Clinical manifestations

Presentation and course

Systemic amyloidosis can be hereditary or acquired. The autosomal dominant hereditary transthyretin amyloidosis (ATTRv, v for variant) and the immunoglobulin light chain amyloidosis, the result of a plasma cell dyscrasia, are the two most common types of amyloidosis associated with peripheral neuropathy. In both, the main presentation is a painful, length-dependent polyneuropathy starting in the distal portions of the limbs, with numbness, burning, and allodynia, which can be particularly worse at night. In the classic presentation, examination at an early stage may show only abnormalities in pinprick sensation and clinical features of median neuropathy at the wrists. However, within months to years, large sensory fibers and motor nerve fibers become involved, resulting in impaired vibration and proprioception, and with weakness starting distally but progressing proximally. Less common are focal cranial neuropathies, or plexopathies from focal deposition (88).

Many patients have a nonmalignant plasma cell dyscrasia. The plasma cells produce monoclonal amyloidogenic light chain immunoglobulin, which is deposited in tissues as amyloid. A minority of patients have multiple myeloma. Weakness, fatigue, and weight loss are the most frequently presenting symptoms. Congestive heart failure and nephrotic syndrome typically dominate the clinical picture in many cases and are usually responsible for the patient’s death (Table 2). Peripheral neuropathy is the most common initial neurologic manifestation (53; 69). In patients with multiple myeloma, neurologic involvement may present with combinations of root pain and compression of the spinal cord or cauda equina (52; 64). Peripheral neuropathy associated with multiple myeloma that is unrelated to therapy is uncommon (less than 5% of multiple myeloma patients), of which about 30% to 40% are due to amyloidosis (52).

Peripheral neuropathy is the presenting sign of immunoglobulin light chain amyloidosis in about 15% of patients (53; 69; 101) and may be the cardinal manifestation. More commonly, however, patients have major systemic disease, and neuropathy is diagnosed as a result of neurologic examination or nerve conduction studies to investigate associated neuropathic symptoms and signs (79). In patients with predominant neuropathy, delay to diagnosis of amyloid is much longer (53; 51). The neuropathy is usually distal, symmetrical, and progressive. Sensory symptoms usually dominate. Rarely, patients may present with neuropathy limited to upper extremity (105) or asymmetric multiple mononeuropathies resembling vasculitis (96). There may be clear sensory dissociation, with temperature and pain perception affected to a greater degree and earlier than vibration and proprioceptive perception. The typical patient presents with painful dysesthesias of the distal legs. Arms become involved soon after. Symptoms of median neuropathy due to compression in the carpal tunnel (carpal tunnel syndrome) can precede or accompany generalized symptoms. Distal weakness and muscle atrophy, although typically present, are not as prominent and rarely become severe (53). Carpal tunnel syndrome may be the presenting feature of primary amyloidosis in about one-quarter of the patients, which is about the same frequency as cardiac failure and slightly more common than peripheral neuropathy and autonomic failure (68). Although carpal tunnel syndrome can be the only symptom in 33% of patients with hereditary transthyretin amyloidosis, for an average period of four to six years before involvement of other organs, in light chain amyloidosis, carpal tunnel syndrome can precede other symptoms by over a year on average (99).

Nephrotic syndrome, however, is the most common presentation (32%). Autonomic failure causes orthostatic hypotension with syncope, gastrointestinal disturbances with diarrhea or pseudoobstruction, bladder dysfunction, and impotence.

Postural hypotension with fainting is the most common and disabling sign of autonomic failure. Autonomic testing in patients with unexplained peripheral neuropathy may give evidence of autonomic involvement and suggest the diagnosis of amyloidosis (108).

Examination discloses symmetrical decrease of temperature and pain perception in the distal legs, with often paradoxical retention of light touch and proprioception (small fiber neuropathy). Some patients, however, have equal involvement of all sensory modalities or even predominant large fiber sensory involvement (53). Mild to moderate distal weakness and atrophy of intrinsic foot muscles are usually present. Deep tendon reflexes are usually decreased or absent distally. Skin trophic changes and reduced sweating are often noted. Neurogenic orthostatic hypotension is unaccompanied by a pulse increase. The sensory dissociation and autonomic findings as well as frequent involvement of the heart, bowel, or kidneys should suggest the diagnosis. Despite amyloid deposition, palpably enlarged nerves are uncommon (53). Although rare, multiple cranial neuropathies can herald amyloidosis that eventually becomes generalized (53).

Asymptomatic amyloid deposits can be found in skeletal muscles in neuropathy patients. Rarely, generalized amyloidosis can present as myopathy (23). Most frequently, patients complain of muscle stiffness with hypertrophy and fatigability. Some may resemble polymyositis (104). They may experience dysphagia, hoarseness, dysarthria, and obstructive sleep apnea due to macroglossia (95). Examination discloses mild to moderately severe generalized muscle weakness. The muscles are characteristically enlarged, with a firm, “wooden-like” feeling with resistance to passive movement. Nodules may be palpable; severe macroglossia may prevent jaw closure and mastication. Deep tendon reflexes and sensation are usually preserved. Occasional patients develop pulmonary failure due to respiratory muscle involvement (04). Patients also may present with a subacute, limb-girdle myopathy, with proximal muscle weakness and atrophy, and no evidence of muscle hypertrophy, induration or macroglossia (46; 85). These patients have proximal and neck extensor muscle weakness and atrophy and are indistinguishable clinically from other types of myopathy.

Amyloid neuropathy can rarely present with a relatively pure autonomic neuropathy due to amyloid deposition restricted to dorsal root ganglia and autonomic fibers and ganglia (108). On rare occasions, typical amyloid polyneuropathy can be associated with signs of more diffuse upper and lower extremity motor involvement. Also, an asymmetric presentation of chronically progressive peripheral motor and sensory deficit has been associated with amyloid involvement of lumbosacral plexus and nerve roots, causing distal axonal degeneration (03).

In addition to neuropathy or myopathy, immunoglobulin light chain amyloidosis usually presents with systemic or generalized symptoms, cardiac or renal insufficiency, or multiple organ involvement (Table 2). Musculoskeletal pain, purpura (especially in the eyelids and face), hepatomegaly, macroglossia, orthostatic hypotension, and edema are most common. Amyloid may involve many other organs (68). Malabsorption with diarrhea and steatorrhea and gastric retention may be a prominent feature of amyloidosis (68; 41; 75). About 40% of patients with primary systemic amyloidosis die of cardiac disease (100). Rarely, amyloid deposits may appear in unusual locations such as trigeminal ganglia or orbital muscles (08; 38; 90).

Optic neuropathy in immunoglobulin light chain amyloidosis is rarely reported. Giant cell arthritis should be ruled out first in all of these cases (87; 22; 35; 47).

Table 2. Organ Involvement with Amyloid

Prognosis and complications

As a general principle, patients with a low burden of amyloid in a nonvital organ survive longer than patients with advanced multiorgan disease. In 1975, the median survival of all patients with primary amyloidosis was two years (65). Survival in primary systemic amyloidosis has improved over the last decade due, in part, to early identification of patients at risk of early death with the development of risk-adapted strategies (62).

In a review of prognosis and treatment in immunoglobulin light chain amyloidosis, several clinical and laboratory features were found to predict survival (28). Patients with peripheral neuropathy as the sole manifestation of their disease had the longest survival, ranging from 40 to 56 months (65; 53; 28). These patients eventually died from involvement of other organs (53). Conversely, patients with congestive heart failure or orthostatic hypotension had the shortest survival, usually less than a year (65; 28). Cardiac involvement is the major determinant of survival. Changes in cardiac function after therapy can be assessed using the cardiac biomarker N-terminal natriuretic peptide type B (61; 89). Nephrotic syndrome and multiple myeloma have a detrimental impact on survival as well (65). Free light chain ratios may help to estimate survival (75; 93). Palladini and colleagues found a strong correlation between the extent of reduction of free light chains (FLCs) and improvement in survival (89).

Also, median survival of patients with increased serum beta-2-microglobulin levels in serum is significantly lower and should be measured in all patients with amyloidosis (30). In a multivariate analysis of prognostic factors, the presence of congestive heart failure, the demonstration of a urinary monoclonal light chain, hepatomegaly, and multiple myeloma all adversely affected survival during the first year. In contrast, increased serum creatinine concentration, orthostatic hypotension, and presence of a monoclonal serum protein were less robust predictors of poor survival (70).

The staging of light chain amyloidosis is based on a scoring system that is calculated by levels of serum cardiac troponin T, N-terminal pro-brain natriuretic peptide (NT-proBNP), and the difference between involved and uninvolved serum free light chain levels.

Clinical vignette

The patient was a 67-year-old man with a six-month history of pain and numbness in his lower extremities. He described the pain as burning in his distal legs that kept him awake at night. This was interspersed with sharp, shooting pains “like needle pricks” in his legs and other parts of his body, including his trunk. He denied weakness or ataxia. He also complained of the recent onset of intermittent numbness of his hands that bothered him at night and was present in the morning on awakening. He would rub and shake them, and they would recover sensation. More recently, he had developed diarrhea after eating and had lost 10% in weight despite a good appetite. He also noted that he felt light-headed on rapidly rising or when he got out of bed in the morning. On one occasion one week prior to examination, he nearly fainted while taking a prolonged hot shower.

Examination disclosed distal sensory loss for pain and temperature. Vibration sense was mildly impaired, and position sense was essentially intact. Sensation was also diminished in the median nerve distribution in both hands. Strength was intact but he had atrophy of distal calf and foot muscles and mild atrophy of the thenar muscles. Ankle jerks were absent, knee reflexes were 1+ and arm reflexes were 2+. Gait was painful and careful. He looked pale and gaunt and had bruises on his trunk and eyelids. Nerves were not palpably enlarged. Supine blood pressure was 146/77 with a regular pulse of 87. After five minutes of standing, blood pressure dropped to 117/57 and pulse was 90. He felt slightly lightheaded.

Laboratory tests showed a mild normocytic anemia with a hemoglobin level of 11 g/dl. The erythrocyte sedimentation rate was elevated at 56. Serum albumin level was slightly low at 3.2 and globulin was normal. The other routine chemical tests were normal including a fasting blood glucose and hemoglobin A1C level. Subsequent 2-hour glucose tolerance test was normal. Protein electrophoresis was normal. Serum immunoelectrophoresis showed a small IgG kappa monoclonal gammopathy. Urinalysis was normal without sugar or protein. EMG showed a distal axonal neuropathy with absent sural nerve potentials and mild slowing of motor nerve conduction with decreased tibial compound muscle action potentials. In the hands, there was evidence of carpal tunnel syndrome, which was worse on the right. Needle EMG showed some active and chronic denervation in distal leg and foot muscles. Cardiac R-R interval variation study showed evidence for autonomic involvement. A subsequent urine immunofixation electrophoresis on a concentrated sample showed a monoclonal kappa light chain with a negative heat test for Bence-Jones proteins. A fat pad aspirate and sural nerve biopsy were both positive for amyloid and subsequent histochemical studies showed kappa light chain type amyloid (AL amyloidosis).

Despite treatment with melphalan and prednisone in addition to supportive measures, the disease progressed, and the patient died approximately one year later.

Biological basis

Etiology and pathogenesis

Amyloidosis is a group of toxic gain-of-function protein-misfolding diseases wherein the normally soluble proteins aggregate in extracellular spaces as insoluble amyloid fibrils with a beta (β)-sheet structure (55). More than 30 causative amyloidogenic proteins have been reported (05), and immunoglobulin light chain is one of the major causative proteins. Immunoglobulin light chain (AL) amyloidosis is caused by the deposition of amyloid fibrils composed of immunoglobulin light chains produced by clonal plasma or B cells (34). Immunoglobulin light chain amyloidosis may be localized due to in situ production of light chains, resulting in a benign clinical course. However, systemic deposition leads to severe multiple organ dysfunction, including neuropathy, cardiomyopathy, and nephrotic syndrome.

In the peripheral nervous system, the deposition of amyloid fibrils induces the degeneration of nerve fibers (ie, axonal degeneration) (55). Axonal degeneration of preferentially small myelinated and unmyelinated fibers is the main finding in sural nerve biopsies, although large myelinated fibers are also affected. Amyloid deposits typically form a cuff around endoneurial vessels, and in the walls of endoneural and epineural vessels, which appear thick on hematoxylin and eosin staining. Diffuse or linear streaks of amyloid can be seen in the epineurium, and globular shaped deposits in the endoneurium (53). These globules may distort the nerve fibers. Teased nerve fibers show a predominance of axonal degeneration (65). In addition to peripheral nerve involvement, neuron cell counts from the intermediolateral column have been found to be reduced by 50% to 75% in patients with orthostatic hypotension (77). Electron microscopy shows striking loss of unmyelinated fibers. Amyloid deposits have a typical beta-pleated sheet appearance on electron microscopy. By immunohistochemistry, amyloid in amyloidosis can be classified as kappa or lambda light chain-derived (11; 107).

How amyloid damages nerves is still unclear. From morphological observations, three theories have evolved. One theory is compression of nerve fibers, with damage to myelin and axons. Another is ischemia provoked by perivascular amyloid infiltration. Both of these have seemed unlikely explanations. The third, and perhaps most likely, is a direct toxic effect of amyloid on nerve fibers. According to study of sural nerve biopsy specimens taken from patients with immunoglobulin light chain amyloidosis, Schwann cells opposed to amyloid fibrils became atrophic, suggesting that amyloid deposits directly affect neighboring tissues (55). Additionally, detachment of the neurilemma from the outermost compacted myelin layer was observed where amyloid fibrils were absent, particularly in patients with abnormalities of nerve conduction velocities or distal motor latencies that fulfill the electrodiagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP). Patients with IgM-derived AL amyloidosis may have antibodies against myelin-associated glycoprotein (anti-MAG antibodies) similar to patients with neuropathy associated with IgM monoclonal gammopathy without amyloidosis. However, abnormalities of myelin were found even in patients without these antibodies (55). Overall, the neuropathy in the IgM primary systemic amyloidosis patients resembles that in the IgG and IgA patients rather than the demyelinating features in IgM anti-MAG neuropathy (24). Rarely, however, primary systemic amyloidosis can present with features of a multifocal demyelinating neuropathy (40).

In myopathy, muscle biopsy characteristically shows mild muscle fiber changes, with absence of necrosis, phagocytosis, or inflammation. Amyloid is found infiltrating the walls of the moderate to large intramuscular vessels (arteries and veins), but with no obstruction of their lumen. In some cases, this and mild deposition of amyloid in the connective tissue is the only finding. Muscle fibers can be compressed and distorted by the amyloid. Esterase stains may show a few esterase-positive angulated fibers, consistent with denervation. Type II fiber atrophy predominates. No amyloid has been found intracellularly, and the myofibrillar structure appears intact (95; 46). The mechanism of muscle fiber damage is unclear. Theories range from a direct toxic effect to physical interference (95; 46).

Epidemiology

Immunoglobulin light chain amyloidosis is an uncommon disorder with a stable incidence at approximately six to 10 cases per million person-year (64).

The incidence of immunoglobulin light chain amyloidosis in Olmsted County, Minnesota is 0.89 out of 100,000 per year (64). From this figure, Kyle has estimated that about 2225 new cases should occur each year in the United States (64).

The median age at diagnosis of immunoglobulin light chain amyloidosis is 63 years, and almost two thirds of the patients are males (65; 66; 69).

Differential diagnosis

From a neurologic standpoint, the axonal neuropathies of late life present the greatest differential difficulty (Table 3). Many of these can present initially with small fiber sensory loss (pain and temperature) with relative sparing of motor and discriminative functions and considerable spontaneous neuropathic pain. These can be separated by laboratory testing and by biopsy if necessary. A more practical approach than early biopsy in undifferentiated cases, especially indolent cases over 60 years of age with negative laboratory studies, is to follow the patients longitudinally. Those with progressive involvement, especially if there is a monoclonal gammopathy or if other organs are involved, may require biopsy.

Table 3. Late-Life Axonal Peripheral Neuropathies

The disorder that most mimics immunoglobulin light chain (AL) amyloidosis, however, is hereditary transthyretin (ATTRv) amyloidosis, both from a clinical and pathological standpoint (01). ATTRv amyloidosis was previously called as familial amyloid polyneuropathy and considered to be restricted to endemic foci in Portugal, Japan, and Sweden. However, it is now considered as prevalent throughout the world due to the increased awareness and development of diagnostic techniques (56). Although the most frequent mutation is a substitution of methionine for valine at position 30 (Val30Met) of transthyretin, more than 150 mutations have been reported so far.

Textbook features of neuropathy resulting from ATTRv amyloidosis are progressive symmetric sensory impairments known as dissociated sensory loss, which is predominantly characterized by a loss of nociception and thermal sensation as well as autonomic dysfunction such as diarrhea/constipation, orthostatic intolerance, dysuria, and erectile dysfunction, which is related to the loss of small-diameter nerve fibers (44). These characteristics are particularly conspicuous during the early phase of neuropathy, and motor dysfunction is considered a later manifestation (58). However, some patients, particularly those with late-onset ATTRv amyloidosis from non-endemic areas, manifest weakness and loss of all sensory modalities without clinically significant autonomic symptoms (58). Cardiac amyloidosis is also frequently found in patients with ATTRv amyloidosis. A characteristic feature of cardiomyopathy resulting from amyloidosis is heart failure with preserved ejection fraction on echocardiography (39). Cardiac conduction abnormalities that necessitate pacemaker implantation also frequently occur (58). Renal involvement is rare in all except in Swedish patients (102). In the Portuguese type of familial amyloid polyneuropathy (Val30Met), microalbuminuria is a predictor of symptomatic renal disease (76). The prognosis is uniformly fatal, and life expectancy is reduced to 7 to 10 years after onset of symptoms.

The diagnosis of amyloidosis depends on identification of amyloid material in tissue. Biopsy sites in ATTRv amyloidosis with a high yield are similar to those in amyloidosis (Table 4) (31). Punch skin biopsy and minor salivary gland biopsy can also be an effective method of early diagnosis (01). However, routine biopsy does not distinguish immunoglobulin light chain (AL) amyloidosis from ATTRv amyloidosis, but requires immunohistochemical tests of amyloid for light chains and transthyretin as well as genetic testing.

Table 4. Biopsy Results in Amyloidosis

Clinical diagnosis of familial amyloid polyneuropathy is straightforward when there is a positive family history and a compatible clinical picture (06). It becomes more difficult when there is no apparent family involvement. In a review of 1233 cases of ATTRv amyloidosis patients from 489 Portuguese families, neither parent showed signs of the disease in 159 cases (13). Positive family history is rather rare in patients from non-endemic areas, leading to a difficulty in early diagnosis (01). In these cases, genetic diagnosis becomes essential. Accurate diagnosis of familial amyloid polyneuropathy is important because patients may be misdiagnosed as immunoglobulin light chain amyloidosis and even be treated with chemotherapeutic drugs. Findings of nerve conduction studies are similar to those of immunoglobulin light chain amyloidosis (57; 59).

The primary findings in a sural nerve biopsy in ATTRv amyloidosis are amyloid deposition within the fascicles and, sometimes, nodules of amyloid indenting myelinated fibers. In individual cases, however, ATTRv amyloidosis cannot be differentiated from immunoglobulin light chain amyloidosis without immunohistochemical studies of amyloid constituent proteins. The absence of a plasma cell dyscrasia suggests ATTRv amyloidosis, but immunohistochemical and genetic studies need to be done in order to further clarify the diagnosis (107). Proteomic typing of amyloid deposits with mass spectrometry has allowed direct typing of amyloid deposits (73).

Although treatment of ATTRv amyloidosis has been mostly limited to supportive care in the past, liver transplantation has been performed since 1990 to prevent the production of variant transthyretin from the liver (42). Also, sequential heart-liver transplantation has been used successfully in a small number of patients (86; 92). Although a long-term efficacy has been confirmed, particularly in early-onset Val30Met patients from conventional endemic foci (111), some of the patients exhibited a progression of neuropathy and cardiomyopathy resulting from wild-type TTR deposition even after liver transplantation (01). Although a split-liver transplantation has been successfully performed from a living donor and promises to increase the use of transplantation in this disease (45), a recent development of other disease-modifying therapies decreased the number of patients who receive liver transplantation. In the beginning of 2010, phase III clinical trials revealed an efficacy of tafamidis and diflunisal to ameliorate the progression of neuropathy (13; 07). These drugs prevent the dissociation of transthyretin tetramers, which are physiologically stable, into unstable monomers, thereby inhibiting the subsequent aggregation of transthyretin. As transthyretin stabilizers are able to administrate orally, late-onset cases who are not eligible to liver transplantation can also receive these drugs. More recently, short interfering RNA (siRNA) and antisense oligonucleotide that suppress the production of both wild-type and variant transthyretin from the liver have been introduced as other therapeutic options for ATTRv amyloidosis. In 2018, the results of phase III clinical trials of intravenously administrated siRNA, patisiran, and subcutaneously administrated antisense oligonucleotide, inotersen, were published (05). According to these reports, even an improvement of neuropathy was observed.

Diagnostic workup

Nerve conduction studies are useful in documenting findings and can often help to differentiate the peripheral neuropathy of immunoglobulin light chain amyloidosis from other paraproteinemia-associated peripheral neuropathies (50). Typical electrophysiologic findings are consistent with a symmetrical, primarily axonal neuropathy predominant in the lower limbs. Although conduction velocities and distal motor latencies are relatively preserved despite severe reduction of compound muscle action potentials and sensory nerve action potentials, some of the patients show nerve conduction parameters indicating demyelination mimicking chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) (55). Routine nerve conduction studies early in the disease may not show clear sensory findings because small myelinated and unmyelinated sensory fibers, not recordable by conventional nerve conduction techniques, are affected first. Autonomic testing batteries can usually detect autonomic dysfunction early in the disease (80). Needle electromyography examination usually shows distal and symmetric chronic and active denervation and reinnervation changes. Abnormalities are usually less prominent in the upper limb. Proximal muscles may rarely show myopathic findings in patients with associated amyloid myopathy.

In patients with amyloid myopathy, creatinine phosphokinase can be mildly elevated (two to three fold). Nerve conduction studies may be normal or show neuropathy. When an associated neuropathy is not present, needle examination is usually consistent with a myopathy, with early recruitment of small, polyphasic, short duration motor unit action potentials, and abundant fibrillation potentials and positive waves at rest. Magnetic resonance imaging studies of these patients can be useful because the appearance of the muscles in amyloid myopathy differs greatly from other myopathies. The T1 and T2 signal characteristics within the muscle are minimally changed but there is a striking reticulation of the subcutaneous fat (83).

Abnormal laboratory findings are the result of amyloid deposition. Anemia is seen in about 50% of the patients (67), secondary to gastrointestinal bleeding, multiple myeloma or renal insufficiency. The factor X level is decreased in less than 5% of patients and is rarely responsible for bleeding. Prothrombin time can be prolonged, and an inhibitor of thrombin, with prolongation of the thrombin time, is found in about 60% of patients (25). Thrombocytosis is detected in 5% to 10% of patients, probably due to functional hyposplenism. About 80% of the patients have proteinuria (65; 53; 69) but Bence-Jones proteins are usually undetectable in patients without multiple myeloma. Serum creatinine levels are above 1.3 mg/dl in half of the patients. Liver function tests are usually normal, although alkaline phosphatase may be elevated.

Serum protein electrophoresis is usually abnormal, showing hypogammaglobulinemia in about 15% of patients with multiple myeloma and 33% of those with amyloidosis (67). A narrow monoclonal peak in the gamma region, usually of moderate size (less than 3 grams), can be seen in about 40% of patients. Patients with a monoclonal spike of more than 3.0 g/dl are more likely to have multiple myeloma. The gamma globulin peak can be small, and immunoelectrophoresis or immunofixation may be necessary to identify the monoclonal protein in these patients. Electrophoresis of an adequately concentrated urine specimen usually shows a large albumin peak. As in the serum, a localized monoclonal band can be seen in almost two thirds of patients with multiple myeloma. Immunoelectrophoresis or immunofixation, however, is usually necessary to reveal a monoclonal light chain, which is seen in approximately 75% of patients. Immunofixation of urine in a patient with unexplained nephrotic syndrome can sometimes help establish a diagnosis of amyloidosis (65; 69).

The diagnosis of amyloidosis depends on the demonstration of amyloid in tissue. Amyloid appears pink with hematoxylin and eosin stains. Congo red is the most commonly used stain to identify amyloid, producing a reddish color routinely but an apple-green birefringence under polarized light, diagnostic of all types of amyloid. This stain, however, is not 100% reliable because some neural structures, boney trabeculae, and connective tissues can display green birefringence as well. In occasional cases, Congo red stain is negative, and electron microscopy is needed to demonstrate the diagnostic amyloid fibrils; this, though, is a tedious process best restricted to suspicious areas seen under light microscopy. Identification of specific types requires staining with antisera to the abnormal proteins (amyloidosis kappa, amyloidosis gamma, secondary amyloidosis, beta-2-microglobulin, transthyretin, etc.) (98). However, newer molecular techniques such as mass spectrophotometry and immunohistochemistry of amyloid show promise in determining types of amyloidosis (12).

The diagnosis of immunoglobulin light chain amyloidosis should be considered in any patient with a sensorimotor peripheral neuropathy who has an abnormal monoclonal protein in serum or urine or a suggestive clinical picture. Diagnosis can be confirmed by obtaining appropriate tissue for histological investigation. We generally recommend biopsy of at least two sites, either at the same time or sequentially, because any individual site, including sural nerve in neuropathy, can be negative. Abdominal fat aspirate or biopsy is an uncomplicated procedure that is positive in about 70% to 80% of patients (65; 69; 02). Fat pad biopsy has been found to be a good site for biopsy with minimal morbidity (54; 110). Bone marrow biopsy is positive in only half of patients with amyloidosis, but it can show an abnormal proliferation of monoclonal plasma cells with appropriate histochemical staining, which is important for diagnosis and prognosis. The presence of more than 20% plasma cells, especially if atypical and nucleated, is associated with overt multiple myeloma (69). Sural nerve biopsy is positive in over 80% of patients with peripheral neuropathy and should be considered when other biopsies are negative. Skin biopsies can reveal amyloid in blood vessels of subcutaneous tissues (43). Rectal biopsy is also positive in over 80% of patients, which is comparable to fat pad aspiration. Care should be taken to include submucosa in the specimen (69). Biopsy of the iliac crest bone marrow combined with abdominal subcutaneous fat aspiration will identify amyloid deposits in 85% of patients with amyloidosis (91; 106).

If both stains come back negative for amyloid, there is still a 15% chance that the patient has amyloidosis, and the appropriate organs (renal, liver, carpal tunnel, small intestine, skin, etc.) should be biopsied if the index of suspicion is high (26). Skin biopsies are generally negative unless there is clinical involvement.

Usefulness of (18)F-FDG PET/CT has been reported. In one study, it showed high uptake in two thirds of the organs involving primary systemic amyloidosis; however, its sensitivity appeared to be low to make differentiation of pathological uptake from physiological uptake (74). F-florbetapir PET/CT might provide another potential tool in the imaging algorithm of these patients, and it may guide targeted fascicular biopsy for pathologic confirmation (10).

Magnetic resonance neurography can be a new method to characterize peripheral neuropathy in light chain amyloidosis. A study of 20 patients with polyneuropathy resulting from immunoglobulin light chain amyloidosis and 25 age- and sex-matched healthy volunteers showed magnetic resonance neurography can detect and quantify peripheral nerve injury in immunoglobulin light chain amyloidosis with high sensitivity and in close correlation with the clinical stage (60).

Diagnostic criteria for immunoglobulin light chain amyloidosis have been developed by the Mayo Clinic and the International Myeloma Working Group and require the presence of all of the following four criteria (72):

(1) Presence of an amyloid-related systemic syndrome (heart, gastrointestinal, renal, liver, or peripheral nerve involvement)

(2) Positive amyloid staining by Congo red tissue (fat aspirate, bone marrow, or organ biopsy) or the presence of amyloid fibrils on electron microscopy

(3) Evidence that the amyloid is light chain (by direct examination of the amyloid using spectrometry-based proteomic analysis or immunoelectron microscopy)

(4) Evidence of a monoclonal plasma cell dyscrasia (eg, presence of a serum or urine M protein, abnormal serum free light chain ratio, or clonal plasma cells in the bone marrow)

Management

All patients with systemic amyloidosis require therapy to prevent deposition of amyloid in other organs and prevent progressive organ failure of involved sites. High-dose melphalan followed by autologous stem cell transplantation is recommended in eligible patients (49). The use of autologous stem cell transplantation in the management of amyloidosis is logical because it could rapidly eradicate the amyloidogenic light chain produced by the clonal plasma cell populations (14; 27). Although eligibility for autologous stem cell transplantation in immunoglobulin light chain amyloidosis varies across countries and institutions, only 20% of patients are eligible due to strict eligibility criteria based on age, performance status, cardiac function, pulmonary function, hepatic function, renal function, and hemodynamic stability (97). Patients not eligible for autologous stem cell transplantation and those who have opted not to receive it can be offered combination chemotherapy without autologous stem cell transplantation. Daratumumab in combination with cyclophosphamide, bortezomib, and dexamethasone has been proven to significantly improve hematologic response, and it has become an important treatment option for treatment option for AL amyloidosis (27; 109). If daratumumab is not available, either cyclophosphamide-bortezomib-dexamethasone or bortezomib-melphalan-dexamethasone is used (109). Other agents worth being considered include thalidomide, lenalidomide, pomalidomide, ixazomib venetoclax, and bendamustine (27; 109).

Cardiac transplantation, hemodialysis, continual peritoneal dialysis, and renal transplantation can improve survival in highly selected patients with immunoglobulin light chain amyloidosis, although amyloid can accumulate in transplanted organs (28; 82).

Unfortunately, the symptoms and findings of peripheral neuropathy usually do not completely disappear despite successful therapy and improvement in other organs. Analgesics, tricyclic antidepressants, and newer anticonvulsants may be helpful. In some cases, low-dose narcotics at bedtime can be helpful either alone or combined with other medications. Side effects can be troublesome in these patients, however, with orthostatic hypotension and worsening of gastrointestinal and genitourinary function. Orthostatic hypotension can be ameliorated with fitted, supportive elastic stockings that extend up to the waist, although patients frequently refuse to wear them. Drugs that promote sodium retention and increase alpha-adrenergic tone can be helpful early but lose their effectiveness as patients develop cardiac, kidney, and autonomic failure.

Following initial relapse or refractory disease in patients with immunoglobulin light chain amyloidosis, treatment with a different therapy at relapse improves time to next therapy but does not impact overall survival (103).

Outcomes

Without modern therapy, the disease has a dismal prognosis (53; 63; 28). An initial meta-analysis by Mhaskar and colleagues in 2009 showed only questionable value of autologous stem cell transplantation for amyloidosis, because the study had included noneligible candidates (84; 81). Later studies showed favorable outcomes for autologous stem cell transplantation, especially in patients with cardiac amyloidosis without advanced congestive heart failure (78). In fact, the major determinant of outcome in amyloidosis is the extent of cardiac involvement (26). On the other hand, the transplant-related mortality rate has been decreased to 1.1% since 2009 (33). Plerixafor definitely had a significant role on reduction of mortality rate in all eligible patients undergoing autologous stem cell transplantation (16). Survival rate was better at centers performing at least four autologous stem cell transplantations annually (21).

The number of organs involved offers the greatest pretreatment prognostic value, whereas the lowest posttransplantation serum free light chain level offers the best posttreatment prognostic value (15). Dispenzieri and colleagues reported posttransplantation survival in light chain amyloidosis has improved, with a dramatic reduction in early posttransplantation mortality and excellent five-year survival (19). The risk-benefit ratio for auto-transplantation has changed; however, a randomized comparison with nontransplantation approaches is again warranted (20).

Gertz and colleagues at the Mayo Clinic presented a series of 66 patients treated with autologous stem cell transplantation (32). Of the 66 patients, seven died during the follow-up period. The two-year actuarial survival was 70%. Patients with limited disease did best (91% survived for two years), whereas those with multiple organ involvement did the worst (33% of patients with three organ involvement and 0% of four organ involvement survived two years). Thus, early autologous stem cell transplantation in the first year for those with minimal organ involvement is now the treatment of choice if the patient qualifies (32; 17; 94; 09).Unfortunately, many patients by the time of diagnosis are too advanced to benefit from this treatment. Dispenzieri and colleagues found that only 234 of 1228 patients with amyloidosis satisfied eligibility criteria for transplantation (18). However, the use of daratumumab combined with standard chemotherapy significantly improved hematologic response even in patients who are not eligible for autologous stem cell transplantation (48).

Special considerations

Anesthesia

Patients with amyloid heart disease are at increased risk for arrhythmia while receiving anesthesia.