What causes numbness and tingling in amyloidosis?

Pathophysiology of Numbness and Tingling in Amyloidosis

Numbness and tingling in amyloidosis occur because insoluble amyloid protein fibrils deposit directly in the endoneurium of peripheral nerves, causing Schwann cell atrophy, blood-nerve barrier disruption, and progressive nerve fiber damage that begins with small unmyelinated sensory fibers. 1, 2

Mechanism of Nerve Damage

Direct amyloid deposition causes the neurological symptoms:

• Amyloid fibrils accumulate in the endoneurium (the connective tissue surrounding individual nerve fibers), particularly concentrated in dorsal root ganglia and sympathetic ganglia 2
• This deposition leads to atrophy of Schwann cells (the cells that support and insulate nerve fibers) in proximity to the amyloid deposits 2
• The blood-nerve barrier becomes disrupted, further compromising nerve function 2
• Nerve damage is not from compression alone but from the toxic effects of amyloid protein aggregation on nerve tissue 3

Pattern of Nerve Fiber Involvement

Small fiber neuropathy develops first and explains the initial symptoms:

• Small unmyelinated C-fibers (responsible for pain and temperature sensation) are affected early and prominently, causing burning pain, tingling, and paresthesias 1, 4
• This small-fiber involvement explains why patients experience numbness, burning sensations, and sharp electrical-like pain in the toes and feet initially 1, 5
• As disease progresses, large myelinated fibers become involved, leading to loss of vibration sense, proprioception, and eventually motor weakness 1, 2

Clinical Progression Pattern

The length-dependent pattern reflects the vulnerability of longer nerve fibers:

• Symptoms begin symmetrically in the toes and feet because the longest nerve fibers are most vulnerable to metabolic stress and amyloid deposition 1
• As neuropathy progresses, fingertips become involved next, following the length-dependent pattern 1
• The progression is rapid—15-20 times faster than diabetic neuropathy—because amyloid deposition is an active, ongoing process 1

Autonomic Involvement

Autonomic dysfunction occurs early because autonomic fibers are predominantly small, unmyelinated C-fibers:

• Autonomic symptoms (orthostatic hypotension, gastrointestinal dysmotility, urinary retention, erectile dysfunction) often appear as initial or early manifestations 1, 4
• This is unusual compared to other neuropathies where autonomic involvement typically occurs late 1
• The early autonomic involvement is a distinguishing feature of amyloid neuropathy 1

Type-Specific Differences

The pattern varies by amyloid type:

• AL amyloidosis: Polyneuropathy occurs in 17-35% of patients, often with both large and small fiber involvement from onset 1
• ATTRv (hereditary): Early-onset Val30Met variant predominantly affects small fibers initially, while other variants and late-onset cases show mixed large and small fiber involvement 1, 2
• ATTRwt (wild-type): Neuropathy is usually milder with less prominent autonomic dysfunction compared to ATTRv 1

Diagnostic Implications

Conventional testing may miss early disease:

• Small-fiber neuropathy will not be detected by conventional nerve conduction studies because these tests only assess large myelinated fibers 1
• Skin biopsy to measure epidermal nerve fiber density is required to confirm small-fiber neuropathy 1
• Sweat gland nerve fiber density with Congo red staining for amyloid can directly demonstrate amyloid deposition 1

Common Pitfall

Do not confuse amyloid neuropathy with carpal tunnel syndrome or lumbar stenosis:

• Carpal tunnel syndrome often precedes polyneuropathy by many years in amyloidosis and represents focal amyloid deposition in the carpal tunnel, not the diffuse polyneuropathy 1
• Lumbar stenosis symptoms worsen with standing/walking and improve with sitting (opposite of polyneuropathy symptoms which worsen at night in bed) 1