Neurologic manifestations and management of systemic amyloidosis

INTRODUCTION — 

Amyloidosis refers to a group of conditions characterized by the pathologic accumulation of misfolded protein fibrils (amyloid) within extracellular spaces of organs and tissues, which can result in organ dysfunction. Amyloid fibrils can accumulate either in the same location where they were produced, leading to localized forms of amyloidosis, or in multiple distant tissues or organs, resulting in systemic amyloidosis.

Several forms of systemic amyloidosis commonly affect the nervous system along with other organs (table 1). Early recognition of neurologic features as manifestations of systemic amyloidosis can help establish a diagnosis and guide treatment.

This topic will review the clinical manifestations and management of neurologic manifestations of systemic amyloidosis. Cerebral amyloid angiopathy, a localized amyloidosis associated with the cerebral deposition of amyloid beta-peptide from amyloid precursor protein chiefly expressed in neurons, is reviewed separately. (See "Cerebral amyloid angiopathy".)

An overview of amyloidosis and other organ-specific manifestations of amyloidosis are discussed elsewhere.

●(See "Overview of amyloidosis".)

●(See "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis" and "Cardiac amyloidosis: Treatment and prognosis".)

●(See "Pleuropulmonary manifestations of amyloidosis".)

●(See "Gastrointestinal amyloidosis: Clinical manifestations, diagnosis, and management".)

●(See "Renal amyloidosis".)

●(See "Musculoskeletal manifestations of amyloidosis".)

●(See "Cutaneous manifestations of amyloidosis".)

TYPES OF AMYLOIDOSIS

Systemic amyloidosis associated with neurologic symptoms — Several forms of systemic amyloidosis may feature or even present with neurologic symptoms (table 1), most commonly including:

●AL amyloidosis — Immunoglobulin light chain (AL) amyloidosis is due to an accumulation of immunoglobulin light chain fragments within tissue and organs in the setting of a plasma cell dyscrasia. The organs most frequently affected are the heart and the kidneys, followed by the nervous system, particularly involving the peripheral and autonomic nerves [1]. (See "Overview of amyloidosis", section on 'AL amyloidosis'.)

●ATTR amyloidosis — Transthyretin (ATTR) amyloidosis is due to tissue accumulation of transthyretin monomers, a protein produced in the liver, pancreas, choroid plexus, and retinal pigment epithelium [2]. There are two forms of ATTR amyloidosis:

•ATTRwt refers to wild-type ATTR, an acquired condition that occurs sporadically in older adults (previously known as senile systemic amyloidosis) [3,4]. It primarily affects the heart, but peripheral neuropathy and mononeuropathies (eg, carpal tunnel syndrome) are also common [3]. (See "Overview of amyloidosis", section on 'Wild-type transthyretin systemic amyloidosis'.)

•ATTRv refers to variant ATTR (also called hereditary ATTR [hATTR]), an autosomal dominant form of amyloidosis caused by one of more than 130 pathogenic variants in the TTR gene. There is a wide range of clinical presentations depending on the specific variant. Some forms are predominantly neuropathic and others are predominantly cardiac, but most have a mixed phenotype [5]. (See "Overview of amyloidosis", section on 'Heritable amyloidoses'.)

●AA amyloidosis — AA amyloidosis is due to the accumulation of fragments of the serum amyloid A protein, an acute phase reactant that may occur in the setting of chronic infectious or inflammatory diseases such as rheumatoid arthritis. The primary organ affected in AA amyloidosis is the kidney, while the liver, spleen, and gastrointestinal tract are less frequently involved. Although AA amyloidosis rarely impacts the nervous system, there have been case reports of autonomic neuropathy associated with this condition [6,7]. (See "Overview of amyloidosis", section on 'AA amyloidosis'.)

Central nervous system-localized amyloid conditions — In addition to systemic types of amyloidosis that feature amyloid deposition in multiple organs, amyloidosis may occur as a localized condition, isolated to a single organ, and resulting in organ-specific syndromes. Localized amyloid conditions specific to the central nervous system (CNS) include:

●Cerebral amyloid angiopathy (CAA) is a brain-specific amyloid condition caused by the deposition of amyloid beta peptide fragments of the amyloid precursor protein expressed in neuronal tissue. Amyloid beta peptides accumulate in the cerebral vasculature, leading to vessel fragility and the risk of intracerebral hemorrhage as well as other cerebral symptoms such as inflammation and cognitive impairment. CAA is discussed separately. (See "Cerebral amyloid angiopathy".)

●Alzheimer disease (AD) is also associated with the pathologic deposition of amyloid beta peptides from overproduction, reduced clearance, or both. Other factors have also been implicated in the pathogenesis of AD, including tau protein and the apolipoprotein E gene. Alzheimer disease is discussed separately. (See "Epidemiology, pathology, and pathogenesis of Alzheimer disease".)

Amyloid conditions localized to the CNS involve different proteins and have distinct pathophysiologies from those of systemic amyloidosis with neurologic manifestations. (See "Cerebral amyloid angiopathy", section on 'Distinction from other amyloid-related conditions' and "Epidemiology, pathology, and pathogenesis of Alzheimer disease", section on 'Pathogenesis'.)

EPIDEMIOLOGY — 

The incidence of the various forms of systemic amyloidosis varies by the prevalence of the specific underlying amyloid protein, including the role of genetic factors in heritable forms. Amyloidosis may be underdiagnosed due to the nonspecific and multisystemic nature of symptoms in many forms. (See "Overview of amyloidosis", section on 'Types of amyloidosis'.)

Neurologic manifestations are common in several types of systemic amyloidosis, occurring in 25 to 50 percent of patients with immunoglobulin light chain (AL) amyloidosis and in up to 80 percent of patients with transthyretin (ATTR) amyloidosis [1,8,9]. However, the overall prevalence of neurologic manifestations is low because amyloidosis is uncommon. Prevalence data are limited due, in part, to the underrecognition of the condition. The global estimated prevalence of polyneuropathy in hereditary (hATTR) or variant ATTR (ATTVRv) is approximately 10,000 individuals [10]. The incidence also varies globally, with an estimated 8.7 cases per million person-years in Portugal [11] and just 0.3 cases per million person-years in the United States [12]. In many parts of the world, however, cases of ATTRv polyneuropathy tend to be sporadic and exhibit considerable genetic heterogeneity [12].

Nervous system involvement with AA amyloidosis is uncommon.

CLINICAL FEATURES — 

The neurologic features of systemic amyloidosis depend on the specific type and extent of accumulated amyloid protein. The most frequent neurologic manifestations include peripheral polyneuropathy, autonomic neuropathy, and carpal tunnel syndrome (CTS), while myopathy is less common [5,9,13]. Central nervous system (CNS) manifestations with systemic amyloidosis are rare [14].

Neurologic symptoms may be the initial manifestation in up to 50 percent of patients with ATTRv amyloidosis and eight percent of patients with AL amyloidosis, with a mean symptom duration until a diagnosis of 29 to 48 months in various series [3,15,16].

Peripheral polyneuropathy and autonomic neuropathy — Neuropathy is the most common neurologic manifestation of systemic amyloidosis. Peripheral neuropathy occurs in about 80 percent of patients with variant transthyretin amyloidosis (ATTVRv), while CTS occurs in up to 50 percent of patients with sporadic, or wild type transthyretin amyloidosis (ATTRwt) [5,12,17]. Peripheral neuropathy occurs in up to 20 percent of patients with immunoglobulin light chain (AL) amyloidosis [1].

●Clinical findings – Amyloid neuropathy can involve both small and large fibers impacting sensory, motor, and autonomic functions. Sensory and motor dysfunction typically show a symmetric, length-dependent pattern, and features are progressive [18,19].

Small myelinated and unmyelinated sensory and autonomic nerve fibers are typically impacted first, leading to symptoms such as pain and tingling in the feet, along with autonomic symptoms such as orthostatic intolerance, dry eyes and mouth, diarrhea, constipation, early satiety, impaired sweating, urinary incontinence, and erectile dysfunction [3]. Pain and temperature sensory modalities are frequently abnormal on examination, while vibration and proprioception functions subserved by large myelinated fibers are preserved [18,20]. As the disease progresses, large myelinated sensory and motor nerve fibers become involved, leading to balance difficulties, gait impairment, weakness, and falls, contributing to the risk of disability and premature death [3]. In many instances of amyloid neuropathy, weakness develops within two years of symptoms onset [3,18].

The specific features and course of amyloid neuropathy can vary according to type. In patients with early-onset (age <50 years) ATTRv polyneuropathy from endemic regions, small fiber sensory loss with profound autonomic neuropathy predominates [21,22]. By contrast, patients with late-onset (>50 years) ATTRv polyneuropathy from nonendemic regions frequently present with combined small and large fiber sensory loss and early weakness but mild or no autonomic disturbances [21-23]. Other patients in the United States with ATTRv frequently present with a late-onset, slowly progressive, mild sensory amyloid neuropathy, clinically indistinguishable from more common distal sensory polyneuropathies (eg, diabetic neuropathy) [17].

●Diagnostic findings – Peripheral polyneuropathy may be identified with electrodiagnostic studies (nerve conduction studies and electromyography) that show features suggestive of nerve demyelination including slowed conduction velocities and/or conduction block, reduced compound muscle action potential amplitudes, or prolonged distal latencies. Amyloid neuropathy typically shows an axonal sensory or sensorimotor peripheral neuropathy. However, demyelinating features may be present in up to 13 percent of patients with ATTRv neuropathy [24]. (See "Overview of nerve conduction studies" and "Overview of electromyography".)

Patients with autonomic neuropathy may have mild or nonspecific findings on standard electrodiagnostic studies. Autonomic testing may be needed. Findings include orthostatic hypotension with or without compensatory tachycardia, abnormal sudomotor axon reflex testing, and abnormal pupillometric testing (table 2). (See "Overview of polyneuropathy", section on 'Autonomic testing'.)

The presence of additional neurologic and nonneurologic features in patients with peripheral or autonomic neuropathy raise suspicion for amyloidosis, such as bilateral median neuropathy and cardiomyopathy (figure 1) [25]. (See 'Mononeuropathies' below and 'Associated nonneurologic features' below.)

Mononeuropathies — CTS is a common mononeuropathy associated with systemic amyloidosis and may be a presenting feature. CTS is common in amyloidosis with a prevalence of 74 percent in ATTRv [26], 48 percent in ATTRwt [27], and 21 percent in AL amyloidosis [28].

●Clinical findings – CTS is characterized by pain and numbness/paresthesias in the thumb, index, and middle fingers. Symptoms may initially be intermittent and most prominent during the night and with hand activities. Symptoms may worsen over time, becoming more constant and including hand weakness. (See "Carpal tunnel syndrome: Clinical manifestations and diagnosis".)

CTS associated with systemic amyloidosis is frequently bilateral. Other features associated with amyloidosis include unilateral onset in the nondominant hand, absent risk factors (eg, diabetes mellitus, arthritis, obesity, occupational factors), severe presentation or rapid progression, and recurrence or progression after carpal tunnel release [13,26,29,30].

CTS can be the initial feature of some types of systemic amyloidosis and may predate the diagnosis of ATTRv and ATTRwt by 10 and 6 years, respectively [26,31]. By contrast, CTS is an uncommon presenting symptom in AL amyloidosis.

●Diagnostic findings – CTS may be identified by characteristic clinical features and confirmed with nerve conduction studies and electromyography that show median mononeuropathy localized to the wrist.

Other mononeuropathies are rare in systemic amyloidosis. Only a few case reports have described multiple mononeuropathies in AL and ATTRv amyloidosis [32,33]. Additional neurologic and nonneurologic features in patients with CTS raise the suspicion for amyloidosis (figure 1). (See 'Peripheral polyneuropathy and autonomic neuropathy' above and 'Associated nonneurologic features' below.)

Myopathy — Skeletal muscle symptoms producing myopathy rarely occur in systemic amyloidosis, are reported in less than 2 percent of patients with AL amyloidosis, and very rarely in patients with transthyretin (ATTR) amyloidosis [34,35].

●Clinical findings – Myopathy associated with amyloidosis typically presents with symmetric proximal weakness, sometimes with axial weakness [35-37]. Jaw claudication from amyloid deposits around the temporal artery is present in 9 to 25 percent of patients with AL amyloid myopathy and can be mistaken for temporal arteritis [34,38]. Additionally, about one-third of patients with AL amyloid myopathy may develop dysphagia, which can be the initial myopathic manifestation [39,40]. Respiratory muscle involvement is also possible, though uncommon.

●Diagnostic findings – The creatine kinase is normal in approximately two-thirds of patients with amyloid myopathy. Electromyography often reveals short-duration, low-amplitude motor unit action potentials with early recruitment, while fibrillation potentials or myotonic discharges are found in only a small percentage of patients.

Amyloid myopathy frequently accompanies peripheral neuropathy, which is found in 40 percent of AL amyloid myopathy cases and 90 percent of ATTR amyloid myopathy cases [35,39]. The presence of proximal weakness in patients with amyloid neuropathy should raise suspicion for a superimposed myopathy. (See "Musculoskeletal manifestations of amyloidosis".)

Ophthalmic features — Ophthalmic symptoms occur in approximately 10 percent of patients with ATTRv amyloidosis, typically as a late finding. These include vitreous opacities, chronic open-angle glaucoma, abnormal conjunctival vessels, keratoconjunctivitis sicca, and corneal neuropathy [41].

Ophthalmic findings are uncommon in patients with AA or AL amyloidosis. Patients with ATTRwt may report impaired visual acuity, but pathologic confirmation of amyloid-related etiology has not been demonstrated [42].

Central nervous system features — Direct brain or spinal cord involvement is uncommon in systemic amyloidosis. However, pathologic evidence of amyloid accumulation in the leptomeninges and meningeal vessels has been reported in some patients with ATTRv amyloidosis associated with specific genetic variants (eg, Ala25Thr, Gly53Glu, Tyr114Cys, Val30Met) (image 1) [14,43-46].

A spectrum of CNS symptoms has been reported in patients with ATTRv amyloidosis, typically as late findings, >10 years after the onset of other systemic features of amyloidosis [44-46].

●Transient focal neurologic episodes (TFNE) appear to be the most common CNS feature in ATTRv amyloidosis [45]. These transient episodes consist of brief, recurring, and stereotyped sensory deficits, focal motor impairments, or aphasia. They occur spontaneously and last for several minutes before resolving, similar to transient ischemic attacks. Sensory symptoms may migrate across contiguous body parts, in some cases, similar to focal seizures. They may also be accompanied by headache, nausea, and vomiting, resembling a migraine.

●Cerebrovascular events such as ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage have been reported in some case reports and series [45,47-49].

In addition, ischemic stroke may occur as a complication of cardiomyopathy associated with amyloidosis [50,51]. (See 'Associated nonneurologic features' below.)

●Memory impairment and executive dysfunction have been reported in as many as one-third of patients with ATTRv amyloidosis, typically occurring in patients older than 50 years with >10 years since onset of amyloidosis [52-54].

●Myelopathy has been reported in a few cases of familial oculoleptomeningeal amyloidosis, a rare ATTRv syndrome described only in several families that also features ocular dysfunction and CNS symptoms [55-59].

●Rare cerebral manifestations include seizures, bilateral hearing loss, headaches from communicating hydrocephalus, or gait impairment [14,54,60-63].

The clinical features of localized amyloid conditions specific to the CNS are discussed separately. (See "Cerebral amyloid angiopathy" and "Clinical features and diagnosis of Alzheimer disease".)

Associated nonneurologic features — Patients with neurologic symptoms of systemic amyloidosis typically also have symptoms due to the involvement of other organ systems. These symptoms are determined by the type of the amyloid protein and the extent of the amyloid deposition and include (figure 1):

●Cardiomyopathy (see "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Clinical manifestations')

●Kidney disease (eg, proteinuria, chronic kidney disease) (see "Renal amyloidosis", section on 'Clinical manifestations')

●Gastrointestinal features (eg, malabsorption with diarrhea, constipation, hepatomegaly) (see "Gastrointestinal amyloidosis: Clinical manifestations, diagnosis, and management", section on 'Clinical features')

●Musculoskeletal features (eg, pseudohypertrophy, macroglossia, arthropathy) (see "Musculoskeletal manifestations of amyloidosis")

●Hematologic features (eg, easy bruising, anemia, bleeding diathesis) (see "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Clinical presentation')

●Pulmonary disease (eg, tracheobronchial thickening, pleural effusions, septal lung infiltration) (see "Pleuropulmonary manifestations of amyloidosis")

●Cutaneous features (eg, skin thickening, purpura) (see "Cutaneous manifestations of amyloidosis")

In many cases, nonneurologic features, such as cardiomyopathy or proteinuria, precede the onset of neurologic manifestations.

DIAGNOSIS

When to suspect amyloidosis as the cause of neurologic symptoms — The diagnosis of amyloidosis should be suspected in patients with characteristic neurologic features whose presence or severity is unexplained and/or is associated with unexplained nonneurologic features (figure 1). Common clinical scenarios include:

●Axonal polyneuropathy that is severe or rapidly progressive (eg, over months)

●Axonal polyneuropathy associated with cardiac and/or autonomic symptoms

●Isolated autonomic neuropathy

●Progressive proximal myopathy associated with cardiac and/or autonomic symptoms

●New bilateral carpal tunnel syndrome (CTS) in an older adult without environmental or medical risk factors

●Neurologic symptoms or signs of amyloidosis in a patient with a known family history of hereditary amyloidosis

In most cases, an evaluation has been performed to exclude more common causes of neuropathy and/or myopathy. (See "Overview of polyneuropathy", section on 'Diagnostic evaluation' and "Approach to the patient with muscle disorder (myopathy)", section on 'Diagnostic investigations'.)

Diagnostic approach — The approach to diagnosing amyloidosis as the underlying cause of neurologic symptoms depends on specific neurologic features, associated nonneurologic features, and family history. Neurologic manifestations alone are generally nonspecific, but their presence may be suggestive of amyloidosis in patients without typical risk factors, those with additional unexplained nonneurologic manifestations, and/or patients with a suggestive family history. (See "Overview of amyloidosis", section on 'Diagnostic approaches'.)

The evaluation typically involves initial laboratory testing performed to identify a monoclonal protein followed by confirmatory genetic or tissue-based testing. For most patients, a tissue biopsy at an accessible site is typically performed to confirm the diagnosis. However, a biopsy may be unnecessary for selected patients with characteristic clinical features and positive genetic tests for ATTRv amyloidosis.

Initial laboratory testing — We typically start with serum protein electrophoresis (SPEP) and immunofixation (IFE) to assess for the presence of a monoclonal protein. A monoclonal protein may be detected by laboratory testing in 85 percent of AL amyloid cases. Adding free light chains assay (FLC) increases the sensitivity to detect AL amyloidosis by up to 99 percent [64]. Therefore, if the SPEP, IFE, and FLC screens are negative, AL amyloidosis is essentially excluded.

However, the presence of monoclonal protein does not exclude other types of systemic amyloidosis, as some patients with AA amyloidosis and up to 50 percent of patients with transthyretin (ATTR) amyloidosis may also have monoclonal gammopathy of uncertain significance [65].

Laboratory testing to assess for evidence of a systemic inflammatory state (eg, C-reactive protein and erythrocyte sedimentation rate) is performed for patients who have a history of rheumatic conditions and suspected AA amyloidosis. (See "AA amyloidosis: Causes and diagnosis", section on 'Laboratory testing'.)

Confirmatory testing — Patients with clinical features suggestive of systemic amyloidosis, including those with positive laboratory testing or suggestive clinical or family history, should undergo confirmatory testing to identify and characterize both the type and extent of amyloid deposition.

Consultation with specialists familiar with the diagnosis and management of systemic amyloidosis can help with the selection of confirmatory testing and interpretation of results as well as guide optimal treatment.

Tissue biopsy — For most patients with neurologic features due to suspected systemic amyloidosis, we perform confirmatory tissue biopsy. A biopsy is helpful to confirm the diagnosis and permit subtyping. It is also helpful to identify amyloidosis in patients with features that are mild or atypical for amyloidosis and for those with multiple possible causes of symptoms. As an example, mild sensory-predominant or demyelinating polyneuropathy may be due to other more common conditions such as diabetes mellitus or a history of alcohol exposure [66].

●Biopsy site – For most patients, tissue biopsy can be performed at accessible sites where amyloid protein commonly accumulates, such as subcutaneous fat or retinal mucosal [66]. The biopsy may also be performed at the site of organ dysfunction and presumed amyloid deposition, such as:

•Tenosynovial tissue during a planned carpal tunnel release surgery for patients with median neuropathy

•Dermal tissue during skin biopsy for patients with small fiber neuropathy

•Sural nerve biopsy for patients with polyneuropathy

•Muscle for patients with myopathy

•Gastric tissue during endoscopy for those with gastrointestinal symptoms

For patients with abnormal serum light chains who have suspected immunoglobulin light chain (AL) amyloidosis, hematologic assessment with bone marrow biopsy is warranted.

An endomyocardial biopsy may be required if more accessible and less risky biopsies are not confirmatory. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)

The sensitivity and accuracy of tissue biopsies can vary based on the tissue type, with fat pad aspirates showing 50 to 80 percent sensitivity [67,68], skin biopsies showing 70 percent [69], and cardiac tissue showing 100 percent. These factors, along with the quality of sampling and processing and the expertise of the performing center, affect the results. A negative biopsy in a patient with high suspicion of variant transthyretin (ATTRv) amyloidosis does not rule out the diagnosis; further investigation, including repeat biopsies or sampling from other tissues or organs, may be necessary [66].

●Histology – Congo red and Thioflavin S are the two primary histologic stains used to detect amyloid. Under light microscopy, amyloid deposits appear as amorphous hyaline material. The fibrils bind to Congo red, which results in green birefringence under polarized light, and to Thioflavin T, producing intense yellow-green fluorescence (picture 1). On electron microscopy, these fibrils measure 7 to 12 nanometers in width and are straight and unbranching (picture 2) [70,71]. (See "Overview of amyloidosis", section on 'Histopathology and protein analysis'.)

Histologic findings in muscle biopsy include rare necrotic and regenerating fibers, variations in fiber size, and interstitial amyloid deposition in intramuscular blood vessels, as well as in the perimysium and endomysium, occasionally encasing muscle fibers. Denervation atrophy is observed in 80 percent of patients, supporting the coexistence of peripheral neuropathy [35,39]. Routine Congo red staining of muscle biopsies can significantly enhance the sensitivity for detecting amyloid myopathy [72].

●Proteomic subtyping – Whenever amyloid is detected on tissue, it is important to perform amyloid subtyping, preferably using mass spectrometry-based proteomic analysis. This method is considered the gold standard for identifying specific amyloidosis subtypes, offering over 90 percent sensitivity and nearly 100 percent specificity [73,74].

Genetic testing for ATTRv amyloidosis — We perform genetic testing for patients with suspected neurologic features of ATTRv amyloidosis to assess for TTR pathologic variants. We typically perform TTR gene sequencing and assessment of copy number variation.

Patients with a pathogenic TTR variant and clinical features typical for ATTRv amyloidosis, such as rapidly progressive axonal neuropathy, may not require diagnostic biopsy for the confirmation of amyloid deposition [75].

MANAGEMENT

Assess involvement of other organ systems — Once the systemic amyloid diagnosis has been confirmed, it is important to establish the extent and sites of organ involvement and assess for any comorbidities that may affect treatment options.

Early consultation with cardiology, hematology, nephrology, and/or ophthalmology, depending on the organs involved and type of amyloidosis, is essential to ensure a multisystemic evaluation and tailored management plan via a multidisciplinary coordinated care team.

Cardiac testing — We perform cardiac imaging for all patients with neurologic symptoms due to transthyretin (ATTR) or immunoglobulin light chain (AL) amyloidosis to assess for cardiomyopathy, a common associated nonneurologic feature. The presence of an unexplained cardiomyopathy may also support the diagnosis of a systemic condition such as amyloidosis in patients with neurologic symptoms awaiting confirmatory testing for amyloidosis. Testing may include:

●Transthoracic echocardiography (see "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Echocardiography')

●Cardiovascular magnetic resonance (see "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Cardiovascular magnetic resonance')

●Cardiac technetium (99mTc)-based tracer scintigraphy scanning (see "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Bone tracer cardiac scintigraphy')

Findings suggestive of cardiac amyloidosis include ventricular hypertrophy, apical sparing of longitudinal strain, diastolic dysfunction, and/or pericardial effusion.

Patients with neurologic manifestations of amyloidosis who have unexplained cardiac symptoms (eg, dyspnea, peripheral edema) or cardiac findings on testing should be referred to cardiology for management. (See "Cardiac amyloidosis: Treatment and prognosis".)

Other testing — We perform laboratory testing for patients with systemic amyloidosis to assess for other organ system involvement including:

●Complete blood count and differential

●Serum electrolytes

●Kidney function tests including blood urea nitrogen, creatinine, and 24-hour urinary protein and creatinine clearance

●Liver function tests

We also measure seated and standing blood pressure to assess for orthostatic hypotension. Techniques for assessing orthostatic hypotension are discussed separately. (See "Mechanisms, causes, and evaluation of orthostatic hypotension", section on 'Techniques to measure blood pressure'.)

Additional testing for amyloid involvement in other organ systems depends on the presence of organ-specific features. (See "Overview of amyloidosis", section on 'Clinical manifestations'.)

Manage neurologic symptoms — Symptomatic treatment is an essential aspect of managing the neurologic complications of systemic amyloidosis. Symptomatic measures for neurologic symptoms are generally managed in the same manner for patients with amyloidosis as for other neurologic conditions. Specific measures depend on the nature and severity of neurologic symptoms.

●Neuropathic pain — Treatment of neuropathic pain is symptomatic and typically involves pharmacotherapy. Frequently used options include [66]:

•Gabapentinoids (eg, gabapentin and pregabalin)

•Serotonin and norepinephrine reuptake inhibitors (eg, duloxetine and venlafaxine)

•Tricyclic antidepressants (eg, amitriptyline and nortriptyline)

•Sodium channel blockers (eg, carbamazepine and oxcarbazepine)

The choice of a specific agent should be tailored to each patient, based on comorbidities, potential drug interactions, adverse effect profiles, and cost (table 3 and table 4).

Tricyclic antidepressants should be used cautiously in patients with amyloidosis due to the risks of cardiac arrhythmia, QTc prolongation, orthostatic hypotension, and urinary retention. Pharmacotherapy for neuropathic pain is discussed in greater detail separately. (See "Overview of pharmacologic management of chronic pain in adults", section on 'Pharmacologic therapy for neuropathic or nociplastic pain'.)

●Carpal tunnel syndrome — Treatment for carpal tunnel syndrome (CTS) varies based on symptom severity. Options include wrist splinting, local glucocorticoid injections, and surgical carpal tunnel release. (See "Carpal tunnel syndrome: Treatment and prognosis".)

●Autonomic symptoms — Autonomic neuropathy can account for multiple symptoms. The approach to orthostatic hypotension management includes nonpharmacologic measures such as discontinuing exacerbating medications, increasing salt and water intake, modifying daily activities, and compression stocking/abdominal binders. Pharmacologic options include fludrocortisone, midodrine, droxidopa, atomoxetine, and pyridostigmine (table 5). (See "Treatment of orthostatic and postprandial hypotension".)

Gastrointestinal autonomic symptoms may include gastroesophageal reflux disease (GERD), gastroparesis, nausea, and diarrhea. GERD can be treated with histamine 2 receptor antagonists (eg, famotidine) or proton pump inhibitors (eg, pantoprazole). Gastroparesis is managed with dietary modification and prokinetic agents (eg, metoclopramide and erythromycin) and/or antiemetics (eg, diphenhydramine and ondansetron), while diarrhea can be treated with peristalsis inhibitors such as loperamide. (See "Diabetic autonomic neuropathy of the gastrointestinal tract".)

Bladder dysfunction treatment includes pelvic floor exercises, bladder training, and pharmacotherapy. Male sexual dysfunction includes erectile dysfunction which may be treated with phosphodiesterase-5 inhibitors (eg, sildenafil) and mechanical devices or local injections. Female sexual dysfunction includes vaginal dryness and dyspareunia which may be treated with lubricants and topical hormonal therapies. (See "Diabetic autonomic neuropathy of the gastrointestinal tract" and "Treatment of male sexual dysfunction" and "Overview of sexual dysfunction in females: Management".)

●Foot care and fall prevention — Patients should inspect their feet daily for dry or cracked skin, fissures, calluses, and early signs of infection. Additionally, physical therapy can help improve gait and balance, and assistive devices such as rollators and ankle-foot orthoses can provide support and reduce fall risk. (See "Management of diabetic neuropathy", section on 'Prevent complications'.)

●Ophthalmic features – Management of uncommon ophthalmic manifestations of systemic amyloidosis varies by specific symptom. Treatment options discussed separately include:

•Keratoconjunctivitis sicca (see "Dry eye disease", section on 'Initial management')

•Glaucoma (see "Open-angle glaucoma: Treatment")

•Ophthalmic neuropathy (see "Overview of craniofacial pain", section on 'Recurrent painful ophthalmoplegic neuropathy')

●Cerebrovascular features – Rare cerebrovascular features of systemic amyloidosis are managed according to the specific manifestation. These include:

•Transient focal neurologic episodes (see "Cerebral amyloid angiopathy", section on 'Transient focal neurologic episodes')

•Intracerebral hemorrhage (see "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis")

•Subarachnoid hemorrhage (see "Nonaneurysmal subarachnoid hemorrhage")

•Ischemic stroke (see "Initial assessment and management of acute stroke")

●Memory impairment – Management of memory impairment involves evaluating and addressing contributing factors, vascular risk factor modification, exercise, and behavioral interventions. (See "Mild cognitive impairment: Prognosis and treatment".)

Amyloid disease-modifying treatment — Specific disease-modifying treatments target amyloid synthesis and deposition in peripheral nerve tissue and also complement symptomatic treatment to help reduce the burden of neurologic symptoms in patients with variant ATTR (ATTRv) amyloidosis.

Polyneuropathy due to ATTRv disease

Transthyretin gene silencers — We suggest disease-modifying therapy with a transthyretin gene silencer for patients with ATTRv amyloidosis polyneuropathy. Transthyretin gene silencers can reduce transthyretin levels and stabilize the disease or slow the progression of ATTRv polyneuropathy.

We do not use disease-modifying therapies for central nervous system (CNS) or ocular manifestations, as efficacy and safety have not been established in these settings. Current gene silencers target hepatic transthyretin synthesis, not production in the CNS, so their effectiveness for CNS or ocular symptoms is unlikely [66].

Transthyretin gene silencers reduce transthyretin protein levels by degrading transthyretin messenger ribonucleic acid (mRNA), targeting both variant and wild-type transthyretin production. Four agents are available and approved by the United States Food and Drug Administration for the treatment of ATTRv polyneuropathy: patisiran and vutrisiran (RNA [ribonucleic acid] interference agents) and inotersen and eplontersen (antisense oligonucleotides).

Comparative data are limited [76]. The selection of a specific agent should be individualized based on patient factors including medical comorbidities, treatment ease of use, cost, local protocols, and availability (table 6) [66,77]. Vutrisiran has good evidence of efficacy, is generally well tolerated, and is administered by subcutaneous injection once every three months. In addition, vutrisiran is approved for use for patients with transthyretin amyloid polyneuropathy and cardiomyopathy. However, some patients may develop bothersome limb pain. Eplontersen may have the best tolerability and can be self-administered by subcutaneous injection once each month. Patisiran can stabilize or even improve symptoms in some patients but requires more complex intravenous infusions every three weeks. Inotersen has limited availability and requires monitoring for the risks of thrombocytopenia and glomerulonephritis.

Administration and evidence of efficacy for these agents is as follows:

●Patisiran — Patisiran is a small interfering RNA agent specific for transthyretin designed to reduce transthyretin synthesis. Treatment with patisiran leads to small but sustained improvements in neuropathy in most patients.

Patisiran is administered at a dose of 0.3 mg/kg intravenously (IV) every three weeks. Patients should be premedicated to reduce the risk of infusion reactions at least 60 minutes prior to each dose with dexamethasone 10 mg IV (or equivalent glucocorticoid), acetaminophen 500 mg orally, diphenhydramine 50 mg orally, and famotidine 20 mg orally (or equivalent). Vitamin A supplementation is advised at appropriate recommended daily allowances (eg, 700 mcg/day for females and 900 mcg/day for males) during therapy due to patisiran-associated decreases in serum vitamin A concentrations.

In a placebo-controlled clinical trial that included 225 patients with ATTRv amyloidosis with polyneuropathy, improvement in the baseline Modified Neuropathy Impairment Score+7 (mNIS+7) was greater in patients assigned to patisiran (least-squares mean change -6 versus 28) [78]. The mNIS+7 is scored from 0 to 244 (with higher scores indicating greater impairment) and includes assessments of polyneuropathy signs (weakness, reflexes, sensation loss) and neurophysiologic tests (nerve conduction, quantitative sensation testing of touch pressure and heat pain, heart rate response to deep breathing) [79]. By 18-month follow-up, 56 percent of patients in the treatment group had improvement in the mNIS+7 scores compared with just 4 percent in the placebo group. Infusion reactions occurred in nearly 20 percent of patients receiving patisiran, but adverse events leading to treatment discontinuation were more common in the placebo group (14 versus 5 percent). In open-label extension studies, patients receiving patisiran continued to experience improvements in neuropathy and quality of life (QoL) at both 24- and 60-month follow ups [80,81]. Additionally, another trial involving postorthotopic liver transplant ATTRv patients found that patisiran reduced transthyretin levels and improved neuropathy, autonomic symptoms, and QoL over 12 months [82].

Common adverse effects with patisiran include infusion reactions, upper respiratory infections, rash, and dyspepsia.

●Vutrisiran — Vutrisiran is a small RNA interference agent that reduces transthyretin production in the liver. Vutrisiran is administered subcutaneously at a dose of 25 mg every three months, which is a more convenient dosing regimen for patients than patisiran. Vitamin A supplementation (eg, 700 mcg/day for females and 900 mcg/day for males) is advised during vutrisiran therapy.

In an open-label study, 164 patients with ATTRv amyloidosis and polyneuropathy were randomized 3:1 to vutrisiran or patisiran; outcomes were compared with those of an external placebo group from a separate trial [83]. The burden of neurologic symptoms (mNIS+7 score) was lower in patients assigned to vutrisiran than in the external placebo group at nine months (least-squares mean change -2.2 versus 14.8). Additionally, serum transthyretin reduction with vutrisiran appeared to be noninferior to that achieved with patisiran. Common adverse effects of vutrisiran included extremity pain, arthralgia, and infusion-related reactions.

Vutrisiran is generally well tolerated but may cause injection site reactions or limb pain and arthralgias that can lead to drug discontinuation.

Vutrisiran is also commonly used and approved for use in ATTR cardiac amyloidosis. (See "Cardiac amyloidosis: Treatment and prognosis", section on 'Disease-specific therapy for ATTR amyloidosis'.)

●Inotersen — Inotersen is an antisense oligonucleotide designed to inhibit hepatic production of transthyretin. It is administered at a dose of 284 mg subcutaneously once weekly. Vitamin A supplementation (eg, 700 mcg/day for females and 900 mcg/day for males) is advised during inotersen therapy.

Evidence of efficacy for inotersen comes from a placebo-controlled clinical trial of 172 patients with ATTRv amyloidosis with polyneuropathy [84]. The burden of neurologic symptoms, assessed by the difference between groups in the least-squares mean mNIS+7 score change from baseline to 66-week follow-up, was lower in those assigned to inotersen (-19.7 points, 95% CI -26.4 to -13.0). Patients who received inotersen experienced either stability or improvement in both neuropathy symptoms and QoL. However, three patients developed severe thrombocytopenia, one of whom had a fatal intracranial hemorrhage, while another three developed glomerulonephritis [84]. As a result, a risk evaluation and mitigation strategy were implemented, which included enhanced monitoring for thrombocytopenia, glomerulonephritis, and liver function in patients receiving inotersen. This made inotersen a more cumbersome and less desirable drug to administer and monitor.

Sustained benefits and tolerability of inotersen were reported in an open-label extension study over 5.2 years [85]. When assessed in nine postorthotopic liver transplant patients, inotersen provided benefits in stabilizing neuropathy, though it was associated with a high rate of adverse events in this small patient sample [86].

In addition to the risk of thrombocytopenia and glomerulonephritis, inotersen can cause injection site reactions, headache, fatigue, peripheral edema, nausea/vomiting, fever, and myalgias. Inotersen has limited availability as it has been discontinued in the United States and Canada.

●Eplontersen — Eplontersen is an antisense oligonucleotide that binds to transthyretin RNA to inhibit hepatic production. Eplontersen is administered subcutaneously at a dose of 45 mg every four weeks. Vitamin A supplementation (eg, 700 mcg/day for females and 900 mcg/day for males) is recommended.

In an open-label study of 168 patients with ATTRv amyloidosis with polyneuropathy who received eplontersen, primary outcome measures favored eplontersen treatment over a historical placebo group from a clinical trial assessing inotersen [87]. Patients treated with eplontersen had greater reductions in serum transthyretin levels (-82 versus -11 percent), more modest changes in mean change in neuropathy impairment (0.3 versus 25.1 on mNIS+7 score), and improved QoL scores. Thrombocytopenia was reported in three patients (2 percent) in the eplontersen group and one patient (2 percent) in the placebo group. All cases of thrombocytopenia in the eplontersen group were mild, did not lead to any bleeding events, and resolved without the need for dose adjustments or interruptions.

Eplontersen is well tolerated but may cause thrombocytopenia or nausea and vomiting.

Other options — For patients with ATTRv polyneuropathy who do not tolerate or respond to treatment with a transthyretin gene silencer, we offer an alternative disease-modifying treatment. Selection among options depends on the severity of symptoms and patient comorbidities.

●Transthyretin stabilizers — Transthyretin stabilizers work to prevent the dissociation of transthyretin tetramers into pathogenic monomers, which helps inhibit amyloid fibril formation. There is only limited evidence of efficacy for these agents in the treatment of polyneuropathy.

•Tafamidis — Tafamidis meglumine 20 mg daily is approved for the treatment of ATTRv polyneuropathy in Europe, South America, and Asia, but it is approved only for ATTR cardiomyopathy in the United States [88-90]. (See "Cardiac amyloidosis: Treatment and prognosis", section on 'Disease-specific therapy for ATTR amyloidosis'.)

A placebo-controlled clinical trial of tafamidis in 128 patients with early-stage Val30Met ATTRv polyneuropathy found only a trend toward higher rates of improvement of neuropathy with treatment (45 versus 30 percent) and similar QoL scores, coprimary endpoints [91]. However, an open-label extension study demonstrated that tafamidis was well-tolerated and effectively slowed neuropathy progression over up to six years of follow up [92]. These benefits appear more modest in patients with mid- to late-stage Val30Met disease or any stage of non-Val30Met forms of ATTRv amyloidosis [93].

•Diflunisal — Diflunisal 250 mg twice a day is used off-label for treating ATTRv polyneuropathy. A randomized controlled trial showed that diflunisal modestly slows the progression of neurologic impairment and helps maintain the QoL in these patients [94]. At two-year follow-up, progression of neuropathy symptoms (NIS+7) was slower in patients assigned to diflunisal (difference 16.3 points, 95% CI 8.1-24.5). Stability of symptoms was more common in the treatment group (30 versus 9 percent). Musculoskeletal adverse effects were more common with diflunisal.

●Liver transplantation — Liver transplantation became the first treatment available for ATTRv amyloidosis in the 1990s [95]. This option has been largely supplanted by the advent of transthyretin gene silencers and stabilizers. In addition, it was found to be less effective for late-onset patients, those who were malnourished, in advanced stages of the disease, with cardiomyopathy, or with non-Val30Met variants [96,97].

Emerging therapies

●Crispr-cas9 — Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 is a gene-editing technology that involves two essential components: the CRISPR sequence, which serves as guide RNA to match a desired target gene, and Cas9, an endonuclease that creates a double-stranded DNA (deoxyribonucleic acid) break, allowing modifications to the genome. NTLA-2001 is a CRISPR-Cas9-based genome-editing therapy designed to treat ATTR amyloidosis by reducing the concentration of transthyretin in serum. A two-part, open-label, single-dose, phase I multicenter study in ATTRv polyneuropathy and ATTR cardiomyopathy patients is ongoing to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of NTLA-2001 [98]. Interim results showed that a single dose of the drug in six patients with ATTRv polyneuropathy demonstrated a 52 percent reduction in transthyretin at a dose of 0.1 mg/kg and an 87 percent reduction at a dose of 0.3 mg/kg, with only mild reactions to the drug [99].

●Monoclonal antibodies — Therapeutic antibodies that target and remove amyloid deposits may be an effective treatment strategy for ATTRv amyloidosis. One such antibody, PRX004, binds to residues 89 to 97 of the transthyretin protein. A phase I study in 21 patients with ATTRv polyneuropathy showed that the drug was found safe and well tolerated. Seventeen of these patients continued in a long-term study where they received up to 15 infusions. After nine months, all seven patients who could be evaluated showed improvement or slowed progression in neuropathy compared with the natural course of the disease [100].

Nonneurologic manifestations — Therapy targeting the pathologic amyloid protein used to treat nonneurologic manifestations varies with the type of amyloidosis and organ system involved.

●Biologic therapies targeting cardiac and other organ systems for ATTRv and ATTRwt (wild-type ATTR) amyloidosis include RNA-targeted agents that reduce transthyretin synthesis and other agents that reduce the production of transthyretin monomers by stabilizing amyloid tetramers. The use of these therapies to treat amyloid pathology systemically or other nonneurologic systems (eg, cardiomyopathy) is discussed separately. (See "Overview of amyloidosis", section on 'Therapies for individual amyloid types' and "Cardiac amyloidosis: Treatment and prognosis", section on 'Disease-specific therapy for ATTR amyloidosis'.)

●The treatment for AL amyloidosis consists of autologous stem cell transplantation (ASCT) and/or other therapies to treat the underlying plasma cell dyscrasia. (See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis", section on 'Initial treatment'.)

●Treatment of AA amyloidosis is directed at the underlying inflammatory condition responsible for the excess production of serum amyloid A protein, such as rheumatoid arthritis, Castleman disease, malignancy, or chronic infections. (See "AA amyloidosis: Treatment", section on 'Treatment of the underlying process'.)

PROGNOSIS — 

The prognosis of amyloidosis associated with neurologic manifestations is variable depending on the type, extent of systemic involvement, and availability of effective disease-modifying treatments.

●AL amyloidosis – Immunoglobulin light chain (AL) amyloidosis often has a poor long-term prognosis when diagnosed at an advanced stage. The median survival can be as short as four to six months, with cardiac or liver failure and infections being the main causes of death. However, patients whose primary symptom is neuropathy tend to have a better median survival of about 25 months compared with those with dominant cardiomyopathy, liver amyloid, or nephrotic syndrome [16]. (See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis", section on 'Prognosis'.)

●ATTRv amyloidosis – For patients with variant transthyretin (ATTRv) amyloidosis, neuropathy typically progresses through several stages: starting with sensory polyneuropathy, which leads to difficulty walking without assistance, then requiring assistance for walking, and eventually resulting in nonambulatory status. Survival in patients with an early-onset presentation is approximately 12 years [101], while those with a late-onset presentation have a median survival of around seven years [19,102,103]. For patients who have both polyneuropathy and cardiomyopathy, survival is typically shorter, averaging around two to five years [104,105]. However, disease-modifying treatments such as transthyretin gene silencers and stabilizers appear to prolong survival [106-108].

●ATTRwt amyloidosis – In wild-type transthyretin (ATTRwt) amyloidosis, cardiomyopathy is the primary driver of mortality. The four-year overall survival rate ranges from 18 to 57 percent, depending on levels of troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Disease-modifying treatments appear to improve survival, and their use is expected to positively impact overall survival rates for the condition [108,109]. (See "Cardiac amyloidosis: Treatment and prognosis", section on 'Prognosis'.)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Immunoglobulin light chain (AL) amyloidosis" and "Society guideline links: Neuropathy" and "Society guideline links: Carpal tunnel syndrome".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (See "Patient education: AL amyloidosis (The Basics)" and "Patient education: Peripheral neuropathy (The Basics)".)

SUMMARY AND RECOMMENDATIONS

●Types of systemic amyloidosis – Several forms of systemic amyloidosis may feature or even present with neurologic symptoms including (see 'Systemic amyloidosis associated with neurologic symptoms' above):

•Immunoglobulin light chain (AL) amyloidosis, due to an accumulation of immunoglobulin light chain fragments within tissue and organs in the setting of a plasma cell dyscrasia.

•Transthyretin (ATTR) amyloidosis, due to tissue accumulation of transthyretin monomers. ATTR amyloidosis occurs in two forms, wild-type ATTR (ATTRwt), an acquired condition that occurs sporadically in older adults, and variant ATTR (ATTRv), a hereditary form of amyloidosis caused by pathogenic variants in the TTR gene.

•AA amyloidosis, due to the accumulation of fragments of the serum amyloid A protein, an acute phase reactant that may occur in the setting of chronic infectious or inflammatory diseases such as rheumatoid arthritis.

●Neurologic features – Peripheral polyneuropathy is the most common neurologic manifestation of systemic amyloidosis. Mononeuropathies such as median neuropathy (carpal tunnel syndrome [CTS]) and autonomic neuropathy may occur with systemic amyloidosis and may be a presenting feature. (See 'Peripheral polyneuropathy and autonomic neuropathy' above.)

Less common neurologic features include myopathy and ophthalmic features (eg, vitreous opacities, chronic open-angle glaucoma, keratoconjunctivitis sicca). (See 'Myopathy' above and 'Ophthalmic features' above.)

Direct brain or spinal cord involvement is uncommon in systemic amyloidoses. However, a spectrum of central nervous system (CNS) symptoms has been reported in patients with ATTRv amyloidosis, typically as late findings. These include transient focal neurologic episodes, cerebrovascular events such as ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage, as well as memory impairment and myelopathy. (See 'Central nervous system features' above.)

●Diagnosis – The diagnosis of amyloidosis should be suspected in patients with characteristic neurologic features (figure 1) whose presence or severity is unexplained, is associated with unexplained nonneurologic features, and/or occurs in a patient with a known family history of hereditary amyloidosis. (See 'When to suspect amyloidosis as the cause of neurologic symptoms' above.)

The diagnosis of systemic amyloidosis starts with laboratory testing performed to identify a monoclonal protein. For most patients, a tissue biopsy at an accessible site is typically performed to confirm the diagnosis. Genetic testing for TTR pathologic variants is performed for patients with suspected neurologic features of ATTRv. (See 'Diagnostic approach' above.)

●Treatment

•Assess for other system involvement – Cardiac imaging should be performed for patients with neurologic symptoms to assess for cardiomyopathy, a commonly associated nonneurologic feature associated with this condition.

We perform screening laboratory testing to assess for other organ system involvement and measure seated and standing blood pressure to assess for orthostatic hypotension. Additional testing for amyloid involvement in other organ systems depends on the presence of organ-specific features. (See 'Assess involvement of other organ systems' above.)

•Symptomatic treatment – Symptomatic treatment is an essential aspect of managing the neurologic complications of systemic amyloidosis. Symptomatic measures for neurologic symptoms are generally managed in the same manner for patients with amyloidosis as for other neurologic conditions. (See 'Manage neurologic symptoms' above.)

•Amyloid-specific treatment for ATTRv amyloidosis with polyneuropathy – We suggest a transthyretin gene silencer for patients with ATTRv polyneuropathy over no disease-modifying therapy (Grade 2B). Transthyretin gene silencers can reduce transthyretin levels and stabilize the disease or slow the progression of ATTRv polyneuropathy. Available options include patisiran and vutrisiran (RNA interference agents) and inotersen and eplontersen (antisense oligonucleotides). The choice of agent is based on shared decision making and individual patient factors based on the following (table 6) (see 'Transthyretin gene silencers' above):

-Ease of administration favors vutrisiran and eplontersen

-More robust evidence of efficacy supports patisiran and vutrisiran

-Presence of coexistent amyloid cardiomyopathy favors vutrisiran, due to evidence of efficacy in both settings

-Adverse effect profile favors eplontersen and vutrisiran, but some patients develop limb pain with vutrisiran

Alternative options for patients with ATTRv polyneuropathy who do not tolerate or respond to treatment with a transthyretin gene silencer include transthyretin stabilizers (eg, tafamidis and diflunisal) and liver transplantation. (See 'Other options' above.)

We do not use disease-modifying therapies for CNS or ocular manifestations, as efficacy and safety have not been established in these settings.

●Prognosis – The prognosis of amyloidosis associated with neurologic manifestations is variable depending on the type, extent of systemic involvement, and availability of effective disease-modifying treatments. (See 'Prognosis' above.)