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This chapter examines pragmatic studies of short patient-performance screening scales, meaning those which can generally be administered in from 5 to 10 minutes. As these tests are quick to administer, they are generally acceptable to patients. All provide quantitative (ordinal) discrete data. Their unitary metrics suggest they may be of use for diagnosis of dementia, more so than for diagnosis of mild cognitive impairment.

This chapter examines combinations of various screeners described individually in previous chapters. As for the combination of cognitive screeners, use of simple logical rules, in series and in parallel, improves specificity and sensitivity respectively. For some of the combinations examined, particularly the combination of functional and cognitive screeners, the unitary metrics are encouraging for the identification of cognitive impairment.

Aim: To examine four different accuracy metrics for assessment of commonly used cognitive screening instruments: correct classification accuracy, area under the receiver operating characteristic curve, F measure (F) or F1 score and Matthews correlation coefficient (MCC). Methods: Raw data were extracted from test accuracy studies of Mini-Mental State Examination. Montreal Cognitive Assessment, Mini-Addenbrooke's Cognitive Examination, Six-item Cognitive Impairment Test, informant AD8 and Free-Cog, and used to calculate the accuracy measures. Results: Each metric resulted in similar ordering of the screening instruments for diagnosis of both dementia and mild cognitive impairment. Area under the receiver operating characteristic curve gave the highest (most optimistic) and MCC the lowest (most pessimistic) accuracy value for each test examined, with correct classification accuracy and F falling between. Conclusion: All the accuracy measures examined have potential shortcomings. None can be recommended as the definitive unitary outcome measure for test accuracy studies. However, MCC has theoretical advantages and might be more widely adopted.

Introduction: Alzheimer's disease may be associated with both clinical and subclinical epileptic seizure activity. Once regarded as an epiphenomenon, epileptiform activity may, in fact, be an integral part of the Alzheimer's phenotype, and may be not only a symptomatic therapeutic target but also a possible mechanism to retard or prevent disease progression. Areas covered: The authors review clinical research articles with a focus on the semiology, epidemiology, and treatment of seizures in Alzheimer's disease, and also look at some experimental animal model studies which have informed clinical thinking on seizure aetiopathogenesis. The evidence base for treatment decisions is sparse. A brief overview of the clinical assessment of Alzheimer's disease patients considering relevant differential diagnoses and diagnostic pitfalls is presented. Expert opinion: Studies of epileptic seizures in Alzheimer's disease have become more frequent over the last 5-10 years. Understanding of seizure semiology, epidemiology, and possible pathogenesis has increased. However, the optimal management of seizures in this context remains unknown, largely due to the paucity of studies sufficient to examine this question. Clearly, such studies will be required, not only to inform clinicians about symptomatic control of seizures in Alzheimer's disease but also to investigate whether this might impact on disease progression.

Many cognitive screening instruments are available to assess patients with cognitive symptoms in whom a diagnosis of dementia or mild cognitive impairment is being considered. Most are quantitative scales with specified cut-off values. In contrast, the cognitive disorders examination or Codex is a two-step decision tree which incorporates components from the Mini-Mental State Examination (MMSE) (three word recall, spatial orientation) along with a simplified clock drawing test to produce categorical outcomes defining the probability of dementia diagnosis and, by implication, directing clinician response (reassurance, monitoring, further investigation, immediate treatment). Codex has been shown to have high sensitivity and specificity for dementia diagnosis but is less sensitive for the diagnosis of mild cognitive impairment (MCI). We examined minor modifications to the Codex decision tree to try to improve its sensitivity for the diagnosis of MCI, based on data extracted from studies of two other cognitive screening instruments, the Montreal Cognitive Assessment and Free-Cog, which are more stringent than MMSE in their tests of delayed recall. Neither modification proved of diagnostic value for mild cognitive impairment. Possible explanations for this failure are considered.

Epileptic seizures have been described as one feature of prion diseases, but are an unusual clinical presentation. The aim of this narrative Review was to summarize current knowledge of epileptic seizures in the various forms of prion diseases, from a clinical perspective. Examination of the published literature identified no systematic studies; the evidence base is largely anecdotal, consisting mainly of case studies and small case series. Hence, uncertainty prevails as to seizure frequency, semiology, treatment, and pathogenesis in prion diseases. Seizures probably occur in around 10% of sporadic cases but less frequently in iatrogenic and familial forms, with the possible exception of the E200K mutation. The literature suggests a predominance of focal motor and nonconvulsive status epilepticus. Electroencephalographic accompaniments include periodic lateralized or generalized periodic epileptiform discharges (PLEDs, GPEDs), sometimes predating the more typical periodic sharp wave complexes. There are no convincing accounts of successful antiepileptic drug therapy. The underlying mechanisms of epileptogenesis in prion diseases may include loss of cellular prion protein function (PrPc) and aggregation of abnormally folded prion protein (PrPSc). The need for systematic studies and clinical trials to expand the evidence base surrounding epilepsy and prion diseases is evident.

Objectives Cognitive screening is recommended in stroke, but test completion may be complicated by stroke related impairments. We described feasibility of completion of three commonly used cognitive screening tools and the effect on scoring properties when cognitive testing was entirely/partially incomplete. Methods We performed a cross-sectional study, recruiting sequential stroke patient admissions from two University Hospital stroke rehabilitation services. We assessed Folstein's mini-mental state examination (MMSE), Montreal cognitive assessment (MoCA) and Addenbrooke's cognitive examination (ACE-III). The multidisciplinary team gave an independent diagnostic formulation. We recorded numbers fully/partially completing tests, assistance and time required for testing. We calculated test discrimination metrics in relation to clinical assessment using four differing statistical approaches to account for incomplete testing. Results We recruited 51 patients. Direct assistance to complete cognitive tests was required for 33 (63%). At traditional cut-offs, the majority screened “positive” for cognitive impairment (ACE-III: 98%; MoCA: 98%; MMSE: 81%). Comparing against a clinical diagnosis, ACE-III and MoCA had excellent sensitivity but poor specificity. Partial completion of cognitive tests was common (ACE-III: 14/51, MMSE: 22/51; MoCA: 20/51 fully complete); greatest non completion was for test items that required copying or drawing. Adapting analyses to account for these missing data gave differing results; MMSE sensitivity ranged from 0.66 to 0.85, and specificity ranged from 0.44 to 0.71 depending on the approach employed. Conclusions For cognitive screening in stroke, even relatively brief tools are associated with substantial incompletion. The way these missing data are accounted for in analyses impacts on apparent test properties. When choosing a cognitive screening tool, feasibility should be considered and approaches to handling missing data made explicit. Copyright © 2016 John Wiley & Sons, Ltd.

Aim: To measure the frequency of scoring and reporting errors in cognitive screening instruments administered in the primary care setting in consecutive referrals to a dedicated secondary care memory clinic. Methods: Using a simple ad hoc classification, referral letters from primary care mentioning cognitive screening instrument use were classified as: unequivocal, incorrect/ambiguous or incomplete. Results: Overall, reported test scores were either ambiguous/incorrect or incomplete in 23% of cases, with higher individual frequencies for two screening instruments recommended for use in primary care, the Six-item Cognitive Impairment Test (26%) and the General Practitioner Assessment of Cognition (32%). Conclusion: Errors are not infrequent in the scoring and reporting of cognitive screening instruments administered in primary care. More training in their correct use and scoring is required.

Mild cognitive impairment (MCI) may represent an early, and potentially treatable, phase of dementing disorders. Its correct clinical identification is therefore of paramount importance. Here, Dr Larner analyses data from a selection of short cognitive screening instruments (CSIs) employed in a secondary care setting to measure various parameters for diagnosis of MCI and to establish whether any of the instruments have superior diagnostic utility.

The differential diagnosis of progressive neurodegenerative disorders may sometimes be challenging, despite longitudinal assessment and access to traditional modalities of structural and functional neuroimaging. In this article, the authors describe a patient tentatively diagnosed with corticobasal syndrome in whom investigation with cerebrospinal fluid biomarkers led to diagnostic revision and new therapeutic options.

A patient presented with fulminant pulmonary oedema and required acute intubation and ventilation. There was no history of a prior cardiac disorder. As he was weaned from sedation, following stabilisation of his pulmonary status, neurological signs suggestive of brainstem dysfunction became apparent. Investigations showed infarcts in the posterior cerebral circulation secondary to a vertebral artery dissection. Neurogenic pulmonary oedema needs to be considered in any patient with fulminant pulmonary oedema without overt evidence or history of cardiac disease.

The clinical syndromes of frontotemporal dementia are clinically and neuropathologically heterogeneous, but processes such as neuroinflammation may be common across the disease spectrum. We investigated how neuroinflammation relates to the aggregation of Tau and TDP-43 in frontotemporal dementia, and to the heterogeneity of clinical disease. We used positron emission tomography in vivo with (a) [11C]PK-11195, a marker of activated microglia and a proxy index of neuroinflammation, and (b) [18F]AV-1451, a radioligand with increased binding to pathologically affected regions in tauopathies and diseases associated with TDP-43 protein aggregation, and which is used as a surrogate marker of non-β-amyloid protein aggregation. We assessed 31 patients with frontotemporal dementia (10 with behavioural variant frontotemporal dementia, 11 with the semantic variant of primary progressive aphasia and 10 with the non-fluent variant of primary progressive aphasia), 28 of whom underwent both [18F]AV-1451 and [11C]PK-11195 PET, and matched controls (14 for [18F]AV-1451 and 15 for [11C]PK-11195). We used univariate region-of-interest analyses, and multivariate analysis of the distribution of binding that explicitly control for individual differences in ligand affinity for TDP-43 and different Tau isoforms. We found differences between patients and controls in frontotemporal regions for both neuroinflammation and protein aggregation, and a strong positive correlation between these two processes in all disease groups. Despite this regional co-localisation, the multivariate distribution of [11C]PK-11195 binding related better to clinical heterogeneity than did the distribution of [18F]AV-1451: distinct spatial modes of neuroinflammation were associated with different frontotemporal dementia syndromes and supported accurate group classification of participants. These in vivo findings indicate a close association between neuroinflammation and protein aggregation in frontotemporal dementia. The inflammatory component may be important in shaping the clinical and neuropathological patterns of the diverse clinical syndromes of frontotemporal dementia.

This chapter examines the presentation of the results of diagnostic test accuracy studies in terms of specific measures of discrimination and comparison. To exemplify the utility of these measures, studies of some of the key investigations currently used in dementia diagnosis, namely cognitive screening instruments (both performance based and informant based) and biomarkers based on functional neuroimaging and cerebrospinal fluid neurochemistry, are used.

This chapter examines the presentation of the results of diagnostic test accuracy studies. It emphasizes the critical importance in reporting specific details about study participants and test results.

This chapter examines some possible future prospects for diagnostic test accuracy studies in dementia, in terms of both potential problems and opportunities. A proposal for the role of pragmatic diagnostic test accuracy studies concludes these considerations.

Aim: To examine features associated with functional cognitive disorders (FCDs) compared with neurological cognitive disorders (dementia, mild cognitive impairment, transient amnesias) in consecutive patients referred to a secondary care cognitive disorders clinic. Methods: Patients diagnosed with either neurological cognitive disorder or FCD were compared by demographic (age, gender, handedness, referral source) and clinical features (family history of dementia, clinical signs, Likert screening measure of subjective memory complaint, mini-Addenbrooke's Cognitive Examination). Results: Patients diagnosed with FCD were younger than those with neurological cognitive disorders, and more likely to attend alone, have a family history of dementia and be categorized as positive for subjective memory complaint. Conclusion: These data suggest features which may be helpful in making a positive diagnosis of FCD and differentiating from neurological cognitive disorders.

Introduction: Short‐form versions of the Montreal Cognitive Assessment (SF‐MoCA) are increasingly used to screen for dementia in research and practice. We sought to collate evidence on the accuracy of SF‐MoCAs and to externally validate these assessment tools. Methods: We performed systematic literature searching across multidisciplinary electronic literature databases, collating information on the content and accuracy of all published SF‐MoCAs. We then validated all the SF‐MoCAs against clinical diagnosis using independent stroke (n = 787) and memory clinic (n = 410) data sets. Results: We identified 13 different SF‐MoCAs (21 studies, n = 6477 participants) with differing test content and properties. There was a pattern of high sensitivity across the range of SF‐MoCA tests. In the published literature, for detection of post stroke cognitive impairment, median sensitivity across included studies: 0.88 (range: 0.70‐1.00); specificity: 0.70 (0.39‐0.92). In our independent validation using stroke data, median sensitivity: 0.99 (0.80‐1.00); specificity: 0.40 (0.14‐0.87). To detect dementia in older adults, median sensitivity: 0.88 (0.62‐0.98); median specificity: 0.87 (0.07‐0.98) in the literature and median sensitivity: 0.96 (range: 0.72‐1.00); median specificity: 0.36 (0.14‐0.86) in our validation. Horton's SF‐MoCA (delayed recall, serial subtraction, and orientation) had the most favorable properties in stroke (sensitivity: 0.90, specificity: 0.87, positive predictive value [PPV]: 0.55, and negative predictive value [NPV]: 0.93), whereas Cecato's “MoCA reduced” (clock draw, animal naming, delayed recall, and orientation) performed better in the memory clinic (sensitivity: 0.72, specificity: 0.86, PPV: 0.55, and NPV: 0.93). Conclusions: There are many published SF‐MoCAs. Clinicians and researchers using a SF‐MoCA should be explicit about the content. For all SF‐MoCA, sensitivity is high and similar to the full scale suggesting potential utility as an initial cognitive screening tool. However, choice of SF‐MoCA should be informed by the clinical population to be studied.

Background/Aims: “Number needed to” metrics may hold more intuitive appeal for clinicians than standard diagnostic accuracy measures. The aim of this study was to calculate “number needed to diagnose” (NND), “number needed to predict” (NNP), and “number needed to misdiagnose” (NNM) for neurological signs of possible value in assessing cognitive status. Methods: Data sets from pragmatic diagnostic accuracy studies examining easily observed and dichotomised neurological signs (“attended alone” sign, “attended with” sign, head turning sign, applause sign, la maladie du petit papier) were analysed to calculate the NND, NNP, and NNM. Results: All measures of discrimination showed broad ranges. The range of NND and NNP suggested that these signs were, with a single exception, of value for correctly diagnosing or predicting cognitive status (presence or absence of cognitive impairment) when between 2 and 4 patients were examined. However, NNM showed similar values (range 1–5 patients) suggesting risk of misdiagnosis. Conclusion: NND, NNP, and NNM may be useful, intuitive, metrics in assessing the utility of diagnostic tests in day-to-day clinical practice. A ratio of NNM to either NND or NNP, termed the likelihood to diagnose or misdiagnose, may clarify the utility or inutility of diagnostic tests.

Objective This study examined cognitive function in patients with epilepsy using the AD8 screening questionnaire to assess the frequency of, and factors associated with, cognitive impairment in these patients. Method The AD8 screening questionnaire for cognitive impairment was administered to one hundred consecutive patients diagnosed with epilepsy who attended a dedicated epilepsy clinic based in a tertiary care neuroscience center. Where possible, accompanying informants also completed AD8 on behalf of the patient. Results Forty-eight percent of patients in this cohort scored above the AD8 cutoff (higher scores are considered worse) for cognitive impairment. Categorizing patient groups by AD8 score showed no difference (null hypothesis not rejected) in patient age, new or follow-up appointment, epilepsy type (partial/generalized), or treatment (monotherapy/polytherapy), but a significant difference (null hypothesis rejected) was found for disee duration, with those scoring above the AD8 cutoff having a significantly longer disease duration. There was no correlation between AD8 scores and patient age but a weak positive correlation with disease duration. AD8 questionnaires completed by informants showed a similar frequency of cognitive impairment (54%), and patient:informant AD8 scores showed substantial agreement beyond chance. Conclusions AD8 is acceptable to patients with epilepsy and their informants for the assessment of cognitive function. In this dedicated epilepsy clinic, its use suggested a high frequency of cognitive impairment in both self-rating and informant assessments. A less sensitive, more specific cognitive screening instrument (CSI) might be more desirable in this population. Duration of epilepsy or some factor related to it may contribute to cognitive symptoms.

Autoimmune encephalitis associated with antibodies (Abs) directed against the synaptic ligand-gated ion channel NMDA receptor (NMDAR) was first described as a paraneoplastic disorder in association with ovarian teratoma. Other forms of neoplasia have subsequently been reported although many patients do not have a tumour. Tumour removal, where applicable, and immunotherapy form the mainstays of treatment. We present a patient who developed NMDAR-Ab encephalitis despite being chronically immunosuppressed following organ transplantation, and who was eventually found to have an occult malignancy in the form of non-Hodgkin’s lymphoma.

The aim of this essay is to elaborate philosophical and ethical underpinnings of posthumous diagnosis of famous historical figures based on literary and artistic products, or commonly called retrospective diagnosis. It discusses ontological and epistemic challenges raised in the humanities and social sciences, and attempts to systematically reply to their criticisms from the viewpoint of clinical medicine, philosophy of medicine, particularly the ontology of disease and the epistemology of diagnosis, and medical ethics. The ontological challenge focuses on the doubt about the persistence of a disease over historical time, whereas the epistemic challenge disputes the inaccessibility of scientific verification of a diagnosis in the past. I argue that the critics are in error in conflating the taxonomy of disease (nosology) and the act of diagnosing a patient. Medical diagnosis is fundamentally a hypothesis-construction and an explanatory device that can be generated under various degrees of uncertainty and limited amount of information. It is not an apodictic judgment (true or false) as the critics presuppose, but a probabilistic (Bayesian) judgment with varying degrees of plausibility under uncertainty. In order to avoid this confusion, I propose that retrospective diagnosis of a historical figure be syndromic without identifying underlying disease, unless there is justifiable reason for such specification. Moreover it should be evaluated not only from the viewpoint of medical science but also in a larger context of the scholarship of the humanities and social sciences by its overall plausibility and consistency. On the other hand, I will endorse their concerns regarding the ethics and professionalism of retrospective diagnosis, and call for the need for situating such a diagnosis in an interdisciplinary scope and the context of the scholarship of the historical figure. I will then enumerate several important caveats for interdisciplinary retrospective diagnosis using an example of the retrospective diagnosis of Socrates for his life-long intermittent neurologic symptoms. Finally, I will situate the present argument in a larger context of the major debate among the historians of medicine and paleopathologists, and discuss the similarities and differences.

Aims: To measure current and comparative frequencies of use of the General Practitioner Assessment of Cognition (GPCOG) scale in consecutive primary care referrals to a dedicated secondary care memory clinic. Methods: Over 6 months (January–June 2015), referral letters from primary care (n = 121) were examined for mention of GPCOG use. Results: The proportion of patients administered any cognitive screening instrument before referral was 41.3%, with 11.6% administered the GPCOG, a significant increase compared with prior cohorts. However, GPCOG was incorrectly used or documented in 29% of cases. Conclusion: GPCOG use is increasing in primary care settings, but training in its correct use and scoring may be required to ensure that its administration makes meaningful information available.

ABSTACTObjective: To examine the diagnostic utility of applause sign scores for the diagnosis of dementia and mild cognitive impairment. Methods: Consecutive unselected new outpatient referrals to a dedicated cognitive disorders clinic over a 12-month period were administered the clapping test. Criterion diagnosis was by usual clinic assessment using standard diagnostic criteria, blind to applause sign score. Results: Applause sign scores differed significantly (p

A patient with rapidly progressive cognitive decline over an approximately four month period was suspected to have sporadic Creutzfeldt-Jakob disease. Features thought to support this diagnosis included psychiatric symptoms (anxiety and depression), visual hallucinations and a visual field defect. However, the finding of papilloedema broadened the differential diagnosis. Although standard brain imaging and electroencephalography had shown only non-specific abnormalities, subsequent cerebral angiography disclosed an intracranial dural arteriovenous fistula. Following embolisation, the patient made a good functional recovery. Intracranial dural arteriovenous fistula merits consideration in any patient with subacute cognitive decline, and should be included in the differential diagnosis of sporadic Creutzfeldt-Jakob disease.

Increased caregiver burden impacts adversely not only on caregivers, in terms of physical and psychological morbidity, but also on people with dementia, since it is associated with an increased likelihood of patient institutionalisation. Here, the authors examine effectiveness and ease of administration of the Zarit Burden Interview (ZBI) tool in day-to-day clinical practice for identifying caregiver burden.

Background/Aims: Single, global or unitary, indicators of test diagnostic performance have intuitive appeal for clinicians. The Q* index, the point in receiver operating characteristic (ROC) curve space closest to the ideal top left-hand corner and where test sensitivity and specificity are equal, is one such measure. Methods: Datasets from four pragmatic accuracy studies which examined the Mini-Mental State Examination, Addenbrooke's Cognitive Examination-Revised, Montreal Cognitive Assessment, Test Your Memory test, and Mini-Addenbrooke's Cognitive Examination were examined to calculate and compare the Q* index, the maximal correct classification accuracy, and the maximal Youden index, as well as the sensitivity and specificity at these cutoffs. Results: Tests ranked similarly for the Q* index and the area under the ROC curve (AUC ROC). The Q* index cutoff was more sensitive (and less specific) than the maximal correct classification accuracy cutoff, and less sensitive (and more specific) than the maximal Youden index cutoff. Conclusion: The Q* index may be a useful global parameter summarising the test accuracy of cognitive screening instruments, facilitating comparison between tests, and defining a possible test cutoff value. As the point of equal sensitivity and specificity, its use may be more intuitive and appealing for clinicians than AUC ROC.

Three patients with the clinical and investigation features of facial onset sensory and motor neuronopathy (FOSMN) syndrome are presented, one of whom came to a post-mortem examination. This showed TDP-43-positive inclusions in the bulbar and spinal motor neurones as well as in the trigeminal nerve nuclei, consistent with a neurodegenerative pathogenesis. These data support the idea that at least some FOSMN cases fall within the spectrum of the TDP-43 proteinopathies, and represent a focal form of this pathology.