Mauermann, Michelle L.

Purpose: Hereditary transthyretin amyloidosis (ATTRv) is a progressive multisystem disease in which median mononeuropathy at the wrist (MNW) is common and often precedes systemic involvement. Nerve conduction studies (NCS) have historically been the gold standard for MNW, but neuromuscular ultrasound (NMUS) is complementary. The aim of this study was to compare NMUS with electrodiagnostic (EDX) testing for the diagnosis of MNW in patients with symptomatic ATTRv. Methods: A retrospective review was performed of patients 18 years and older with ATTRv confirmed by genetic testing who underwent both EDX testing and NMUS of the median nerve between 2019 and 2025. Demographic, NMUS, and EDX data were collected. Results: Data from 15 upper limbs in 10 patients were analyzed. Median nerve cross‐sectional area at the wrist was significantly greater than reference values ( P = 0.041). MNW was identified in 80% of wrists by NMUS and 100% by NCS, with no significant difference between modalities. Median nerve cross‐sectional area at the wrist did not significantly correlate with MNW severity determined by NCS ( r = −0.018; P = 0.941) or with any NCS parameters (all P > 0.080). Concurrent polyneuropathy was diagnosed in 60% of patients, but there was no association between polyneuropathy and MNW detection by either modality ( P > 0.197). Conclusions: NMUS and NCS demonstrate comparable diagnostic accuracy for MNW in ATTRv. Given its noninvasive nature and efficiency, NMUS may serve as an adjunct to classic EDX testing in this population.

Abstract Gastrointestinal (GI) involvement is a clinically relevant but undercharacterized manifestation of systemic light chain amyloidosis (AL). We aimed to define the clinical spectrum, histologic patterns, and outcomes of symptomatic GI involvement in AL. We retrospectively analyzed 4396 patients with AL from 2010 to 2024, of whom 521 (11.9%) had provider-attributed symptomatic GI involvement; 66% had biopsy-proven GI AL. Symptoms most commonly included early satiety (61%), bowel irregularities (58%), nausea (35%), abdominal pain (28%), and dysphagia (23%). Autonomic neuropathy was frequent (43% clinician attributed; 23% via autonomic reflex testing) and contributed to dysmotility-related symptoms, often without GI biopsy positivity. Among 747 GI biopsies, mucosal infiltration predominated (71%) and was associated with bleeding (22% vs 9%), cachexia, and inferior survival, whereas vascular involvement was associated with lower bleeding risk. Combined involvement of mucosa, submucosa, and vessels conferred the worst prognosis (median overall survival [mOS], 2.4 vs 5.1 vs 7.8 years for 3 vs 2 vs 1 layer); mOS was 6.8 years and was primarily driven by cardiac stage and hematologic response (very good partial response [VGPR] or better: hazard ratio, 0.20; 95% CI 0.13-0.32), with more favorable outcomes in patients with isolated GI involvement. Cachexia and persistent diarrhea were the main drivers of morbidity, need for nutritional support, and GI-related mortality (odds ratio, 2.7 for the combined end point). GI bleeding rarely recurred after achieving VGPR or better. Overall, mucosal involvement, cachexia, and dysmotility define clinically meaningful GI AL and support systematic assessment of autonomic dysfunction as well as evaluation of the need for nutritional support as a GI-specific end point for AL trials.

Abstract Background: Gastrointestinal (GI) symptoms are frequent in patients (pts) with systemic light chain amyloidosis (AL), yet their clinical significance remains poorly defined. We investigated the role of symptomatic GI involvement in disease burden, survival, and organ-specific outcomes in a large single-center cohort. Methods From 2010–2025, 4,396 AL pts were evaluated at our center; 560 pts (13%) had provider-attributed symptomatic GI AL. Pts with localized AL or positive biopsy without GI symptoms were excluded (n=38). We analyzed relationships between GI symptoms, anatomic/histologic involvement, laboratory parameters, survival, and need for nutritional support using Wilcoxon rank-sum, Chi-square, Kaplan-Meier, and logistic regression tests. Results GI symptoms included early satiety (n=320/57%), diarrhea (n=189/34%), nausea (n=184/33%), abdominal pain (n=148/26%), dysphagia (n=119/21%), vomiting (n=75/13%), GI bleeding (n=74/13%), and heartburn (n=71/13%). Only nausea and GI bleeding were not associated with cardiac (n=366/65%) renal (n=274/49%) or hepatic (n=84/15%) AL, whereas dysphagia, early satiety and heartburn were more frequent with cardiac (all OR=1.7), abdominal pain and diarrhea with hepatic (OR=2 and 1.6, respectively), and vomiting with renal involvement (OR=2; all p<0.04). Autonomic involvement impacted GI symptoms, often without proof of parenchymal GI amyloid. Of the 124 pts with formal autonomic testing, only 44 (35%) had positive GI biopsies as compared to AL GI pts without proven autonomic involvement (240/436, 55%). Pts with autonomic involvement were more symptomatic than pts with positive GI biopsies, suffering more often from dysphagia (29% vs 19%), diarrhea (41% vs 32%), and gastroparesis (34% vs 9%, all p<0.001). We screened changes in body weight, calcium, VitB12, Hb, PO4, and albumin at diagnosis. Of the 175 pts with documented weight loss in this cohort, pts with GI AL lost more weight compared to those with other organ involvement (21% vs 14% of weight, p=0.002), and had lower phosphate (3.7 vs 4.0 mg/dL, p=0.06). In our cohort of pts with GI symptoms, 298 (53%) had a positive GI biopsy. Biopsy-proven anatomic involvement dictated symptoms (all p<0.05): Of the 20 pts with positive esophageal biopsy, dysphagia was present in 45%; only 33% of the pts without an esophageal biopsy had dysphagia. Similar patterns were seen for the 170 pts with a positive gastric biopsy (n=170) in terms of heartburn (21% vs 11%), for the 165 pts with positive small bowel biopsies in terms of abdominal pain (68% vs 32%), and for the 130 pts with positive colon biopsies and diarrhea (46% vs 33%). Specific histopathological patterns were prognostic. Mucosal involvement (n=161) was an independent risk factor for survival compared to submucosal (n=64) and vascular (n=102) involvement throughout the GI tract (HR 1.83; p=0.03). Three-layer GI infiltration was associated with inferior mOS (2.4 vs 5.1 vs 7.8 y for 3 vs 2 vs 1-layer involvement, HR 3.19/1.56/1; p<0.05). Counterintuitively, vascular involvement had the lowest risk of bleeding in all GI anatomic sites (p=0.02). In the colon, only mucosal involvement was associated with a higher risk of bleeding (OR=5; p=0.04). GI involvement in AL pts did not worsen prognosis (mOS 10.0/6.3y, p=0.02), and pts with isolated GI AL (n=74/13%) had an even better survival (55% surviving at 10 y). Cachexia (n=120; mOS 3.5 vs 7.8 y, p<0.001), need for nutritional support (n=36; mOS 0.9 vs 7.0 y, p<0.001), and diarrhea (mOS 5.8 vs 6.9 y, p=0.06) were risk factors for death. In pts with hematologic response (≥PR), bleeding did not recur within 3 y (n=27), but even with response, diarrhea (n=160) persisted in 39%. Resolution was less frequent without hematologic response (persistence in 69%, OR=3.5). Improvement was most often due to treatment of bacterial overgrowth (11/35 pts; 68%) and loperamide (54/59 pts; 91%). Conclusion In AL, meaningful GI involvement is defined by nausea, diarrhea, occurrence of bleeding, and malnutrition. These are primarily associated with mucosal infiltration. GI symptoms can occur in the face of autonomic involvement. While long-term persistence of GI bleeding is rare after serologic response, cachexia and persistent diarrhea drive morbidity, need for nutritional support, and poor survival.

Importance Peripheral neuropathy, defined as damage to peripheral nerves, affects approximately 1% of adults worldwide. More than 200 causes of peripheral neuropathy exist, with symptoms ranging in severity from mild toe numbness to debilitating symptoms that can require a wheelchair. Diabetes is the most common cause of neuropathy, affecting approximately 206 million people worldwide. Observations Peripheral neuropathy is typically length-dependent, which means that symptoms appear in the longest nerve axons (toes) and progress proximally over time. Peripheral neuropathy is typically symmetric and affects sensory axons more than motor axons. Diabetic neuropathy, which is often associated with both sensory symptoms, such as pain, tingling, or numbness; mild weakness; and autonomic symptoms, such as orthostatic hypotension, accounts for more than 50% of peripheral neuropathy in Western populations. Other causes of neuropathy include hereditary causes, such as Charcot-Marie-Tooth disease, toxic neuropathy from medications (chemotherapies [eg, cisplatin, paclitaxel, vincristine], amiodarone, or HIV nucleotide reverse transcriptase inhibitors [eg, stavudine, zalcitabine]); alcohol; vitamin deficiencies such as vitamin B 12 ; and monoclonal gammopathies. Up to 27% of adults with neuropathy have no identifiable etiology for their neuropathy after diagnostic testing. Recommended initial testing includes blood glucose (for diabetes), serum B 12 with metabolites (methylmalonic acid with or without homocysteine), and serum protein electrophoresis with immunofixation (for monoclonal gammopathies). First-line medications for neuropathic pain are the α2-δ calcium channel subunit ligands, such as gabapentin and pregabalin; serotonin norepinephrine reuptake inhibitors, such as duloxetine and venlafaxine; and tricyclic antidepressants, such as amitryptyline and nortriptyline. Pain often persists despite medical management. At least a 50% reduction in pain was observed in 38% of those with painful diabetic peripheral neuropathy receiving 1200 mg of gabapentin daily. Combination drug therapies for neuropathic pain may provide added benefit. The prognosis of peripheral neuropathy depends on its underlying cause, but complete reversal of nerve damage is uncommon even in cases for which there are available treatments. Conclusions and Relevance Peripheral neuropathy affects approximately 1% of adults worldwide and may cause sensory, motor, and autonomic symptoms. Diabetes is the most common cause of peripheral neuropathy in Western countries. First-line therapies for neuropathic pain include gabapentin, pregabalin, duloxetine, and amitriptyline.