). In the current study, 61 healthy adults (ages: 18-74 years) completed two fMRI paradigms for language mapping. One paradigm used visually based stimuli and has shown good face validity to date in our center. The second paradigm used auditory stimuli presented at slowed speed and was designed for individuals with visual or cognitive dysfunction but has not yet been used clinically. The paradigms demonstrated 97% agreement in classifying individuals as left-hemisphere, right-hemisphere, and bilaterally dominant. Cases that were classified differently showed bilateral dominance in response to either paradigm. Dominance classification rates for right- and left-handed individuals were largely in keeping with published data. Within the left-handed group, IQ and education were positively correlated with laterality indices generated by both paradigms (r values range: 0.44-0.95, p<0.01), suggesting that individuals with higher IQ and formal education were more likely to be classified as left-hemisphere dominant in the current sample. This study will help improve clinical interpretation of language fMRI maps by identifying factors that might impact results (like IQ). It also offers an alternative paradigm to make this procedure more accessible to a broader range of patients. Future studies will replicate results with a sample of patients with epilepsy across a broad range of intellectual abilities.

Attentional dysfunction and recovery in concussion: effects on the P300m and contingent magnetic variation.

PRIMARY OBJECTIVE: To examine the effect of concussion on indices of attention using magnetoencephalography. METHODS AND PROCEDURES: Thirteen patients were recruited from the emergency department and scanned within 3-6 days of injury. Five returned for follow-up scans one and three months post-injury. Thirteen healthy controls also completed testing. During MEG acquisition, participants performed the Attention Network Test (ANT). Cognitive evoked responses to this task include a cue-evoked P300m, a contingent magnetic variation (CMV) and a target-evoked P300m. The Rivermead Postconcussion Symptom Questionnaire and Sport Concussion Assessment Tool (SCAT3) were administered in all sessions. RESULTS: Patients suffering from concussion had slower response times and benefitted more from spatial cues than did controls. Global activation for all three evoked responses was lower for patients than controls. In a small sample of patients who returned for follow-up, the CMV and target P300m improved with recovery. CONCLUSIONS: MEG-evoked responses to the ANT reveal neurophysiological evidence of attentional dysfunction within days of injury. A pattern of improvement was also observed over the course of three months for the P300m, while behavioural performance did not change significantly. Further development of this method may yield a useful adjunct to neurological examination for concussion diagnosis and monitoring.

Language lateralization of a bilingual person with epilepsy using a combination of fMRI and neuropsychological assessment findings.

This report describes the findings of language functional magnetic resonance imaging (fMRI) in a left-handed Urdu and English speaker with right hemisphere-originating epilepsy and unclear language dominance. fMRI is a reliable method for determining hemispheric language dominance in presurgical planning. However, the effects of bilingualism on language activation depend on many factors including age of acquisition and proficiency in the tested language, and morphological properties of the language itself. This case demonstrates that completing fMRI in both spoken languages and interpreting the results within the context of a neuropsychological assessment are essential in arriving at accurate conclusions about language distribution in bilingual patients.

Intra-individual variability in information processing speed reflects white matter microstructure in multiple sclerosis.

Slowed information processing speed is commonly reported in persons with multiple sclerosis (MS), and is typically investigated using clinical neuropsychological tests, which provide sensitive indices of mean-level information processing speed. However, recent studies have demonstrated that within-person variability or intra-individual variability (IIV) in information processing speed may be a more sensitive indicator of neurologic status than mean-level performance on clinical tests. We evaluated the neural basis of increased IIV in mildly affected relapsing-remitting MS patients by characterizing the relation between IIV (controlling for mean-level performance) and white matter integrity using diffusion tensor imaging (DTI). Twenty women with relapsing-remitting MS and 20 matched control participants completed the Computerized Test of Information Processing (CTIP), from which both mean response time and IIV were calculated. Other clinical measures of information processing speed were also collected. Relations between IIV on the CTIP and DTI metrics of white matter microstructure were evaluated using tract-based spatial statistics. We observed slower and more variable responses on the CTIP in MS patients relative to controls. Significant relations between white matter microstructure and IIV were observed for MS patients. Increased IIV was associated with reduced integrity in more white matter tracts than was slowed information processing speed as measured by either mean CTIP response time or other neuropsychological test scores. Thus, despite the common use of mean-level performance as an index of cognitive dysfunction in MS, IIV may be more sensitive to the overall burden of white matter disease at the microstructural level. Furthermore, our study highlights the potential value of considering within-person fluctuations, in addition to mean-level performance, for uncovering brain-behavior relationships in neurologic disorders with widespread white matter pathology.

Indices of cognitive dysfunction in relapsing-remitting multiple sclerosis: intra-individual variability, processing speed, and attention network efficiency.

Impairments in attention and information processing speed are common in multiple sclerosis (MS) and may contribute to impairments of other cognitive abilities. This study examined attentional efficiency, information processing speed and intra-individual variability in response speed using the Attention Network Test-Interactions (ANT-I) in mildy-affected patients with MS. Thirty-one patients with relapsing-remitting MS and 30 age, sex, and education-matched controls completed the ANT-I, as well as the Paced Auditory Serial Attention Test (PASAT), as a standard clinical measure of information processing efficiency. As expected, patients with MS were slower in reaction time performance on the ANT-I and had poorer performance on the PASAT compared to controls. Patients with MS also demonstrated poorer efficiency in their executive control of attention on the ANT-I, suggesting difficulties with top-down allocation of attention. In addition, the MS group demonstrated greater intra-individual variability in the responses to the ANT-I even when their slower overall response time and other factors such as practice were accounted for. Intra-individual variability was found to best predict group membership compared to PASAT scores and other ANT-I scores. These results suggest that intra-individual variability may provide sensitive, unique and important information regarding cognitive functioning in early MS.

Longitudinal neuropsychological findings in amyloid beta-related angiitis (AßRA): a case report.

Amyloid ß-related angiitis (AßRA) is a clinicopathological diagnosis of primary central nervous system angiitis theoretically triggered by vascular deposition of amyloid ß peptide. Deposits of Aß are associated with degeneration of the vasculature, thereby increasing risks of a stroke and/or cognitive impairment. Despite this, no prior studies have presented a detailed neuropsychological profile associated with AßRA. We present longitudinal neuropsychological findings for the case of a 58-year-old man with biopsy-diagnosed AßRA. Neuropsychological test results and clinical presentation demonstrated a mild to moderate dysexecutive syndrome implicating dorsolateral frontal and orbitofrontal-subcortical systems involvement. Despite prior reports of cognitive decline following a diagnosis of AßRA, cognitive functioning remained relatively stable over a 15-month period after immunosuppressive treatment. For the most part, objective measures did not demonstrate a measurable change in cognitive functioning, except for a mild decline in memory. There were subjective reports of improvement in cognitive and adaptive functioning from the patient and his spouse over this time period. The clinical significance of these results is discussed in the context of theories of executive dysfunction, and with reference to previously-published cases of AßRA.

Screening for cognitive impairment in systemic lupus erythematosus.

OBJECTIVE: We examined the association between responses on a screening questionnaire and objective performance on a computer-administered test of cognitive abilities in systemic lupus erythematosus (SLE). METHODS: The Cognitive Symptom Inventory (CSI) and Hospital Anxiety and Depression Scales (HADS) questionnaires were compared in patients with SLE or rheumatoid arthritis (RA). The Automated Neuropsychological Assessment Metrics (ANAM) was used to evaluate cognitive performance in patients with SLE. Efficiency of performance was measured by "throughput" (number of correct responses per minute) and "inverse efficiency" (response speed/proportion of correct responses). Linear regression was applied to log-transformed CSI scores to examine their associations with ANAM scores and other factors. RESULTS: Patients with SLE (n = 68) or RA (n = 33) were similar in age, sex, ethnicity, and education status (p > 0.05). Patients with SLE had higher total CSI scores (33.6 ± 10.5 vs 29.4 ± 6.8, respectively; p = 0.041) and attention/concentration subscale CSI scores (15.7 ± 5.3 vs 13.3 ± 3.4; p = 0.016) compared to patients with RA. In patients with SLE there was a positive association between CSI scores and neuropsychiatric (NP) events at the time of testing (p = 0.0006), HADS anxiety (p < 0.0001), and depression (p < 0.0001) scores. After adjustment for age, education, disease duration, and NP events at the time of testing, there was no significant association (p > 0.05) between ANAM and CSI scores in patients with SLE. The results were similar using either "throughput" or "inverse efficiency" or the number of impaired ANAM subscales after adjustment for simple reaction time. CONCLUSION: The CSI self-report questionnaire of cognitive symptoms does not reliably screen for efficiency of cognitive processing in patients with SLE. Rather, cognitive complaints reported in the CSI are influenced by the presence of anxiety and depression.

Information processing and magnetic resonance imaging indices of brain pathology in multiple sclerosis.

Accumulation of central nervous system (CNS) pathology affects cognitive processing speed and efficiency and is thought to underlie attentional and executive deficits in multiple sclerosis (MS). Most clinical neuropsychological tests are multifactorial and are limited in their sensitivity to specific cognitive processes. This may, in part, account for the low to moderate correlations between clinical test results and magnetic resonance imaging (MRI) indices of brain pathology. We compared the ability of a clinical and an experimental test of cognitive processing speed to differentiate domain-specific cognitive changes in MS, and examined relations between test performance and MRI measures of brain pathology. Twelve MS patients and 12 controls completed the Paced Auditory Serial Addition Test (PASAT) and the Attention Networks Test-Interactions (ANT-I), a computerized response latency task. Subjects also had MRI scans that included T1, T2, and fluid-attenuated inversion recovery (FLAIR) sequences that provided global and localized volumetric measures. Patients made more errors on the PASAT and were slower on the ANT-I. The ANT-I also revealed specific deficits in response inhibition. In addition, ANT-I performance was associated with changes in a number of MRI measures, which was not the case for the PASAT. Reaction time paradigms that manipulate within-task demands on distinct cognitive functions may provide meaningful markers of brain disease burden in MS.

Impact of acute sleep restriction on cortisol and leptin levels in young women.

Sleep restriction alters hormone patterns and appetite in men, but less is known about effects on women. We assessed effects of overnight sleep restriction on cortisol and leptin levels and on appetite in young women. Participants' baseline sleep duration and eating habits were monitored for a week before the study. Salivary cortisol and leptin were sampled from fifteen healthy women (aged 18-25) during two consecutive days: first after a 10h overnight sleep opportunity (Baseline day) and then after a night including only 3h sleep (Post sleep-restriction day). Participants also completed appetite questionnaires on both days. Sleep restriction significantly reduced morning cortisol levels (p=0.02), elevated morning leptin levels (p=0.04), elevated afternoon/evening cortisol area under the curve values (p=0.008), and slowed the decline in cortisol concentration during the day (p=0.04). Hunger and craving scores did not differ significantly between days. A single night of restricted sleep affected cortisol rhythms and morning leptin levels in young women.

Assessment of cognitive function in systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis by computerized neuropsychological tests.

OBJECTIVE: Computerized neuropsychological testing may facilitate screening for cognitive impairment in systemic lupus erythematosus (SLE). This study was undertaken to compare patients with SLE, patients with rheumatoid arthritis (RA), and patients with multiple sclerosis (MS) with healthy controls using the Automated Neuropsychological Assessment Metrics (ANAM). METHODS: Patients with SLE (n = 68), RA (n = 33), and MS (n = 20) were compared with healthy controls (n = 29). Efficiency of cognitive performance on 8 ANAM subtests was examined using throughput (TP), inverse efficiency (IE), and adjusted IE scores. The latter is more sensitive to higher cognitive functions because it adjusts for the impact of simple reaction time on performance. The results were analyzed using O'Brien's generalized least squares test. RESULTS: Control subjects were the most efficient in cognitive performance. MS patients were least efficient overall (as assessed by TP and IE scores) and were less efficient than both SLE patients (P = 0.01) and RA patients (P < 0.01), who did not differ. Adjusted IE scores were similar between SLE patients, RA patients, and controls, reflecting the impact of simple reaction time on cognitive performance. Thus, 50% of SLE patients, 61% of RA patients, and 75% of MS patients had impaired performance on >or=1 ANAM subtest. Only 9% of RA patients and 11% of SLE patients had impaired performance on >or=4 subtests, whereas this was true for 20% of MS patients. CONCLUSION: ANAM is sensitive to cognitive impairment. While such computerized testing may be a valuable screening tool, our results emphasize the lack of specificity of slowed performance as a reliable indicator of impairment of higher cognitive function in SLE patients.