Transthyretin amyloidosis (ATTR) is an underdiagnosed multisystem disease. More than 140 known mutations are pathologic, and organ tropism can vary significantly based on the causative mutation. An elderly man with neuropathy and congestive heart failure was found to have left ventricular hypertrophy on echocardiogram. Subsequent endomyocardial biopsy demonstrated transthyretin amyloid deposition. On referral to our centre, genetic testing was performed, demonstrating a missense mutation, c.229G>A, that results in the amino acid substitution p.Gly77Arg. This mutation had only been reported in one other case of amyloidosis internationally. Cascade genetic testing ensued, which resulted in multiple family members having the same mutation with varying stages of disease activity. This case highlights the importance of genetic testing for all individuals diagnosed with ATTR regardless of age and the variable organ tropism of the disease.

REMOTE-CIPN is an NCI funded multi-center randomized controlled trial of a novel technology based CIPN care model intended to reduce CIPN symptoms.

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) must be considered for patients with chronic inflammatory demyelinating polyradiculopathy (CIDP) not responding to corticosteroids, IV immunoglobulin (IVIg) therapy, or plasmapheresis.

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) must be considered for patients with chronic inflammatory demyelinating polyradiculopathy (CIDP) not responding to corticosteroids, IV immunoglobulin (IVIg) therapy, or plasmapheresis.

Cardiac amyloidosis is a growing field, with advancements in diagnosis and management. Cardiac biomarkers are used to predict survival and to develop severity staging systems. Cardiac biomarkers are also used in clinical practice to stratify patients for treatment and to evaluate response to therapies. The current review summarizes the major clinical utility of current biomarkers in patients with cardiac amyloidosis and provides insights about future areas of investigation.

Peripheral neuropathy is a commonly encountered disorder in clinical practice. In light of an aging population and the diabetes and obesity pandemic, the prevalence of peripheral neuropathy is increasing, posing a significant public health concern. This article provides a diagnostic framework for neuropathies and summarizes treatment options.

The Peripheral Neuropathy Research Registry (PNRR) is a prospective cohort of peripheral neuropathy (PN) patients focused on idiopathic axonal peripheral neuropathy. Patients with diabetic, human immunodeficiency virus‐, and chemotherapy‐induced peripheral neuropathies are enrolled as comparison groups. The PNRR is a multi‐center collaboration initiated and funded by the Foundation for Peripheral Neuropathy (FPN) with the objective to recruit a well characterized cohort of patients with different phenotypes and symptoms in each diagnostic category, and to advance research through development of biomarkers and identification of previously unknown causes of PN. The overall goal of the initiative is to find disease‐altering treatments and better symptom relief for patients. We present the study design, types of data collected, and characteristics of the first 1150 patients enrolled. We also discuss ongoing analyses on this dataset, including untargeted‐omics methodologies.

HomeCirculation: Heart FailureVol. 11, No. 7Unmasking Early Wild-Type Transthyretin Amyloidosis Cardiomyopathy in a Patient With Refractory Atrial Fibrillation and Unremarkable Cardiac Imaging Free AccessCase ReportPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessCase ReportPDF/EPUBUnmasking Early Wild-Type Transthyretin Amyloidosis Cardiomyopathy in a Patient With Refractory Atrial Fibrillation and Unremarkable Cardiac Imaging Danny Varedi, BS, Tibor Kovacsovics, MD, Erinn Downs Kelly, DO, Jo Abraham, MD, Jared Cowley, RN, Kelsey Barrell, MD, Monica P. Revelo, MD, Josef Stehlik, MD, Stavros Drakos, MD, Nassir Marrouche, MD, Brent Wilson, MD, PhD, Eric A. Swanson, MD, James Fang, MD and Jose Nativi-Nicolau, MD Danny VarediDanny Varedi University of Utah Health, Salt Lake City (D.V., J.A., K.B., M.P.R., J.S., S.D., N.M., B.W., E.A.S., J.F., J.N.-N.). , Tibor KovacsovicsTibor Kovacsovics Huntsman Cancer Institute, Salt Lake City, UT (T.K., J.C.). , Erinn Downs KellyErinn Downs Kelly Cleveland Clinic, OH (E.D.K.). , Jo AbrahamJo Abraham University of Utah Health, Salt Lake City (D.V., J.A., K.B., M.P.R., J.S., S.D., N.M., B.W., E.A.S., J.F., J.N.-N.). , Jared CowleyJared Cowley Huntsman Cancer Institute, Salt Lake City, UT (T.K., J.C.). , Kelsey BarrellKelsey Barrell University of Utah Health, Salt Lake City (D.V., J.A., K.B., M.P.R., J.S., S.D., N.M., B.W., E.A.S., J.F., J.N.-N.). , Monica P. ReveloMonica P. Revelo University of Utah Health, Salt Lake City (D.V., J.A., K.B., M.P.R., J.S., S.D., N.M., B.W., E.A.S., J.F., J.N.-N.). , Josef StehlikJosef Stehlik University of Utah Health, Salt Lake City (D.V., J.A., K.B., M.P.R., J.S., S.D., N.M., B.W., E.A.S., J.F., J.N.-N.). , Stavros DrakosStavros Drakos University of Utah Health, Salt Lake City (D.V., J.A., K.B., M.P.R., J.S., S.D., N.M., B.W., E.A.S., J.F., J.N.-N.). , Nassir MarroucheNassir Marrouche University of Utah Health, Salt Lake City (D.V., J.A., K.B., M.P.R., J.S., S.D., N.M., B.W., E.A.S., J.F., J.N.-N.). , Brent WilsonBrent Wilson University of Utah Health, Salt Lake City (D.V., J.A., K.B., M.P.R., J.S., S.D., N.M., B.W., E.A.S., J.F., J.N.-N.). , Eric A. SwansonEric A. Swanson University of Utah Health, Salt Lake City (D.V., J.A., K.B., M.P.R., J.S., S.D., N.M., B.W., E.A.S., J.F., J.N.-N.). , James FangJames Fang University of Utah Health, Salt Lake City (D.V., J.A., K.B., M.P.R., J.S., S.D., N.M., B.W., E.A.S., J.F., J.N.-N.). and Jose Nativi-NicolauJose Nativi-Nicolau Jose Nativi-Nicolau, MD, University of Utah Health, 50 N Medical Dr, Salt Lake City, UT 84132, E-mail E-mail Address: [email protected] University of Utah Health, Salt Lake City (D.V., J.A., K.B., M.P.R., J.S., S.D., N.M., B.W., E.A.S., J.F., J.N.-N.). Originally published19 Jun 2018https://doi.org/10.1161/CIRCHEARTFAILURE.117.004812Circulation: Heart Failure. 2018;11:e004812Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: June 19, 2018: Previous Version of Record IntroductionA 78-year-old man with atrial flutter/fibrillation unresponsive to 3 cardioversions, 1 flutter, and 2 left atrial ablations, myocardial infarction in 2000 treated with a stent to the left anterior descending coronary, hypertension, bilateral carpal tunnel surgery (15 years before), and lumbar spinal stenosis presented with anemia in March 2015. He also complained of dysphagia and was referred for an esophagogastroduodenoscopy. Esophageal biopsies revealed esophagitis. The submucosal vessels in both the duodenal and gastric biopsies showed the presence of a slight thickening by acellular eosinophilic material that raised the possibility of amyloid on routine hematoxylin and eosin–stained slides (Figure [A] and [B]). This finding prompted investigation with Congo red stain, which demonstrated gastric and duodenal amyloid deposition within the submucosal blood vessels.Download figureDownload PowerPointFigure. Patient with wild-type cardiac amyloidosis. A, Duodenal submucosa with abnormal vessels that appear thickened by waxy, eosinophilic amorphous material suggestive of amyloid. B, Gastric biopsy with abnormal vessels within the muscularis mucosae wherein the vessels appear thickened by waxy, eosinophilic amorphous material suggestive of amyloid. C, Transthoracic echocardiogram in the parasternal view demonstrates septal thickness of 1.1 cm and posterior wall thickness of 0.9 cm. D, Cardiac magnetic resonance with septal thickness of 1.4 cm. E, 12-lead ECG shows atrial fibrillation, mild criteria for left ventricular hypertrophy, and nonspecific ST-T changes. F, Hemotoxylin and eosin–stained section of myocardium shows small arteries (black arrow) with pale glassy material within the wall. There is focal myocyte hypertrophy and interstitial fibrosis. G, Congo red stain under polarized light demonstrates characteristic apple-green birefringence of amyloid material in small arteries (black arrows).He was referred to the Utah Amyloidosis Program for further evaluation. His hematologic workup was unimpressive with κ free light chains of 2.29 mg/dL (range, 0.33–1.94 mg/dL), λ free light chains of 2.31 mg/dL (range, 0.57–2.63 mg/dL), κ/λ free light chain ratio of 0.99 (range, 0.26–1.65), serum protein electrophoresis with slight β-γ bridging, and immunofixation showed polyclonal increase in IgA, without monoclonal proteins seen; a bone marrow biopsy was deferred. His renal evaluation demonstrated normal renal function with a creatinine of 1.01 mg/dL, blood urea nitrogen of 15 mg/dL, calculated glomerular filtration rate of 71 mL/min per 1.73 BSA, and no proteinuria. His cardiac studies revealed troponin I of 0.01 ng/mL (range, 0.00–0.03 ng/mL), NT-proBNP (N-terminal pro-B-type natriuretic peptide) of 478 pg/mL (range, 0–449 pg/mL), transthoracic echocardiogram with septal wall thickness of 1.1 cm, posterior wall thickness of 0.9 cm, left ventricular systolic function of 70%, longitudinal strain of −22.3%, relative apical longitudinal strain of 0.71 (normal range, <1.0), and pseudonormal pattern of left ventricular filling (Figure [C]). Cardiac magnetic resonance was negative for infiltrative cardiomyopathy by late gadolinium enhancement and normal left ventricular mass of 109 g (range, 92–176 g) with a mild increase in septal wall thickness of 1.4 cm (Figure [D]). A 12-lead ECG demonstrated atrial fibrillation with minimal criteria for left ventricular hypertrophy and nonspecific ST-T changes (Figure [E]).Further testing of the duodenal biopsy by mass spectroscopy detected a peptide profile consistent of wild-type amyloid transthyretin amyloidosis (ATTR). To confirm this result and to detect cardiac involvement, the patient underwent endomyocardial biopsy, despite the lack of infiltrative features in the echocardiogram, cardiac magnetic resonance, and biomarkers. The heart biopsy confirmed the presence of interstitial and vascular ATTR amyloidosis (Figure [F] and [G]). Genetic testing was negative for transthyretin mutations. Based on the above studies, the patient was diagnosed with wild-type ATTR amyloidosis with cardiac and gastrointestinal involvement. He was treated with the transthyretin stabilizer diflunisal 250 mg BID.DiscussionThis case demonstrates that there are patients with early cardiac amyloidosis (CA) whose diagnosis may be missed because of the absence of typical infiltrative features in cardiac magnetic resonance imaging, echocardiography, electrocardiography, and cardiac biomarkers. For the diagnosis of CA, previous studies have reported a sensitivity of 85% and specificity of 92% with gadolinium enhancement by cardiac magnetic resonance1; and a sensitivity of 93% and specificity of 82% using relative apical longitudinal strain by echocardiography.2 Despite the relatively high diagnostic accuracy of these tests, CA can be missed by conventional techniques and remains underdiagnosed in earlier stages. It seems that lately CA is being suspected and worked up more frequently in patients with cardiac symptoms. For instance, González-López et al3 reported on amyloidosis being detected in 13% of their patients with heart failure with preserved ejection fraction. Wild-type ATTR predominantly affects the cardiac, neurological, gastrointestinal, and renal systems, and based on the Transthyretin Amyloidosis Outcomes Registry, the most common symptoms include heart failure, 87%; arrhythmias, 65%; carpal tunnel, 33%; numbness, 22%; and dizziness, 20%.4Endomyocardial biopsy is currently the gold standard for diagnosing CA but is not always practical because of its invasive nature and limited availability. Novel noninvasive tests are emerging as potential tools for earlier diagnosis. In 2016, a group of international investigators reported a sensitivity of 74% and specificity of 100% to diagnose cardiac ATTR amyloidosis using a grade 2 or 3 myocardial uptake on bone scintigraphy in the absence of a monoclonal protein.5 Our patient presented in 2015 when this approach was not yet validated; however, it could have been of potential utility during the initial evaluation. The recent commercial availability of pulse sequences and postprocessing software facilitates the use of cardiac magnetic resonance imaging parametric mapping techniques to enable earlier diagnosis. Noncontrast, native T1 mapping has a reported sensitivity of 92% and specificity of 91%.6 In addition, extracellular volume as assessed by postcontrast T1 mapping correlates with amyloid burden and may be useful in both detection and in tracking response to therapy. Both native T1 and extracellular volume become abnormal before being able to detect late gadolinium enhancement and should enable earlier detection of amyloidosis. Novel noninvasive tests could potentially be used to screen broader populations in which initial conventional evaluations could miss CA, such as patients with atrial fibrillation, especially if they have other known symptoms associated with amyloidosis like heart failure, bilateral carpal tunnel, or neuropathy.DisclosuresDr Nativi-Nicolau is a member of the advisory board at Alnylam Pharmaceuticals. Dr Marrouche receives consulting fees/royalties from Abbott, Biotronik, Wavelet Health, Cardiac Design, Medtronic, Preventice, Vytronus, Biosense Webster, Marrek, Inc, and Boston Scientific; receives research support from Abbott, Boston Scientific, GE Healthcare, Siemens, Biotronik, Vytronus, and Biosense Webster; and also declares company interest from Marrek, Inc, and Cardiac Design. The other authors report no conflicts.Footnoteshttps://www.ahajournals.org/journal/circheartfailureGuest Editor for this article was Ray E. Hershberger, MD.Jose Nativi-Nicolau, MD, University of Utah Health, 50 N Medical Dr, Salt Lake City, UT 84132, E-mail jose.[email protected]utah.eduReferences1. Zhao L, Tian Z, Fang Q, . Diagnostic accuracy of cardiovascular magnetic resonance for patients with suspected cardiac amyloidosis: a systematic review and meta-analysis.BMC Cardiovasc Disord. 2016; 16:129. doi: 10.1186/s12872-016-0311-6.CrossrefMedlineGoogle Scholar2. Phelan D, Collier P, Thavendiranathan P, Popović ZB, Hanna M, Plana JC, Marwick TH, Thomas JD, . Relative apical sparing of longitudinal strain using two-dimensional speckle-tracking echocardiography is both sensitive and specific for the diagnosis of cardiac amyloidosis.Heart. 2012; 98:1442–1448. doi: 10.1136/heartjnl-2012-302353.CrossrefMedlineGoogle Scholar3. González-López E, Gallego-Delgado M, Guzzo-Merello G, de Haro-Del Moral FJ, Cobo-Marcos M, Robles C, Bornstein B, Salas C, Lara-Pezzi E, Alonso-Pulpon L, Garcia-Pavia P, . Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction.Eur Heart J. 2015; 36:2585–2594. doi: 10.1093/eurheartj/ehv338.CrossrefMedlineGoogle Scholar4. Maurer MS, Hanna M, Grogan M, Dispenzieri A, Witteles R, Drachman B, Judge DP, Lenihan DJ, Gottlieb SS, Shah SJ, Steidley DE, Ventura H, Murali S, Silver MA, Jacoby D, Fedson S, Hummel SL, Kristen AV, Damy T, Planté-Bordeneuve V, Coelho T, Mundayat R, Suhr OB, Waddington Cruz M, Rapezzi C, ; THAOS Investigators. Genotype and phenotype of transthyretin cardiac amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey).J Am Coll Cardiol. 2016; 68:161–172. doi: 10.1016/j.jacc.2016.03.596.CrossrefMedlineGoogle Scholar5. Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, Wechalekar AD, Berk JL, Quarta CC, Grogan M, Lachmann HJ, Bokhari S, Castano A, Dorbala S, Johnson GB, Glaudemans AW, Rezk T, Fontana M, Palladini G, Milani P, Guidalotti PL, Flatman K, Lane T, Vonberg FW, Whelan CJ, Moon JC, Ruberg FL, Miller EJ, Hutt DF, Hazenberg BP, Rapezzi C, Hawkins PN, . Nonbiopsy diagnosis of cardiac transthyretin amyloidosis.Circulation. 2016; 133:2404–2412. doi: 10.1161/CIRCULATIONAHA.116.021612.LinkGoogle Scholar6. Karamitsos TD, Piechnik SK, Banypersad SM, Fontana M, Ntusi NB, Ferreira VM, Whelan CJ, Myerson SG, Robson MD, Hawkins PN, Neubauer S, Moon JC, . Noncontrast T1 mapping for the diagnosis of cardiac amyloidosis.JACC Cardiovasc Imaging. 2013; 6:488–497. doi: 10.1016/j.jcmg.2012.11.013.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails July 2018Vol 11, Issue 7 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.117.004812PMID: 29921704 Originally publishedJune 19, 2018 Keywordsprealbuminatrial fibrillationamyloidosisagedhumansPDF download Advertisement SubjectsAtrial FibrillationCardiomyopathy

Peripheral neuropathy is a commonly encountered disorder in clinical practice. In light of an aging population and the diabetes and obesity pandemic, the prevalence of peripheral neuropathy is increasing, posing a significant public health concern. This article provides a diagnostic framework for neuropathies and summarizes treatment options.

Objective: To determine whether Parkinson disease (PD) patients with (VH) have different clinical characteristics and gray-matter volume than those with visual misperceptions (VM) or other visual symptoms (OvS). Background: The spectrum of visual complaints in PD is broad and complex. Methods: We conducted a retrospective chart review of 525 PD patients to identify the frequency of visual symptoms and the association with clinical and radiological features. Brain volumetric MRI data was analyzed using multivariate logistic regression to differentiate cases with and without visual symptoms. Results: Among 525 PD cases, visual complaints were documented in 177 (33.7%). Among these, 83 (46.9%) had VH, 31 (17.5%) had VM, and 63 (35.6%) had OvS (diplopia, blurry vision, photophobia, dry eyes, and eye pain or soreness). When compared to OvS, patients with VH had significantly higher age, duration of disease, rate of REM sleep behavior disorder, and cognitive impairment. Visual hallucinations patients had decreased age-adjusted volumetric averages in 28/30 gray-matter regions when compared to PD without visual symptoms and 30/30 gray-matter regions when compared to VM patients. Conclusions: Visual symptoms in PD may represent a spectrum from OvS to VM to VH, with progression of the latter associated with older age, duration of disease, presence of REM sleep behavior disorder, cognitive impairment, and decreased gray-matter volume.