Clinical Red Flags Research Articles

Calcium Release Deficiency Syndrome (CRDS): Rethinking “Atypical” Catecholaminergic Polymorphic Ventricular Tachycardia

Since the first description of catecholaminergic polymorphic ventricular tachycardia (CPVT) in the 1970s, new insights have progressively unraveled the understanding of this inherited arrhythmia syndrome. The identification of new distinct clinical entities related to RYR2, the gene encoding the cardiac ryanodine receptor, has allowed significant refinement in the diagnosis of previously labeled “atypical” CPVT cases. Among RYR2-ryanodinopathies, the characterization of calcium release deficiency syndrome (CRDS) is still in its infancy and represents a diagnostic challenge due to the need for functional studies which may confirm the loss-of-function nature of the RYR2 variant. The present review summarizes current evidence on CRDS. First, by providing an overview on RYR2 structure and function, we will elucidate the different pathophysiological underpinnings of CRDS and CPVT. Second, by retrieving in detail reported CRDS variants and their clinical phenotypes, we will provide, if any, genetic and clinical red flags that should raise suspicion for CRDS in daily clinical practice. Finally, we will discuss available therapies to provide clinicians with practical therapeutic options for CRDS management.

Hereditary and wild type transthyretin amyloid cardiomyopathy in Bulgaria in patients suspected for cardiac amyloidosis

Introduction: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a severe progressive disease, more common than previously expected. The main objectives were to evaluate hereditary and wild type ATTR-CM frequency and clinical manifestations. Material and methods: One hundred seventy-eight patients at mean age 68 ± 13 years (129 males), referred by cardiologists with suspected cardiac amyloidosis (left ventricular wall thickness ≥ 12 mm and red flags) were evaluated. Pyrophosphate scintigraphy (99mTc-PYP) grade 2-3 myocardial uptake in the absence of monoclonal protein confirmed the diagnosis. Genetic test differentiated variant from wild type ATTR-CM. Endomyocardial biopsy with amyloid typing was performed in two patients. Results: Cardiac amyloidosis was diagnosed in 69 patients: light chain in 24 (13%) and ATTR-CM in 45 patients (25%). Wild type (ATTRwt) was found in 21 (12%) male patients at mean age 81 ± 6 years and variant type (ATTRv) in 24 patients (13%) at mean age 58 ± 7 years (15 males). In all ATTRv-CM patients some degree of peripheral polyneuropathy was found. The most common clinical red flags at diagnosis in both ATTRv and ATTRwt were heart failure in all patients, atrial fibrillation (16; 36%), pacemaker (5; 11%), and carpal tunnel syndrome (8; 18%). Severe aortic stenosis (4; 19%), spinal stenosis (2;10%), biceps tendon rupture (1; 5%) were characteristic for the wild type. At follow up, four patients needed a pacemaker for high degree AV block, six patients developed new onset atrial fibrillation, seventeen patients needed either initiation or an increase of the dose of loop diuretic, another 7 patients were hospitalized for heart failure exacerbation. Eight patients (18%) died, 7 (33%) with ATTRwt-CM and 1 (4%) with ATTRv-CM, all with advanced heart failure, 4 with concomitant severe aortic stenosis. Conclusions: This study provides the first nationwide estimates of the frequency and the clinical manifestations of ATTR-CM. Confirming the severity of the disease and poor prognosis, a low threshold for screening is needed for early diagnosis and timely treatment.

Repeat length in spinocerebellar ataxia type 4 (SCA4) predicts age at onset and disease severity

BackgroundRecently, an exonic GGC repeat expansion (RE) was identified by long-read genome sequencing in the ZFHX3 gen, causing spinocerebellar ataxia type 4 (SCA4), a dominant form of ataxia with sensory neuropathy. However, the analysis of larger cohorts of patients remained demanding, resulting in a challenge to diagnose patients and leaving the question of anticipation in SCA4 unanswered.ObjectivesWe aimed to develop a GGC repeat test for clinical SCA4 screening and to apply this test to screen two large German SCA pedigrees and samples of unrelated patients collected over the last 25 years.MethodsWe modulated a commercial GGC-RE kit (Bio-Techne AmplideX® Asuragen® PCR/CE FMR1 Reagents) with ZFHX3-specific primers and adapted PCR conditions. The test was applied to patients and 50 healthy controls to determine the exact repeat number. Clinical data were revised and correlated with the expanded allele sizes and an exploratory analysis of structural MRI was performed.ResultsRepeat size, determined by our protocol for (GGC)n RE analysis shows a strong inverse correlation between repeat length and age at onset and anticipation in subsequent generations. The phenotype also appears to be more strongly expressed in carriers of longer RE. Clinical red flags were slowed saccades, sensory neuropathy and autonomic dysfunction.ConclusionOur protocol enables cost-effective and robust screening for the causative SCA4 RE within ZFHX3. Furthermore, detailed clinical data of our patients gives a more precise view on SCA4, which seems to be more common among patients with ataxia than expected.

An exploratory study of the damage markers NfL, GFAP, and t-Tau, in cerebrospinal fluid and other findings from a patient cohort enriched for suspected autoimmune psychiatric disease

There is growing evidence suggesting that immunological mechanisms play a significant role in the development of psychiatric symptoms in certain patient subgroups. However, the relationship between clinical red flags for suspected autoimmune psychiatric disease and signs of central nervous system (CNS) pathology (e.g., routine cerebrospinal fluid (CSF) alterations, CNS damage markers, neurophysiological or neuroimaging findings) has received limited attention. Here, we aimed to describe the prevalence and distribution of potential CNS pathologies in psychiatric patients in relation to clinical red flags for autoimmune psychiatric disease and psychiatric symptoms. CSF routine findings and CNS damage markers; neurofilament light chain protein (NfL), glial fibrillary acidic protein (GFAP) and total Tau (t-Tau), in CSF from 127 patients with psychiatric disease preselected for suspected immunological involvement were related to recently proposed clinical red flags, psychiatric features, and MRI and EEG findings. Twenty-one percent had abnormal routine CSF findings and 27% had elevated levels of CNS damage markers. Six percent had anti-neuronal antibodies in serum and 2% had these antibodies in the CSF. Sixty-six percent of patients examined with MRI (n = 88) had alterations, mostly atrophy or nonspecific white matter lesions. Twenty-seven percent of patients with EEG recordings (n = 70) had abnormal findings. Elevated NfL levels were associated with comorbid autoimmunity and affective dysregulation symptoms. Elevated t-Tau was associated with catatonia and higher ratings of agitation/hyperactivity. Elevated GFAP was associated with acute onset, atypical presentation, infectious prodrome, tics, depressive/anxiety symptom ratings and overall greater psychiatric symptom burden. In conclusion, preselection based on suspected autoimmune psychiatric disease identifies a population with a high prevalence of CSF alterations suggesting CNS pathology. Future studies should examine the value of these markers in predicting treatment responses.

Dual novel variants in CD40 leading to hyper IgM syndrome: a case report of a school-aged female with new-onset recurrent pneumonia

Introduction: Hyper IgM (HIGM) syndrome is an inborn error of immunity (IEI) that occurs due to defects in immunoglobulin class switch recombination (Ig-CSR). HIGM syndrome typically presents with recurrent infections in early childhood, and is often characterized on investigation with decreased IgG, IgA, and IgE titres, alongside normal or elevated IgM. A common cause of HIGM syndrome is a disruption to the CD40-CD40 ligand (CD40L) interaction that triggers Ig-CSR, of which variants in CD40 are much rarer than those in CD40L. We present a case of an 11-year-old female with HIGM syndrome caused by two novel variants of in the CD40 gene. Aim: To describe a case report of an eleven-year-old female with HIGM syndrome presenting with recurrent pneumonia. Methods: Data was collected retrospectively from the patient’s medical records. Laboratory investigations included quantitative immunoglobulins, quantitative B and T cell subsets, genetic testing using a primary immunodeficiency panel, and a functional assay for CD40 expression. Results: The proband is an 11-year-old female, who presented with recurrent pneumonia, otitis, and septic arthritis. Investigations revealed neutropenia, low IgA, elevated IgM and normal IgG, along with absent vaccine responses. She was identified to harbour two novel variants in CD40: an intronic variant c.52-13A>G p.(?) and a missense variant c.466T>C p.(Ser156Pro). Functional assay indicated low expression of CD40 compared to healthy control, confirming the diagnosis of CD40 deficiency. Conclusion: Class switch defects, such as CD40 deficiency, are rare but significant diagnoses within the spectrum of IEI. This case demonstrates that despite the absence of some clinical red flags for immunodeficiency in infancy, IEIs remain an important consideration in pediatric patients regardless of age. Increasing clinical awareness of IEI will lead to earlier diagnoses, initiation of appropriate treatment, and prevention of potential complications. Statement of novelty: We describe a patient with a late presentation of hyper IgM syndrome due to two novel variants in the CD40 gene, thus expanding the spectrum of CD40 gene variants.

Best Practices in Nuclear Imaging for the Diagnosis of Transthyretin Amyloid Cardiomyopathy (ATTR-CM) in KSA: The Eagle Eyes of Local Experts.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a complex and serious form of heart failure caused by the accumulation of transthyretin amyloid protein in the heart muscle. Variable symptoms of ATTR-CM can lead to a delayed diagnosis. Recognizing the diagnostic indicators is crucial to promptly detect this condition. A targeted literature review was conducted to examine the latest international consensus recommendations on a comprehensive diagnosis of ATTR-CM. Additionally, a panel consisting of nuclear medicine expert consultants (n = 10) and nuclear imaging technicians (n = 2) convened virtually from the Kingdom of Saudi Arabia (KSA) to formulate best practices for ATTR-CM diagnosis. The panel reached a consensus on a standard diagnostic pathway for ATTR-CM, which commences by evaluating the presence of clinical red flags and initiating a cardiac workup to assess the patient's echocardiogram. Cardiac magnetic resonance imaging may be needed, in uncertain cases. When there is a high suspicion of ATTR-CM, patients undergo nuclear scintigraphy and hematologic tests to rule out primary or light-chain amyloidosis. The expert panel emphasized that implementing best practices will support healthcare professionals in KSA to improve their ability to detect and diagnose ATTR-CM more accurately and promptly. Diagnosing ATTR-CM accurately and early can reduce morbidity and mortality rates through appropriate treatment.

Rapid identification of primary atopic disorders (PAD) by a clinical landmark-guided, upfront use of genomic sequencing.

Primary atopic disorders (PAD) are monogenic disorders caused by pathogenic gene variants encoding proteins that are key for the maintenance of a healthy skin barrier and a well-functioning immune system. Physicians face the challenge to find single, extremely rare PAD patients/families among the millions of individuals with common allergic diseases. We describe case scenarios with signature PAD. We review the literature and deduct specific clinical red flags for PAD detection. They include a positive family history and/or signs of pathological susceptibility to infections, immunodysregulation, or syndromic disease. Results of conventional laboratory and most immunological lab studies are not sufficient to make a definitive diagnosis of PAD. In the past, multistep narrowing of differential diagnoses by various immunological and other laboratory tests led to testing of single genes or gene panel analyses, which was a time-consuming and often unsuccessful approach. The implementation of whole-genomic analyses in the routine diagnostics has led to a paradigm shift. Upfront genome-wide analysis by whole genome sequencing (WGS) will shorten the time to diagnosis, save patients from unnecessary investigations, and reduce morbidity and mortality. We propose a rational, clinical landmark-based approach for deciding which cases pass the filter for carrying out early WGS. WGS result interpretation requires a great deal of caution regarding the causal relationship of variants in PAD phenotypes and absence of proof by adequate functional tests. In case of negative WGS results, a re-iteration attitude with re-analyses of the data (using the latest data base annotation)) may eventually lead to PAD diagnosis. PAD, like many other rare genetic diseases, will only be successfully managed, if physicians from different clinical specialties and geneticists interact regularly in multidisciplinary conferences.

Clinical red flags associated with transthyretin amyloid cardiomyopathy in patients with left ventricular hypertrophy: results of the TTRACK study

Abstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is a life-threatening, systemic disorder that results in progressive physical disability, substantially reduced quality of life, and high morbidity and mortality rates. ATTR-CM is an underrecognized cause of increased left ventricular (LV) wall thickness in older adults, and delayed diagnosis can lead to worse clinical outcomes. To facilitate early identification of patients with LV hypertrophy (LVH) at risk for ATTR-CM, greater recognition of diagnostic ‘red flags’ is required. Purpose To determine the association between diagnostic red flags and ATTR-CM in patients with LVH. Methods TTRACK is a multicentre, non-interventional epidemiological study (ClinicalTrials.gov: NCT03842163). Eligible patients were ≥50 years of age and had unexplained LVH (LV maximum wall thickness ≥15 mm [echocardiogram]). After undergoing technetium-99m-DPD/-PYP/-HMDP-labelled bone scintigraphy, scans were categorized by the degree of tracer uptake in the heart; Perugini grades 0, 1, 2 and 3 represented absent, low, moderate and high uptake, respectively. Immunofixation electrophoresis was used to detect monoclonal protein abnormalities; grade 2 and 3 scans without evidence of monoclonal gammopathy were considered diagnostic for ATTR-CM. The frequency of predetermined clinical disease markers was compared in patients without monoclonal protein abnormalities and grade 0 or grade 2/3 scans. Results Of 766 eligible patients with scintigraphy data, 521 (68.0%) had grade 0 cardiac uptake; 37 (4.8%) had grade 1; and 208 (27.2%) had grade 2/3. Among patients with moderate/high uptake, 137 (65.9% of those with grade 2/3 uptake; 17.9% of the overall cohort) had no monoclonal protein abnormalities (ATTR-CM); 56 (26.9%) had monoclonal gammopathy of undetermined significance or light chain amyloidosis; and 15 (7.2%) patients had unknown monoclonal test findings. On univariable analysis, carpal tunnel syndrome (odds ratio [95% CI], 27.7 [16.7, 46.1]), permanent atrial fibrillation (3.4 [2.2, 5.2]), male sex (2.9 [1.8, 4.8]) and advanced heart failure (1.8 [1.2, 2.9]) were the strongest predictors for grade 2/3 scans; on multivariable analysis, carpal tunnel syndrome (50.3 [23.4, 108.0]), male sex (9.1 [3.9, 21.3] and age (1.7 [1.4, 2.1]) were the strongest predictors (Figure). Conclusions In the TTRACK study, 18% of patients ≥50 years of age with unexplained LVH ≥15 mm had ATTR-CM. Carpal tunnel syndrome, male sex and advanced age were associated with a greater likelihood of ATTR-CM.

A practical approach to assessment of non-adherence to antihypertensive treatment.

Non-adherence to antihypertensive treatment is frequent, complicates the care of hypertensive patients, represents one of the major causes of treatment failure and is linked with the increased risk of cardiovascular events. Identifying a non-adherent patient is one of the recent daily-practice tasks for which the ideal solution has not yet been found. Presence of certain clinical red flags should prompt the clinician to consider non-adherence. Chemical adherence testing using serum or urine antihypertensive levels is regarded as the best method so far and should be used if available. Alternatively, the check for prescription refills in the patient electronic medical records, or directly observed therapy with subsequent ambulatory blood pressure monitoring may be used. We suggest a simple algorithm to guide the clinicians to detect non-adherence in the practice.

Diagnostic momentum in physical therapy clinical reasoning.

Diagnostic momentum refers to ruling in a particular diagnosis without adequate evidence. As the field of physical therapy continues to transition more towards autonomous practitioners with direct access, there is a need to identify the effect of a physician diagnosis on a therapist's examination and treatment. The purpose of this study was to identify if diagnostic momentum exists in physical therapy and whether this phenomenon could affect the ability of the therapist to identify clinical red flags. An online survey with randomized case scenarios was completed by 75 licensed practicing physical therapists. Participants received one of two scenarios: a case vignette where the patient was referred to physical therapy for left shoulder pain and presented with 'red flags' indicative of myocardial infarction, or a similar vignette with additional results from an exercise stress test that ruled out myocardial infarction. The subjects were asked if they would 'treat' or 'refer' to another healthcare provider and the reason behind their decision. Independent t-tests and χ2 analyses were conducted to understand the differences between the groups. A thematic analysis was used to explore the therapists' responses regarding the reasoning for their decision. There was no significant difference in clinical decision making based on age, gender, years of experience, advanced certification, primary caseload or primary practice setting. Among those who received the case without the stress test, 31.4% of participants indicated that they would refer, compared to 12.5% of the participants that had the additional stress test result included within their case. The presence of the negative stress test was indicated as the main reason for choosing to treat without referral by 65.7% of the subjects that received the additional stress test result. This study suggests that practicing physical therapists may be influenced by diagnostic decisions made by other clinicians, causing them to overlook signs and symptoms of possible myocardial infarction.

Cardiac Amyloidosis Imaging, Part 3: Interpretation, Diagnosis, and Treatment.

Cardiac amyloidosis was thought to be rare, undiagnosable, and incurable. However, recently it has been discovered to be common, diagnosable, and treatable. This knowledge has led to a resurgence in nuclear imaging with 99mTc-pyrophosphate-a scan once believed to be extinct-to identify cardiac amyloidosis, particularly in patients with heart failure but preserved ejection fraction. The renewed interest in 99mTc-pyrophosphate imaging has compelled technologists and physicians to reacquaint themselves with the procedure. Although 99mTc-pyrophosphate imaging is relatively simple, interpretation and diagnostic accuracy require an in-depth knowledge of amyloidosis etiology, clinical manifestations, disease progression, and treatment. Diagnosing cardiac amyloidosis is complicated because typical signs and symptoms are nonspecific and usually attributed to other cardiac disorders. In addition, physicians must be able to differentiate between monoclonal immunoglobulin light-chain amyloidosis (AL) and transthyretin amyloidosis (ATTR). Several clinical and noninvasive diagnostic imaging (echocardiography and cardiac MRI) red flags have been identified that suggest a patient may have cardiac amyloidosis. The intent of these red flags is to raise physician suspicion of cardiac amyloidosis and guide a series of steps (a diagnostic algorithm) for narrowing down and diagnosing the specific amyloid type. One element in the diagnostic algorithm is to identify monoclonal proteins indicative of AL. Monoclonal proteins are detected by serum or urine immunofixation electrophoresis and serum free light-chain assay. Another element is identifying and grading cardiac amyloid deposition using 99mTc-pyrophosphate imaging. When monoclonal proteins are present and the 99mTc-pyrophosphate scan is positive, the patient should be further evaluated for cardiac AL. The absence of monoclonal proteins and a positive 99mTc-pyrophosphate scan is diagnostic for cardiac ATTR. Patients with cardiac ATTR need to undergo genetic testing to differentiate between wild-type ATTR and variant ATTR. This article is the third in a 3-part series in this issue of the Journal of Nuclear Medicine Technology Part 1 reviewed amyloidosis etiology and outlined 99mTc-pyrophosphate study acquisition. Part 2 described 99mTc-pyrophosphate image quantification and protocol technical considerations. This article discusses scan interpretation along with cardiac amyloidosis diagnosis and treatment.

P208 PREVALENCE OF TRANSTHYRETIN CARDIAC AMYLOIDOSIS IN PATIENTS HOSPITALIZED FOR HEART FAILURE

Abstract Background Bone scintigraphy with labeled diphosphonates allows for the non–invasive diagnosis of transthyretin cardiac amyloidosis, in case of high cardiac uptake of the radiotracer and concomitant absence of serum monoclonal component (Gillmore algorithm). Objective The aim of this study was to establish the prevalence of transthyretin cardiac amyloidosis in a population of patients hospitalized for heart failure. Methods In this prospective observational study, patients hospitalized for heart failure at the Cardiology Unit of Castelsangiovanni Hospital were evaluated in the period from 1 January 2021 to 31 July 2022. Twenty–five of them, who presented with echocardiographic moderate to severe left ventricular hypertrophy (i.e. maximum end–diastolic thickness of the interventricular septum ≥ 15 mm), were included in the study. All patients underwent anamnesis, physical examination, 12–lead electrocardiogram and transthoracic echocardiogram. Patients were divided into 2 groups according to the presence or absence of the following clinical, electrocardiographic and echocardiographic diagnostic red flags: history of carpal tunnel syndrome and/or rupture of the long head of the brachial biceps, low voltage QRS, granular sparkling of the ventricular myocardium, apical sparing pattern of the global longitudinal strain. Results Fifteen patients with heart failure, left ventricular hypertrophy and at least one diagnostic red flag were screened for cardiac amyloidosis by: a) search for a serum monoclonal component; b) bone scintigraphy with labeled diphosphonates. In thirteen patients, an high cardiac uptake of the radiotracer was found on bone scintigraphy. One patient with high cardiac uptake also presented a serum monoclonal component and was referred for tissue biopsy. In the remaining twelve patients (85% of the cases studied) a non–invasive diagnosis of transthyretin cardiac amyloidosis was made. In six patients affected by transthyretin cardiac amyloidosis, a salivary genetic test was also performed to search for mutations in the transthyretin gene, which resulted negative in all cases examined. Conclusions In this study of patients hospitalized for decompensated heart failure, rigorous application of Gillmore‘s algorithm in suspected cases led to non–invasive diagnosis of cardiac transthyretin amyloidosis in 85% of cases, without wasting healthcare resources.

Significance of clinical symptoms and red flags in early differential diagnosis of Parkinson’s disease and atypical Parkinsonian syndromes

The clinical presentation of Parkinson’s disease and atypical Parkinsonian syndromes is often heterogeneous. Additional diagnostic procedures including brain imaging and biomarker analyses can help to appreciate the various syndromes, but a precise clinical evaluation and differentiation is always necessary. To better assess the relevance of distinct clinical symptoms that arose within 1 year of disease manifestation and evaluate their indicative potential for an atypical Parkinsonian syndrome, we conducted a modified Delphi panel with seven movement disorder specialists. Five different topics with several clinical symptom items were discussed and consensus criteria were tested. This resulted in distinct symptom patterns for each atypical Parkinsonian syndrome showing the multitude of clinical involvement in each neurodegenerative disease. Strongly discriminating clinical signs were few and levels of indication were variable. A prospective validation of the assessments made is needed. This demonstrates that both clinical evaluation and elaborate additional diagnostic procedures are needed to achieve a high diagnostic standard.

Detection and Diagnosis of Cardiac Amyloidosis in Egypt.

Cardiac amyloidosis is a life-threatening disease that occurs when amyloid proteins, most commonly immunoglobulin light chain or transthyretin, mutate or become unstable, misfold, deposit as amyloid fibrils, and accumulate in the myocardium. Early diagnosis of cardiac amyloidosis is hindered by insufficient awareness, specifically regarding clinical red flags and diagnostic pathways. Cardiac amyloidosis diagnosis comprises two important phases, clinical suspicion (phase one) followed by definitive diagnosis (phase two). Each phase is associated with specific clinical techniques. For example, clinical features, electrocardiography, echocardiography, and cardiac magnetic resonance imaging serve to raise suspicion of cardiac amyloidosis and facilitate early diagnosis, whereas laboratory tests (i.e., blood or urine electrophoresis with immunofixation), biopsy, scintigraphy-based nuclear imaging, and genetic testing provide a definitive diagnosis of cardiac amyloidosis. In Egypt, both the lack of cardiac amyloidosis awareness amongst healthcare providers and the unavailability of clinical expertise for the use of diagnostic techniques must be overcome to improve the prognosis of cardiac amyloidosis in the region. Previously published diagnostic algorithms for cardiac amyloidosis have amalgamated techniques that can raise clinical suspicions of cardiac amyloidosis with those that definitively diagnose cardiac amyloidosis. Though such algorithms have been successful in developed countries, diagnostic tools like echocardiography, scintigraphy, and cardiac magnetic resonance imaging are not ubiquitously available across Egyptian facilities. This review presents the current state of knowledge regarding cardiac amyloidosis in Egypt and outlines a new diagnostic algorithm which leverages regional nuclear imaging expertise. Importantly, the proposed diagnostic algorithm guides accurate amyloid-typing to mitigate misdiagnosis and erroneous treatment selection and improve the cardiac amyloidosis diagnostic accuracy in Egypt.

External anal sphincter electromyography in multiple system atrophy: implications for diagnosis, clinical correlations, and novel insights into prognosis.

Multiple system atrophy is a sporadic, progressive, adult-onset, neurodegenerative disorder characterized by autonomic dysfunction symptoms, parkinsonian features, and cerebellar signs in various combinations. An early diagnosis of multiple system atrophy is of utmost importance for the proper prevention and management of its potentially fatal complications leading to the poor prognosis of these patients. The current diagnostic criteria incorporate several clinical red flags and magnetic resonance imaging markers supporting diagnosis of multiple system atrophy. Nonetheless, especially in the early disease stage, it can be challenging to differentiate multiple system atrophy from mimic disorders, in particular Parkinson's disease. Electromyography of the external anal sphincter represents a useful neurophysiological tool for differential diagnosis since it can provide indirect evidence of Onuf's nucleus degeneration, which is a pathological hallmark of multiple system atrophy. However, the diagnostic value of external anal sphincter electromyography has been a matter of debate for three decades due to controversial reports in the literature. In this review, after a brief overview of the electrophysiological methodology, we first aimed to critically analyze the available knowledge on the diagnostic role of external anal sphincter electromyography. We discussed the conflicting evidence on the clinical correlations of neurogenic abnormalities found at external anal sphincter electromyography. Finally, we reported recent prognostic findings of a novel classification of electromyography patterns of the external anal sphincter that could pave the way toward the implementation of this neurophysiological technique for survival prediction in patients with multiple system atrophy.

The labiopalatal impacted canine: Accurate diagnosis based on the position and size of adjacent teeth: A cone-beam computed tomography study

Labiopalatal impacted canines (L-PICs) occur when the canines lie between central and lateral incisors, with their tip palatal to the central incisor and part of their crown labial to the lateral incisor. Because of their unusual position, they are often misdiagnosed, and their orthodontic resolution fails. This study aims to provide clinicians with pathognomonic features for early and accurate positional diagnosis of L-PICs. The L-PIC sample included 21 subjects with full diagnostic records. The control group of normally erupted canines was taken from a previous study. Clinical photographs, 2-dimensional radiographs, and cone-beam computed tomography were used to evaluate the positions of the adjacent incisors and first premolars, the canine incisor index, and the mesiodistal width of the lateral vs central incisors. Central incisors adjacent to L-PICs showed significant mesial root angulation, labial root inclination, and mesiolabial crown rotation, whereas lateral incisors presented significant distal root angulation, palatal root inclination, and mesiolabial crown rotation, in comparison to controls. The roots of the central and lateral incisors were divergent, in contrast to the controls, in which they were slightly convergent. The first premolar positions were not affected. The mean canine incisor index was significantly bigger in L-PICs vs the controls, suggesting a palatal canine. The lateral incisor widths were similar between the groups. This study provides the orthodontist with evidence-based clinical and radiographic red flags for diagnosing L-PIC, which may allow timely initiation of orthodontic treatment and correct planning of mechanotherapy.

Prevalence and clinical correlates of clinical red flags for rare diseases in consecutive patients presenting with HCM phenotype

Abstract Introduction For patients presenting with primary Left Ventricular Hypertrophy (LVH), the ESC recommends systematic search for diagnostic clues or “red flags” (cardiac and non-cardiac) that can identify particular treatable disorders and guide rational selection of diagnostic tests. To date, a systematic evaluation of this recommendation has not been performed Purpose We sought to determine prevalence and predictive accuracy of clinical markers (red flags, RF), known to be associated with specific systemic disease in a consecutive cohort of patients with hypertrophic cardiomyopathy (HCM). Methods We studied 210 consecutively genotyped patients (54±21 years, 118 (56% males) referred to our center for the suspicion of primary LVH. Pre-specified RF were categorized into four domains: family history; signs/symptoms; electrocardiography and imaging. Results Of the 210 patients, 84 (40%) were diagnosed with sarcomeric HCM, 56 (27%) with TTR amyloidosis, 44 (21%) with Fabry disease (FD), 7 (4%) with a mitochondrial disease, 4 (2%) with Pompe disease, 4 (2%) with PRKAG2 cardiomyopathy, 3 (1%) with Noonan, 3 (1%) with Friederich's Ataxia, 3 (1%) with LEOPARD and 2 (1%) with Danon disease. A total of 942 RF has been identified in the cohort. Concerning family history, autosomal dominant pattern was specific for sarcomeric HCM (66/84, 79%), whereas X-linked inheritance was frequently observed in Fabry disease (40/44, 91%). Non-sarcomeric causes of HCM were the most prevalent in ages <1yo and >55yo. Ophthalmological signs/symptoms (22/23) were specifically find in FD, whereas muscolo-skeletal RF were rare and non-specific. Neurological phenotype was prevalent in FD patients (38/44, 86%), as well as in TTR amyloidosis (carpal tunnel in 29/56, (52%)), in mithocondropathies and Friederich's Ataxia. Cutaneous involvement was frequent in FD (12 patients with angiokeratomata) (Tab.1). Giant T waves inversion was the most prevalent ECG alteration, but aspecific (61 patients, 32/84 sarcomeric HCM, 16/44 FD). Short PR interval was found in 24 (12%) of patients and specific for FD (15/44) and mitochondrial disease (3/7). Low QRS voltage was present in 17 (8%) patients, and of these 16 had TTR amyloidosis. Inferior leads Q waves was uncommon and non-specific. Mitral valve disease (SAM and anterior mitral leaflet elongation) and apical LVH were present respectively in 57/210 (28%) and 9/210 (4%) of the patient and were almost entirely observed in sarcomeric HCM. Concentric LVH and severe left posterior wall hypertrophy were extremely specific for non sarcomeric HCM (108/109 cases). Strain apical sparing was useful in the identification of TTR amyloidosis. Conclusions Clinical RF in patients with primary LVH are common and can be highly specific for correct phenotypisation of the patient. An extensive diagnostic work-up should therefore be conducted by the physician to identify potentially treatable primary LVH causes. Funding Acknowledgement Type of funding sources: None.

Multimodality imaging in cardiac amyloidosis: State-of-the-art review.

Amyloidosis is a systemic disease, characterized by deposition of amyloid fibrils in various organs, including the heart. For the diagnosis of cardiac amyloidosis (CA) it is required a high level of clinical suspicion and in the presence of clinical, laboratorial, and electrocardiographic red flags, a comprehensive multimodality imaging evaluation is warranted, including echocardiography, magnetic resonance, scintigraphy, and computed tomography, that will confirm diagnosis and define the CA subtype, which is of the utmost importance to plan a treatment strategy. We will review the use of multimodality imaging in the evaluation of CA, including the latest applications, and a practical flow-chart will sum-up this evidence.

OA05 Clinical presentation, risk factors and prognosis of MDA5-positive JDM; clinical diversity and red flags

Introduction/BackgroundMDA5-positive juvenile dermatomyositis (JDM) represents a distinct clinical phenotype associated with skin and oral ulceration, milder muscle involvement and a higher incidence of interstitial lung disease (ILD) and severe rapidly progressive ILD (RP-ILD).Description/MethodThe objectives were to describe the presenting clinical characteristics of patients with MDA5-positive JDM, the incidence of ILD and risk factors associated with development of RP-ILD. Retrospective clinical notes review of patients with MDA5-positive JDM managed at Great Ormond Street Hospital (GOSH) over a 24-year period.Discussion/Results DemographicsTwenty-five patients were managed at our centre with MDA5-positive JDM. One additional patient was excluded as no notes available. Sixty-four % females. Sixty % were White British, 20% Black African, 8% Mixed, 8% Asian, 8% European and 4% South Asian. Median age of presentation was 10.0 years (IQR 6.9,12.3). Diagnostic delay was significant, with median 14 weeks (8,26) between initial symptoms and diagnosis. 24% of this cohort were also Ro-52 positive. Presentation: All patients had skin involvement; 52% ulcerating skin disease, 64% heliotrope rash and 100% Gottrons papules on initial presentation. Forty-four % had peri-ungal changes, 35% digital pitting/infarcts and 64% nailfold changes. 40% had peri-orbital oedema. Muscle involvement was present in all, with median CMAS 40/52 (36,44) and MMT8 57/80 (51,62). Eighty-eight % had arthritis; initial active joint count was available for 16 patients with median 5.5 joints (3,16). 40% had gastrointestinal symptoms; fever, weight loss and mouth ulcers were present in 52%, 52% and 60% respectively. Twenty-four % had respiratory symptoms at diagnosis. Interstitial lung disease: 52% were diagnosed with ILD and a further 20% had abnormal pulmonary CT scans not thought to be diagnostic of ILD. 13% (2 patients) had RP-ILD; both of whom died despite immunosuppression and extracorporeal membrane oxygenation. There were no other deaths amongst this cohort. No respiratory involvement was identified in 28%. Of 19 patients who had a CT chest at diagnosis, 84% were abnormal. Only 1 patient developed respiratory involvement during disease course whilst on treatment; the other 93% with ILD had evidence of ILD at diagnosis. Out of 58 putative variables, 4 risk factors were associated with development of RP-ILD which reached statistical significance, a further 3 factors were significantly protective, as is shown in Table 1. 2 patients had pneumocystis pneumonia (PCP), both of whom required intensive care and one associated with death.OA05 Table 1shows risk factors at presentation which were found to be significantly associated with RP-ILD Factorp valueRisk factor Periungal erythema0.024Heliotrope rash0.06Respiratory symptoms0.017Haemoglobin0.0129Protective factor Normal CT0.01Normal lung function0.008Normal CXR0.005Key learning points/ConclusionSkin and muscle involvement were identified in all patients, with the majority also presenting with ulcerating skin disease, oral ulceration and arthritis. The majority of this cohort had lung involvement and 2 patients died of RP-ILD. Four risk factors were found to be predictive of RP-ILD and a further 3 protective factors were identified. Rapid deterioration of respiratory symptoms was associated with PCP, while ILD was unlikely to develop whilst on treatment if not present at diagnosis. These findings need to be validated in a larger cohort of patients.

Assessment of clinical characteristics of cardiac amyloidosis as a potential underlying etiology in patients diagnosed with heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is heterogeneous clinical syndrome. Transthyretin cardiac amyloidosis (CA) is an underdiagnosed cause of HFpEF. Red flags are extremely useful for suspecting CA. We aimed to evaluate the frequency of cardiac and extracardiac manifestations of CA in HFpEF patients based on red flags. Baseline characteristics of 85 patients were recorded during admission. Electrocardiogram and echocardiography were performed. All patients were examined for red flags. Cardiac scintigraphy was performed in 85 patients. The mean (standard deviation [SD]) age of the study group was 67.9 (9.8) years, and 52 (61.2%) patients were female. At least 1 red flag was observed in 67% of HFpEF patients. Only 4 of the patients had more than 3 red flags. The mean number of red flags in a patient with HFpEF was 1.3. Extracardiac clinical red flags were observed in only 9 (10.5%) patients. Cardiac clinical red flags were extremely rare. An electrocardiographic red flag was detected in 2 out of 10 patients and an echocardiographic red flag in 4 out of 10 patients with HFpEF. Scintigraphy showed that 17.6% of all patients have had a grade 2 or 3 cardiac uptake. The patients with wild-type transthyretin CA had twice as many red flags as those without. The results of the study showed that patients diagnosed with HFpEF had an average of 1.3 red flags suggestive of CA. In real life, extracardiac red flags are rare, while electrocardiographic and echocardiographic red flags are more common in patients with HFpEF.