Sympathetic Ganglia Research Articles

Aggressive Pediatric Primitive Round Cell Tumors with MN1::ZNF341 Fusion: A Mimic of Neuroblastoma.

Neuroblastoma is one of the most common tumors in young children, arising from the adrenal medulla or paraspinal sympathetic ganglia. We describe primitive round cell tumors presenting in three patients less than 1.5years old, with striking clinical and pathologic similarities to neuroblastoma. Unlike neuroblastoma, however, these primitive tumors did not show specific histologic or immunophenotypic evidence of neuroblastic differentiation, and harbored a MN1::ZNF341 fusion. All patients progressed through neuroblastoma therapy and ultimately died of disease. These highly aggressive tumors mimicking neuroblastoma appear to be a novel and distinctive entity in need of further characterization.

The effects of lumbar sympathetic ganglion block therapy on secondary lower limb lymphedema among patients with gynecologic cancer surgery

The effects of lumbar sympathetic ganglion block therapy on secondary lower limb lymphedema among patients with gynecologic cancer surgery

Efficacy comparison of transcatheter aorticorenal ganglion ablation and renal denervation in a hypertensive canine model

Abstract Background Transcatheter renal sympathetic denervation (RDN) has been proposed to be an adjunctive treatment in uncontrolled hypertension. However, non-responders to RDN were not rare. Considering the lack of a procedure endpoint and the limitation of anatomic-based ablation strategy, incomplete or futile denervation may contribute to non-responsiveness. Aorticorenal ganglion (ARG) is a purely sympathetic ganglion that projects to the proximal and distal renal artery, forming the peri-arterial nerve network. Ablation of this ganglion results in significant renal denervation. However, it remains unknown whether ARG ablation has a superior effect in lowering blood pressure (BP) compared to RDN. Purpose The aim of the study was to determine whether ARG ablation improved the BP-lowering effect compared to RDN in a hypertensive canine model. Methods A total of 21 male Chinese Kunming dogs were included and randomized into three groups: ARG ablation group (n=7), RDN group (n=7) and control group (n=7). In the ARG ablation group, anatomically based high-frequency stimulation (HFS) was performed in the aorta and inferior vena cava (IVC) under the guidance of 3D anatomical construction (Figure 1A). ARG ablation sites were identified by HFS-induced BP elevation response (>10mmHg) and renal artery vasoconstriction (Figure 1B). In the RDN group, HFS-guided ablation was conducted at the positive site (BP elevation response >5mmHg) from the distal to proximal renal artery. Endpoint of the procedure was defined as the elimination or attenuation of BP elevation induced by HFS. BP was assessed at baseline and 4 weeks after the procedure. Results The left ARG ablations were performed at the inferior aspect of superior mesenteric artery (4/7), the abdominal aorta (2/7) and the proximal renal artery (1/7), while the right ARG ablations were performed at the posterior aspect of the IVC (6/7) and the ostium of the left renal vein (1/7). The gross anatomy of bilateral ARGs was shown in Figure 1C. The hemodynamic response to ARG stimulation was significantly greater than that of renal artery stimulation (40.0±13.4 vs 13.3±3.7 mmHg, Figure 2A, B); meanwhile, ARG ablation is more effective in blunting the BP elevation response compared to RDN (30.7±11.7 vs 9.6±2.6, P=0.001, Figure 2A, C). With a 4-week follow-up, ARG ablation demonstrated a greater systolic BP-lowering effect than RDN (-29.6±12.0 vs -15.3±6.9 mmHg, P=0.018, Figure 2D). No complications were found during the procedure or follow-up. Conclusion Our study suggests that ARG ablation could lead to a more efficient BP-lowering effect compared to RDN, which provides a novel paradigm for autonomic modulation in the treatment of hypertension.Figure 1Figure 2

6997 Atypical Presentation of Hereditary Paraganglioma

Abstract Disclosure: O. Abdulhussein: None. R.R. Correa: None. M.D. Lundholm: None. J. Ferri-Guerra: None. G. Madrigol: None. Introduction: Paraganglioma (PGL) is a rare neuroendocrine, highly vascular tumor arising from sympathetic or parasympathetic ganglia chromaffin cells. Some PGL functional while others biochemically silent. Given the possible lack of classic symptoms or convincing catecholamine elevation. They are closely related to pheochromocytomas.• However, the distinction between pheochromocytoma and paraganglioma is essential because of the implication for associated neoplasm and syndromes; paraganglioma is more metastatic. Case: 32-year-old otherwise healthy female presented to primary care clinic for 1 year of dry cough. She was a non-smoker. She denied voice changes, palpitations, hypertension, palpitations, pallor, headache, or diaphoresis, but had noticed a mass growing in her right neck for a year. On exam her blood pressure 107/73 and there was a mobile, round mass felt at the right mandible. CT neck at the time showed reactive lymphadenopathy. She referred to pulmonology and ENT, spirometry and flexible laryngoscopy were unremarkable. For persistent mass 1year later, an MRI of the neck showed a 2.8x2.3x3.8 cm right carotid mass, likely PGL. Biochemical testing revealed elevations in plasma normetanephrine (NM) (269 pg/mL, 18-101 pg/mL) and 24-hour urinary NM (848 ug/24hr, 88-444 ug/24hr) with mild elevation in 24-hour urinary metanephrine (982 ug/24 hr, 140-785 ug/24 hr) and normal plasma metanephrine. The mass was intensely avid on DOTATATE scan without other lesions. Genetic testing uncovered SDHB mutation. She was started on preoperative alpha-blockade with successful resection. She had pathology confirmation of PGL and was set up for annual SDHB surveillance testing. Discussion: A minority of patients with PCC or PGL present with classical “5 P” catecholamine symptoms: pallor, pain, pressure, perspiration, or palpitations. One main reason is a lack of excess catecholamine secretion; 17 years of retrospective data at our center showed that 61% (N=50/82) of patients with PGL with preoperative catecholamine labs had normal levels. Additionally, mild to moderate increases to 2-3x upper limit of normal may be attributed to stress or medications, which obfuscates the distinction between secretory disease and physiologic elevation.Given the infrequency of catecholamine symptoms or secretion, PGL is frequently discovered incidentally. Indeed, 92% (N=110/119) of our PGL cases were found incidentally on imaging or pathology. Alpha-blockade is the preoperative standard of care, many patients are only diagnosed post-operatively by pathology findings. Further study is needed to determine if pre-operative alpha-blockade is needed in all PGL cases, and if so, how we can better identify these patients before they go to the operating room. For now, a high level of suspicion is needed to make a timely PGL diagnosis and facilitate genetic testing. Presentation: 6/1/2024

Optimization of an autaptic culture system for studying cholinergic synapses in sympathetic ganglia.

An autaptic synapse (or 'autapse') is a functional connection between a neuron and itself, commonly used in studying the molecular mechanisms underlying synaptic transmission and plasticity in central neurons. Most previous studies on autonomic synaptic functions have relied on spontaneous connections among neurons in mass cultures. However, growing evidence supports the utility of microcultures cultivating autaptic neurons for examining cholinergic transmission within sympathetic ganglia. Despite these advancements, standardized protocols for culturing autaptic sympathetic neurons have yet to be established. Drawing on historical literature, this study delineates optimal experimental conditions to efficiently and reliably produce cholinergic synapses in sympathetic neurons within a short time frame. Our research emphasizes five key factors: (i) the generation of uniformly sized microislands of growth permissive substrates; (ii) the addition of nerve growth factor, ciliary neurotrophic factor (CNTF), and serum to the culture medium; (iii) independence from specific serum and neuronal medium types; (iv) the reciprocal roles of CNTF and glial cells; and (v) the promotion of cholinergic synaptogenesis in SCG neurons through indirect glia co-cultures, rather than direct glial feeder layer cultures. In conclusion, glia-free monocultures of SCG neurons are relatively simple to prepare and yield robust and reliable synaptic currents. This makes them an effective model system for straightforwardly addressing fundamental questions about neurogenic mechanisms involved in cholinergic synaptic transmission in autonomic ganglia. Furthermore, autaptic culture experiments could eventually be implemented to investigate the roles of functional neuron-satellite glia units in regulating cholinergic functions under physiological and pathological conditions.

Procedural interventions for erythromelalgia: A narrative review.

Erythromelalgia is a rare disorder characterized by episodic burning pain with redness and warmth of the extremities. Topical and systemic medications are the mainstay of management. We reviewed the published evidence for using procedural interventions to manage erythromelalgia, including their proposed mechanism of action and possible adverse effects, and included information in this review on epidural infusion, sympathetic ganglion block, sympathectomy, pulsed radiofrequency, spinal cord stimulation, dorsal root ganglion stimulation, brain stimulation, transcranial magnetic stimulation, and botulinum toxin injections. Both successful and unsuccessful outcomes have been reported. Although these procedural interventions extend the therapeutic options for erythromelalgia, the evidence for their use is limited. Case reports and small case series comprise most of the evidence. Based on our review, a multidisciplinary approach to management may be needed for patients with erythromelalgia.

Organ-specific Sympathetic Innervation Defines Visceral Functions.

The autonomic nervous system orchestrates the brain and body functions through the sympathetic and parasympathetic pathways. However, our understanding of the autonomic system, especially the sympathetic system, at the cellular and molecular levels is severely limited. Here, we show unique topological representations of individual visceral organs in the major abdominal sympathetic ganglion complex. Using multi-modal transcriptomic analyses, we identified distinct sympathetic populations that are both molecularly and spatially separable in the celiac-superior mesenteric ganglia (CG-SMG). Notably, individual CG-SMG populations exhibit selective and mutually exclusive axonal projections to visceral organs, targeting either the gastrointestinal (GI) tract or secretory areas including the pancreas and bile tract. This combinatorial innervation pattern suggests functional segregation between different CG-SMG populations. Indeed, our neural perturbation experiments demonstrated that one class of neurons selectively regulates GI food transit. Another class of neurons controls digestion and glucagon secretion independent of gut motility. These results reveal the molecularly diverse sympathetic system and suggest modular regulations of visceral organ functions through distinct sympathetic populations.

Dissection of the Sympathetic Nerves Around the Mesorectum at the Abdominopelvic Border.

Introduction Along the border between the abdominal cavity and pelvis are nervous structures that belong to the autonomous nervous system, which is delicate. These can be easily injured during regional surgical procedures such as the total mesorectal excision, where the preservation of the nervous structures should be one of the main objectives. In our study, we aimed to dissect all the sympathetic nerve formations listed at the abdominopelvic border and to present their formation, anatomical routes, and relations, as well as the surgical importance of their preservation. Method We performed anatomical dissections on eight 60- to 75-year-old cadavers (three male and five female) in the Dissection Laboratory of Carol Davila University of Medicine and Pharmacy, Bucharest, ROM. We sectioned each pelvis along the right pararectal line and exposed the hypogastric plexuses and their branches, following their pathways toward the pelvic viscera. Results We highlight the main nervous structures in the pelvis, namely the paravertebral sympathetic ganglion chain, which continues into the pelvis with the sacral ganglion chain, and the prevertebral component of the abdominal sympathetic system, represented by the superior hypogastric plexus and its continuation via the hypogastric nerves toward the inferior hypogastric plexuses. We followed the pathway of the superior hypogastric plexus from its origin down to its bifurcation into the two hypogastric nerves. We then followed the nerves into the pelvis and observed the formation of the inferior hypogastric plexuses, from which branches emerged toward the pelvic organs. Along the way, we point out anatomical landmarks that are crucial in an attempt to spare these nervous structures during regional surgical procedures. Conclusions While performing surgeries such as rectal resection with the excision of the mesorectum, radical hysterectomy, and radical prostatectomy, a thorough knowledge of the sympathetic nerve structures that pass from the abdominal cavity into the pelvis is required to spare pelvic innervation. In such a context, the dissection and anatomical assessment of regional sympathetic nerves can prove to be crucial in establishing operative protocols.

CN78 The effects of lumbar sympathetic ganglion block therapy on secondary lower limb lymphedema

CN78 The effects of lumbar sympathetic ganglion block therapy on secondary lower limb lymphedema

264. SIGNIFICANCE AND USEFULNESS OF PLASMA SUBSTANCE P CONCENTRATION IN PREDICTING HIGH-RISK PATIENTS FOR ASPIRATION AFTER ESOPHAGEAL CANCER SURGERY

Abstract Background The greatest challenge in postoperative complications of esophageal cancer is the prevention of pulmonary complications, especially aspiration pneumonia. Although the introduction of minimally invasive surgery and intervention in breathing and swallowing rehabilitation can improve the motor function of breathing and swallowing, we reported the possibility that a decline in the swallowing reflex may play a significant role in esophageal cancer patients, many of whom are elderly. In fact, about 80% of esophageal cancer patients in Japan are over 60 years old, and 53% of them have asymptomatic cerebral infarction, about half of which are reported to be found near the basal ganglia, which control the swallowing reflex. The swallowing reflex is controlled by the secretion of substance P, synthesized in the cervical sympathetic ganglia, into the pharynx and trachea upon stimulation of dopamine synthesized in the basal ganglia. Methods To test the hypothesis that patients with preoperative subclinical cerebral infarction are more likely to develop aspiration postoperatively due to decreased substance P secretion. To compare the association between the presence or absence of cerebral infarction near the basal ganglia and serum substance P levels and the development of postoperative aspiration or aspiration pneumonia due to videoendoscopy and video fluorography in patients with thoracic esophageal cancer scheduled for video-assisted esophagectomy by preoperative brain MRI imaging and blood sampling. Results We report the results of an interim analysis of 54 cases in which the measurement of substance P was completed. Male: 39 cases, female: 15 cases. Mean age: 69.3 (49-82) years. Tumor location: Ut/Mt/Lt=13/25/14. MRI showed infarction in or near the basal ganglia in only 2 cases. Median preoperative blood substance P concentration: 48.2 pg/ml. Eleven one patients had postoperative aspiration. Preoperative substance P levels ≥48.2 pg/ml were defined as the High group, and those below 48.2 pg/ml were defined as the Low group. Postoperative aspiration was observed in 2/27 (7.4%) patients in the High group, while 9/26 (34.6%) patients in the Low group, which was significantly higher (p=0.015). Conclusion In fact, subclinical cerebral infarction was much less common than reported and was not useful as a predictor of postoperative aspiration. On the other hand, patients with low preoperative blood substance P levels had a very high risk of developing aspiration postoperatively due to impaired swallowing reflexes, suggesting that preoperative blood substance P levels may be useful in assessing postoperative aspiration risk in patients with thoracic esophageal cancer.

Opiorphin: an endogenous human peptide with intriguing application in diverse range of pathologies.

Mammalian zinc ectopeptidases have significant functions in deactivating neurological and hormonal peptide signals on the cell surface. The identification of Opiorphin, a physiological inhibitor of zinc ectopeptidases that inactivate enkephalin, has revealed its strong analgesic effects in both chemical and mechanical pain models. Opiorphin achieves this by increasing the transmission of endogenous opioids, which are dependent on the body's own opioid system. The function of opiorphin is closely linked to the rat sialorphin peptide, which inhibits pain perception by enhancing the activity of naturally occurring enkephalinergic pathways that depend on μ- and δ-opioid receptors. Opiorphin is highly intriguing in terms of its physiological implications within the endogenous opioidergic pathways, particularly in its ability to regulate mood-related states and pain perception. Opiorphin can induce antidepressant-like effects by influencing the levels of naturally occurring enkephalin, which are released in response to specific physical and/or psychological stimuli. This effect is achieved through the modulation of delta-opioid receptor-dependent pathways. Furthermore, research has demonstrated that opiorphin's impact on the cardiovascular system is facilitated by the renin-angiotensin system (RAS), sympathetic ganglia, and adrenal medulla, rather than the opioid system. Hence, opiorphin shows great potential as a solitary candidate for the treatment of several illnesses such as neurodegeneration, pain, and mood disorders.

Motor innervation directs the correct development of the mouse sympathetic nervous system

The sympathetic nervous system controls bodily functions including vascular tone, cardiac rhythm, and the “fight-or-flight response”. Sympathetic chain ganglia develop in parallel with preganglionic motor nerves extending from the neural tube, raising the question of whether axon targeting contributes to sympathetic chain formation. Using nerve-selective genetic ablations and lineage tracing in mouse, we reveal that motor nerve-associated Schwann cell precursors (SCPs) contribute sympathetic neurons and satellite glia after the initial seeding of sympathetic ganglia by neural crest. Motor nerve ablation causes mispositioning of SCP-derived sympathoblasts as well as sympathetic chain hypoplasia and fragmentation. Sympathetic neurons in motor-ablated embryos project precociously and abnormally towards dorsal root ganglia, eventually resulting in fusion of sympathetic and sensory ganglia. Cell interaction analysis identifies semaphorins as potential motor nerve-derived signaling molecules regulating sympathoblast positioning and outgrowth. Overall, central innervation functions both as infrastructure and regulatory niche to ensure the integrity of peripheral ganglia morphogenesis.

Radiofrequency ablation of superior hypogastric ganglion and dorsal root ganglion reduces neuropathic pain in L5-S1 disc anterior protrusion: a case report

Approximately 36%-55% of patients with chronic low back pain (LBP) have neuropathic pain syndrome. Prescription of adjuvant analgesics or antidepressants is effective in reducing pain but requires special attention. A female patient, 57 y, presented with complaints of LBP for 5-7 days. Pain was spread bilateral in the hips-groin, as well as to the fingers and soles (NRS 6-8, PainDETECT 35). She had history of falls 10 y ago, but still worked for 5 hours daily. She had allodynia, dysesthesia, hyperalgesia, and L4-5 and L5-S1 hypesthesia. Magnetic resonance imaging (MRI) showed postero-central and lateral bulged L4-5 and L5-S1 discs. Radiofrequency ablation (RFA) 70o of superior hypogastric ganglion for 90 sec, and pulsed radiofrequency (PRF) 42o of dorsal root ganglion (DRG) L4-5, L5-S1 bilaterally for 2 min reduced nociceptive pain (NRS 2-3) and neuropathic pain (PainDETECT 12). Post-surgical medication included levofloxacin, gabapentin, paracetamol, amitriptyline and Vitamin B12. The sympathetic ganglia supply the anterior segments of the lumbar vertebrae and the anterior longitudinal ligament, often overlooked as a cause of pain. The management of LBP patient depends upon the etiology, whether associated to structural abnormalities or nerve dysfunction. Keywords: anterior disc herniation, dorsal root ganglion, lumbar disc herniation, neuropathic pain, superior hypogastric ganglion, radiofrequency Citation: Budisulistyo T. Radiofrequency ablation of superior hypogastric ganglion and dorsal root ganglion reduces neuropathic pain in L5-S1 disc anterior protrusion: a case report. Anaesth. pain intensive care 2024;28(4):757−761; DOI: 10.35975/apic.v28i4.2523 Received: August 02, 2023; Reviewed: December 26, 2023; Accepted: December 26, 2023

Sympathetic Motor Neuron Dysfunction is a Missing Link in Age-Associated Sympathetic Overactivity.

Overactivity of the sympathetic nervous system is a hallmark of aging. The cellular mechanisms behind this overactivity remain poorly understood, with most attention paid to likely central nervous system components. In this work, we hypothesized that aging also affects the function of motor neurons in the peripheral sympathetic ganglia. To test this hypothesis, we compared the electrophysiological responses and ion-channel activity of neurons isolated from the superior cervical ganglia of young (12 weeks), middle-aged (64 weeks), and old (115 weeks) mice. These approaches showed that aging does impact the intrinsic properties of sympathetic motor neurons, increasing spontaneous and evoked firing responses. A reduction of M current emerged as a major contributor to age-related hyperexcitability. Thus, it is essential to consider the effect of aging on motor components of the sympathetic reflex as a crucial part of the mechanism involved in sympathetic overactivity.

Postoperative Horner Syndrome: A Case Report Describing a Rare Complication After Anterior Cervical Discectomy and Fusion

The gold standard for correcting cervical degenerative disc disease (CDDD) is anterior cervical discectomy and fusion (ACDF), which is a safe, effective procedure. Horner syndrome (HS) is an extremely rare complication immediately post-ACDF due to impairment of the sympathetic trunk. Herein, we present the case of a 48-year-old woman with CDDD-related pain and radiculopathy who was counselled and consented for C5–6 and C6–7 ACDF. ACDF was performed with standard anterior left-sided incisions at appropriate levels. Unlike our usual practice, deeper-toothed retractors were employed for better exposure. Two cages were inserted at C5–6 and C6–7. The procedural time was standard (180 minutes), without intraoperative complications. The patient experienced significant symptom relief immediately post-ACDF, but developed sudden onset left-sided HS, with ptosis, miosis, and anhidrosis, approximately 48 hours post-ACDF. At a 2-week postoperative follow-up, she exhibited clinical improvement, and by 12 weeks, her HS had completely resolved. To our knowledge, this case is the first documented instance of delayed-onset HS post-ACDF. It may be associated with the type of retractors used, resulting in neuropraxia or strain on the sympathetic chain ganglia. We recommend adequate exposure while minimizing excessive retraction of the longus colli muscle to reduce irritation to the sympathetic trunk.

Esophageal ganglioneuromatosis; a rare cause of intractable esophageal stenosis: a case report

BackgroundGanglioneuromatosis is a rare type of benign neurogenic tumor that usually affects the sites of the major sympathetic ganglia in the retroperitoneum and the posterior mediastinum. Affection of the gastrointestinal tract is rare, and involvement of the esophagus is exceptional. To the best of our knowledge, only 4 cases of esophageal ganglioneuromatosis in adults were reported in the literature. No cases have been reported in the pediatric age group.Case presentationAn 11-year-old boy presented with dysphagia due to severe esophageal stenosis caused by esophageal ganglioneuromatosis.ConclusionsDespite its rarity, the present case implies that ganglioneuromatosis should be considered in children with idiopathic esophageal stenosis.

Anatomical assessments of injectate spread stratified by the volume of the intertransverse process block at the T2 level

BackgroundThis cadaveric study aimed to analyze injectate spread to target nerves during a single-injection, ultrasound-guided intertransverse process block.MethodsAn ultrasound-guided intertransverse process block with three different injectate volumes was administered to...

Surgical Lumbar Sympathectomy in Mice.

Peripheral nerve injuries are common, and full functional recovery after injury is achieved in only 10% of patients. The sympathetic nervous system plays many critical roles in maintaining bodily homeostasis, but it has rarely been studied in the context of peripheral nerve injury. The extent of postganglionic sympathetic neuronal functions in distal targets in the periphery is currently unclear. To better explore the role of sympathetic innervation of peripheral targets, a surgical "knock-out" model provides an alternative approach. Although this can be achieved chemically, chemical destruction of postganglionic sympathetic neurons can be nonspecific and dose-dependent. The use of a surgical lumbar sympathectomy in mice, once thought to be "virtually not practicable" in small animals, allows for specific targeting of postganglionic sympathetic neurons that innervate the hind limbs. This manuscript describes how to surgically remove the L2-L5 lumbar sympathetic ganglia from a mouse as a survival surgery, which reliably decreases the hind paw sweat response and the number of sympathetic axons in the sciatic nerve.

Impact of RAAS Receptors and Membrane-Bound Transporter System in the Left Ventricle during the Long-Term Control of Hypertension.

The Renin-Angiotensin-Aldosterone System (RAAS) has been implicated in systemic and neurogenic hypertension. The infusion of RAAS inhibitors blunted arterial pressure and efficacy of use-dependent synaptic transmission in sympathetic ganglia. The current investigation aims to elucidate the impact of RAAS-mediated receptors on left ventricular cardiomyocytes and the role of the sarcolemma-bound carrier system in the heart of the hypertensive transgene model. A significant increase in mRNA and the protein expression for angiotensin II (AngII) receptor subtype-1 (AT1R) was observed in (mREN2)27 transgenic compared to the normotensive rodents. Concurrently, there was an upregulation in AT1R and a downregulation in the MAS1 proto-oncogene protein receptor as well as the AngII subtype-2 receptor in hypertensive rodents. There were modifications in the expressions of sarcolemma Na+-K+-ATPase, Na+-Ca2+ exchanger, and Sarcoendoplasmic Reticulum Calcium ATPase in the transgenic hypertensive model. These observations suggest chronic RAAS activation led to a shift in receptor balance favoring augmented cardiac contractility and disruption in calcium handling through modifications of membrane-bound carrier proteins and blood pressure. The study provides insight into mechanisms underlying RAAS-mediated cardiac dysfunction and highlights the potential value of targeting the protective arm of AngII in hypertension.

Amyloid Neuropathy: From Pathophysiology to Treatment in Light-Chain Amyloidosis and Hereditary Transthyretin Amyloidosis.

Amyloid neuropathy is caused by deposition of insoluble β-pleated amyloid sheets in the peripheral nervous system. It is most common in: (1) light-chain amyloidosis, a clonal non-proliferative plasma cell disorder in which fragments of immunoglobulin, light or heavy chain, deposit in tissues, and (2) hereditary transthyretin (ATTRv) amyloidosis, a disorder caused by autosomal dominant mutations in the TTR gene resulting in mutated protein that has a higher tendency to misfold. Amyloid fibrils deposit in the endoneurium of peripheral nerves, often extensive in the dorsal root ganglia and sympathetic ganglia, leading to atrophy of Schwann cells in proximity to amyloid fibrils and blood-nerve barrier disruption. Clinically, amyloid neuropathy is manifested as a length-dependent sensory predominant neuropathy associated with generalized autonomic failure. Small unmyelinated nerves are involved early and prominently in early-onset Val30Met ATTRv, whereas other ATTRv and light-chain amyloidosis often present with large- and small-fiber involvement. Nerve conduction studies, quantitative sudomotor axon testing, and intraepidermal nerve fiber density are useful tools to evaluate denervation. Amyloid deposition can be demonstrated by tissue biopsy of the affected organ or surrogate site, as well as bone-avid radiotracer cardiac imaging. Treatment of light-chain amyloidosis has been revolutionized by monoclonal antibodies and stem cell transplantation with improved 5-year survival up to 77%. Novel gene therapy and transthyretin stabilizers have revolutionized treatment of ATTRv, improving the course of neuropathy (less change in the modified Neuropathy Impairment Score + 7 from baseline) and quality of life. With great progress in amyloidosis therapies, early diagnosis and presymptomatic testing for ATTRv family members has become paramount. ANN NEUROL 2024;96:423-440.