Can amyloidosis, particularly in older adults with conditions such as familial amyloid polyneuropathy or wild-type transthyretin amyloidosis, cause tremor?

Can Amyloidosis Cause Tremor?

Amyloidosis does not typically cause tremor as a primary manifestation; the characteristic neurologic presentation is a length-dependent sensory and autonomic polyneuropathy, not movement disorders. 1, 2

Primary Neurologic Manifestations of Amyloidosis

The neurologic involvement in amyloidosis, particularly in hereditary transthyretin (ATTRv) and AL amyloidosis, follows a predictable pattern that does not include tremor:

Polyneuropathy Pattern

• Distal symmetric sensory loss beginning in the feet with burning sensations, numbness, and paresthesias in a length-dependent distribution 1, 2
• Small-fiber neuropathy presenting with burning pain, tingling, and autonomic dysfunction (orthostatic hypotension, gastrointestinal dysmotility, urinary retention, sexual dysfunction) 3, 4
• Progressive proximal spread from toes to feet to fingertips as disease advances 2
• Reduced or absent distal reflexes, typically starting with ankle jerks 2
• Distal muscle weakness and atrophy when motor axons become affected 2

Autonomic Dysfunction

• Orthostatic hypotension requiring medications (midodrine, droxidopa) in severe cases 1
• Gastrointestinal dysmotility with early satiety, nausea, constipation, and diarrhea 1
• Urinary retention potentially requiring catheterization 1

Why Tremor Is Not a Feature

The pathophysiology of amyloid-related neurologic disease involves:

• Amyloid deposition in peripheral nerves, particularly affecting small unmyelinated C-fibers and large myelinated fibers 2, 5
• Endoneurial microvascular involvement with basement membrane thickening 5
• Toxicity from nonfibrillar TTR oligomers causing direct nerve damage 5

This pattern of peripheral nerve and autonomic involvement does not affect the central motor pathways or basal ganglia circuits that generate tremor.

Clinical Implications

When Evaluating Suspected Amyloidosis with Neurologic Symptoms:

• Look for length-dependent sensory symptoms starting in the feet, not tremor 2, 6
• Assess for autonomic dysfunction (orthostatic hypotension, gastrointestinal symptoms, urinary retention) 1, 4
• Examine for carpal tunnel syndrome, which often precedes polyneuropathy by years in amyloidosis 2
• Check for wide-based, unsteady gait from proprioceptive sensory loss, not from cerebellar or extrapyramidal dysfunction 1, 2

If Tremor Is Present:

• Consider alternative or concurrent diagnoses rather than attributing tremor to amyloidosis 2
• Evaluate for essential tremor, Parkinson's disease, or other movement disorders as separate entities
• Assess for medication-induced tremor from drugs used to treat amyloidosis complications

Rare Exception: Leptomeningeal Involvement

In extremely rare cases of TTR amyloidosis with leptomeningeal deposition, central nervous system manifestations can occur, including seizures, depression, and decreased consciousness, but tremor is still not described as a feature 7. This presentation is exceptional and extends beyond typical familial amyloid polyneuropathy 7.

Diagnostic Approach for Amyloid Neuropathy

When amyloidosis is suspected based on appropriate symptoms:

• Nerve conduction studies for large-fiber involvement 4
• Skin biopsy with epidermal nerve fiber density for small-fiber neuropathy (conventional nerve conduction studies are often normal) 3, 4
• Genetic testing for TTR variants in ATTRv amyloidosis 3, 6
• Tissue biopsy (nerve, muscle, or other tissue) with Congo red staining and mass spectrometry for amyloid typing 6

Common Pitfall

Do not attribute tremor to amyloidosis without thoroughly investigating other causes. The presence of tremor in a patient with confirmed amyloidosis suggests a concurrent neurologic condition requiring separate evaluation and management 2.