Consensus Clinical Diagnostic Criteria Research Articles

Clinical and molecular characterization of patients with hereditary hemorrhagic telangiectasia from two different regions of Brazil

Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia characterized hemorrhagic diseases described in consensus clinical diagnostic criteria (Curaçao). We describe the clinical and molecular characteristics of HHT patients from two different geographic regions of Brazil (São Paulo and Manaus). Demographic and clinical data were obtained from the electronic medical records and molecular analysis was performed by Sanger sequencing. We present here the first clinical characterization concomitantly with a molecular study of patients with THH in Brazil. These clinical characterizations may reveal differences in the molecular pathophysiology of HHT in Brazil - that our phenotypic database opens the way to be studied, or indicate limitations in the care of these patients, who need a multidisciplinary attention to prevent and treat the complications of this condition. Our results, combined with our previous data with patients presenting mutation rate to 93,75% (n=15/16) in Brazilians patients with a confirmed clinical diagnosis. Also emphasize the higher numbers of intronic mutations and three large deletions 5ÙTR regions and the predominance of ACVRL1 over ENG mutations.

Brain regions show different metabolic and protein arginine methylation phenotypes in frontotemporal dementias and Alzheimer's disease.

Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disease with multiple histopathological subtypes. FTD patients share similar symptoms with Alzheimer's disease (AD). Hence, FTD patients are commonly misdiagnosed as AD, despite the consensus clinical diagnostic criteria. It is therefore of great clinical need to identify a biomarker that can distinguish FTD from AD and control individuals, and potentially further differentiate between FTD pathological subtypes. We conducted a metabolomic analysis on post-mortem human brain tissue from three regions: cerebellum, frontal cortex and occipital cortex from control, FTLD-TDP type A, type A-C9, type C and AD. Our results indicate that the brain subdivisions responsible for different functions show different metabolic patterns. We further explored the region-specific metabolic characteristics of different FTD subtypes and AD patients. Different FTD subtypes and AD share similar metabolic phenotypes in the cerebellum, but AD exhibited distinct metabolic patterns in the frontal and occipital regions compared to FTD. The identified brain region-specific metabolite biomarkers could provide a tool for distinguishing different FTD subtypes and AD and provide the first insights into the metabolic changes of FTLD-TDP type A, type A-C9, type C and AD in different regions of the brain. The importance of protein arginine methylation in neurodegenerative disease has come to light, so we investigated whether the arginine methylation level contributes to disease pathogenesis. Our findings provide new insights into the relationship between arginine methylation and metabolic changes in FTD subtypes and AD that could be further explored, to study the molecular mechanism of pathogenesis.

ASNC Imaging Indications (ASNC-I2): Multisocietal indications for radionuclide imaging in the multimodality context—Series rationale and methodology

BackgroundAppropriate use criteria (AUC) enhance application of cardiovascular imaging techniques but have been applied in limited settings, primarily in common cardiovascular disease processes. There are several complex systemic diseases with cardiovascular implications and special populations with unique cardiovascular considerations that could benefit from appropriateness analysis. Moreover, the high medical complexity of these topics indicate they would benefit from high-yield expert consensus recommendations of the available imaging options. The ASNC Imaging Indications (ASNC-I2) Series will provide a concise overview of relevant disease processes and their multimodality evaluation and will provide consensus clinical indications, diagnostic criteria, and clinical algorithms with representative clinical cases. MethodsFor each ASNC-I2 document, a diverse writing group and rating panel will be composed of experts from societies pertinent to the topic, including relevant imaging societies and clinical societies that manage the disease under evaluation. The rating panel will follow robust modified Delphi methodology and commonly-accepted appropriateness methods to create consensus diagnostic criteria, clinical algorithms, and clinical indications that they will then rate with level of agreement recorded. The clinical and imaging experts will provide concise, high-yield clinical summaries of the disease process, the non-imaging evaluation, and multimodality imaging. Relevant cases will be provided highlighting application of the diagnostic criteria and clinical algorithms. ConclusionThe ASNC Imaging Indications (ASNC-I2) Series will complement the diverse portfolio of documents from ASNC. It will use a multisocietal approach with robust appropriateness methodology to guide use of radionuclide imaging in the multimodality imaging context for the cardiovascular care of patients.

Phenotypes and Biomarkers in Posterior Cortical Atrophy: Application of Consensus Clinical Diagnostic Criteria and the AT(N) Framework (P5.1-026)

Phenotypes and Biomarkers in Posterior Cortical Atrophy: Application of Consensus Clinical Diagnostic Criteria and the AT(N) Framework (P5.1-026)

Role of Neuroimaging as a Biomarker for Neurodegenerative Diseases.

It has recently been recognized that neurodegenerative diseases are caused by common cellular and molecular mechanisms including protein aggregation and inclusion body formation. Each type of neurodegenerative disease is characterized by the specific protein that aggregates. In these days, the pathway involved in protein aggregation has been elucidated. These are leading to approaches toward disease-modifying therapies. Neurodegenerative diseases are fundamentally diagnosed pathologically. Therefore, autopsy is essential for a definitive diagnosis of a neurodegenerative disease. However, recently, the development of various molecular brain imaging techniques have enabled pathological changes in the brain to be inferred even without autopsy. Some molecular imaging techniques are described as biomarker in diagnostic criteria of neurodegenerative disease. Magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), positron emission tomography (PET), and amyloid imaging are described in the diagnostic guidelines for Alzheimer’s disease in the National Institute on Aging-Alzheimer’s Association. MRI, dopamine transporter (DAT) imaging, and 123I-metaiodobenzyl-guanidine (MIBG) myocardial scintigraphy listed in the guidelines for consensus clinical diagnostic criteria for dementia with Lewy bodies are described as potential biomarkers. The Movement Disorder Society Progressive Supranuclear Palsy Study Group defined MRI, SPECT/PET, DAT imaging, and tau imaging as biomarkers. Other diagnostic criteria for neurodegenerative disease described neuroimaging findings as only characteristic finding, not as biomarker. In this review, we describe the role of neuroimaging as a potential biomarker for neurodegenerative diseases.

Clinical Practice Guidelines for Management of Dementia.

Indian Psychiatric Society (IPS) published Clinical Practice Guidelines (CPGs) for management of dementia, in the year 2007. (http://www.indianjpsychiatry.org/cpg2007.asp). The current version of the CPG is an update of the earlier version of CPGs for management of dementia There were three separate CPGs for management of dementia, one each for Reversible Dementias, Alzheimer's Disease and Vascular Dementia, Please note that the present CPG on dementia deals all types of dementia together. The current version of the CPGs for dementia in elderly must be read in conjunction with the previous version of CPGs for dementia. The focus of the present CPG is to provide suggestions and clinical tips to differentiate dementia syndrome from other clinical conditions, identify the subtypes of dementia and then offer suggestions for management. These guidelines only provide a broad framework for assessment, management and follow-up of older people with dementia. While most of the recommendations are evidence based, these guidelines should not be considered as a substitute of professional knowledge and clinical judgment. The recommendations made as part of these guidelines should be tailored to address the clinical needs of the individual patient and the treatment setting.

Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era.

Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia characterized by telangiectases and arteriovenous malformations (AVMs) in particular locations described in consensus clinical diagnostic criteria published in 2000. Two genes in the transforming growth factor-beta (TGF-β) signaling pathway, ENG and ACVRL1, were discovered almost two decades ago, and mutations in these genes have been reported to cause up to 85% of HHT. In our experience, approximately 96% of individuals with HHT have a mutation in these two genes, when published (Curaçao) diagnostic criteria for HHT are strictly applied. More recently, two additional genes in the same pathway, SMAD4 and GDF2, have been identified in a much smaller number of patients with a similar or overlapping phenotype to HHT. Yet families still exist with compelling evidence of a hereditary telangiectasia disorder, but no identifiable mutation in a known gene. Recent availability of whole exome and genome testing has created new opportunities to facilitate gene discovery, identify genetic modifiers to explain clinical variability, and potentially define an increased spectrum of hereditary telangiectasia disorders. An expanded approach to molecular diagnostics for inherited telangiectasia disorders that incorporates a multi-gene next generation sequencing (NGS) HHT panel is proposed.

The usefulness of the consensus clinical diagnostic criteria in Brugada syndrome

BackgroundConsensus statements were proposed for the diagnosis of Brugada syndrome (BS). The clinical diagnostic criteria were defined as documented ventricular fibrillation or ventricular tachycardia (VT), family history of sudden cardiac death at <45years, diagnostic ECGs of family members, inducibility of VT during electrophysiological study, syncope or nocturnal agonal respiration. The clinical validation of these criteria is still missing.Methods and results280 patients (41±18years, male: 168 pts) with diagnostic coved type I ECG were included. Consensus clinical diagnostic criteria were present in 244 (87%) patients (40±18y, 142 males). In 36 pts (13% of the 280 pts, 51±12years, 27 males) consensus clinical diagnostic criteria were not met. Nine patients (25%) presented with spontaneous type I ECG. Ten of the 36 patients (28%) had a history of atrial fibrillation and 13 (36%) had conduction disease on the baseline ECG. In 23 patients (64%) family screening was not performed. Two of the 36 patients had undocumented syncope during follow-up. Univariate analysis showed no significant difference in event free survival between patients with or without consensus clinical diagnostic criteria. ConclusionsIn a significant number of patients with diagnostic ECG pattern the current diagnostic criteria for BS are not met. These patients have frequently spontaneous type I ECG and clinical signs of Brugada syndrome as paroxysmal atrial fibrillation or conduction disturbances. Our results suggest that in patients with a diagnostic type I ECG pattern the current clinical consensus diagnostic criteria have limited added diagnostic value.

Diagnostic Performance of Three-Phase Bone Scan for Complex Regional Pain Syndrome Type 1 with Optimally Modified Image Criteria

Although the three-phase bone scan (TBPS) is one of the widely used imaging studies for diagnosing complex regional pain syndrome type I (CRPS-1), there is some controversy regarding the TPBS image criteria for CRPS-1. In this study, we modified the image criteria using image pattern and quantitative analysis in the patients diagnosed using the most recent consensus clinical diagnostic criteria. The study included 140 patients with suspected CRPS-1 (CRPS-1, n = 79; non-CRPS, n = 61; mean age 39 ± 15 years) who underwent TPBS. The clinical diagnostic criteria for CRPS-1 revised by the Budapest consensus group were used for confirmative diagnosis. Patients were classified according to flow/pool and delayed uptake (DU) image patterns, and the time interval between the initiating event and TPBS (TIevent-scan). Quantitative analysis for lesion-to-contralateral ratio (LCR) was performed. Modified TPBS image criteria were created and evaluated for optimal diagnostic performance. Both increased and decreased periarticular DU were significant image findings for CRPS-1 (CRPS-1 positive-rate = 73% in the increased DU group, 75% in the decreased DU group). The TIevent-scan did not differ significantly between the different image pattern groups. Quantitative analysis revealed an LCR of 1.43 was the optimal cutoff value for CRPS-1 and diagnostic performance was significantly improved in the increased DU group (area under the curve = 0.732). Given the modified image criteria, the sensitivity and specificity of TPBS for diagnosing CRPS-1 were 80% and 72%, respectively. Optimally modified TPBS image criteria for CRPS-1 were suggested using image pattern and quantitative analysis. With the criteria, TPBS is an effective imaging study for CRPS-1 even with the most recent consensus clinical diagnostic criteria.

Frontotemporal Dementia—A Chameleon?

To the Editor: Frontotemporal dementia (FTD) is a pathologically heterogeneous illness characterized by progressive atrophy of the frontal and anterior temporal cortex. Some cases are familial, but the etiology is more often idiopathic.1 There is no known treatment, and the illness progresses inexorably to death, with a mean survival of about 8 years.1 FTD is often misdiagnosed because of its confusing initial presentation.2–4 A variety of psychiatric symptoms may be seen during the course of illness. We describe a patient with FTD who presented initially with mood and psychotic symptoms. Case report. Ms A, a 45-year-old woman, was in good health until May 2008. Her initial symptoms were depressed mood, crying spells, decreased energy, anhedonia, and poor appetite and sleep and were attributed to her father's death. She also reported that the police were keeping her under surveillance and that a neighbor was “messing with my head” and trying to harm her children, leading to homicidal threats. After accosting the neighbor, she was admitted with a diagnosis of bipolar disorder, mixed, with psychotic features (DSM-IV criteria). Results of routine laboratory work, urine drug screen, and computed tomography scan were unremarkable. After 3 weeks of inpatient treatment, she was discharged with improvement of symptoms and resolution of the homicidal ideation. Within 1 month, a change in her behavior was noticed; she became loud and aggressive, started making obscene calls to her mother, and developed pressured speech. She quickly deteriorated, becoming dependent in activities of daily living. She was readmitted in December 2008; this admission lasted for about 3 months. Results from full medical and neurologic evaluation, including magnetic resonance imaging scan, electroencephalogram, and lumbar puncture, were unrevealing. Neuropsychological testing revealed prominent executive dysfunction, and positron emission tomography scan revealed severe frontal and temporal hypometabolism. The DSM-IV criteria for dementia were used and, furthermore, were also correlated with the Consensus Clinical Diagnostic Criteria for frontotemporal dementia.5 On presentation to our Memory Disorder Clinic in November 2009, she was mute, minimally interactive, and markedly apathetic; there was also some evidence of dysphagia. The family reported trials of numerous psychotropic medications, all with minimal effect. She had an unsteady gait, swaying from side to side and magnetic in nature. She was restless, repeatedly rising from her seat, but was easily redirected. Her mood could not be assessed, but her affect was flat. It did not appear that she was responding to internal stimuli. She died in January 2010. Frontotemporal dementia is the second most common dementia in younger individuals.6 A young person presenting with psychotic and mood symptoms may suggest a primary psychiatric diagnosis, but the clinician must consider a neuropsychiatric syndrome such as FTD. Often, the clinical picture will evolve over time. Importantly, the consensus criteria for diagnosis of FTD do not emphasize psychiatric features.3 For our patient, the onset of what appeared to be a typical depressive illness after her father's death proved to be a “red herring.” While she clearly presented with symptoms of a delusional depression, the clinical picture quickly evolved with increasing dependence in activities of daily living and mutism, and death soon followed. A review of the literature reveals cases in which the initial presentation of FTD was suggestive of a primary psychotic illness or a mood disorder.4,7 A greater index of suspicion for FTD in younger patients with new-onset psychiatric symptoms, and a longitudinal view as the disease progresses, will lead to better clinical diagnosis.

A validation exercise on the new consensus criteria for multiple system atrophy

The revised (new) consensus clinical diagnostic criteria for multiple system atrophy (MSA) were published in 2008. To validate these criteria, we utilized the same cohort that we reported previously, which included 59 patients with a clinical diagnosis of MSA that was confirmed neuropathologically in 51 of them at the Queen Square Brain Bank for Neurological Disorders. At the first clinic visit, sensitivity with new consensus possible category was higher, and PPV marginally higher, than for clinical diagnosis and old consensus possible category. New consensus probable category showed marginally higher sensitivity than, and the same PPV as, old consensus probable category. At the last clinic visit, new consensus possible category had exactly the same sensitivity and only marginally higher PPV compared with old consensus possible category. New consensus probable category showed the same sensitivity and PPV as old consensus probable category. Our data indicate that in this case material the new consensus criteria for possible MSA could improve diagnostic accuracy at first neurological evaluation compared with the old consensus criteria. Prospective clinicopathological validation studies of the new consensus criteria, particularly incorporating in vivo structural and functional imaging results, are required to extend the current findings.

Evidence-Based Evaluation of Diagnostic Accuracy of Resting EEG in Dementia and Mild Cognitive Impairment

Cognitive impairment is the most frequent chronic condition in the elderly, and dementia is the most disabling form of cognitive impairment in elderly. In the absence of specific and reliable markers of etiologically different dementia syndromes and their preclinical stages, diagnosis in living patients is probabilistic and based on standardized clinical diagnostic criteria. There is still not enough information on the validity of the EEG method in dementia work-up, and an updated evidence-based consensus on appropriateness of this method in the initial evaluation of patients with suspected cognitive disorder and dementia is missing. Using an evidence-based technique we searched for articles on diagnostic accuracy of spontaneous EEG in dementia disorders published from 1980 until June 2008. Inclusion criteria were: original article published in English with 10 or more subjects per diagnostic group, diagnosed according to the established consensus clinical diagnostic criteria used as a "gold standard." In addition, it should have been possible to calculate from the reported results indexes of diagnostic test accuracy: sensitivity, specificity, likelihood ratios and diagnostic odds ratios. Forty-six articles were retrieved that satisfied eligibility criteria. Thirty-four (74%) studies employed case-control design where study population was recruited from consecutive patients at specialist clinic settings, 12 (26%) were prospective in terms of reported clinical followup of study population. Four (9%) studies used population-based samples and 5 (11%) studies stated in methods the recruitment procedures for patients and healthy subjects. Number of patients included in diagnostic groups and healthy subjects varied in included studies between 10 and 180 and 10 and 171, respectively. Figures on sensitivity and specificity across the studies varied widely. Positive likelihood ratio in studies reporting classification accuracies between Alzheimer's disease and controls ranged between 2.3 and 38.5, and diagnostic odds ratios consequently showed large variations between 7 and 219. In conclusion, despite the wealth of published research and reported high indexes of diagnostic accuracy of EEG, and qEEG in particular, in individual studies, evidence of diagnostic utility of resting EEG in dementia and mild cognitive impairment (MCI) is still not sufficient to establish this method for the initial evaluation of subjects with cognitive impairment in the routine clinical practice. Joint effort of preferably multicenter studies using uniform standards should develop optimized methods, investigate added diagnostic value of EEG in clinically established dementia diagnosis and predictive utility of EEG in MCI and questionable dementia.

Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): Report of the Consortium on DLB International Workshop

Dementia with Lewy bodies (DLB) was considered to be an uncommon cause of dementia until improved neuropathological staining methods for ubiquitin were developed in the late 1980's. Subsequent recognition that 10-15% of dementia cases in older people were associated with Lewy body pathology led to the publication in 1996 of Consensus clinical and pathological diagnostic criteria for the disorder. These have greatly raised global awareness of DLB and helped to generate a body of knowledge which informs modern clinical management of this pharmacologically sensitive group of patients. They have also enabled important issues surrounding the relationships of DLB with Alzheimer's disease and Parkinson's disease to be addressed and partially resolved. A recent re-evaluation of the Consensus criteria has confirmed many aspects of the original recommendations, supplementing these with suggestions for improved pathological characterisation, clinical detection and management. Virtu-ally unrecognised 20 years ago, DLB could within this decade be one of the best characterised and potentially treatable neurodegenerative disorders of late life.

Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome).

Hereditary Hemorrhagic Telangiectasia (HHT) is easily recognized in individuals displaying the classical triad of epistaxis, telangiectasia, and a suitable family history, but the disease is more difficult to diagnosis in many patients. Serious consequences may result if visceral arteriovenous malformations, particularly in the pulmonary circulation, are unrecognized and left untreated. In spite of the identification of two of the disease-causing genes (endoglin and ALK-1), only a clinical diagnosis of HHT can be provided for the majority of individuals. On behalf of the Scientific Advisory Board of the HHT Foundation International, Inc., we present consensus clinical diagnostic criteria. The four criteria (epistaxes, telangiectasia, visceral lesions and an appropriate family history) are carefully delineated. The HHT diagnosis is definite if three criteria are present. A diagnosis of HHT cannot be established in patients with only two criteria, but should be recorded as possible or suspected to maintain a high index of clinical suspicion. If fewer than two criteria are present, HHT is unlikely, although children of affected individuals should be considered at risk in view of age-related penetration in this disorder. These criteria may be refined as molecular diagnostic tests become available in the next few years.

Dementia with Lewy bodies

Dementia with Lewy bodies (DLB), the second most frequent cause of primary degenerative dementias following Alzheimer's disease, has been increasingly recognized since the proposal of the consensus name and clinical diagnostic criteria. Although DLB overlaps in clinical, pathological, and genetic features with Alzheimer's disease and Parkinson's disease, DLB should be understood as an entity with the essential feature of the presence of Lewy bodies in the brain stem and cerebral cortex. From the clinical point of view, DLB is characterized by the presence of progressive dementia without severe memory disorders at the early stage, with significant cognitive fluctuations, well-formed recurrent visual hallucinations, and spontaneous Parkinsonism. This article reviews recent clinical and research findings, including our own, to facilitate clinical recognition of DLB. In addition to the supportive features described in the consortium clinical diagnostic criteria for DLB such as falls and great sensitivity to neuroleptic drugs, our studies found other frequent disorders including disproportionately severe visuoconstructive and visuoperceptual disturbances, transitory alterations in consciousness with reduplication phenomena, misidentification delusions, and non-aphasic misnamings. Neuroimaging features include relatively preserved hippocampal volume on MRI and occipital involvement on metabolic and blood flow imagings. The correct diagnosis of DLB is important to administer adequate treatment, to avoid adverse effects with neuroleptic drugs, and to establish precise prognosis. The present summary of the clinical features is hopefully helpful for clinical diagnosis of DLB. From a therapeutic point of view, cholinesterase inhibitors seemingly show some efficacy in the treatment of cognitive alterations. Further research would result in advances in diagnostic methods and therapeutic approaches in the near future.