Clin Rheumatol DOI 10.1007/s10067-014-2782-0
CASE BASED REVIEW
Neuroarthropathy of the foot revealing primary systemic amyloidosis: case report and literature review Irina Adriana Andrei & Thierry Kuntzer & Johannes Alexander Lobrinus & Arnaud Jaccard & Pascal Zufferey
Received: 22 July 2014 / Accepted: 7 September 2014 # International League of Associations for Rheumatology (ILAR) 2014
Abstract The aims of this review were to describe the case of a patient with debilitating neuroarthropathy of the ankles and feet and reveal a primary systemic (amyloid light chain, AL) amyloidosis and to review the relevant literature concerning the peripheral neuropathy and neuroarthropathy due to amyloidosis. We will emphasize the diagnostic pitfalls and discuss prognosis and treatments of both the peripheral neuropathy and the arthropathy related to AL amyloidosis. This is a descriptive case report of a patient with neuroarthropathy of the lower limbs due to AL amyloidosis. A review and discussion of relevant literature were conducted, based on a PubMed search from 1973 to December 2013. A 51-year-old female was diagnosed with AL amyloidosis after 20 months of investigation of small painful deformities of the feet. Chronic peripheral neuropathy occurs as a manifestation of AL amyloidosis in 25 % of cases. It may exceptionally be complicated by neuroarthropathy. In this case, the paucity of clinical and electrophysiological signs of the neuropathy delayed the diagnosis, leading to a severe arthropathy. The massive destruction of the joints dominated the clinical and the poor functional outcome. Diagnosis of AL I. A. Andrei : P. Zufferey (*) Service de Rhumatologie/DAL, CHUV, Av. Pierre Decker 4, 1011 Lausanne, Switzerland e-mail: [email protected] T. Kuntzer Service de Neurologie/DNC, CHUV, Rue du Bugnon 46, 1011 Lausanne, Switzerland J. A. Lobrinus Service de Pathologie Clinique, Hôpitaux Universitaires de Genève, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva 14, Switzerland A. Jaccard Service d’ Hématologie clinique et Thérapie cellulaire/CHU, Av. Martin Luther King 2, 87042 Limoges, France
amyloidosis should be considered in the presence of a mild peripheral neuropathy and a distal destructive and painless arthropathy. The two key diagnostic procedures are serum protein electrophoresis and nerve biopsy. Delay in treatment worsens the prognosis.
Keywords Amylosis . Charcot arthropathy . Diabetic foot . MRI . Nerve biopsy . Neuroarthropathy
Introduction Amyloid light chain (AL) amyloidosis due to deposition of monoclonal immunoglobulin light chains, usually the lambda (λ) isotype, called “immunoglobulin light chain (AL) amyloidosis,” is a rare hematologic disease and little known to rheumatologists [1–4]. In 15–20 % of cases, it is accompanied by a peripheral neuropathy. This involvement may mark the beginning of the disease [5–7]. However, the appearance of a neuroarthropathy (Charcot arthropathy) in AL amyloidosis has seldom been reported in the literature.
Methods In addition to the case presented, a literature search (PubMed) of articles published between 1973 and December 2013 was performed using MEDLINE heading key words “amyloidosis,” “AL amyloidosis,” “peripheral neuropathy,” “neuroarthropathy,” “Charcot arthropathy,” and “diabetic foot” in different combinations. Forty-seven articles were retrieved and additional references obtained from those quoted in the articles.
Clin Rheumatol
We report the case of a 51-year-old Egyptian woman who consulted us because of deformities and slightly painful swellings of the ankles and feet. She announced no significant medical history or family pathology. The symptoms started 15 months earlier, without trauma or systemic manifestations and with the appearance of a painless swelling of the left foot/ankle, initially treated with antibiotics for 10 days. The symptoms progressed in 6 months to the right side, in the form of recurrent acute inflammatory attacks, followed by progressive static disorders of the midfoot, making walking difficult. Clinical examination showed bilateral deformities and swelling of the ankles and midfoot, including the back of the tarsus with complete collapse of the talar arch. The swellings were not inflammatory or very painful on palpation. Neurological examination revealed normal muscle strength, abolition of ankle reflexes, a discreet reduction in touch and pain sensation on the plantar surfaces, and a reduced pallesthesia of both feet, but proprioception was normal. The patient had already been investigated in several different countries before our consultation. X-rays of the feet showed significant postural disorders and a destructive arthropathy of the tarsal and tarso-metatarsal joints with multiple subluxations, bone erosion, and bone formation, predominantly on the right side (Fig. 1a). Magnetic resonance imaging (MRI) of the right foot showed bone resorption with extensive bone edema in the anterior part of the calcaneus, cuboid, and tarsal bones. The tibio-talar joint was intact. There was no effusion, synovitis, or abscess, but soft tissue edema was seen. The first electromyography (EMG) demonstrated a discrete sensory neuropathy (sural nerve sensory potential at the lower limits of the normal range). A bone scan confirmed a bilateral isolated uptake in the tarsal regions.
Based on these data, a possible diagnosis of neuroarthropathy was envisaged. To identify the cause, several laboratory tests were performed. Diabetes, syphilis, Lyme disease, as well as syringomyelia (normal brain and spine MRI) were excluded. Negative serology for hepatitis B; hepatitis C; rheumatoid factor; anti-CCP antibodies; and antinuclear, anti-dsDNA, anti-nucleoprotein, and anti-neutrophil cytoplasmic antibodies confirmed the absence of underlying auto-immune diseases. The only biological abnormality was a fluctuant moderate inflammatory state; the maximum erythrocyte sedimentation rate was 65 mm/ h and C-reactive protein was 25 mg/l (normal 2.5) for the peroneal and posterior tibial nerves. Sensory nerve action potentials (SNAP) were absent on left sural and superficial peroneal nerves and of very low amplitude (about 1 μV, standards >8) on the right side. Abnormalities at rest with fibrillation potentials of the tibialis anterior muscles were also recorded. EMG of the upper limbs was normal. A neuromuscular biopsy (sural nerve and peroneus muscle) was carried out. Histological examination showed significant myelin axonal loss, predominantly on large fibers with endoneurial fibrosis, without evidence of vasculitis. Congo red staining demonstrated confluent partially nodular amyloid deposits, partly located in the endoneurium (Fig. 2) and in the wall of small blood vessels. Immunohistochemical staining of the deposits was positive for lambda light chains. In the muscle, chronic neurogenic atrophy was found (Fig. 3), as well as rare amyloid deposits in the wall of small vessels.
Fig. 1 Radiographs of the right foot: right side, oblique, and profile. a June 2011: reaching the tarsus and tarso-metatarsal joints with collapse of the arch of the foot; in multiple joint dislocations, bone erosions with
bone formation. b June 2013: progression of joint destruction to the ankle (which was free in 2011) with lytic lesion of the distal tibia and fracture of the lateral malleolus
Results Case report
Clin Rheumatol
The patient was advised to wear orthopedic shoes and to reduce lower limb weight bearing where possible. She was treated with a combination of bortezomib (1.3 mg/m2/week) and dexamethasone 40 mg/week (in total 16 cycles) and zoledronic acid (4 mg/month). Five months after starting this therapy, light chains were no longer detectable and the k/λ ratio was normal. However, the static disorders of the feet progressed, making walking impossible without crutches (Fig. 1b). Pressure ulcers appeared and were complicated by local infections requiring prolonged antibiotic treatment. Literature review
Fig. 2 Nerve histology showing endoneurial, nodular, and partly confluent amyloid deposits in red (Congo red stain, original magnification ×200, ×400 inset)
Causal investigations were repeated. The blood count showed hemoglobin 10.2 g/dl with rolls of erythrocytes. Chemistry was normal for creatinine, β-2-microglobulin, alkaline phosphatase, and serum calcium. Immunoelectrophoresis of serum proteins revealed a monoclonal gammopathy, type IgG λ. The level of IgG was 18.3 g/l and free λ light chains 86 mg/l, with k/λ ratio of 0.2. The search for BenceJones proteinuria was negative. The bone marrow cytology showed 11 % plasma cell infiltration suggesting an early stage of multiple myeloma. However, none of the classic features of myeloma were found including lytic bone lesions, bone pain, hypercalcemia, or renal failure. There was also no evidence of cardiac involvement. Cytogenetic study showed a normal karyotype, and FISH analysis for t(4;14)(p16.3;q32.3), del.(13q14.3), del.(17p13.1) showed no abnormalities. There were no bone lesions on radiographs of the complete skeleton.
Fig. 3 Muscle histology showing chronic neurogenic atrophy, characterized by the presence of groups of small fibers with angular contour (arrows, anti-dysferlin immunohistochemistry, original magnification ×200)
A literature search (PubMed; see “Methods”) yielded 47 articles, and 24 are included and cited here as relevant to our case. Amyloid neuropathy clinically resembles chronic diabetic neuropathy [8] and involves mainly the distal lower limbs. Typically, it is symmetrical and progressive, involving the sensitive rather than motor function. The temperature and pain involvement may predominate over the loss of proprioception, because the amyloid is mainly deposited in small myelinated and unmyelinated fibers [2, 4, 5, 8–10]. The initial damage of nonmyelinated fibers may explain the discrepancy between the development of neuropathy and the subtle abnormalities in the measurement parameters of nerve conduction [9]. Dysautonomic features can be present and a carpal tunnel syndrome occurs in approximately 25 % of cases [11]. Atypical clinical presentations, such as mononeuritis multiplex or an asymmetric neuropathy can also be observed [11]. Before the 2000s and the emergence of effective treatments for patients with isolated amyloid peripheral neuropathy, the median survival was 25 versus 4–6 months for patients with clinical signs of heart failure [4, 5, 8]. The treatment of amyloidosis using new drugs or therapeutic protocols, including bortezomib, improves prognosis [1, 3]. Compared to other organ damage, isolated neurological impairment has a better survival prognosis [2, 7]. Moreover, the new treatments may lead to a slow and partial recovery of the neurological symptoms (peripheral or autonomic neuropathy) over several years. However, the results are often limited by irreversible histological damage. This may be explained by the insidious and chronic nature of the damage, which is characterized by multiple amorphous deposits along the nerve fibers, disturbing nerve regeneration [4, 5, 8]. Delayed recognition of the diagnosis seems to worsen the therapeutic outcome [5, 7, 9]. Charcot arthropathy following joint denervation due to amyloidosis is exceptional. The PubMed search combining two key words “Charcot arthropathy” and “amyloidosis” found 12 articles (for the period 1973 to 2013) and identified only seven cases, meeting the diagnostic criteria, published in six articles, as “case reports” [12–17]. The main clinical
Clin Rheumatol Table 1 Main characteristics of patients diagnosed with Charcot arthropathy secondary to amyloid neuropathy Clinical features
Age (years) Sex/origin Amyloidosis Diagnosis (B) Synovial F. Synovial B
References 1973 (13)
1976 (14)
1981 (15)
1981 (15)
1997 (16)
2009 (17)
2012 (18)
51 M/− AL/Wald. Kidney Nd Nd
50 M/− AL Kidney A− A−
36 M/P ATTR Muscle A− Nd
53 M/P ATTR Nerve Nd Nd
37 M/J ATTR Articular vTTR+ A+
39 M/P ATTR Liver Tr. Nd Nd
46 F/P ATTR PCR (V30M) Nd A−
A amyloid, B biopsy, F. fluid, F female, M male, M/− male/origin undetermined, Nd no data, P/J=portugese/japanese origine, Tr transplant, ATTR transthyretin (TTR) amyloidosis or familial amyloid polyneuropathy (FAP) type I, vTTR variant TTR, PCR (V30M) DNA polymerase-amplifying method (mutation V30M on chromosome 18) for FAP’s diagnosis, Wald. Waldenström’s macroglobulinemia
characteristics of the seven cases are shown in Table 1. The joints most frequently involved were the knees and ankles, but the distal feet were also affected. Only two cases were related to AL amyloidosis. In one patient (with familial amyloid polyneuropathy), amyloid deposit in the joint (synovial fluid, synovial membrane, bone, and cartilage) was demonstrated [14, 18]. Apart from these clear cases, in 1976, Lithner reported that 3 out of 21 patients with familial amyloid polyneuropathy (FAP) from Sweden showed similar foot destruction to that seen in diabetic foot [19]. Joint pain is usually mild although the deformities are obvious. The exposure of the joints to mechanical stress not limited by pain facilitates joint destruction. Disorders of local micro-vascularization also participate in progressive damage [8]. Recently, research into the pathophysiology of diabetic foot revealed the involvement of the receptor activator of nuclear factor-κβ (RANK) ligand (RANK-L)/RANK/osteoprotegerin system. The existence of polymorphic variants of the osteoprotegerin gene may predispose some diabetic patients to develop neuroarthropathy [20–23]. This aspect deserves to be investigated in rare cases associated with amyloidosis. Considering the rarity of the link of joint damage to amyloid neuropathy (AL amyloidosis), the natural evolution of the disease and response of the neuroarthropathy to light chain eradication treatment are poorly documented. Once bone and joint destruction installs, chances of recovery appear limited and the only hope is to stabilize the lesions. Orthopedic correction should be evaluated case by case, determined by the local status with prognosis depending on the response to systemic treatments.
The initial clinical presentation was dominated by chronic and painless peripheral paucisymptomatic neuropathy, complicated by Charcot arthropathy of the feet. The diagnosis required 20 months of investigation. This delay is unfortunately common to the diagnosis of AL amyloid neuropathy and is usually greater than 2 years [5, 9]. It can be explained by the chronicity and non-specificity of symptoms. The paucity of the neurological clinical and electrophysiological signs is often, as in our case, misleading. For this patient, the clinical and radiological joint presentations were suggestive of neuroarthropathy and prompted us to perform neuromuscular biopsy leading to the diagnosis. This case report therefore emphasizes the importance of performing serum protein immunoelectrophoresis in cases of an unexplained persistent inflammatory state. Performed earlier in the course of the disease, this exam would have certainly oriented the clinician more rapidly to the diagnosis. Neuroarthropathy due to AL amyloidosis remains, however, exceptional. To our knowledge, this is the first reported case of AL amyloidosis diagnosed from Charcot arthropathy. It illustrates that this diagnosis should be considered when confronted with signs of peripheral neuropathy or an unusual distal arthropathy. Specific and efficient treatments are now available, especially if diagnosis is managed before development of irreversible lesions. Acknowledgments The authors thank Alexander Kai-Lik So, PhD, FRCP, for his review of the manuscript and helpful comments. Disclosures None.
Discussion References In the presented patient, we retained the diagnosis of systemic AL amyloidosis with peripheral neurological manifestations inducing an unusually severe neuroarthropathy of the feet and ankles.
1. Gertz MA (2011) Immunoglobulin light chain amyloidosis: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol 86(2):180–186. doi:10.1002/ajh.21934
Clin Rheumatol 2. Gertz MA, Kyle RA (1989) Primary systemic amyloidosis—a diagnostic primer. Mayo Clin Proc Mayo Clin 64(12):1505–1519 3. M'Bappe P, Grateau G (2012) Osteo-articular manifestations of amyloidosis. Best Pract Res Clin Rheumatol 26(4):459–475. doi:10. 1016/j.berh.2012.07.003 4. Simmons Z, Specht CS (2010) The neuromuscular manifestations of amyloidosis. J Clin Neuromuscul Dis 11(3):145–157. doi:10.1097/ CND.0b013e3181d05994 5. Rajkumar SV, Gertz MA, Kyle RA (1998) Prognosis of patients with primary systemic amyloidosis who present with dominant neuropathy. Am J Med 104(3):232–237 6. Duston MA, Skinner M, Anderson J, Cohen AS (1989) Peripheral neuropathy as an early marker of AL amyloidosis. Arch Intern Med 149(2):358–360 7. Kyle RA, Greipp PR (1983) Amyloidosis (AL). Clinical and laboratory features in 229 cases. Mayo Clin Proc Mayo Clin 58(10):665–683 8. Gertz MA (2013) Immunoglobulin light chain amyloidosis: 2013 update on diagnosis, prognosis, and treatment. Am J Hematol 88(5):416–425. doi:10.1002/ajh.23400 9. Kelly JJ Jr, Kyle RA, O’Brien PC, Dyck PJ (1979) The natural history of peripheral neuropathy in primary systemic amyloidosis. Ann Neurol 6(1):1–7. doi:10.1002/ana.410060102 10. Gertz MA, Lacy MQ, Dispenzieri A (1999) Amyloidosis: recognition, confirmation, prognosis, and therapy. Mayo Clin Proc Mayo Clin 74(5):490–494. doi:10.4065/74.5.490 11. Gherardi R, Zuber M, Viard JP (1988) Dysglobulinemic neuropathies. Rev Neurol 144(6–7):391–408 12. Scott RB, Elmore SM, Brackett NC Jr, Harris WO Jr, Still WJ (1973) Neuropathic joint disease (Charcot joints) in Waldenstrom’s macroglobulinemia with amyloidosis. Am J Med 54(4):535–538 13. Peitzman SJ, Miller JL, Ortega L, Schumacher HR, Fernandez PC (1976) Charcot arthropathy secondary to amyloid neuropathy. JAMA: J Am Med Assoc 235(13):1345–1347
14. Pruzanski W, Baron M, Shupak R (1981) Neuroarthropathy (Charcot joints) in familial amyloid polyneuropathy. J Rheumatol 8(3):477–481 15. Shiraishi M, Ando Y, Mizuta H, Nakamura E, Takagi K, Ando M (1997) Charcot knee arthropathy with articular amyloid deposition in familial amyloidotic polyneuropathy. Scand J Rheumatol 26(1):61–64 16. Duarte C, Serrano PR, Mariano JC (2009) Charcot arthropathy in a patient with hereditary paramyloidosis. Acta Reumatol Port 34(2B): 436–437 17. Wilmes D, Wautier D, Jonckheere S, Cornu O, Yombi JC (2012) Neuroarthropathy secondary to transthyretin amyloidosis (ATTR V30M). Acta Clin Belg 67(5):372–374. doi:10.1179/ACB.67.5. 2062694 18. Lakhanpal S, Li CY, Gertz MA, Kyle RA, Hunder GG (1987) Synovial fluid analysis for diagnosis of amyloid arthropathy. Arthritis Rheum 30(4):419–423 19. Lithner F (1976) Skin lesions of the legs and feet and skeletal lesions of the feet in familial amyloidosis with polyneuropathy. Acta Med Scand 199(3):197–202 20. Richard JL, Almasri M, Schuldiner S (2012) Treatment of acute Charcot foot with bisphosphonates: a systematic review of the literature. Diabetologia 55(5):1258–1264. doi:10.1007/s00125-0122507-3 21. Wukich DK, Sung W (2009) Charcot arthropathy of the foot and ankle: modern concepts and management review. J Diabetes Complicat 23(6):409–426. doi:10.1016/j.jdiacomp.2008.09.004 22. Molines L, Darmon P, Raccah D (2010) Charcot’s foot: newest findings on its pathophysiology, diagnosis and treatment. Diabetes Metab 36(4):251–255. doi:10.1016/j.diabet.2010.04.002 23. Rogers LC, Frykberg RG, Armstrong DG, Boulton AJ, Edmonds M, Van GH, Hartemann A, Game F, Jeffcoate W, Jirkovska A, Jude E, Morbach S, Morrison WB, Pinzur M, Pitocco D, Sanders L (2011) The Charcot foot in diabetes. Diabetes Care 34(9):123-9. doi10.2337/ dc11-0844
CASE BASED REVIEW
Neuroarthropathy of the foot revealing primary systemic amyloidosis: case report and literature review Irina Adriana Andrei & Thierry Kuntzer & Johannes Alexander Lobrinus & Arnaud Jaccard & Pascal Zufferey
Received: 22 July 2014 / Accepted: 7 September 2014 # International League of Associations for Rheumatology (ILAR) 2014
Abstract The aims of this review were to describe the case of a patient with debilitating neuroarthropathy of the ankles and feet and reveal a primary systemic (amyloid light chain, AL) amyloidosis and to review the relevant literature concerning the peripheral neuropathy and neuroarthropathy due to amyloidosis. We will emphasize the diagnostic pitfalls and discuss prognosis and treatments of both the peripheral neuropathy and the arthropathy related to AL amyloidosis. This is a descriptive case report of a patient with neuroarthropathy of the lower limbs due to AL amyloidosis. A review and discussion of relevant literature were conducted, based on a PubMed search from 1973 to December 2013. A 51-year-old female was diagnosed with AL amyloidosis after 20 months of investigation of small painful deformities of the feet. Chronic peripheral neuropathy occurs as a manifestation of AL amyloidosis in 25 % of cases. It may exceptionally be complicated by neuroarthropathy. In this case, the paucity of clinical and electrophysiological signs of the neuropathy delayed the diagnosis, leading to a severe arthropathy. The massive destruction of the joints dominated the clinical and the poor functional outcome. Diagnosis of AL I. A. Andrei : P. Zufferey (*) Service de Rhumatologie/DAL, CHUV, Av. Pierre Decker 4, 1011 Lausanne, Switzerland e-mail: [email protected] T. Kuntzer Service de Neurologie/DNC, CHUV, Rue du Bugnon 46, 1011 Lausanne, Switzerland J. A. Lobrinus Service de Pathologie Clinique, Hôpitaux Universitaires de Genève, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva 14, Switzerland A. Jaccard Service d’ Hématologie clinique et Thérapie cellulaire/CHU, Av. Martin Luther King 2, 87042 Limoges, France
amyloidosis should be considered in the presence of a mild peripheral neuropathy and a distal destructive and painless arthropathy. The two key diagnostic procedures are serum protein electrophoresis and nerve biopsy. Delay in treatment worsens the prognosis.
Keywords Amylosis . Charcot arthropathy . Diabetic foot . MRI . Nerve biopsy . Neuroarthropathy
Introduction Amyloid light chain (AL) amyloidosis due to deposition of monoclonal immunoglobulin light chains, usually the lambda (λ) isotype, called “immunoglobulin light chain (AL) amyloidosis,” is a rare hematologic disease and little known to rheumatologists [1–4]. In 15–20 % of cases, it is accompanied by a peripheral neuropathy. This involvement may mark the beginning of the disease [5–7]. However, the appearance of a neuroarthropathy (Charcot arthropathy) in AL amyloidosis has seldom been reported in the literature.
Methods In addition to the case presented, a literature search (PubMed) of articles published between 1973 and December 2013 was performed using MEDLINE heading key words “amyloidosis,” “AL amyloidosis,” “peripheral neuropathy,” “neuroarthropathy,” “Charcot arthropathy,” and “diabetic foot” in different combinations. Forty-seven articles were retrieved and additional references obtained from those quoted in the articles.
Clin Rheumatol
We report the case of a 51-year-old Egyptian woman who consulted us because of deformities and slightly painful swellings of the ankles and feet. She announced no significant medical history or family pathology. The symptoms started 15 months earlier, without trauma or systemic manifestations and with the appearance of a painless swelling of the left foot/ankle, initially treated with antibiotics for 10 days. The symptoms progressed in 6 months to the right side, in the form of recurrent acute inflammatory attacks, followed by progressive static disorders of the midfoot, making walking difficult. Clinical examination showed bilateral deformities and swelling of the ankles and midfoot, including the back of the tarsus with complete collapse of the talar arch. The swellings were not inflammatory or very painful on palpation. Neurological examination revealed normal muscle strength, abolition of ankle reflexes, a discreet reduction in touch and pain sensation on the plantar surfaces, and a reduced pallesthesia of both feet, but proprioception was normal. The patient had already been investigated in several different countries before our consultation. X-rays of the feet showed significant postural disorders and a destructive arthropathy of the tarsal and tarso-metatarsal joints with multiple subluxations, bone erosion, and bone formation, predominantly on the right side (Fig. 1a). Magnetic resonance imaging (MRI) of the right foot showed bone resorption with extensive bone edema in the anterior part of the calcaneus, cuboid, and tarsal bones. The tibio-talar joint was intact. There was no effusion, synovitis, or abscess, but soft tissue edema was seen. The first electromyography (EMG) demonstrated a discrete sensory neuropathy (sural nerve sensory potential at the lower limits of the normal range). A bone scan confirmed a bilateral isolated uptake in the tarsal regions.
Based on these data, a possible diagnosis of neuroarthropathy was envisaged. To identify the cause, several laboratory tests were performed. Diabetes, syphilis, Lyme disease, as well as syringomyelia (normal brain and spine MRI) were excluded. Negative serology for hepatitis B; hepatitis C; rheumatoid factor; anti-CCP antibodies; and antinuclear, anti-dsDNA, anti-nucleoprotein, and anti-neutrophil cytoplasmic antibodies confirmed the absence of underlying auto-immune diseases. The only biological abnormality was a fluctuant moderate inflammatory state; the maximum erythrocyte sedimentation rate was 65 mm/ h and C-reactive protein was 25 mg/l (normal 2.5) for the peroneal and posterior tibial nerves. Sensory nerve action potentials (SNAP) were absent on left sural and superficial peroneal nerves and of very low amplitude (about 1 μV, standards >8) on the right side. Abnormalities at rest with fibrillation potentials of the tibialis anterior muscles were also recorded. EMG of the upper limbs was normal. A neuromuscular biopsy (sural nerve and peroneus muscle) was carried out. Histological examination showed significant myelin axonal loss, predominantly on large fibers with endoneurial fibrosis, without evidence of vasculitis. Congo red staining demonstrated confluent partially nodular amyloid deposits, partly located in the endoneurium (Fig. 2) and in the wall of small blood vessels. Immunohistochemical staining of the deposits was positive for lambda light chains. In the muscle, chronic neurogenic atrophy was found (Fig. 3), as well as rare amyloid deposits in the wall of small vessels.
Fig. 1 Radiographs of the right foot: right side, oblique, and profile. a June 2011: reaching the tarsus and tarso-metatarsal joints with collapse of the arch of the foot; in multiple joint dislocations, bone erosions with
bone formation. b June 2013: progression of joint destruction to the ankle (which was free in 2011) with lytic lesion of the distal tibia and fracture of the lateral malleolus
Results Case report
Clin Rheumatol
The patient was advised to wear orthopedic shoes and to reduce lower limb weight bearing where possible. She was treated with a combination of bortezomib (1.3 mg/m2/week) and dexamethasone 40 mg/week (in total 16 cycles) and zoledronic acid (4 mg/month). Five months after starting this therapy, light chains were no longer detectable and the k/λ ratio was normal. However, the static disorders of the feet progressed, making walking impossible without crutches (Fig. 1b). Pressure ulcers appeared and were complicated by local infections requiring prolonged antibiotic treatment. Literature review
Fig. 2 Nerve histology showing endoneurial, nodular, and partly confluent amyloid deposits in red (Congo red stain, original magnification ×200, ×400 inset)
Causal investigations were repeated. The blood count showed hemoglobin 10.2 g/dl with rolls of erythrocytes. Chemistry was normal for creatinine, β-2-microglobulin, alkaline phosphatase, and serum calcium. Immunoelectrophoresis of serum proteins revealed a monoclonal gammopathy, type IgG λ. The level of IgG was 18.3 g/l and free λ light chains 86 mg/l, with k/λ ratio of 0.2. The search for BenceJones proteinuria was negative. The bone marrow cytology showed 11 % plasma cell infiltration suggesting an early stage of multiple myeloma. However, none of the classic features of myeloma were found including lytic bone lesions, bone pain, hypercalcemia, or renal failure. There was also no evidence of cardiac involvement. Cytogenetic study showed a normal karyotype, and FISH analysis for t(4;14)(p16.3;q32.3), del.(13q14.3), del.(17p13.1) showed no abnormalities. There were no bone lesions on radiographs of the complete skeleton.
Fig. 3 Muscle histology showing chronic neurogenic atrophy, characterized by the presence of groups of small fibers with angular contour (arrows, anti-dysferlin immunohistochemistry, original magnification ×200)
A literature search (PubMed; see “Methods”) yielded 47 articles, and 24 are included and cited here as relevant to our case. Amyloid neuropathy clinically resembles chronic diabetic neuropathy [8] and involves mainly the distal lower limbs. Typically, it is symmetrical and progressive, involving the sensitive rather than motor function. The temperature and pain involvement may predominate over the loss of proprioception, because the amyloid is mainly deposited in small myelinated and unmyelinated fibers [2, 4, 5, 8–10]. The initial damage of nonmyelinated fibers may explain the discrepancy between the development of neuropathy and the subtle abnormalities in the measurement parameters of nerve conduction [9]. Dysautonomic features can be present and a carpal tunnel syndrome occurs in approximately 25 % of cases [11]. Atypical clinical presentations, such as mononeuritis multiplex or an asymmetric neuropathy can also be observed [11]. Before the 2000s and the emergence of effective treatments for patients with isolated amyloid peripheral neuropathy, the median survival was 25 versus 4–6 months for patients with clinical signs of heart failure [4, 5, 8]. The treatment of amyloidosis using new drugs or therapeutic protocols, including bortezomib, improves prognosis [1, 3]. Compared to other organ damage, isolated neurological impairment has a better survival prognosis [2, 7]. Moreover, the new treatments may lead to a slow and partial recovery of the neurological symptoms (peripheral or autonomic neuropathy) over several years. However, the results are often limited by irreversible histological damage. This may be explained by the insidious and chronic nature of the damage, which is characterized by multiple amorphous deposits along the nerve fibers, disturbing nerve regeneration [4, 5, 8]. Delayed recognition of the diagnosis seems to worsen the therapeutic outcome [5, 7, 9]. Charcot arthropathy following joint denervation due to amyloidosis is exceptional. The PubMed search combining two key words “Charcot arthropathy” and “amyloidosis” found 12 articles (for the period 1973 to 2013) and identified only seven cases, meeting the diagnostic criteria, published in six articles, as “case reports” [12–17]. The main clinical
Clin Rheumatol Table 1 Main characteristics of patients diagnosed with Charcot arthropathy secondary to amyloid neuropathy Clinical features
Age (years) Sex/origin Amyloidosis Diagnosis (B) Synovial F. Synovial B
References 1973 (13)
1976 (14)
1981 (15)
1981 (15)
1997 (16)
2009 (17)
2012 (18)
51 M/− AL/Wald. Kidney Nd Nd
50 M/− AL Kidney A− A−
36 M/P ATTR Muscle A− Nd
53 M/P ATTR Nerve Nd Nd
37 M/J ATTR Articular vTTR+ A+
39 M/P ATTR Liver Tr. Nd Nd
46 F/P ATTR PCR (V30M) Nd A−
A amyloid, B biopsy, F. fluid, F female, M male, M/− male/origin undetermined, Nd no data, P/J=portugese/japanese origine, Tr transplant, ATTR transthyretin (TTR) amyloidosis or familial amyloid polyneuropathy (FAP) type I, vTTR variant TTR, PCR (V30M) DNA polymerase-amplifying method (mutation V30M on chromosome 18) for FAP’s diagnosis, Wald. Waldenström’s macroglobulinemia
characteristics of the seven cases are shown in Table 1. The joints most frequently involved were the knees and ankles, but the distal feet were also affected. Only two cases were related to AL amyloidosis. In one patient (with familial amyloid polyneuropathy), amyloid deposit in the joint (synovial fluid, synovial membrane, bone, and cartilage) was demonstrated [14, 18]. Apart from these clear cases, in 1976, Lithner reported that 3 out of 21 patients with familial amyloid polyneuropathy (FAP) from Sweden showed similar foot destruction to that seen in diabetic foot [19]. Joint pain is usually mild although the deformities are obvious. The exposure of the joints to mechanical stress not limited by pain facilitates joint destruction. Disorders of local micro-vascularization also participate in progressive damage [8]. Recently, research into the pathophysiology of diabetic foot revealed the involvement of the receptor activator of nuclear factor-κβ (RANK) ligand (RANK-L)/RANK/osteoprotegerin system. The existence of polymorphic variants of the osteoprotegerin gene may predispose some diabetic patients to develop neuroarthropathy [20–23]. This aspect deserves to be investigated in rare cases associated with amyloidosis. Considering the rarity of the link of joint damage to amyloid neuropathy (AL amyloidosis), the natural evolution of the disease and response of the neuroarthropathy to light chain eradication treatment are poorly documented. Once bone and joint destruction installs, chances of recovery appear limited and the only hope is to stabilize the lesions. Orthopedic correction should be evaluated case by case, determined by the local status with prognosis depending on the response to systemic treatments.
The initial clinical presentation was dominated by chronic and painless peripheral paucisymptomatic neuropathy, complicated by Charcot arthropathy of the feet. The diagnosis required 20 months of investigation. This delay is unfortunately common to the diagnosis of AL amyloid neuropathy and is usually greater than 2 years [5, 9]. It can be explained by the chronicity and non-specificity of symptoms. The paucity of the neurological clinical and electrophysiological signs is often, as in our case, misleading. For this patient, the clinical and radiological joint presentations were suggestive of neuroarthropathy and prompted us to perform neuromuscular biopsy leading to the diagnosis. This case report therefore emphasizes the importance of performing serum protein immunoelectrophoresis in cases of an unexplained persistent inflammatory state. Performed earlier in the course of the disease, this exam would have certainly oriented the clinician more rapidly to the diagnosis. Neuroarthropathy due to AL amyloidosis remains, however, exceptional. To our knowledge, this is the first reported case of AL amyloidosis diagnosed from Charcot arthropathy. It illustrates that this diagnosis should be considered when confronted with signs of peripheral neuropathy or an unusual distal arthropathy. Specific and efficient treatments are now available, especially if diagnosis is managed before development of irreversible lesions. Acknowledgments The authors thank Alexander Kai-Lik So, PhD, FRCP, for his review of the manuscript and helpful comments. Disclosures None.
Discussion References In the presented patient, we retained the diagnosis of systemic AL amyloidosis with peripheral neurological manifestations inducing an unusually severe neuroarthropathy of the feet and ankles.
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