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Although CSI and GS are established prediction metrics in meteorological literature,3-6, 8, 10-12 few texts have translated them into medical literature.9, 13 We provide here the first translation of CSI and GS into epilepsy literature. We suggest CSI may be an appropriate measure to complement Sens, Spec, PPV and NPV, particularly as it allows combined interpretation of PPV and Sens whilst also avoiding the inflation of NPV and Spec when there are many TNs. GS may be a better metric when there are fewer TN and more CH. Based on the current findings, we suggest a CSI of ≥0.8 would be a reasonable threshold score for achieving diagnostic accuracy. Optimal diagnostic thresholds for GS remain to be elucidated.

Free-Cog is a recently described, hybrid screening instrument incorporating tests of cognitive and executive function. In this study, Free-Cog was reformulated as separate tests of cognitive function and executive function to examine whether this might improve screening accuracy for cognitive impairment (dementia and mild cognitive impairment) compared to the standard, unitary Free-Cog. The two separate tests, designated “Free-Cog-Cog” and “Free-Cog-Exec,” were either combined using the Boolean logical “AND” and “OR” operators (serial and parallel combination) or used to construct a stepwise decision tree. Serial combination improved specificity and positive predictive value whereas parallel combination improved sensitivity, findings typically observed when applying these operators. Stepwise application identified groups with high and low probability of cognitive impairment but failed to adequately differentiate those in the intermediate uncertain diagnosis group. Although the dataset used was relatively small, the findings of this study suggest little benefit for reformulations of Free-Cog compared to the standard, unitary instrument.

Many metrics exist for the evaluation of binary classifiers, all with their particular advantages and shortcomings. Recently, an “Efficiency Index” (EI) for the evaluation of classifiers has been proposed, based on the consistency (or matching) and contradiction (or mismatching) of outcomes. This metric and its confidence intervals are easy to calculate from the base data in a 2 × 2 contingency table, and their values can be qualitatively and semi-quantitatively categorised. For medical tests, in which context the Efficiency Index was originally proposed, it facilitates the communication of risk (of the correct diagnosis versus misdiagnosis) to both clinicians and patients. Variants of the Efficiency Index (balanced, unbiased) which take into account disease prevalence and test cut-offs have also been described. The objectives of the current paper were firstly to extend the EI construct to other formulations (balanced level, quality), and secondly to explore the utility of the EI and all four of its variants when applied to the dataset of a large prospective test accuracy study of a cognitive screening instrument. This showed that the balanced level, quality, and unbiased formulations of the EI are more stringent measures.

Epileptic seizures are increasingly recognized as part of the clinical phenotype of patients with Alzheimer’s disease (AD). However, the evidence base on which to make treatment decisions for such patients is slim, there being no clear recommendation based on systematic review of the few existing studies of anti-seizure drugs in AD patients. Here the authors examine the potential implications for the treatment of seizures in AD of the results of the recently published SANAD II pragmatic study, which examined the effectiveness of levetiracetam, zonisamide, or lamotrigine in newly diagnosed focal epilepsy, and of valproate and levetiracetam in generalized and unclassifiable epilepsy.

Over 20 years ago, Charles Warlow, the founding editor ofPractical Neurology, offered a copy of his stroke textbook to anyone diagnosing an intracranial arteriovenous malformation by auscultation of the skull alone. This article examines the possible diagnostic value of intracranial bruit in terms of the 2×2 contingency table for diagnostic tests and recounts an historical case.

Aim: To examine whether two existing cognitive screeners might be adapted for telephone administration by omission of item content requiring visual cues or assessment. Materials & methods: Data from a test accuracy study of Mini-Addenbrooke’s Cognitive Examination (MACE) and Free-Cog were used to derive scores for ‘Tele-MACE’ and ‘Tele-Free-Cog’. Results: As in the index study, both Tele-MACE and Tele-Free-Cog proved sensitive for dementia diagnosis. Tele-MACE had a better balance of sensitivity and specificity than observed with MACE. Tele-MACE was sensitive for mild cognitive impairment diagnosis, whereas Tele-Free-Cog was more specific for mild cognitive impairment. Conclusion: Existing cognitive screeners may be adapted for telephone administration. Such developments may prove necessary in the COVID-19 era as remote rather than face-to-face cognitive assessment increasingly becomes the established norm.

SUMMARYPsychiatrists may be daunted by the prospect of undertaking a neurological examination. In this article we briefly review the neurological signs that may be seen in the context of some common neurological disorders of cognition and movement which may present with neurobehavioural symptoms and therefore may be seen initially by psychiatrists. This approach emphasises that neurological examination is not simply an operationalised procedure but an interpretative process. We propose a minimum neurological examination suitable for use by psychiatrists. Many of the signs included are relatively simple to observe or elicit, require no special equipment, and the examination techniques involved are easy to master.

Background The Mini-Addenbrooke’s Cognitive Examination (MACE) is a recently described brief cognitive screening instrument. Objective To examine the test accuracy of MACE for the identification of dementia and mild cognitive impairment (MCI) in a cohort of older patients assessed in a neurology-led dedicated cognitive disorders clinic. Methods Cross-sectional assessment of consecutive patients with MACE was performed independent of the reference standard diagnosis based on clinical interview of patient and, where possible, informant and structural brain imaging, and applying standard clinical diagnostic criteria for dementia and MCI. Various test accuracy metrics were examined at two MACE cut-offs ( ≤ 25/30 and ≤ 21/30), comparing the whole patient cohort with those aged ≥ 65 or ≥ 75 years, hence at different disease prevalences. Results Dependent upon the chosen cut-off, MACE was either very sensitive or very specific for the identification of any cognitive impairment in the older patient cohorts with increased disease prevalence. However, at both cut-offs the positive predictive values and post-test odds increased in the older patient cohorts. At the more sensitive cut-off, improvements in some new unitary test metrics were also seen. Conclusion MACE is a valid instrument for identification of cognitive impairment in older people. Test accuracy metrics may differ with disease prevalence.

Many patients referred to cognitive disorders clinics are not found to have evidence of any neurological disorder(s) to account for their symptoms. Many demonstrate incongruence between their subjective cognitive symptoms and preserved social and occupational functions. The term ‘functional cognitive disorders’ (FCD) has been used to denote this diagnostic category. This article aims to review the current state of knowledge regarding FCD. Studies of FCD are in their infancy, but available evidence suggests positive diagnosis may be made based on typical clinical profiles, including language discourse and simple clinical signs. Concurrent mood disorder and sleep disturbance are common, as well as other functional disorders. Pathogenesis is yet to be determined, but a disorder of metamemory has been suggested.

Objectives: To examine the diagnostic utility of the 'attended alone' (AA) and 'attended with' (AW) signs for the diagnosis of major and minor neurocognitive disorder. Methods: Consecutive unselected new outpatient referrals (N = 1209) to a dedicated cognitive disorders clinic over a 5-year period (2015-2019 inclusive) were observed for the AA and AW signs. Criterion diagnoses were by usual clinic assessment using standard (DSM-5) diagnostic criteria. Results: AW proved to be very sensitive for the identification of major and minor neurocognitive disorder but with generally low positive predictive values. In the subgroup of patients attending with more than one informant, the AW2+ sign, positive predictive value was higher and likewise with increasing patient age where the prevalence of AW was higher. Diagnostic utility of AW and AA was independent of patient gender. Conclusion: AW and AA are easily observed and categorized signs. AW has a high sensitivity for cognitive impairment while AA has a high positive predictive value for its absence.

Aim: To examine three different accuracy metrics for evaluation of cognitive screening instruments: overall correct classification accuracy (Acc), the sum of true positives and negatives divided by the total number tested; balanced accuracy (balanced Acc), half of the sum of sensitivity and specificity; and unbiased accuracy (unbiased Acc), removing biasing effects of random associations between test results and disease prevalence. Materials & methods: Data from a prospective test accuracy study of Mini-Addenbrooke’s Cognitive Examination were used to calculate and plot the Acc measures. Results: Each Acc metric resulted in a similar pattern of results across the range of Mini-Addenbrooke’s Cognitive Examination cut-offs for diagnosis of both dementia and mild cognitive impairment. Acc and balanced Acc gave more optimistic outcomes (closer to possible maximum value of 1) than unbiased Acc. Conclusion: Unbiased Acc may have advantages over Acc and balanced Acc by removing biasing effects of random associations between test result and disease prevalence.

An “efficiency index” (EI) for the evaluation of binary classifiers was recently characterised, where EI is the ratio of classifier accuracy to inaccuracy. The purpose of this study was to further develop EI by substituting balanced accuracy and unbiased accuracy in place of accuracy, and their respective complements in place of inaccuracy, to construct balanced EI and unbiased EI measures. Additional investigations, using the dataset of a prospective pragmatic test accuracy study of a cognitive screening instrument, explored use of the log method to calculate confidence intervals for the various EI formulations; the dependence of EI formulations on prevalence; and comparison of EI formulations with analogous formulations based on the Identification Index (II), a previously described metric which is also based on accuracy and inaccuracy, where II is accuracy minus inaccuracy. EI formulations are shown to have advantages over II formulations, in particular their boundary values (0 and ∞) mean that negative values never occur, unlike the case for II, and the inflection point of 1 demarcates likelihood of correct versus incorrect classification.

This chapter considers the differential diagnosis of TGA. Key considerations include cerebrovascular disease (TIA, stroke), epilepsy (transient epileptic amnesia, TEA), and psychological causes, as well as a variety of other causes of transient amnesia (migraine, drugs, hypoglycaemia, head injury). On clinical grounds alone, it is often possible to distinguish TGA from other causes of transient amnesia.

This chapter begins with a consideration of the typical clinical features of an attack of TGA. Although relatively stereotyped, nevertheless different authors have used the “TGA” terminology to describe different events characterised by transient amnesia. Following the description of possible boundaries for what might be included or excluded from the TGA label, diagnostic criteria were developed by Hodges and Warlow in 1990 for definite or pure TGA. Whether variants of TGA exist is still uncertain; if so, they are much rarer, gauged by the frequency of published reports.

Cognitive screening instruments (CSIs) for dementia and mild cognitive impairment are usually characterized in terms of measures of discrimination such as sensitivity, specificity, and likelihood ratios, but these CSIs also have limitations. Objective: The aim of this study was to calculate various measures of test limitation for commonly used CSIs, namely, misclassification rate (MR), net harm/net benefit ratio (H/B), and the likelihood to be diagnosed or misdiagnosed (LDM). Methods: Data from several previously reported pragmatic test accuracy studies of CSIs (Mini-Mental State Examination, the Montreal Cognitive Assessment, Mini-Addenbrooke’s Cognitive Examination, Six-item Cognitive Impairment Test, informant Ascertain Dementia 8, Test Your Memory test, and Free-Cog) undertaken in a single clinic were reanalyzed to calculate and compare MR, H/B, and the LDM for each test. Results: Some CSIs with very high sensitivity but low specificity for dementia fared poorly on measures of limitation, with high MRs, low H/B, and low LDM; some had likelihoods favoring misdiagnosis over diagnosis. Tests with a better balance of sensitivity and specificity fared better on measures of limitation. Conclusions: When deciding which CSI to administer, measures of test limitation as well as measures of test discrimination should be considered. Identification of CSIs with high MR, low H/B, and low LDM, may have implications for their use in clinical practice. RESUMO Os instrumentos de rastreio cognitivo (IRCs) para demência e comprometimento cognitivo leve são geralmente caracterizados em termos de medidas de discriminação, como sensibilidade, especificidade e razões de probabilidade, mas esses IRCs também têm limitações. Objetivo: Calcular várias medidas de limitação de testes para IRC comumente usados, a saber: taxa de classificação incorreta; relação entre dano líquido e benefício líquido; e probabilidade de diagnóstico ou diagnóstico incorreto. Métodos: Os dados de vários estudos de precisão de teste pragmático de IRC relatados anteriormente (MMSE, MoCA, MACE, 6CIT, AD8, TYM, Free-Cog) e realizados em uma única clínica foram reanalisados para calcular e comparar a taxa de classificação incorreta, o dano líquido para a relação de benefício líquido e a probabilidade de diagnóstico ou diagnóstico incorreto para cada teste. Resultados: Alguns IRC com sensibilidade muito alta, mas baixa especificidade para demência, tiveram desempenho ruim em medidas de limitação, com altas taxas de classificação incorreta, baixo prejuízo líquido para relações de benefício líquido e baixa probabilidade de diagnóstico ou diagnóstico incorreto; alguns tinham probabilidades de favorecer o diagnóstico incorreto ao invés do diagnóstico. Testes com melhor equilíbrio de sensibilidade e especificidade saíram-se melhor nas medidas de limitação. Conclusões: Ao decidir qual IRC administrar, as medidas de limitação, bem como as medidas de discriminação do teste, devem ser consideradas. A identificação de IRC com alta taxa de classificação incorreta, baixa relação de prejuízo e benefício e baixa probabilidade de diagnóstico ou diagnóstico incorreto pode ter implicações para seu uso na prática clínica.

To coincide with the 100th anniversary of the publication of Ludwig Wittgenstein's Tractatus Logico-Philosophicus, Andrew Larner considers some of the implications of philosophical themes in this and his posthumously published works, chiefly the Philosophical Investigations, for the disciplines of neurology and neuroscience.

Diagnostic and screening tests may have risks such as misdiagnosis, as well as the potential benefits of correct diagnosis. Effective communication of this risk to both clinicians and patients can be problematic. The purpose of this study was to develop a metric called the “efficiency index” (EI), defined as the ratio of test accuracy and inaccuracy, to evaluate screening tests for dementia. This measure was compared with a previously described “likelihood to be diagnosed or misdiagnosed” (LDM), also based on “numbers needed” metrics. Datasets from prospective pragmatic test accuracy studies examining four brief cognitive screening instruments (Mini-Mental State Examination, Montreal Cognitive Assessment, Mini-Addenbrooke’s Cognitive Examination (MACE), and Free-Cog) were analysed to calculate values for EI and LDM, and to examine their variation with test cut-off for MACE and dementia prevalence. EI values were also calculated using a modification of McGee’s heuristic for the simplification of likelihood ratios to estimate percentage change in diagnostic probability. The findings indicate that EI is easier to calculate than LDM and, unlike LDM, may be classified either qualitatively or quantitatively in a manner similar to likelihood ratios. EI shows the utility or inutility of diagnostic and screening tests, illustrating the inevitable trade-off between diagnosis and misdiagnosis. It may be a useful metric to communicate risk in a way that is easily intelligible for both clinicians and patients.

Aim: To examine whether receiver operating characteristic plots and area under the curve (AUC) values may be potentially misleading when assessing cognitive screening instruments as binary predictors rather than as categorical or continuous scales. Materials & methods: AUC was calculated using different methods (rank-sum, diagnostic odds ratio) using data from test accuracy studies of two binary classifiers of cognitive status (applause sign, attended with sign), a screener producing categorical data (Codex), and a continuous scale screening test (Mini-Addenbrooke’s Cognitive Examination). Results: For all screeners, AUC calculated using diagnostic odds ratio method was greater than using rank-sum method. When Codex and Mini-Addenbrooke’s Cognitive Examination were analyzed as binary (single fixed threshold) tests, AUC using rank-sum method was lower than when screeners were analyzed as categorical or continuous scales, respectively. Conclusion: If cognitive screeners producing categorical or continuous measures are dichotomized, calculated AUC may be an underestimate, thus affecting screening test accuracy.

Diagnostic and screening tests may have risks such as misdiagnosis, as well as the potential benefits of correct diagnosis. Effective communication of this risk to both clinicians and patients can be problematic. The purpose of this study was to develop a metric called the “efficiency index” (EI), defined as the ratio of test accuracy and inaccuracy, or the number needed to misdiagnose divided by number needed to diagnose. This was compared with a previously described “likelihood to be diagnosed or misdiagnosed” (LDM), also based on “numbers needed” metrics. Datasets from prospective pragmatic test accuracy studies examining four brief cognitive screening instruments (Mini-Mental State Examination; Montreal Cognitive Assessment; Mini-Addenbrooke’s Cognitive Examination, MACE; and Free-Cog) were analysed to calculate values for EI and LDM, and to examine their variation with test cut-off for MACE. EI values were also calculated using a modification of McGee’s heuristic for the simplification of likelihood ratios to estimate percentage change in diagnostic probability. The findings indicate that EI is easier to calculate than LDM and, unlike LDM, may be classified either qualitatively or quantitatively in a manner similar to likelihood ratios. EI shows the utility or inutility of diagnostic and screening tests, illustrating the inevitable trade-off between diagnosis and misdiagnosis. It may be a useful metric to communicate risk in a way that is easily intelligible for both clinicians and patients.

Functional cognitive disorders (FCD) have become a subject of increasing clinical interest in recent years, in part because of their high prevalence amongst patients attending dedicated memory clinics. Empirical understanding of FCD based on observational studies is growing, suggesting a relationship to other functional neurological disorders (FND) based on shared phenomenology. However, understanding of FCD at the theoretical level has been lacking. One suggestion has been that FCD are disorders of metacognition, most usually of metamemory. In this article, a brief overview of these constructs is presented along with existing evidence for their impairment in FCD. Previous adaptations of theoretical models of FND to accommodate FCD are reviewed. A novel application to FCD of Nelson and Narens’ monitoring and control model of metamemory is then attempted, positing an improper setting of the monitoring function, with examples of ecological relevance. Formulation of FCD in light of a metacognitive model of anosognosia is also considered. Although lacking mechanistic and neuroanatomical sophistication, this metacognitive formulation of FCD may give pointers for future hypothesis-driven research and a pragmatic basis for management strategies.

Remote systems of care have become necessary in the COVID-19 pandemic This study examined the feasibility of telephone screening of cognitive function in patients with epilepsy to assess the frequency of, and factors associated with, cognitive impairment in these patients Administration of the Six-item Cognitive Impairment Test, a brief cognitive screening instrument that eschews visuospatial or visuoperceptual tests, proved acceptable to patients with epilepsy

First published over 400 years ago, this new edition of Robert Burton's The Anatomy of Melancholy still has the capacity to engage and edify readers in ways which may impact on their clinical practice.

Background/Aims: Sensitivity and specificity (Sens, Spec) are not invariant properties of diagnostic and screening tests, but vary in different patient samples. Kraemer [Evaluating medical tests. Objective and quantitative guidelines. 1992] used the level of test, Q, also known as “positive sign rate” (sum of true and false positives divided by sample size), to calculate quality sensitivity and specificity (QSN, QSP). These scaled indices may be more comparable across different patient samples, but have been little studied hitherto. Methods: The dataset of a pragmatic test accuracy study of the Mini-Addenbrooke’s Cognitive Examination (MACE) was re-interrogated to calculate values of QSN and QSP and other paired and unitary test outcome measures based on them, and comparison was made with outcomes previously calculated by standard methods. Results: QSN and QSP values in this cohort (n = 755; overall prevalence of dementia and mild cognitive impairment [MCI] 0.15 and 0.29, respectively) were inferior to Sens and Spec, as were all other outcome measures for MACE for the diagnosis of both dementia and MCI. QSN was relatively preserved, indicating the sensitivity of MACE. Conclusion: Indices of test outcome scaled according to Kraemer’s Q, the positive sign rate, are less impressive than outcomes calculated by standard methods. These discrepancies may have implications for test evaluation.

Aim: To extend use of the recently described ‘likelihood to be diagnosed or misdiagnosed’ (LDM) metric for test accuracy studies through application to recent meta-analytic data of commonly used cognitive screening instruments. Methods: Raw data (true positives and negatives, false positives and negatives) were extracted from meta-analyses (minimum 5 studies or 1000 patients), from which LDM was calculated. LDM values were compared with those previously reported for single test accuracy studies. Results: LDM values for diagnosis of dementia ranged from around two to seven, and for diagnosis of mild cognitive impairment from two to three. LDM values based on meta-analytic data were larger than those reported for individual studies. Conclusion: LDM is an easily calculated and potentially useful unitary, global metric for test accuracy studies.

Transient global amnesia (TGA) is a rare but well-described neurological disorder characterised by an acute self-limited episode of dense anterograde amnesia with retrograde amnesia of variable extent. Although the clinical phenomenology, neuropsychology, neuroimaging, prognosis, and precipitating and predisposing factors of TGA are well described, the pathogenesis is not currently understood. Existing proposals - epileptic seizure, stroke or transient ischaemic attack, migraine aura - all have shortcomings. Based on a computational neural network model of mnemonic function, a new model of TGA pathogenesis is suggested, along with potential mechanisms, thus generating a potentially testable hypothesis of TGA pathogenesis. Based on the intrinsic neuronal circuitry of the hippocampal formation, specifically the rich CA3 recurrent collateral projections which have previously been characterised as a global autoassociative attractor network, a model of TGA is developed in which loss of fault tolerance, a property of attractor networks, results in catastrophic rather than graceful degradation. Excessive positive feedback through the CA3 recurrent collaterals produces runaway neural firing, with infinite gain in the short CA3 feedback loops, resulting in a singularity or discontinuity manifest as failure of synaptic transmission. In terms of the energy landscape, the system flips to a shallower, low firing rate, basin of attraction. At the mechanistic level, spreading depolarization is suggested to underpin these changes. These considerations permit the construction of a hypothesis of TGA pathogenesis which may have testable, falsifiable, predictions.

Receiver operating characteristic (ROC) plots are a performance graphing method showing the relative trade-off between test benefits (true positive rate) and costs (false positive rate) with the area under the curve (AUC) giving a scalar value of test performance. It has been suggested that ROC and AUC may be potentially misleading when examining binary predictors rather than continuous scales. The purpose of this study was to examine ROC plots and AUC values for two binary classifiers of cognitive status (applause sign, attended with sign), a cognitive screening instrument producing categorical data (Codex), and a continuous scale screening test (Mini-Addenbrooke’s Cognitive Examination), the latter two also analysed with single fixed threshold tests. For each of these plots, AUC was calculated using different methods. The findings indicate that if categorical or continuous measures are dichotomised then the calculated AUC may be an underestimate, thus affecting screening or diagnostic test accuracy which in the context of clinical practice may prove to be misleading.