INTRODUCTION
Amyloidosis is the deposition of abnormal proteins and accumulation of insoluble
amyloid fibrils in the tissues and organs1-3. This process
occurs through the aggregation of proteins, production of ordered polymers, and
formation of protofilaments and fibrils. Recent theories have suggested that the
lesions result from multiple mechanisms, not only fibrin deposition but also the
precursor structures (transthyretin, apolipoproteins, insulin, prion proteins,
lysozyme, cystatin C) that interact with the affected cells2,3.
A disease-related mutation in the TTR gene has been described. Associations with
pathological inflammatory states and neoplastic and hereditary factors have been
identified. Some of these associations do not seem to have clinical impacts.
However, the criteria for amyloidosis include age > 50 years, chronic
infection or inflammatory disease, family history of amyloidosis, multiple
myeloma, renal disease, and dialysis.
Nevertheless, depending on fibril deposition amount and location, the disease may
be more aggressive, affecting any organ, including the kidneys, heart, and
nerves1-3. Different types of amyloidosis have been
classified and described, including primary, secondary, familial, microglobulin
beta 2, and localized.
The association between amyloidosis and carpal tunnel syndrome (CTS) has a
prevalence of 2–8%4-6. This association is usually followed by
hemodialysis or familial amyloidosis. The clinical diagnosis of CTS includes
paresthesia, pain, weakness in the hands, and thenar atrophy. Nerve conduction
studies by electroneuromyography are useful for detecting the peripheral nerve
involvement present in cases of neuropathic amyloidosis7-9.
The gold standard diagnostic method for amyloidosis is a biopsy of the affected
tissue after staining with hematoxylin-eosin and Congo red. Although median
nerve compression can be caused by extrinsic and intrinsic factors, amyloid
deposition alone can cause nerve compression, being an already established
association; however, the clinical evolution of the operated cases merits
study4,6.
METHODS
A total of 807 patients underwent CTS surgery at our institution over a 5-year
interval; of them, 436 underwent biopsy and synovectomy. This procedure was
performed in accordance with the transoperative findings of synovial thickening.
The removed synovial tissue was sent for histopathological study, which revealed
that 12 (3%) patients tested positive for amyloidosis.
This was a retrospective study that included analysis of these patients’ medical
records with respect to their clinical findings, history, comorbidities,
diagnostic tests performed, and postoperative follow-up. The study was submitted
and approved by the CEP/APS Ethics Committee (CAEE no.
53326916.2.0000.0022).
Pre-operative evaluation
The patients were clinically evaluated for symptoms of paresthesia, numbness,
tingling, and pain. The physical assessment included Tinel’s test, Phalen’s
test, the Semmes–Weinstein monofilament test, the short thumb abductor and
opponens pollicis rating scale (0–5, such as the British Medical Research
Council Scale), and dynamometer force measurements.
Complementary examinations, such as electroneuromyography of the limbs,
radiography of the wrist, and magnetic resonance imaging, were also
performed. The severity criteria for CTS were classified according to the
neurophysiological rating scale described by Bland (Chart 1)10. The
diagnosis of reflex sympathetic dystrophy was made in accordance with
International Association for the Study of Pain guidelines8. The surgeries were performed in the
Departments of Plastic Surgery and Orthopedics of our institution, and the
surgeons performed the pre- and post-operative ratings.
Chart 1 - Grading of electroneuromyography findings according to the Bland
classification.
Degree |
|
0 |
Normal |
I |
Very mild; demonstrable only with more
sensitive tests
|
II |
Mild; sensory nerve conduction slow velocity,
normal motor latency
|
III |
Moderate; sensory potential preserved with
motor slowing, motor latency of the abductor pollicis brevis
(APB) < 6.5 ms
|
IV |
Severe; sensory potential absent, but motor
response preserved, distal motor latency to APB < 6.5
ms
|
V |
Very severe; terminal latency to APB > 6.5
ms
|
V |
Extremely severe; sensory and motor potentials
unrecordable (surface motor potential from APB < 0.2 mV
amplitude)
|
Chart 1 - Grading of electroneuromyography findings according to the Bland
classification.
Surgical procedure
All procedures were performed under general anesthesia or a regional brachial
plexus block. Tourniquets were used in the arm after exsanguination of the
limb with a systolic pressure of 100–120. The classic open volar incision
was used to release the carpal tunnel and the fascia of the forearm. The
median nerve and flexor tendon sheath were inspected (Figure 1). During surgery, the flexor tendon sheath and
transverse carpal ligament were biopsied when thickening and macroscopic
changes were evident (Figure 1).
Figure 1 - Intraoperative retinaculotomy of the flexors and partial
synovectomy showing a segment of the synovium referred for
biopsy.
Figure 1 - Intraoperative retinaculotomy of the flexors and partial
synovectomy showing a segment of the synovium referred for
biopsy.
The histopathological studies included staining with hematoxylin-eosin and
Congo red, and the assessment of amyloid deposits was performed using
polarized light (Figure 2). Chart 1 summarizes the disease
severity.
Figure 2 - Hematoxylin-eosin staining; and Congo red staining, which
emits apple green birefringent fluorescence under polarized
light and electron microscopy evaluation.
Figure 2 - Hematoxylin-eosin staining; and Congo red staining, which
emits apple green birefringent fluorescence under polarized
light and electron microscopy evaluation.
RESULTS
Charts 2 and 3 describe the clinical and demographic distribution of the
12 patients (nine females, three males). Eleven patients were >50 years of
age. The time between the onset of the initial symptoms and surgery ranged from
6 months to 17 years; 11 patients had the disease for more than 1 year; and the
follow-up period was 1–9 years.
Chart 2 - Clinical, intraoperative, and histopathological examination
criteria.
Grading of symptoms |
|
Grade I |
Intermittent symptoms of pain and paresthesia,
nocturnal paresthesia in the distribution of the median nerve,
motor and sensory exam normal.
|
Grade II |
Constant symptoms with a reduction of the fine
pincer grasp and sensory alterations in the Semmes-Weinstein
Monofilament test with weakness of the thenar muscles.
|
Grade III |
Extensive sensory loss and atrophy of the thenar
muscles.
|
Perioperative findings |
|
I - Normal |
Thickening and flattening of the nerve with normal
vascularization and structures of the epineurium, without
fibrosis.
|
II - Moderate |
Moderate decrease in vascularization, mild to
moderate fibrosis in some part of the nerve, mild to moderate
synovial thickening.
|
III - Severe |
Loss of vascularization, diffuse fibrosis around
the nerve, large synovial thickening, and appearance of
pseudoneuroma.
|
Histopathological findings |
Fibrosis, thickening of the collagen bundles,
hyaline degeneration, proliferation of the synovia, edema and
vascular lesions, amyloid deposits.
|
Chart 2 - Clinical, intraoperative, and histopathological examination
criteria.
Chart 3 - Demographic and clinical aspects of patients studied.
Age |
Sex |
Musculoskeletal change |
Clinical score |
EMG score |
Surgical score |
Time between symptom onset and treatment |
Follow-up |
Postoperative evolution |
38 |
F |
Wrist, elbow, and shoulder |
III |
6 |
III |
17 years |
9 years |
Dystrophy |
74 |
F |
Elbow and shoulder |
II |
6 |
II |
2 years |
3 years |
Dystrophy |
72 |
F |
Knee |
II |
5 |
III |
2 years |
6 years |
Normal |
62 |
F |
Cervical spine |
III |
5 |
III |
1 year |
3 years |
Improvement |
71 |
M |
Shoulder |
III |
5 |
II |
6 months |
4 years |
Improvement |
56 |
F |
Tenosynovitis |
III |
5 |
III |
2 years |
1 year |
Dystrophy |
48 |
M |
Tenosynovitis |
III |
5 |
I |
1 year |
3 years |
Chronic pain and atrophy |
50 |
F |
Cervical spine |
I |
5 |
II |
2 years |
5 years |
Normal |
64 |
M |
Column and polyarthralgia |
II |
5 |
III |
1 year |
1 year |
Normal |
53 |
F |
Cervical and dorsal |
III |
5 |
III |
3 years |
6 years |
Improvement |
73 |
F |
Tenosynovitis |
III |
5 |
III |
5 years |
1 year |
Improvement |
72 |
F |
Shoulder, knee, and cervical |
III |
5 |
III |
5 years |
5 years |
Neuropathic pain, polyneuropathy |
Chart 3 - Demographic and clinical aspects of patients studied.
All patients had associated musculoskeletal complaints, such as polyarticular
pain, stenosing tenosynovitis, and shoulder bursitis. One case of associated
polyneuropathy with no family history was found. Some erythrocyte sedimentation
rates were slightly elevated (26–27 mm in the first hour). Only one patient
presented radiographic changes in the wrist that were associated with a history
of trauma.
Six patients had degenerative changes in the joints (cervical, shoulder, or
knee). No patient had a history of cancer or hemodialysis. However, two patients
had a family history of intestinal and brain cancer. One man reported acute
myocardial infarction. One woman presented with CTS and the deposition of
adipose tissue and previous trauma of the wrist associated with radiocarpal
joint degeneration.
In this series of 12 patients, five (41.6%) had complex regional pain and symptom
recurrence after the carpal tunnel release. Three patients had difficulty
controlling reflex sympathetic dystrophy with the recommended treatment. All
cases presented CTS associated with flexor tenosynovitis and a localized form of
amyloidosis.
The prevalence of chronic pain as a complication after the surgical procedure was
45.5%; consequently, analgesics including paracetamol, gabapentin,
amitriptyline, codeine, and corticosteroids were administered. Among the five
patients who presented with this undesirable surgical complication, three were
diagnosed with reflex sympathetic dystrophy, one with neuropathic pain, and one
with effort-related pain.
Synovectomy was performed in all cases of this series, although epineurolysis was
not necessary and not performed in any case because no neural invasion by the
amyloidotic tissues was observed. Instead, the flexor sheath was invaded by
these tissues. As there was no cleavage plan to remove all tissues, a partial
synovectomy was used to reduce local volume and enable the histopathological
examination.
DISCUSSION
The association between amyloidosis and peripheral neuropathy was reported for
the first time by De Navasquez in 1938 andKyle et al.6. Several proteins and its precursors have been implicated
in amyloidosis (transthyretin, apolipoprotein AI, apolipoprotein AII, cystatin
C, gelsolin, fibrinogen alpha chain, lysozyme, and β2 microglobulin
(Aβ2-M)2,11-16. In addition, more than 80 transthyretin mutations have
been described, and evidence indicates that the fibrinogen and other protein
aggregations perform an important role in the pathogenesis of CTS17.
The main clinical manifestations and syndromes associated with neuropathy are
related to light-chain or primary amyloidosis and familial forms of the
autosomal dominant disease2,13. The
diagnosis of amyloidosis is usually made at approximately 60 years of age with a
male predominance of 2:12,4,5. The most common presentation is peripheral neuropathy, although
CTS can occur without alterations in the skin, proteinuria, or skeletal
manifestations (degenerative arthropathy, chronic arthralgia, or arthritis)16-20.
CTS may be associated with different types of amyloidosis, especially their
primary forms, in patients on chronic hemodialysis14,18,21. In this disease, the
first stages of nerve compression involve progressive ischemia and a local
inflammatory process. During the gradual compressive process, demyelination
occurs and nerve conduction velocity decreases in the area of compression.
Our study found that all patients had axon loss, demyelination, low focal
conduction, and signs of denervation, which are classified as grade V
electroneuromyography findings. For these patients, a differential diagnosis,
including radiculopathy, motor neuron disease, polyneuropathy, ulnar neuropathy,
and other deposition diseases such as gout and rheumatoid arthritis, is
important.
Virchow introduced the first histochemical diagnostic test for amyloidosis, later
perfected by Benhold (1922) with Congo red staining that emits a light apple
green fluorescence under polarized light4,5. This test is
considered the gold standard for the diagnosis of amyloidosis6. Based on the literature, this test was
used to confirm the disease in our series of cases, and an additional electronic
microscopy assessment was performed.
On electronic microscopy, major and minor fibrillar components were identified
that presented a pentamer aspect, known as P component8. We believe that complementary clinical and
electrophysiological tests are important for the early diagnosis of CTS, the
identification of amyloidosis, and an early therapeutic plan. We recognize the
challenges of grading the symptoms, signs, and surgical findings since their
accuracy depends on clinician experience and knowledge of the natural
characteristics of the disease.
During the clinical follow-up, the cohort showed a high prevalence of chronic
pain compared with patients with idiopathic CTS9. Based on the experience of the authors, chronic pain was
controlled more effectively by combining analgesics and non-steroidal and
steroidal anti-inflammatory agents. Some surgeons have postulated that chronic
postoperative pain can be related with the anesthetic technique or tourniquet
used.
Nevertheless, another study performed at our institution did not demonstrate this
association22. We believe that the
systemic disease (amyloidosis) can influence peripheral nerve recovery after
surgical trauma and may even increase the cases of chronic pain. The risk
factors for the association between amyloidosis and CTS may not have been well
evaluated in this study due to the small sample size and the limitations of
retrospective cases series.
Patients with a long history of compressive symptoms of the median nerve,
associated with severe changes on an EMG examination, complaints,
musculoskeletal disorders, and a history of myocardial infarction, hemodialysis,
and family history of neuropathy, are indications for intraoperative biopsy
during the surgical nerve decompression and amyloidosis assessment.
The authors believe that the poor result may have occurred for various reasons
such as the fact that the patients had a severe form of CTS before surgery, as
indicated by clinical scores, EMG, and surgery; and associated articular
diseases. Although one of the limitations of the present study our inability to
assess risk factors between amyloidosis and CTS since the 12 evaluated patients
had equally poor postoperative courses, it could also have been seen for a
variety of other reasons, or simply been a group of most severely affected
patients regardless of whether they had amyloid deposits.
However, our findings call attention to this group of patients with poor
preoperative presentation possibly associated with amyloidosis and worse
postoperative prognosis. This study’s findings emphasize the importance of this
association and the need for more research to increase our understanding of the
risk factors and consequences of the association between peripheral nerve
disease and amyloidosis.
CONCLUSION
This infrequent association affected the results of this case study, with a
higher prevalence of postoperative pain. The strategies adopted for treating
patients with CTS associated with amyloidosis in our institution include the
assessment of amyloidosis when treating patients with other musculoskeletal
complaints, especially those older than 60 years of age who present with
symptoms of CTS, thenar atrophy, and electroneuromyography grade V findings. We
suggest treating these patients with early nerve decompression, synovectomy,
assessing amyloid deposits, and effectively controlling postoperative pain.
COLLABORATIONS
KTB
|
Conception and design study, data curation, project
administration.
|
GCSA
|
Analysis and/or data interpretation, final manuscript approval,
writing - original draft preparation.
|
UPS
|
Investigation, methodology, supervision.
|
GBM
|
Methodology, project administration, writing - review &
editing.
|
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1. Rede Sarah de Hospitais de Reabilitação,
Brasília, DF, Brazil.
Corresponding author: Katia Torres
Batista SMHS 501 bloco A , Brasília, DF, Brazil Zip Code 70335-901
E-mail: katiatb@terra.com.br
Article received: October 23, 2018.
Article accepted: February 10, 2019.
Conflicts of interest: none.