General Child Neurology
May. 31, 2021
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Amyloidosis is a generic term and refers to the extracellular deposition of fibrils composed of low weight chain of a variety of normal serum proteins.
Amyloid neuropathy remains a serious, usually rapidly fatal disease. However, in this updated article, the authors discuss evidence indicating that peripheral blood stem cell transplantation has proven to be effective treatment in carefully chosen patients. Patients with limited organ involvement have shown a good response to autologous hematopoietic cell transplantation with prolongation of survival. Early hematopoietic cell transplantation in well-selected patients is the current treatment of choice for amyloid neuropathy. Thus, early diagnosis and referral for treatment is essential before the disease spreads to multiple organs. Prognosis has improved with the use of early mortality risk scores to recognize those patients most at risk for early death. Diagnosis is still based on discovery of amyloid deposits in tissue biopsy identified by immunohistochemistry, but new techniques, such as mass spectrometry, show promise in determining amyloid types. Neurologists, who are most likely to see patients with neuropathy only, are in a favorable position to make an early diagnosis. The discussion of the clinical presentation and laboratory findings in this article can aid in early recognition of this disease. Review of neurologic manifestations of primary systemic amyloidosis, early recognition of the disease by new methods, and considering early treatment (especially autologous hematopoietic cell transplantation) with prolongation of survival are all covered.
Primary systemic amyloidosis or light chain amyloidosis is caused by the secretion of a monoclonal serum protein (M-protein) by a plasma cell dyscrasia. The serum proteins, derived from immunoglobulin light chain fragments, are degraded locally in tissues and are deposited in sheets that are insoluble and damage organs. Primary systemic amyloidosis is a malignant plasma cell dyscrasia that is treated with autologous hematopoietic cell transplantation or chemotherapy to eradicate the underlying clone and should be differentiated from other forms of amyloidosis (eg, secondary amyloidosis and hereditary amyloidosis) as they are nonneoplastic and will not benefit from chemotherapy. Other forms of amyloid are caused by genetic changes in circulating proteins or chronic inflammation.
The term "amyloid" denotes a waxy, amorphous, eosinophilic material named by botanist Mathias Schlieden in 1838 for the waxy components of plants and later used by Virchow in 1853 to describe similar pathological findings in humans. Virchow believed that it was composed of polysaccharides. All varieties of amyloid have similar physical properties such as staining red with Congo-red dye and showing a distinctive apple-green birefringence under polarized light.
Initially, the classification of amyloidosis (Table 1) was based on the clinical and pathological presentation and familial attributes (47; 48). Most current classifications are based on the molecular composition of amyloid (14), as determined by immunohistochemical testing or direct gene studies. Clinically, however, classification of these disorders into localized and systemic forms is still useful. In localized forms, amyloid can be deposited in the brain (hereditary cerebral hemorrhage with amyloidosis of the Icelandic and the Dutch type, and Alzheimer disease), or in the endocrine system (medullary carcinoma of the thyroid). Systemic amyloidosis includes familial amyloid polyneuropathy, primary and myeloma-associated amyloidosis, secondary amyloidosis, senile amyloidosis, and hereditary renal amyloidosis. This review will focus on primary systemic amyloidosis and associated neurologic and medical manifestations, but will also discuss familial amyloid polyneuropathy because it often enters into the differential diagnosis of primary systemic amyloidosis.
Immunoglobulin light chain (AL) amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of immunoglobulin light chain are deposited in tissues. Presentation includes restrictive cardiomyopathy, nephrotic syndrome, hepatic failure, peripheral/ autonomic neuropathy, and atypical multiple myeloma based on involved organ.
Acquired light chain amyloidosis should be considered in the differential diagnosis of any patient with chronic inflammatory demyelinating polyneuropathy and a monoclonal protein or a monoclonal gammopathy in a patient with unexplained fatigue and paresthesia.
Primary systemic amyloidosis
Monoclonal light chain, kappa or lambda
Secondary amyloidosis due to infection and inflammation
Protein A, fibrils are composed of fragments of the acute phase reactant serum amyloid A
Familial (hereditary) amyloid
Due to mutated forms of transthyretin (TTR), the alpha chain of fibrinogen A, apolipoprotein AI and AII, lysozyme, and gelsolin
Systemic amyloidosis can be hereditary or acquired. The autosomal dominant hereditary transthyretin amyloidosis (hATTR) and the acquired light chain (AL)-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 small fiber neuropathy starting in the feet, 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 (109).
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 (64; 78). In patients with multiple myeloma, neurologic involvement most often presents with combinations of root pain and compression of the spinal cord or cauda equina (63; 73). 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 (63). Amyloid neuropathy occurring in the setting of myeloma is clinically indistinguishable from primary systemic amyloidosis, and the clinical features will be discussed together.
Peripheral neuropathy is the presenting sign of systemic amyloidosis or multiple myeloma in about 15% of patients (64; 78; 122) 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 EMG to investigate associated neuropathic symptoms and signs (91). In patients with predominant neuropathy, delay to diagnosis of amyloid is much greater (64; 62). The neuropathy is usually distal, symmetrical, and progressive. Sensory symptoms usually dominate. Rarely, patients may present with neuropathy limited to upper extremity (130) or asymmetric multiple mononeuropathies resembling vasculitis (116). 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 (64). 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 (77). 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 (118).
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 (33).
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 (135).
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 (64). 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 (64). Although rare, multiple cranial neuropathies can herald amyloidosis that eventually becomes generalized (64; 131).
Asymptomatic amyloid deposits can be found in skeletal muscles in neuropathy patients. Rarely, generalized amyloidosis can present as myopathy (32). Most frequently, patients complain of muscle stiffness with hypertrophy and fatigability. Some may resemble polymyositis (129). They may experience dysphagia, hoarseness, dysarthria, and obstructive sleep apnea due to macroglossia (137; 113). 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. 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 (56; 99). 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 (85; 135). On rare occasions, typical amyloid polyneuropathy can be associated with signs of more diffuse upper and lower extremity motor involvement (01). 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 (08).
In addition to neuropathy or myopathy, primary systemic amyloidosis usually presents with systemic or generalized symptoms, cardiac or renal insufficiency or multiple organ involvement (Table 2). Musculoskeletal pain, purpura (especially eyelids and face), hepatomegaly, macroglossia, orthostatic hypotension, and edema are most common. Amyloid may involve many other organs (77). Malabsorption with diarrhea and steatorrhea and gastric retention may be a prominent feature of amyloidosis (77; 52; 86). About 40% of patients with primary systemic amyloidosis die of cardiac disease (121). Rarely, amyloid deposits may appear in unusual locations such as trigeminal ganglia or orbital muscles (11; 49; 106).
Optic neuropathy in light chain amyloidosis is reported rarely. Giant cell arthritis should be ruled out first in all of these cases. There is only one case report of bilateral ischemic optic neuropathy as the presenting manifestation of systemic amyloidosis (102; 30; 46; Kannan et al 2017.)
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 (74). 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 (71).
In a review of prognosis and treatment in primary systemic amyloidosis, several clinical and laboratory features were found to predict survival (38). Patients with peripheral neuropathy as the sole manifestation of their disease had the longest survival, ranging from 40 to 56 months (74; 64; 28; 38). These patients eventually died from involvement of other organs (64). Conversely, patients with congestive heart failure or orthostatic hypotension had the shortest survival, usually less than a year (74; 38). Cardiac involvement is the major determinant of survival, and changes in cardiac function after therapy can be assessed using the cardiac biomarker N-terminal natriuretic peptide type B (70; 103). Nephrotic syndrome and multiple myeloma have a detrimental impact on survival as well (74). Free light chain ratios may help to estimate survival (86; 110). Palladini and colleagues found a strong correlation between the extent of reduction of free light chains (FLCs) and improvement in survival (103).
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 (40). 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. After these, increased serum creatinine concentration, orthostatic hypotension, and presence of a monoclonal serum protein were less robust predictors of poor survival (79).
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.
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 (primary systemic amyloidosis).
Despite treatment with melphalan and prednisone in addition to supportive measures, the disease progressed, and the patient died approximately one year later.
The etiology of primary systemic amyloidosis is not known. The clonal expansion of plasma cells is unexplained. The approximate cause for disease is amyloid accumulation that is toxic of tissue.
In primary systemic amyloidosis and myeloma-associated amyloidosis, the amyloid fibrils are composed of monoclonal light chain immunoglobulins. L-chains of the lambda type are twice as likely to be associated with amyloidosis as kappa, even though the opposite occurs in myeloma without amyloid. The monoclonal light chains are absorbed and processed by macrophages to produce the amyloid fibrils that, when deposited, are resistant to dissolution and proteolysis (27).
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 H and E staining. Diffuse or linear streaks of amyloid can be seen in the epineurium, and globular shaped deposits in the endoneurium (29; 64). These globules may distort the nerve fibers (29). Teased nerve fibers show a predominance of axonal degeneration (74). 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 (88). 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 (20; 15; 134).
How amyloid damages nerves is 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. Amyloid deposition in the proximal dorsal root and autonomic ganglia, with their deficient blood-nerve barrier, has also been suggested as a primary site of injury in amyloid neuropathy. Patients with IgM-derived primary systemic amyloidosis may have antibodies against myelin associated glycoprotein (anti-MAG antibodies) similar to patients with neuropathy associated with IgM monoclonal gammopathy without amyloidosis. However, unlike the latter patients, 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 (34). Rarely, however, primary systemic amyloidosis can present with features of a multifocal demyelinating neuropathy (50).
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 (137). No amyloid has been found intracellularly, and the myofibrillar structure appears intact (113; 56). The mechanism of muscle fiber damage is unclear. Theories range from a direct toxic effect to physical interference (113; 56).
Primary systemic amyloidosis is an uncommon disorder with a stable incidence at approximately six to 10 cases per million person-year (73).
The incidence of primary systemic amyloidosis in Olmsted County, Minnesota is 0.89 out of 100,000 per year (73). From this figure, Kyle has estimated that about 2500 new cases will appear each year (73).
The median age at diagnosis of primary systemic amyloidosis is 63 years, and almost two thirds of the patients are males (74; 75; 78).
From a neurologic standpoint, the axonal neuropathies of late life present the greatest differential difficulty (Table 3). All 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.
Type of neuropathy (all or some features)
SM, AN, AX
SM: small fibers predominantly affected with pain
LF: large fibers predominantly affected with discriminative sensory loss
AN: autonomic neuropathy may occur
AX: predominantly axonal pattern by EMG or biopsy
DM: predominantly demyelinating pattern by EMG or biopsy
The disorder that most mimics primary systemic amyloidosis, however, is hereditary or familial amyloid polyneuropathy, both from a clinical and pathological standpoint (14). Familial amyloid polyneuropathy is relatively uncommon but is prevalent in some small, circumscribed populations as well as in widely scattered areas. It has great clinical and genetic heterogeneity. Autosomal dominant familial amyloid polyneuropathy is the most frequent form. Other varieties of hereditary amyloidosis do not have significant neurologic manifestations and will not be discussed. Hundreds of kindreds have now been described since Andrade originally described this disease in 1952 (06).
Original classification systems were based on locale of index cases, distribution of findings, or name of first author. There are several distinctive clinical syndromes (Table 4). Familial amyloid polyneuropathy type I (Andrade type or Portuguese, Swedish, Japanese) had the clinical features described by Andrade (06) and initially affects the lower limbs. Familial amyloid polyneuropathy type II (Indiana, Swiss, Maryland) presents with carpal tunnel syndrome, followed by neuropathy affecting first the upper extremities and later the lower extremities with vitreous opacities. Type III (Iowa) is characterized by polyneuropathy affecting mainly the lower extremities, nephropathy and peptic ulcers. Type IV (Finnish) presents with lower cranial neuropathies, lattice corneal dystrophy, and skin abnormalities. Because of clinical variability within genotypes, however, this classification may not help in the clinical recognition of individual cases. The phenotype within individual families, however, is usually homogeneous. Both familial amyloid polyneuropathy types I and II are most commonly caused by a point mutation in the transthyretin gene on chromosome 18. The most frequent mutation is a substitution of methionine for valine at position 40 (met 40). However, other substitutions have been described on this and other chromosomes. Fortunately, diagnostic tests for the abnormal proteins and genes are now available for most cases.
Differentiating the familial amyloid polyneuropathy types on clinical grounds is sometimes difficult but certain features can help. Types I and II represent the bulk of the cases. Familial amyloid polyneuropathy type I typically presents with loss of pain and temperature sensation in the lower extremities, which frequently results in painless ulcers and auto-amputations. Later, paresthesia and dysesthesia become prominent, and later loss of proprioception and light touch appear. Over the years, symptoms spread to the upper extremities (Ikeda et al 1987). Muscle weakness does not develop until much later; it is accompanied by prominent distal muscle wasting and decreased deep tendon reflexes. In a U.S. study of familial amyloid polyneuropathy, autonomic neuropathy ultimately developed in 70% of patients (41). To make matters more difficult, the Japanese have shown that familial amyloid polyneuropathy Met 30 in transthyretin in Japan, which presents in older patients, often appears to be sporadic (68; 05). Orthostatic hypotension, syncope, and gastrointestinal disturbances (diarrhea, incontinence, intestinal pseudo-obstruction, and gastric fullness) are frequent and indicate debilitating autonomic dysfunction. Impotence is frequent and early. Ocular manifestations, such as vitreous opacities and occasional scalloping of the pupils, occur. Cardiac amyloidosis is commonly found at autopsy. However, cardiac failure or disturbances of rhythm are uncommon in the typical Portuguese and Japanese (06). On the contrary, two thirds of American families develop cardiac amyloidosis with congestive heart failure and arrhythmia (41). Renal involvement is rare in all except in Swedish patients (125). In the Portuguese type of familial amyloid polyneuropathy (Val30Met), microalbuminuria is a predictor of symptomatic renal disease (87). The prognosis is uniformly fatal, and life expectancy is reduced to seven to 10 years after onset of symptoms.
Familial amyloid polyneuropathy type II was first described in a Swiss family living in Indiana (114). These patients developed their first symptoms in the fourth or fifth decade. Carpal tunnel symptoms due to deposition of amyloid in the flexor retinaculum are the earliest, and often the sole, manifestation of the illness for long periods. A sensorimotor peripheral neuropathy eventually develops in the arms and later in the legs. This disease has a more benign course and usually spares the autonomic nervous system. Vitreous opacities are prominent and can lead to blindness. Heart involvement is not pronounced.
The diagnosis of amyloidosis depends on identification of amyloid material in tissue. Biopsy sites in familial amyloid polyneuropathy with a high yield are similar to those in amyloidosis (Table 5) (41). Punch skin biopsy can also be an effective method of early diagnosis, and in one study was positive in seven of 11 patients with familial amyloid polyneuropathy (115). However, routine biopsy does not distinguish primary systemic amyloidosis from familial amyloidosis, but requires histochemical tests of amyloid for light chains or genetically altered proteins with subsequent genetic testing.
Adapted from (72)
Clinical diagnosis of familial amyloid polyneuropathy is straightforward when there is a positive family history and a compatible clinical picture (09). It becomes more difficult when there is no apparent family involvement. In a review of 1233 cases of familial amyloid polyneuropathy from 489 Portuguese families, neither parent showed signs of the disease in 159 cases (17). There was no clear evidence of new mutations. In these cases, molecular diagnosis becomes essential because apparently unaffected family members can carry the same Met-30 mutation (Mascarenhas et al 1986; 100). Accurate diagnosis of familial amyloid polyneuropathy is important because it is not unusual for a patient with the disorder to carry the diagnosis of primary systemic amyloidosis for years and even be treated with chemotherapeutic drugs. Neurophysiological testing results are similar to those of primary systemic amyloidosis except that, in late stages, there may be some “demyelinating” features on nerve conduction studies (67).
The primary findings in a sural nerve biopsy in familial amyloid polyneuropathy are linear deposits of amyloid within the fascicles and, sometimes, nodules of amyloid indenting myelinated fibers. In individual cases, however, familial amyloid polyneuropathy cannot be differentiated from primary systemic amyloidosis without histochemical studies of amyloid constituent proteins. The absence of a plasma cell dyscrasia suggests familial amyloid polyneuropathy, but histochemical or genetic studies need to be done in order to further clarify the diagnosis (134). Proteomic typing of amyloid deposits with mass spectrometry has allowed direct typing of amyloid deposits (82).
Treatment of familial amyloid polyneuropathy has been mostly limited to supportive care in the past. For the past decade, however, liver transplantation has become the first successful treatment for the disease (119; 124). The fact that transthyretin is synthesized in the liver prompted the first experimental liver transplant in Sweden in 1990, in the hope of removing the major source of mutant transthyretin (Ericzon et al 1995). Seventeen of 24 familial amyloid polyneuropathy patients were alive three to 52 months after liver transplantation. The peripheral neuropathy as measured by EMG was unchanged in 13 patients evaluated one or more years after transplant. Improvement was noticed in walking capacity, gastrointestinal symptoms such as diarrhea, constipation and vomiting, urinary problems (with complete resolution in some cases) and nutritional status. Adverse factors in the survival and recuperation were poor nutritional status and prolonged disease. Subsequent studies and a review have concluded that Met 30 transthyretin patients with nonadvanced disease can benefit from liver transplantation (03; 127; 84; 120). Neuropathy often stabilizes but rarely improves and may on occasion continue to worsen despite apparently successful transplantation with improvement of other organs (124). A split-liver transplantation has been successfully performed from a living donor and promises to increase the use of transplantation in this disease (55). Also sequential heart-liver transplantation has been used successfully in a small number of patients (101; 108).
At the molecular level, several promising treatments are being investigated. One involves the use of antisense oligonucleotides to suppress the production of amyloidogenic TTR (10; 02). This technique inhibited 80% of amyloidogenic TTR production in a mouse model of TTR amyloidosis. Another approach involves attempts to stabilize the mutant protein. Because amyloid deposition is caused by missense amyloidogenic mutations in the TTR gene that destabilize heterotetramers and lead to toxic misfolding, variants of TTR that stabilize the heterotetramers may help. Researchers introduced a stabilizing T119M TTR mutation into an amyloidogenic TTR mouse model with resultant increased stabilization (57).
EMG is useful in documenting findings and can often help to differentiate the peripheral neuropathy of primary amyloidosis from other paraproteinemia-associated peripheral neuropathies (61). Typical EMG findings are consistent with a symmetrical, primarily axonal neuropathy affecting the longest axons. Conduction velocities are usually minimally slowed despite reduction in motor responses and sensory nerve responses are often absent (94; 61). When sensory nerve action potentials are present, distal latencies are only mildly delayed proportional to the slowing of conduction velocities if temperature is well controlled, except in the presence of a superimposed carpal tunnel syndrome. 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, even in asymptomatic familial amyloidosis carriers (04; 92). Needle EMG 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. The picture, thus, resembles polymyositis, especially if creatine kinase is elevated. 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 (96).
Abnormal laboratory findings are the result of amyloid deposition. Anemia is seen in about 50% of the patients (76), 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 (35). Thrombocytosis is detected in 5% to 10% of patients, probably due to functional hyposplenism. About 80% of the patients have proteinuria (74; 64; 78) 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 (76). 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, however, and immunoelectrophoresis or immunofixation may be necessary to identify the monoclonal protein in some 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 (74; 78).
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 (66). Metachromatic stains such as cresyl violet or methyl violet can be useful, especially in sural nerve biopsies, where metachromasia stands out from the background. In occasional cases all these stains are 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. High-resolution scintigraphic studies, using 123-I labeled purified human serum amyloid P component, can reveal focal deposits of all varieties of amyloid (51). Identification of specific types requires staining with antisera to the abnormal proteins (amyloidosis kappa, amyloidosis gamma, secondary amyloidosis, beta-2-microglobulin, transthyretin, etc.). However, newer molecular techniques such as mass spectrophotometry and immunohistochemistry of amyloid show promise in determining types of amyloidosis (16; 117).
The diagnosis of primary 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 (Table 5). 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 (45; 74; 78; 07). Fat pad biopsy has been found to be a good site for biopsy with minimal morbidity (65; 136). 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 (78). 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 (53). 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 (78). Biopsy of the iliac crest bone marrow combined with abdominal subcutaneous fat aspiration will identify amyloid deposits in 85% of patients with amyloidosis (107; van Gameren II et al 2010).
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 (36). Skin biopsies are generally negative unless there is clinical involvement.
Utilization of (18) F-FDG PET/CT is under investigation. It is approved for imaging amyloid-B proteins of Alzheimer disease (36). 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 (83). 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 (13). However, due to the small number of cases, further study of the role of (18)F-FDG PET/CT in amyloidosis is warranted.
MRN biomarkers can be a new method to characterize peripheral neuropathy in light chain amyloidosis. A study of 20 patients with light chain polyneuropathy (PNP) and 25 age- and sex-matched healthy volunteers showed MRN can detect and quantify peripheral nerve injury in light chain amyloidosis with high sensitivity and in close correlation with the clinical stage (69).
Diagnostic criteria for primary 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 (81):
(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)
All patients with a systemic amyloid syndrome require therapy to prevent deposition of amyloid in other organs and prevent progressive organ failure of involved sites. High-dose melphalan followed by autologous hematopoietic stem cell transplantation is recommended in all patients (60). The use of autologous hematopoietic 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 (18; 36). Although eligibility for autologous hematopoietic stem cell transplantation in primary systemic amyloidosis varies across countries and institutions, approximately 80% of new cases are not good candidates for transplant due to advanced age, renal insufficiency, advanced heart failure, and other organ involvement (44; 24), and only 20% of patients are eligible (36). Indications for safe autologous hematopoietic stem cell transplantation include systolic blood pressure greater than 90 mmHg, troponin T less than 0.06 ng/mL, age younger than70 years, and serum creatinine 1.7/mg dL (Gertz et al 2016).
Nontransplant candidates can be offered a bortezomib-based triplet regimen such as bortezomib, cyclophosphamide, dexamethasone or bortezomib, melphalan, and dexamethasone (98; 133; 36; 105; 59). For patients who are not candidates for autologous hematopoietic stem cell transplantation and bortezomib based treatment, melphalan-dexamethasone regimen is the preferred option (104; 60). Antibodies designed to dissolve existing amyloid deposits such as Daratumumab, an IgG1k monoclonal antibody directed against CD 38, appear to be highly active in light chain amyloidosis (37). However, following initial relapse or refractory disease in patients with systemic light chain amyloidosis, treatment with a different therapy at relapse improves time to next therapy but does not impact overall survival (128).
Cardiac transplantation, hemodialysis, continual peritoneal dialysis, and renal transplantation can improve survival in highly selected patients with primary amyloidosis, although amyloid can accumulate in transplanted organs (Gertz et al 1994; 95).
Unfortunately, the symptoms and findings of peripheral neuropathy usually continue to worsen despite therapy and improvement in other organs. Dysesthesias tend to disappear or spread proximally as analgesia becomes more prominent. 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.
Intravenous infusion of patisiran was generally well tolerated and resulted in significant dose-dependent knockdown of transthyretin protein in patients with transthyretin-mediated familial amyloid polyneuropathy (FAP). Patisiran 0.3 mg/kg every three weeks is currently in phase III development (126).
Following initial relapse or refractory disease in patients with systemic light chain amyloidosis, treatment with a different therapy at relapse improves time to next therapy but does not impact overall survival (128).
Without modern therapy, the disease has a dismal prognosis (64; 72; 38). An initial meta-analysis by Mhaskar and colleagues in 2009 showed only questionable value of autologous hematopoietic stem cell transplantation for amyloidosis, because the study had included noneligible candidates (97; 93). Later studies showed favorable outcomes for autologous hematopoietic stem cell transplantation, especially in patients with cardiac amyloidosis without advanced congestive heart failure (89). In fact, the major determinant of outcome in amyloidosis is the extent of cardiac involvement (36). On the other hand, the transplant-related mortality rate has been decreased to 1.1% since 2009 (43). Plerixafor definitely had a significant role on reduction of mortality rate in all eligible patients undergoing autologous hematopoietic stem cell transplantation (21). Survival rate was better at centers performing at least four autologous hematopoietic stem cell transplantations annually (26).
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 (19). 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. The risk-benefit ratio for auto-transplantation has changed; however, a randomized comparison with nontransplantation approaches is again warranted (25).
Gertz and colleagues at the Mayo Clinic presented a series of 66 patients treated with autologous hematopoietic stem cell transplantation (42). 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 hematopoietic stem cell transplantation in the first year for those with minimal organ involvement is now the treatment of choice if the patient qualifies (42; 22; 111; 12).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 (23). Diagnosis is delayed most (median 26 months) in patients with relatively pure neuropathies without significant organ failure, a group that is the most likely to benefit from autologous hematopoietic stem cell transplantation (64; 112; 123).
Patients with amyloid heart disease are at increased risk for arrhythmia while receiving anesthesia.
Francesc Graus MD PhD
Dr. Graus, Emeritus Professor, Laboratory Clinical and Experimental Neuroimmunology, Institut D’Investigacions Biomédiques August Pi I Sunyer, Hospital Clinic, Spain, has no relevant financial relationships to disclose.See Profile
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