Functional brain networks in Developmental Topographical Disorientation.

Despite a decade-long study on Developmental Topographical Disorientation, the underlying mechanism behind this neurological condition remains unknown. This lifelong selective inability in orientation, which causes these individuals to get lost even in familiar surroundings, is present in the absence of any other neurological disorder or acquired brain damage. Herein, we report an analysis of the functional brain network of individuals with Developmental Topographical Disorientation ($n = 19$) compared against that of healthy controls ($n = 21$), all of whom underwent resting-state functional magnetic resonance imaging, to identify if and how their underlying functional brain network is altered. While the established resting-state networks (RSNs) are confirmed in both groups, there is, on average, a greater connectivity and connectivity strength, in addition to increased global and local efficiency in the overall functional network of the Developmental Topographical Disorientation group. In particular, there is an enhanced connectivity between some RSNs facilitated through indirect functional paths. We identify a handful of nodes that encode part of these differences. Overall, our findings provide strong evidence that the brain networks of individuals suffering from Developmental Topographical Disorientation are modified by compensatory mechanisms, which might open the door for new diagnostic tools.

Lost in space(s): Multimodal neuroimaging of disorientation along the Alzheimer's disease continuum.

Orientation is a fundamental cognitive faculty and the bedrock of the neurologic examination. Orientation is defined as the alignment between an individual's internal representation and the external world in the spatial, temporal, and social domains. While spatial disorientation is a recognized hallmark of Alzheimer's disease (AD), little is known about disorientation beyond space in AD. This study aimed to explore disorientation in spatial, temporal, and social domains along the AD continuum. Fifty-one participants along the AD continuum performed an ecological orientation task in the spatial, temporal, and social domains while undergoing functional MRI. Disorientation in AD followed a three-way association between orientation domain, brain region, and disease stage. Specifically, patients with early amnestic mild cognitive impairment exhibited spatio-temporal disorientation and reduced brain activity in temporoparietal regions, while patients with AD dementia showed additional social disorientation and reduced brain activity in frontoparietal regions. Furthermore, patterns of hypoactivation overlapped different subnetworks of the default mode network, patterns of fluorodeoxyglucose hypometabolism, and cortical atrophy characteristic of AD. Our results suggest that AD may encompass a disorder of orientation, characterized by a biphasic process manifesting as early spatio-temporal and late social disorientation. As such, disorientation may offer a unique window into the clinicopathological progression of AD. SIGNIFICANCE STATEMENT: Despite extensive research into Alzheimer's disease (AD), its core cognitive deficit remains a matter of debate. In this study, we investigated whether orientation, defined as the ability to align internal representations with the external world in spatial, temporal, and social domains, constitutes a core cognitive deficit in AD. To do so, we used PET-fMRI imaging to collect behavioral, functional, and metabolic data from 51 participants along the AD continuum. Our findings suggest that AD may constitute a disorder of orientation, characterized by an early spatio-temporal disorientation and followed by late social disorientation, manifesting in task-evoked and neurodegenerative changes. We propose that a profile of disorientation across multiple domains offers a unique window into the progression of AD and as such could greatly benefit disease diagnosis, monitoring, and evaluation of treatment response.

The neural correlates of topographical disorientation-a lesion analysis study.

Topographical disorientation refers to the selective inability to orient oneself in familiar surroundings. However, to date its neural correlates remain poorly understood. Here we use quantitative lesion analysis and a lesion network mapping approach in order to investigate seven patients with topographical disorientation. Our findings link not only the posterior parahippocampal gyrus (PHG) and retrosplenial cortex but also the lingual gyrus, the precuneus and the fusiform gyrus to topographical disorientation. We propose that topographical disorientation is due to the inability to integrate familiar landmarks within a framework of allocentric and egocentric orientation, supported by a neural network including the posterior PHG, the retrosplenial and the lingual cortex.

A neural circuit for spatial orientation derived from brain lesions.

There is disagreement regarding the major components of the brain network supporting spatial cognition. To address this issue, we applied a lesion mapping approach to the clinical phenomenon of topographical disorientation. Topographical disorientation is the inability to maintain accurate knowledge about the physical environment and use it for navigation. A review of published topographical disorientation cases identified 65 different lesion sites. Our lesion mapping analysis yielded a topographical disorientation brain map encompassing the classic regions of the navigation network: medial parietal, medial temporal, and temporo-parietal cortices. We also identified a ventromedial region of the prefrontal cortex, which has been absent from prior descriptions of this network. Moreover, we revealed that the regions mapped are correlated with the Default Mode Network sub-network C. Taken together, this study provides causal evidence for the distribution of the spatial cognitive system, demarking the major components and identifying novel regions.

Remote spatial and autobiographical memory in cases of episodic amnesia and topographical disorientation.

A number of theories have postulated that there is a strong relationship between episodic memory and spatial processes mediated by the hippocampus. Evidence for episodic amnesia following damage to the medial temporal lobes is extensive, but less is known about the types of spatial memory affected by damage to these regions. In this study, we compared episodic memory with detailed scene memory, landmark recognition and schematic (map-based) spatial memory in a group of individuals with amnesia related to damage to the medial temporal lobes (MTL) including the hippocampus. We compared their performance to matched controls, and to an individual with topographical disorientation, a selective spatial memory deficit relating to more posterior temporal and occipital lobe damage. For individuals with MTL lesions, impairments to scene memory were comparable to those in episodic memory. Landmark recognition was impaired only for less familiar landmarks, and schematic spatial memory was not impaired compared to controls. Despite the absence of hippocampal damage, the individual with topographical disorientation, like the MTL amnesic patients, demonstrated impairments to scene memory and recognition of less familiar landmarks, and intact schematic spatial memory, but with less severe episodic memory loss. These results highlight the similarities between detailed scene memory and episodic memory, including their reliance on the medial temporal lobe, and suggest that more schematic forms of spatial memory may be unaffected by medial temporal damage. In addition, the results suggest that damage to more posterior temporal or occipital regions that leads to spatial memory deficits may entail some impairment to episodic memory even if the hippocampus is spared.

Pituitary Metastasis in a Patient with Pulmonary Adenocarcinoma Presenting with a Disturbance of Consciousness.

BACKGROUND: Brain metastases are one of the main causes of morbidity and mortality of patients with oncological disease. In non-small cell lung carcinoma (NSCLC), the risk of CNS secondary development is 30-50%. An unusual diagnostic and therapeutic problem is the finding of suspicious pituitary lesions. Obtaining a differential diagnosis relies on evaluating the clinical course of the disease (visual disturbances, diabetes insipidus (DI), weakness etc.), and performing endocrinological examinations and imaging analyses (CT, but mainly MRI). Sometimes, however, definitive resolution of the problem requires histological assessment of the tumor. CASE REPORT: A 65-year-old patient with a newly diagnosed metastatic lung adenocarcinoma was admitted to our department for a first cycle of chemotherapy consisting of cisplatin and navelbine. However, at the beginning of hospitalization, the patient developed qualitative disturbances in consciousness and disorientation. Emergency CT of the CNS revealed a tumor of the pituitary gland, and a subsequent MRI showed intraseller and suprasellar masses making contact with the optic chiasma. An endocrinological examination revealed panhypopituitarism. Pituitary metastasis of NSCLC was confirmed by tumor histology using the trans-sphenoid approach. CONCLUSION: Lung and breast carcinomas are among the most common cancers to metastasize to the pituitary gland. The incidence of pituitary metastases is reported to be 0.4-28.1%. Clinically, they are mostly silent, but may manifest as endocrine disorders, such as DI, hypothyroidism, and hypocorticism, or as visual disturbances due to compression of the optic nerve. Management depends on the establishment of a correct diagnosis. Key words: hypopituitarism - magnetic resonance imaging - pituitary neoplasm - radiosurgery - targeted therapy The authors declare they have no potential confl icts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 26. 4. 2018 Accepted: 27. 6. 2018.

Splenial Lesions of the Corpus Callosum: Disease Spectrum and MRI Findings.

The corpus callosum (CC) is the largest white matter structure in the brain, consisting of more than 200-250 million axons that provide a large connection mainly between homologous cerebral cortical areas in mirror image sites. The posterior end of the CC is the thickest part, which is called the splenium. Various diseases including congenital to acquired lesions including congenital anomalies, traumatic lesions, ischemic diseases, tumors, metabolic, toxic, degenerative, and demyelinating diseases, can involve the splenium of the CC and their clinical symptoms and signs are also variable. Therefore, knowledge of the disease entities and the imaging findings of lesions involving the splenium is valuable in clinical practice. MR imaging is useful for the detection and differential diagnosis of splenial lesions of the CC. In this study, we classify the disease entities and describe imaging findings of lesions involving the splenium of the CC based on our experiences and a review of the literature.

Developmental Topographical Disorientation.

Developmental topographical disorientation (DTD) refers to the lifelong inability to orient in extremely familiar surroundings despite the absence of any acquired brain damage or neurological disorder. Here, we describe the findings of this newly discovered condition, and highlight how this phenomenon provides novel insights into the mechanisms underlying human spatial navigation.

Delírium en la versión en español del DSM-5: ¿más confusión? / Delirium in the Spanish version of the DSM-5: more confusion?

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Lost in spatial translation - A novel tool to objectively assess spatial disorientation in Alzheimer's disease and frontotemporal dementia.

Spatial disorientation is a prominent feature of early Alzheimer's disease (AD) attributed to degeneration of medial temporal and parietal brain regions, including the retrosplenial cortex (RSC). By contrast, frontotemporal dementia (FTD) syndromes show generally intact spatial orientation at presentation. However, currently no clinical tasks are routinely administered to objectively assess spatial orientation in these neurodegenerative conditions. In this study we investigated spatial orientation in 58 dementia patients and 23 healthy controls using a novel virtual supermarket task as well as voxel-based morphometry (VBM). We compared performance on this task with visual and verbal memory function, which has traditionally been used to discriminate between AD and FTD. Participants viewed a series of videos from a first person perspective travelling through a virtual supermarket and were required to maintain orientation to a starting location. Analyses revealed significantly impaired spatial orientation in AD, compared to FTD patient groups. Spatial orientation performance was found to discriminate AD and FTD patient groups to a very high degree at presentation. More importantly, integrity of the RSC was identified as a key neural correlate of orientation performance. These findings confirm the notion that i) it is feasible to assess spatial orientation objectively via our novel Supermarket task; ii) impaired orientation is a prominent feature that can be applied clinically to discriminate between AD and FTD and iii) the RSC emerges as a critical biomarker to assess spatial orientation deficits in these neurodegenerative conditions.

What to see when you are looking at confusion: a review of the neuroimaging of acute encephalopathy.

Acute encephalopathy is a clinical conundrum in neurocritical care facing physicians with diagnostic and therapeutic challenges. Encephalopathy arises from several concurrent causes, and delayed diagnosis adds to its grim prognosis. Diagnosis is reached by melding clinical, neurophysiological and biochemical features with various neuroimaging studies. We aimed to compile the pathophysiology of acute encephalopathies in adults, and the contribution of cerebral CT, MRI, MR spectroscopy (MRS), positron emission tomography (PET) and single-photon emission CT (SPECT) to early diagnosis, treatment and prognostication. Reports from 1990 to 2013 were identified. Therefore, reference lists were searched to identify additional publications. Encephalopathy syndromes best studied by neuroimaging emerge from hypoxic-ischaemic injury, sepsis, metabolic derangements, autoimmune diseases, infections and rapidly evolving dementias. Typical and pathognomonic neuroimaging patterns are presented. Cerebral imaging constitutes an important component of diagnosis, management and prognosis of acute encephalopathy. Its respective contribution is dominated by rapid exclusion of acute cerebral lesions and further varies greatly depending on the underlying aetiology and the range of possible differential diagnoses. CT has been well studied, but is largely insensitive, while MRI appears to be the most helpful in the evaluation of encephalopathies. MRS may provide supplementary biochemical information and determines spectral changes in the affected brain tissue. The less frequently used PET and SPECT may delineate areas of high or low metabolic activity or cerebral blood flow. However, publications of MRS, PET and SPECT are limited only providing anecdotal evidence of their usefulness and sensitivity.

Rehabilitation in a complex case of topographical disorientation.

This paper describes the rehabilitation process of a patient with severe topographical disorientation. The study demonstrates the sustained effects of a tailor-made, meticulous rehabilitation programme based on the gradual development of compensatory strategies. The patient (RB) had a memory impairment specific to environmental landmarks. He was able to recognise objects in his environment, but was unable to identify any salient object as a landmark and was also unable to derive any directional information from a chosen landmark. As such, his topographical disorientation syndrome was complex in that he had elements of both landmark agnosia and a heading disorientation, as described by Aguirre and D'Esposito (1999). Because of this dual damage to the exocentric framework, the tools and methods used in RB's rehabilitation programme were all based on his intact egocentric frame of reference. Remarkable training effects were found for routes he used frequently. After years of training he could walk these routes without the aid of the written information he had used previously, which can be interpreted as a form of implicit learning. In the 12 years we followed this patient some transfer occurred, as the patient was ultimately able to identify his own landmarks. However, RB remains dependent on other people to construct new routes for him on the basis of these landmarks.

What does a comparison of the alcoholic Korsakoff syndrome and thalamic infarction tell us about thalamic amnesia?

In this review, the clinical, neuropsychological, and neuroimaging findings in the alcoholic Korsakoff syndrome and in thalamic amnesia, resulting from focal infarction, are compared. In both disorders, there is controversy over what is the critical site for anterograde amnesia to occur-damage to the anterior thalamus/mammillo-thalamic tract has most commonly been cited, but damage to the medio-dorsal nuclei has also been advocated. Both syndromes show 'core' features of an anterograde amnesic syndrome; but retrograde amnesia is generally much more extensive (going back many years or decades) in the Korsakoff syndrome. Likewise, spontaneous confabulation occurs more commonly in the Korsakoff syndrome, although seen in only a minority of chronic cases. These differences are attributed to the greater prevalence of frontal atrophy and frontal damage in Korsakoff cases.

Posterior reversible encephalopathy syndrome secondary to blood transfusion.

The appearance of posterior reversible encephalopathy syndrome (PRES) after blood transfusion is rare and has only been reported in three patients to our knowledge. We report a fourth patient with PRES secondary to blood transfusion. A 36-year-old woman with a history of menorrhagia presented to the emergency department with severe fatigue. She had a hemoglobin of 1.7 g/dl and received four units of red blood cells over 15 hours. On day 6 post-transfusion she returned with confusion, headache and a generalized tonic-clonic seizure. The MRI of her brain was consistent with PRES. The following day her confusion worsened, repeat MRI of the brain showed new T2-weighted lesions. Over next 10 days her mental status gradually improved close to her baseline. A repeat MRI of the brain showed resolution of the T2-weighted lesions. The clinical presentation, radiological findings and disease progression in our patient was consistent with PRES. Other than the blood transfusions, there were no apparent risk factors for PRES. The prior three patients with post-transfusion PRES have been reported in middle-aged women with uterine fibroids. It is suspected that these patients have a subacute to chronic anemic state due to ongoing menorrhagia. It is interesting to note that no cases of PRES post-transfusion have been reported in the setting of acute blood loss, such as from trauma. It is postulated that an abrupt increase in hemoglobin causes a rapid rise in blood viscosity and loss of hypoxic vasodilation. Subsequent endothelial damage and brain capillary leakage results in PRES. This constellation of changes may not occur after transfusion in patients with more acute blood loss.

Brain MRI in neuropsychiatric lupus: associations with the 1999 ACR case definitions.

The purpose of this study was to identify the characteristic magnetic resonance imaging (MRI) findings in neuropsychiatric systemic lupus erythematosus (NPSLE) and to investigate the association between MRI findings and neuropsychiatric manifestations in SLE. Brain MRIs with a diagnosis of SLE from 2002 to 2013 from three tertiary university hospitals were screened. All clinical manifestations evaluated by brain MRI were retrospectively reviewed. If the clinical manifestations were compatible with the 1999 NPSLE American College of Rheumatology (ACR) nomenclature and case definitions, the brain MRIs were assessed for the presence of white matter hyperintensities, gray matter hyperintensities, parenchymal defects, atrophy, enhancement, and abnormalities in diffusion-weighted images (DWI). The number, size, and location of each lesion were evaluated. The neuropsychiatric manifestation of each brain MRI was classified according to the 1999 ACR NPSLE case definitions. The associations between MRI findings and NPSLE manifestations were examined. In total, 219 brain MRIs with a diagnosis of SLE were screened, and 133 brain MRIs met the inclusion criteria for NPSLE. The most common MRI abnormality was white matter hyperintensities, which were observed in 76 MRIs (57.1 %). Gray matter hyperintensities were observed in 41 MRIs (30.8 %). Parenchymal defects were found in 31 MRIs (23.3 %), and atrophy was detected in 20 MRIs (15.0 %). Patients who had seizures were more associated with gray matter hyperintensities than patients with other neuropsychiatric manifestations. Patients with cerebrovascular disease were more associated with gray matter hyperintensity, parenchymal defects, and abnormal DWI than patients with other neuropsychiatric manifestations. In addition to white matter hyperintensities, which were previously known as SLE findings, we also noted the presence of gray matter hyperintensities, parenchymal defects, and abnormal DWI in a substantial portion of SLE patients, particularly in those with cerebrovascular disease or seizures.

The usefulness of confusion, urea, respiratory rate, and shock index or adjusted shock index criteria in predicting combined mortality and/or ICU admission compared to CURB-65 in community-acquired pneumonia.

BACKGROUND AND OBJECTIVES: The study aims to assess the usefulness of age-independent criteria CURSI and temperature adjusted CURSI (CURASI) compared to CURB-65 in predicting community-acquired pneumonia (CAP) mortality. The criteria, CRSI and CRASI, were adapted for use in primary care and compared to CRB-65. METHODS: A retrospective analysis of a prospectively identified cohort of community-acquired pneumonia inpatients was conducted. Outcomes were (1) mortality and (2) mortality and/or ICU admission within six weeks. RESULTS: 95 patients (median age = 61 years) were included. All three criteria had similar sensitivity in predicting mortality alone, with CURB-65 having slightly higher specificity. When predicting mortality and/or intensive care admission, CURSI/CURASI showed higher sensitivity and slightly lower specificity. CRSI and CRASI had higher sensitivity and lower specificity when compared with CRB-65 for predicting both primary and secondary outcomes. Results for both analyses had P values >0.05. CONCLUSIONS: In a cohort of younger patients CURSI and adjusted CURSI perform at least as well as CURB-65, with a similar trend for CRSI and adjusted CRSI compared to CRB-65. Further studies are needed in different age groups and in primary and secondary care settings.

Non-focal neurological symptoms associated with classical presentations of transient ischaemic attack: qualitative analysis of interviews with patients.

BACKGROUND: Improving the recognition of transient ischaemic attack (TIA) at initial healthcare contact is essential as urgent specialist assessment and treatment reduces stroke risk. Accurate TIA detection could be achieved with clinical prediction rules but none have been validated in primary care. An alternative approach using qualitative analysis of patients' experiences of TIA may identify novel features of the TIA phenotype that are not detected routinely, as such techniques have revealed novel early features of other important conditions such as meningococcaemia. We sought to determine whether the patient's experience of TIA would reveal additional deficits that can be tested prospectively in cohort studies to determine their additional diagnostic and prognostic utility at the first healthcare contact. METHODOLOGY AND FINDINGS: Qualitative semi-structured interviews with 25 patients who had experienced definite TIA as determined by a stroke specialist; framework analysis to map symptoms and key words or descriptive phrases used against each individual, with close attention to the detail of the language used. All interview transcripts were reviewed by a specialist clinician with experience in TIA/minor stroke. Patients described non-focal symptoms consistent with higher function deficits in spatial perception and awareness of deficit, as well as feelings of disconnection with their immediate surroundings. Of the classical features, weakness and speech disturbance were described in ways that did not meet the readily recognisable phenotype. CONCLUSION/SIGNIFICANCE: Analysis of patients' narrative accounts reveals a set of overlooked features of the experience of TIA which may provide additional diagnostic utility so that providers of first contact healthcare can recognise TIA more easily. Future research is required in a prospective cohort of patients presenting with transient neurological symptoms to determine how frequent these features are, what they add to diagnostic information and whether they can refine measures to predict stroke risk.

False positives to confusable objects predict medial temporal lobe atrophy.

Animal models agree that the perirhinal cortex plays a critical role in object recognition memory, but qualitative aspects of this mnemonic function are still debated. A recent model claims that the perirhinal cortex is required to recognize the novelty of confusable distractor stimuli, and that damage here results in an increased propensity to judge confusable novel objects as familiar (i.e., false positives). We tested this model in healthy participants and patients with varying degrees of perirhinal cortex damage, i.e., amnestic mild cognitive impairment and very early Alzheimer's disease (AD), with a recognition memory task with confusable and less confusable realistic object pictures, and from whom we acquired high-resolution anatomic MRI scans. Logistic mixed-model behavioral analyses revealed that both patient groups committed more false positives with confusable than less confusable distractors, whereas healthy participants performed comparably in both conditions. A voxel-based morphometry analysis demonstrated that this effect was associated with atrophy of the anteromedial temporal lobe, including the perirhinal cortex. These findings suggest that also the human perirhinal cortex recognizes the novelty of confusable objects, consistent with its border position between the hierarchical visual object processing and medial temporal lobe memory systems, and explains why AD patients exhibit a heightened propensity to commit false positive responses with inherently confusable stimuli.

Circulating microparticles in neuropsychiatric systemic lupus erythematosus.

AIM: Phosphatidylserine-rich microparticles derived from endothelial cells, platelets and leukocytes have been implicated as surrogate markers of cellular activation in systemic lupus erythematosus (SLE). Because microparticles have also been associated with many primary neurologic diseases, this study investigated whether cellular-derived microparticles are also implicated in neuropsychiatric SLE (NPSLE). METHOD: Plasma microparticles were measured in 51 SLE patients and 22 age- and gender-matched controls. Acute NPSLE was defined as major NPSLE (acute stroke, transient ischemic attack, psychosis, isolated seizures, major cognitive disorder, or acute confusional state) and NPSLE disease activity was measured with the neurologic components of the SLE Disease Activity Index (Neuro-SLEDAI). RESULTS: Neuro-SLEDAI levels varied widely in SLE patients, consistent with variable NPSLE activity. When considering all patients with SLE, there was no difference in total microparticles relative to matched controls, 2158/µL (interquartile range [IQR] 1214-3463) versus 2782/µL (IQR 1586-2990; P = 0.57) nor differences in microparticles derived from either platelets (P = 0.40), monocytes (P = 0.15) or endothelial cells (P = 0.32). However, levels of circulating monocyte-derived microparticles significantly and independently correlated with NPSLE (r = -0.28; P = 0.045), corticosteroid dosage (r = -0.38; P = 0.006) and levels of circulating C5a (r = 0.54; P < 0.0001). Non-neurologic SLE disease activity was not associated with microparticles. CONCLUSION: Circulating cell-derived microparticles are reduced in active NPSLE, although the relative contribution of reduced microparticle production, increased consumption or intravascular sequestration, remain uncertain.