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Verriello et al. Vessel Plus 2021;5:51 https://dx.doi.org/10.20517/2574-1209.2021.69 Page 7 of 11

Table 3. Severity of ATTRv amyloidosis with polyneuropathy, measured by Coutinho FAP stage
Stage FAP stage
0 Asymptomatic
I Walking is autonomous with mild distal symptoms to lower limbs
II Walking is possible only with one or two supports
III Walking is not possible. Patient confined to wheelchair/bed

FAP: Familial amyloid polyneuropathy.

Cranial neuropathy is the main neurological manifestation, presenting with facial nerve palsy and
trigeminal neuropathy. Later, lower cranial nerves, such as hypoglossal, glossopharyngeal, and vagal nerves,
are involved, resulting in bulbar palsy. After the age of 40-50 years, patients develop a length-dependent
sensorimotor peripheral neuropathy, sometimes with mild autonomic dysfunction [42-44] .

ACQUIRED FORMS OF AMYLOID NEUROPATHY
Acquired forms of amyloid neuropathy are caused by the misfolding of monoclonal k or λ light chains in the
primary systemic form (AL), serum amyloid A protein in the secondary form (AA), and beta-2
microglobulin (B2M) in dialysis-associated amyloidosis [Table 4].

AL amyloidosis
The incidence of AL amyloidosis is approximately 12 cases per million persons per years; there is an
estimate prevalence of 30,000 to 45,000 cases in the European Union and the United States [45,46] . It consists of
a multisystem disease where amyloid fibrils, made of monoclonal immunoglobulins light chains, are
deposited in many tissues. The organs usually involved are: kidney (74%), heart (60%), liver (27%),
[47]
peripheral (22%), and autonomic nervous system (18%) . If not treated, the prognosis of AL amyloidosis is
unfavorable.

The majority of patients are middle aged to elderly males, who present with symptoms and signs including:
congestive heart failure, cardiac arrhythmias, peripheral edema, orthostatic hypotension, weight loss,
diarrhea, abdominal pain, purpura, nephrotic syndrome, hepatomegaly, renal failure, macroglossia, CTS,
[3]
and neuropathy .
Up to 35% of patients with AL amyloidosis develop peripheral neuropathy . It usually starts by affecting
[48]
small fibers, with distal and symmetric distribution. When large fibers become affected, patients develop
numbness, tactile hypoesthesia, and hypopallesthesia. As the disease progresses, loss of strength and
autonomic dysfunctions may occur. Among the latter, orthostatic hypotension is the main symptom , but
[39]
urinary retention, fecal incontinence, and erectile dysfunction can also be observed. Over time, symptoms
can progress requiring orthopedic appliance and wheelchair. Electrophysiological examination discloses an
axonal length-dependent polyneuropathy .
[48]

CTS occurs in up to 21% of patients . In 7%-17% of cases , peripheral neuropathy is the first clinical sign
[49]
[49]
and it may precede the diagnosis of amyloidosis AL by up to 48 months, which can result in misdiagnosing
of idiopathic neuropathy.

As in the case of ATTRv, patients with AL amyloidosis may present atypical manifestations, such as: mono-
or multi-cranial neuropathy, mononeuropathies, multiplex mononeuritis, motor neuron diseases, and
demyelinating polyradiculoneuropathies . Particularly, different cases of demyelinating neuropathies have
[50]