Overview of Amyloid Neuropathy

Educational Objectives

The goal of this program is to improve diagnosis and management of amyloid polyneuropathy. After hearing and assimilating this program, the clinician will be better able to:

1. Recognize “red flag” signs and symptoms that increase suspicion of amyloid polyneuropathy.
2. Implement multidisciplinary management strategies for amyloid polyneuropathy.

Summary

Amyloid polyneuropathy: refers to the structure or functional disruption of the peripheral nervous system as a result of amyloid deposits in the nerve; it affects sensory, motor, and autonomic nerves; the familial form (hereditary amyloidogenic transthyretin [ATTRv] amyloidosis) is divided into early and late; early forms are aggressive with prominent autonomic neuropathy; penetrance rates are high in patients with TTR mutations; late-onset forms occur in individuals >50 yr of age; light chain (AL) and amyloid A (AA) forms are acquired; ATTR wild type is often associated with an increased risk for polyneuropathy; it is debatable whether the amyloid itself is the direct cause

Clinical presentation: polyneuropathy, or peripheral neuropathy may manifest in various patterns; the most common is a distal symmetric form, affecting the longest nerves first, starting in the feet and progressing upwards to the hands once it reaches the knees; other presentations include mononeuropathies (affecting single nerves, often asymmetrically), multiple mononeuropathies, plexopathies or radiculopathies; it is important to evaluate progression rate, distribution, affected nerve fibers, and underlying pathology (axonal or demyelinating); amyloid neuropathy commonly presents as a distal symmetric polyneuropathy affecting the longest nerves

Risk factors: Hanewinckel et al (2016) showed that the risk of developing polyneuropathy increased with age; presence and duration of diabetes is also a risk factor; 8% to 9% of individuals 40 to 70 yr of age in the United States have polyneuropathy; this increases to ≈25% in those >70 yr of age

Red flag signs and symptoms: systemic involvement (cardiac, musculoskeletal, ophthalmologic, or renal) suggests a systemic cause for polyneuropathy; a key distinguishing factor is the rate of progression; most distal symmetric polyneuropathies progress slowly over years; the progression rate is faster in polyneuropathy associated with ATTRv amyloidosis than in diabetic polyneuropathy; patients with polyneuropathy associated with ATTRv amyloidosis have a larger increase in the modified neuropathy impairment score (mNIS+7) over a short period of time

Autonomic dysfunction: early prevalent autonomic dysfunction is a sign of amyloid; evaluating autonomic dysfunction is challenging because symptoms are vague and difficult for patients to describe; standard neurologic tests, eg, electromyography (EMG), nerve conduction studies (NCS), do not assess the autonomic nervous system; specialized autonomic reflex testing is not widely accessible; evaluating autonomic dysfunction often relies on identifying multiple signs and symptoms, with early indicators including abnormal pupillary light reactivity; clinicians should look for facial flushing and cold hands and feet; patients may report feeling cold hands and feet despite the limbs being warm to the touch; this discrepancy may occur because of small nerve fiber involvement affecting temperature regulation and the sensation of temperature; other symptoms include dry eyes and mouth and changes in sweat; a key indicator of autonomic dysfunction is orthostatic hypotension without the expected increase in heart rate upon standing; experiencing multiple autonomic symptoms and observing several related findings on examination strengthens the likelihood of autonomic nervous system involvement; medications with anticholinergic effects, sometimes used to treat neuropathy symptoms, may complicate the evaluation of autonomic dysfunction

Sensory symptoms: may be negative (loss of feeling, temperature sensation, proprioception leading to balance issues) or positive (pain described as burning, prickling, or tingling, typically in a distal symmetric pattern, often worse in the evenings)

Motor symptoms: include loss of function, eg, weakness, leading to difficulties with walking, eg, foot drop when lifting the foot or climbing stairs because of dorsiflexion weakness

Diagnosis: neurologic examination is performed to assess sensory and motor nerves; staging and severity scores include Functional Ambulation Profile (FAP), Polyneuropathy Disability (PND) score, and mNIS+7; EMG and NCS are useful; EMG does not assess small unmyelinated nerve fibers, which can be affected in conditions causing pain and tingling despite a normal EMG; in these cases, a skin biopsy is useful to detect amyloid deposits in nerve fibers; various autonomic function tests exist but may not be widely accessible; in clinical practice, checking orthostatic vital signs is a helpful basic assessment; for specific urinary or bowel symptoms, consulting specialists is recommended; ophthalmologists can perform Schirmer tests to evaluate dry eye

Differential diagnoses: once polyneuropathy is confirmed, the next step involves identifying “red flags” that suggest amyloid as a potential cause, while ruling out more common etiologies, eg, diabetes, alcohol use, chemotherapy, vitamin deficiencies; the clinician may check for paraproteinemia; if amyloid is suspected, genetic testing is recommended, followed by confirming amyloid deposition in an end organ; nerves are not commonly biopsied because of low yield; common misdiagnoses — for length dependent neuropathy, common causes, eg, diabetic, idiopathic, and alcohol-related neuropathy, are more prevalent; rapid progression or early autonomic involvement is suggestive of amyloid polyneuropathy; differentiating between diabetic neuropathy and amyloid neuropathy involves assessing the severity of diabetes and the polyneuropathy and assessment of amyloid deposits in organs

Treatment: differs by type; for variant TTR, gene silencing therapies are available; no specific targeted therapy is available for wild-type TTR neuropathy; AL amyloidosis management relies on chemotherapy from hematology or oncology, while neuropathic symptoms are also addressed; symptomatic treatment requires a multidisciplinary approach; for neuropathic pain, common medications include gabapentinoids, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants (may worsen dysautonomia), and sodium channel blockers; physical therapy is recommended for managing motor weakness with ankle-foot orthotics and exercises to strengthen the muscles

Readings

Adams D, Ando Y, Beirão JM, et al. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy. J Neurol. 2021;268(6):2109-2122. doi:10.1007/s00415-019-09688-0; Benson MD, Kincaid JC. The molecular biology and clinical features of amyloid neuropathy. Muscle Nerve. 2007;36(4):411-423. doi:10.1002/mus.20821; Hanewinckel R, Drenthen J, van Oijen M, et al. Prevalence of polyneuropathy in the general middle-aged and elderly population. Neurology. 2016;87(18):1892-1898. doi:10.1212/WNL.0000000000003293; Magrinelli F, Fabrizi GM, Santoro L, et al. Pharmacological treatment for familial amyloid polyneuropathy. Cochrane Database Syst Rev. 2020;4(4):CD012395. Published 2020 Apr 20. doi:10.1002/14651858.CD012395.pub2; Planté-Bordeneuve V, Said G. Familial amyloid polyneuropathy. Lancet Neurol. 2011;10(12):1086-1097. doi:10.1016/S1474-4422(11)70246-0; Shin SC, Robinson-Papp J. Amyloid neuropathies. Mt Sinai J Med. 2012;79(6):733-748. doi:10.1002/msj.21352; Wang AK, Fealey RD, Gehrking TL, et al. Patterns of neuropathy and autonomic failure in patients with amyloidosis. Mayo Clin Proc. 2008;83(11):1226-1230. doi:10.4065/83.11.1226.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Ferrey was recorded at Scripps Cardiomyopathy and Cardio-Oncology Symposium, held October 5, 2024, in La Jolla, CA, and presented by Scripps. For information on upcoming CME activities from this presenter, please visit scripps.org. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0.50 CE contact hours.

Lecture ID:

NE161102

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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