Paraproteinemia associated peripheral neuropathy

Definition

Paraproteinemic neuropathy describes a heterogeneous set of neuropathies characterized by the presence of homogeneous immunoglobulin in the serum.  They occur as a result of paraproteinemias related to disorders in which monoclonal plasma cells proliferate and result in deposition of monoclonal (M) proteins on the nerves.  From a hematologic standpoint, a monoclonal gammopathy may be of undetermined significance (MGUS) or can be associated with underlying myeloma, lymphoplasmacytic lymphoma, or amyloidosis.

Paraproteinemias associated with polyneuropathy:

MGUS, MM, smoldering myeloma, osteosclerotic myeloma, POEMS syndrome, Waldenstrom's macroglobulinemia, systemic amyloidosis, cryoglobulinemia , lymphoma. 

Key concepts:

MGUS primer:

MGUS is monoclonal that is it is made of one type of protein.  Essentially what is happening is that you have the presence of an abnormal amount of one type of intact, either whole immunoglobulin (monoclonal) or the corresponding light chain fraction such as kappa light chain or lambda light chain by itself.  This intact monoclonal protein is sometimes what people refer to as M protein or M spike on SPEP/SIFE.  MGUS, therefore is a plasma cell disorder arising in the bone marrow.  It is important because patients with MGUS have a lifetime risk of progression to serious hematological disorder such as multiple myeloma, light chain amyloidosis, or other low-grade lymphoproliferative disorders.  Patient have a lifetime risk of 1 %/year of developing plasma cell dyscrasia that requires intervention such as multiple myeloma, light chain amyloidosis, or other low-grade lymphoproliferative disorders.  At the time when someone sees a patient with MGUS, you do not when they will develop a serious hematological disorder or whether they will develop at all.  That is the reason why the undetermined significance part of the name and MGUS comes from.

So what is happening in the bone marrow with these abnormal plasma cells.  These plasma cells are similar to other plasma cell that they go through the process of differentiation from B cells.  However, the unique thing about them is that the abnormally regain the capacity to proliferate.  All the other normal plasma cells are stagnant and do not proliferate.  So as a result, you are get a clonal population of plasma cells in the bone marrow which are genotypically and immunophenotypically abnormal from normal plasma cells.  We know the genomic factors that make them abnormal.  Almost all of them can be put into 2 categories.  Either they have some genomic abnormalities with extra copies of the odd number chromosomes, that is they are hyperdiploid genomic abnormalities (trisomies or extra copies of 3, 5, 7, or 9) in terms of chromosome numbers.  The other category is that they have some primary translocation of the immunoglobulin heavy chain gene which is on chromosome 14 and that is a key initiating factor that makes abnormal plasma cell clonal or precancerous.  What actually causes that to happen, we do not quite know yet.  What is the inciting event?  What are the sequences that lead to this development?

Risk factors for MGUS:  

Include age.  In patients who are 50 years and older, the risk of developing MGUS in this population is roughly about 3%.  In patients over 70 and older the prevalence increases to over 5%.  The risk is directly proportional to age.  The other key factor is race.  African-Americans are twice as likely to get MGUS than their Caucasian counterparts.  People of Asian descent have a lower incidence of developing MGUS than Caucasians.  They are likely something genetic involved with this predisposition.  People of African origin such as in Ghana, have an increased prevalence of MGUS compared to a matched Caucasian population.  Other host derived factors include obesity, family history with first-degree relatives with MGUS or multiple myeloma.  Immune dysregulation in patients who have undergone solid organ transplant and on chronic immunosuppression such as an inflammatory bowel disease, there is a slightly higher risk of developing MGUS.  Patient with Gaucher's disease have a much higher risk of developing MGUS.

The environmental factors include exposures to pesticides, herbicides including agent orange and insecticides.

The monoclonal protein is most commonly an immunoglobulin, composed of 2 heavy chains and 2 light chains:

Light chains: kappa and lambda. 

Epidemiology:

Monoclonal proteins are found in close to 1% of the general population. Monoclonal gammopathy of undetermined significance (MGUS), the most common paraproteinemia, was present in 56% of all patients with an M-protein seen at Mayo Clinic in the course of a year.  MGUS is monoclonal,

MGUS occurs in only 0.3% of those <50 yr of age, 3.2% in individuals >50 years of age, 5.3% for those  >70 years of age, and 8.9% in those  85 years of age.  Approximately 10% of patients referred to a tertiary neurology center during a 1-year period for polyneuropathy of unknown cause were found to have a serum monoclonal gammopathy. Conversely, 17–71% of patients with an MGUS at large referral centers had an associated peripheral neuropathy.  The clinical features of paraproteinemias vary widely, ranging from benign and subclinical MGUS to systemic malignant disorders such as multiple myeloma, Waldenstrom macroglobulinemia, POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, M-protein and Skin changes) syndrome, and primary (AL) amyloidosis.

For unclear reasons, IgD and IgE monoclonal gammopathies are extremely rare; therefore, neurologists will mainly encounter monoclonal gammopathies of the IgG, IgA, or IgM heavy chain subtypes and either kappa or lambda light chain subtypes.  It is also possible for the monoclonal gammopathy to be light chain only.

Types of MGUS: I

gM MGUS and non-IgM MGUS (IgA or IgG) very rarely IgD or IgE. 

Non IgM MGUS types (IgG or IgA) are more likely to progress into multiple myeloma.

IgM MGUS are more likely to progress into Waldenstrom macroglobulinemia than multiple myeloma (very rare to happen).

Light chain MGUS..  Its not a whole intact immunoglobulin and the clonal plasma cells are relieving out in the blood circulation.  It is just a fragment of the immunoglobulin or excess amounts of kappas or excess amounts of lambdas.  These patients are at high risk of progressing into light chain multiple myeloma.

If you order serum protein electrophoresis and find presence of monoclonal protein, you have to order immunofixation electrophoresis, so it is better to order both SPEP/serum immunofixation electrophoresis.  The SPEP tells you that there is the presence of monoclonal protein but does not tell you what is it.  It essentially quantifies the abnormal protein but does not specifically tell what type of protein it is.  Is it IgG kappa, or IgA or is it IgM lambda?  That is where the immunofixation is key as it identifies this specific type of monoclonal protein (heavy and light chain).  So if both SPEP and SIFE are ordered together you will get the specific type of monoclonal protein as well a quantification of that of hat monoclonal protein.  Also order free light chain assay as it will give you a more clear picture of whether there is presence of a light chain along with the heavy chain.  Once you detect monoclonal gammopathy reported in the clinical context to assess if it is truly causing clinical symptoms.  Does this patient have multiple myeloma?  On the presence of any CRAB features?  So you would get a CBC with differential, CMP to include serum creatinine, serum calcium.  If there are CRAB features, order UPEP/IFE and skeletal bone survey.  

IgM MGUS Neuropathy 

IgM is the most common monoclonal gammopathy subtype encountered in patients with peripheral neuropathy, whereas IgG is the most common in the general population.  Furthermore, IgM is the only MGUS subtype that has been definitively associated so far with a peripheral neuropathy without an underlying hematologic malignancy or amyloidosis.  IgM is not typically associated with multiple myeloma (very rarely).  

MGUS  from a hematologic standpoint is when the patient has a low serum monoclonal protein level (<3 g/dL), less than 10% plasma cells in the bone marrow, and less than 500mg/24 hour of M protein in the urine) and no evidence of end organ damage as expressed by the acronym CRAB (C: hypercalcemia, R: renal insufficiency, A: anemia, B: bone lesions - lytic bone lesions), and most important, stability of the monoclonal protein and failure of development of other abnormalities. 

Once a monoclonal gammopathy is detected, the patient should be referred to a hematologist or an internist for further investigation and to determine the need for long-term monitoring. The three main high-risk factors for progression into a lymphoplasmacytic malignancy are IgM subtype, M-spike greater than or equal to 1.5 g/dL, and abnormal serum free light chain ratio. The presence of one of these risk factors should prompt further investigation to rule out an underlying malignancy, including a bone marrow biopsy in patients with all subtypes and the addition of a skeletal survey in patients with IgG and IgA subtypes.  All patients with MGUS should have a repeat evaluation with complete blood cell count, serum protein electrophoresis, free light chains, and calcium and creatinine levels in 6 months and on a yearly basis thereafter.  MGUS carries an inherent lifelong risk of progression into a lymphoplasmacytic malignancy of about 1% per year. 

Features of MGUS Neuropathy:

The most common clinical picture of MGUS neuropathy is a slowly progressive, distal, symmetrical, sensorimotor polyneuropathy.   Sensory symptoms are predominant in 80% of patients, and are prominent early in the course. Most patient develop motor symptoms, and some develop predominantly motor symptoms severely.  Cranial nerve are usually spared and autonomic involvement is rare.  Hypo or areflexia is typical.  IgM-MGUS neuropathy patients usually have tremor and ataxia when compared to IgA and IgG MGUS.  IgM-MGUS is slowly progressive, although some patients have a stable course for years without treatment.  Rarely, patients can progress rapidly and be severely disabled within a few years.  

IgG, IgA MGUS without reactivity to MAG has lambda light chains in 80% of cases; consider POEMS in these cases.

IgM MGUS and neuropathy have anti-MAG (myelin-associated glycoprotein) antibodies that cross-react with the peripheral nerve glycolipids sulfated glucuronyl paragloboside (SGPG) and sulfated glucoronyl lactosaminyl paragloboside (SGLPG) mostly, and few against sulfatide and gangliosides.  

Chronic idiopathic axonal peripheral neuropathy in the presence of an MGUS should prompt exclusion of amyloidosis in the right clinical context, such as in patients presenting with rapidly progressive neuropathy or marked systemic or autonomic symptoms. 

EDX:  Mixed features of axonal degeneration and demyelination.  SNAPs are reduced in amplitude or absent. CV are slowed in the demyelinating range in 40% of all MGUS neuropathy patients, more often in IgM-MGUS.  F-wave latencies are normal or prolonged corresponding to degree of peripheral conduction slowing.  Denervation (fibrillations and positive sharp waves) is present in 80% of patients and be prominent with an axonal electrophysiology. 

Nerve biopsy is indicated in patients with monoclonal gammopathy, to search for amyloid deposition.  This is especially the case for patients with IgG and IgA monoclonals.  They may be evidence of either predominantly axonal or demyelinating changes.  Not infrequently both processes can occur producing a mixed picture.  IgG or IgA reactivity in patients with these gammopathies is almost invariably negative.  Similarly, patients with IgM monoclonals without anti-MAG reactivity have no IgM deposition in nerve.  Patients with IgM gammopathies and anti-MAG reactivity demonstrate both unique pathologic features and rather dramatic deposits of IgM on nerve in most cases. 

Response to immunotherapy generally is poor in patients with IgM MGUS of the DADS-M phenotype. This is in contrast to those with idiopathic CIDP and those who have DADS without an M-protein, both of whom generally respond well to immunotherapy.  Rituximab has been shown to be beneficial for patients with IgM anti-MAG neuropathy in several case reports, small series, and open studies.

DDx of MGUS neuropathy: 

Risk stratification of MGUS: Look at 3 key factors

0 points = low risk (absolute risk for progressing in  the next 20 years = <2%).  1 point = low intermediate risk (10%). 2 point = high intermediate risk (20%).  3 = high risk (30-40%). 

Low risk don't need imaging cross-sectional study or bone-marrow.  Anyone who is above low-risk needs referral to a hematologist/oncologist to make that decision.   Repeat SPEP/SIFE, FLCs and UPEP/IFE in 6 months, if stable, do yearly follow-up. 

Prognosis in MGUS: 

The risk of progression of MGUS to multiple myeloma or a related disorder 20 years after diagnosis of MGUS was dependent on the concentration of the monoclonal protein in the serum at the time of Dx of MGUS:

Patients with MGUS must be followed indefinitely as they may develop disease MM, 20 or more years later after recognition of the monoclonal protein. 

Disease associations with MGUS: 

Lympoproliferative d/o (NHL), myelodysplasia, chronic neutrophilic leukemia, acquive vWF disease, Castleman's disease, lichen myxedematosus, pyoderma gangrenosum, sucorenal pustular dermatosis, necrobiotic xanthogranuloma, and cutaneous lymphomas, RA.  

In polyneuropathy and MGUS, progressive weight loss, progression of the neuropathy and an M-protein level of >1 g/L have been reported as independent predictors for malignancy.

Paraproteinemia evaluation:  

CBC, CMP, ESR, LFT, UA, SPEP with IFE, UPEP with IFE, light-chains, anti-MAG (if IgM paraprotein and demyelinating polyneuropathy), VEGF (POEMS), TTR (amyloid), Bone marrow bx if M proten >15 g/L.  Quantitation of heavy and light chains (if a monoclonal protein is present), the former by blood testing for quantitative immunoglobulins and the latter via a 24-hour urine collection, CT skeletal survey, CT scans of the chest, abdomen, and pelvis are useful to assess for subclinical lymphadenopathy, organomegaly, or underlying malignancy.  EMG/NCS.  Consult hematologist/oncologist.  Most hematologist will perform bone-marrow exam on all patients with monoclonal gammopathies, but is necessary for patients with M-protein level of >15 g/L.

According to the International Myeloma Working Group, serum protein electrophoresis, serum immunofixation, and quantification of free light chains in the serum should be sufficient to screen for a monoclonal gammopathy, with a sensitivity of more than 97%. Patients with high suspicion for amyloidosis should also have 24-hour urine protein electrophoresis and immunofixation; 24-hour urine testing should also be obtained in all patients with abnormal serum testing as part of the workup.

Anti-MAG neuropathy (DADS-M)

MM, macroglobulinemia, amyloidosis, or a malignant lymphoproliferative process develops in 16% of patients after 10 years and 33% at 20 years. The interval from the time of recognition of the monoclonal gammopathy to the diagnosis of MM ranged from 23 to 251 months (median 115 months = 9.6 years); for macroglobulinemia (8.5 years), amyloidosis (6 to 16.5 years). The cumulative probability of progression to one of these disorders was 12% at 10 years, 25% at 20 years, and 30% at 25 years, with a risk of progression of about 1 - 2% per year.  This annual risk of malignant transformation can persist for decades, and annual surveillance is therefore recommended indefinitely.  A family history of multiple myeloma or MGUS increases the risk of developing MGUS.

Acute worsening of symptoms with anti-MAG has been described, and paradoxical worsening with rituximab has also been reported.  Plasmapheresis can then be tried.

Clinical Vignette anti-MAG:

A 73-year-old man was referred by his primary neurologist for neuropathy evaluation. He presented with a 3-year history of progressive distal sensory symptoms and imbalance. He was found to have an IgM kappa monoclonal gammopathy after 3 years of symptoms. His hematologist diagnosed him with monoclonal gammopathy of undetermined significance (MGUS) because additional hematologic workup was unrevealing. He was diagnosed by his primary neurologist as having chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and was started on IV immunoglobulin (IVIg). Initially, it was thought his numbness decreased, but the improvement was arrested despite adjusting the IVIg dose and frequency. At the time of the initial neuromuscular consultation, he was noted to have decreased sensation affecting large more than small fiber modalities in a length-dependent pattern with sensory ataxia, a positive Romberg sign, and intact strength. Motor nerve conduction studies demonstrated the presence of a severe demyelinating motor neuropathy with distal preponderance, manifested as short terminal latency index. There was no conduction block or temporal dispersion. His myelin-associated glycoprotein (MAG) antibody level was elevated at 19,000 Bühlmann titer units (BTU) with confirmed positive Western blotting. His serum IgM level was 362 mg/dL (normal range, 40 to 130 mg/dL). After discussion, the decision was made to treat him with rituximab. He had mild to moderate improvement in sensory symptoms after one cycle of treatment (375 mg/m2 weekly for 4 weeks), but his response seemed to plateau, and he did not have further neurologic improvement with two additional treatment cycles. On his last evaluation, the decision was made to monitor him clinically while continuing neurorehabilitation 

Clinical features: Patients have paresthesias, ataxia, and pain. CN are not affected. Later (months to years), symptomatic muscle weakness occurs. Symptoms begins in the toes, feet, or legs, and although they might begin in one foot, they usually become symmetrical. Reflexes are absent or reduced. The course was one of chronic progression or stepwise progression or recurring symptoms in others. Death was not attributed to the neuropathy. There is an increased CSF protein (~100 mg/dL) or elevated above normal in 85% of cases, but no increase in cells (albuminocytologic dissociation). 

NCS and EMG features suggestive of both segmental demyelination and axonal degeneration. 

Peripheral nerve is infiltrated with IgM-producing lymphocytes as well as IgM.

Waldenstrom's macroglobulinemia

Cryoglobulinemia

Cryoglobulins are immunoglobulins that precipitate in vitro at temperatures less than normal body temperature (<37°C [98.6°F]) and redissolve on rewarming.  In type I cryoglobulinemia, the cryoglobulins are monoclonal immunoglobulins (in descending order of likelihood: IgM, IgG, IgA, and light chain).  It develops in the setting of monoclonal gammopathies.  40% of cases have MGUS, and the remaining 60% have B-cell lineage malignancy (eg, multiple myeloma, Waldenström macroglobulinemia, or chronic lymphocytic leukemia).  Type II is a mixed cryoglobulinemia and is usually associated with hepatitis C virus infection but may occur in lymphoproliferative disorders as well.  Peripheral neuropathy can be seen in about 30% of cases.  It usually manifests as a painful sensory neuropathy affecting predominantly small fibers, sparing autonomic nerves, or as mononeuritis multiplex (ie, vasculitic neuropathy). Early recognition of cryoglobulinemia is essential to diagnose and treat any underlying or associated systemic or hematologic condition.

Neurolymphomatosis

Neurolymphomatosis is a rare manifestation of non-Hodgkin lymphoma and leukemia characterized by direct malignant lymphocytic invasion of the peripheral nervous system.  It can affect cranial nerves, peripheral nerves, and nerve roots or plexus, and thus, the clinical picture is extremely heterogeneous presenting with neuropathies, painful radiculopathies, cranial neuropathies, mononeuropathies, and polyradiculopathies.  Neurolymphomatosis should, therefore, be considered in all patients with lymphoma with unexplained peripheral nervous system dysfunction (polyneuropathy, mononeuropathy, or radiculopathy) or in patients with severe pain with an asymmetric distribution and rapid progression of neurologic symptoms.  Nerve biopsy is the gold standard test for the diagnosis of neurolymphomatosis, but neuroimaging and PET-CT have greatly contributed to the diagnostic yield.  According to the International Primary Central Nervous System Lymphoma Collaborative Group report, the diagnostic yield of MRI and PET-CT is high, with abnormal findings found in 77% and 84%, respectively.  CSF studies show elevated protein, low glucose, and elevated white blood cell counts in most patients.  However, in the International Primary Central Nervous System Lymphoma Collaborative Group study, malignant cells and suspicious cytology were reported only in 40% and 13% of cases, respectively.  CSF flow cytometry must be used to confirm the diagnosis.  The prognosis of neurolymphomatosis is poor, but early diagnosis and aggressive therapy can help prevent neurologic deterioration and are associated with a prolonged survival in a subset of patients. 

CANOMAD and CANDA

CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins, and disialosyl antibodies) and CANDA (chronic ataxic neuropathy with antidisialosyl IgM antibodies) are rare sensory ataxic neuropathies associated with disialosyl antibodies, monoclonal proteins, and cold agglutinins characterized by chronic neuropathy with sensory ataxia, areflexia, and motor weakness occasionally involving the ocular motor and bulbar muscles.  The exact pathogenesis of these syndromes is not fully understood, but evidence suggests that direct damage to dorsal root ganglia underlies most of the morbidity seen in these disorders.  The largest retrospective study of CANOMAD revealed that one-third of the patients had an overt hematologic malignancy, mainly Waldenström macroglobulinemia.  Acquired demyelinating features are common findings on electrodiagnostic studies, but pure axonal polyneuropathy may also be seen.  Nerve ultrasound studies of four patients with CANOMAD demonstrated features of an acquired demyelinating polyneuropathy in all patients, including one patient with axonal features on electrodiagnostic testing.

IVIg and rituximab-based regimens were the most effective therapies in one large, multicenter, retrospective study.  Rituximab was most effective at halting the disease progression in eight of nine patients treated in another retrospective study; IVIg prevented relapses in approximately half of the treated patients in this cohort. 

IgM deposition neuropathy

Non IgM associated disorders

IgG and IgA monoclonal gammopathy can be associated with underlying myeloma or amyloidosis, both of which may present with their neurologic manifestations.  However, no clear association between IgG and IgA MGUS and peripheral neuropathy has been established.  Therefore, in the absence of underlying multiple myeloma, osteosclerotic myeloma, or amyloidosis, the presence of an IgG or IgA monoclonal gammopathy in a patient with a peripheral neuropathy is more likely to be coincidental.  IgG- and IgA-associated CIDP is labeled as CIDP with a coincidental paraprotein, with 80% of these patients having a response to conventional CIDP therapy.

POEMS syndrome

POEMS syndrome is a rare multisystem paraneoplastic syndrome due to an underlying plasma cell neoplasm. 

 The pathogenesis of POEMS syndrome is not well understood but is likely related to cytokine imbalance outlined by excessive production of multiple proinflammatory and angiogenic cytokines, including but not limited to vascular endothelial growth factor (VEGF). 

Making the diagnosis can be a challenge, but a good history and physical examination followed by appropriate testing—most notably radiographic assessment of bones, measurement of VEGF, and careful analysis of a bone marrow biopsy—can differentiate this syndrome from other conditions like CIDP, immunoglobulin light chain amyloidosis, and MGUS neuropathy.  In patients with strong suspicion for CIDP, one needs to ask how long was IVIG used (3-4 months) before not seeing much improvement.  If so, one needs to reconsider diagnosis of CIDP as most patients with CIDP do improve with IVIG Tx,  0.4 gm/kg, qweekly for at least 12 weeks.  The diagnosis one should think about is POEMS syndrome.  Check X-rays of long bone, SPEP with IFX, free light chains, UPEP, HIV.

CIDP vs POEMS syndrome similarities and differences

In a patient with suspected CIDP who does not respond to IVIG for 3 - 4 months, POEMS syndrome should be in the top of the DDx.  POEMS don't response to PLEX and may show little or partial response to steroids (prednisone is one of the treatments for POEMS). 

POEMS, which is an acronym for polyradiculoneuropathy, organomegaly, endocrinopathy, monocolonal plasma cell disorder and skin changes, is a rare disorder that often looks like CIDP when encountered in the neuromuscular or neurology clinic.  

What distinguishes POEMS syndrome from CIDP?

Pain is an important distinguishing feature and is prominent in POEMS than in CIDP.  It starts in the feet and associated with sensory loss.  Weakness is severe and progression is rapid (unlike CIDP). There is profound distal weakness and lower extremity atrophy.  Thrombocytosis, more uniform demyelination which almost looks like an inherited polyneuropathy, and severe axonal loss, very high VEGF.  CB is less common in POEMS than in CIDP.  Demyelination in POEMS syndrome is more uniform, and conduction slowing is prominent in the intermediate nerve segments, as opposed to multifocal demyelination involving distal and proximal nerve segments in CIDP.  CMAPs and sensory nerve action potentials (SNAPs) of the lower limbs are disproportionally more severely affected in POEMS syndrome compared with CIDP (CMAP amplitude is more attenuated in the lower limbs than in the upper limbs in POEMS syndrome); axonal loss is more prominent in POEMS syndrome than in CIDP. 

Clinical features of POEMS: Polyradiculoneuropathy, demyelinating features, sensory loss, weakness.  POEMS has a lot more pain than CIDP.  Pain may be burning, sharp shooting sensation.  Generally POEMS patient do not feel well (malaise, fatigue) unlike CIDP patients who appear relatively well.  POEMS patient have lower extremity edema, volume overload, pleural effusion, pericardial effusion, darkening of skin, increased and coarse hair growth. Glomeruloid angiomata over body, whitening of the nails, hepatosplenomegaly, and lymphadenopathy.  Look for a monoclonal protein disorder, SPEP with IFE, 24 hour UPEP with IFE, free light chains, CT bone survey to look for osteosclerotic myeloma.   Presence of significant leg edema and thrombocytosis.  EPO levels are low.  Hypothyroidism.

Screening for concurrent endocrinopathy is indicated and includes testing serum testosterone, follicle-stimulating hormone, luteinizing hormone, estradiol, prolactin, thyroid-stimulating hormone (TSH), free thyroxine, fasting glucose, cortisol, and adrenocorticotropic hormone (ACTH). 

Usually CSF protein and VEGF levels are quite higher in POEMS, usually many hundreds if not thousands.  IgA lamda, clearly demyelinating neuropathy unresponsive to steroids and IVIG, subsequent development of bad axonal loss with plentiful fibrillations in affected muscles, etc.   

Hem/Onc consult, imaging of chest/abdomen/pelvis to look for organomegaly, signs of volume overload, opthalmologic exam for papilledema, etc. Sometimes a PET may pick up a sclerotic bone lesion when routine X rays fail to find it, or  adenopathy suggestive of Castleman's disease.

POEMS patients have a plasmacytoma and this needs to be looked at vigorously.  A lambda light chain monoclonal protein is seen in 90% of cases, however, it does not mean a kappa light chain can't be a POEMS syndrome but is unlikely.  Often the monoclonal protein is IgA followed by IgG for the most part, with lambda.  Often the kappa/lambda ratio is normal.  So, despite the lambda being elevated the ratio is normal in 80% of cases. Thrombocytosis (4K to 1 million) is seen over 1/2 of POEMS patients.  The platelet count in POEMS can normalize with steroids.  So thrombocytosis may not be seen in POEMS if corticosteroids have been tried as a treatment in these patients who are mistaken as CIDP.  

VEGF (vascular endothelial growth factor) is a very useful biomarker in POEMS syndrome.  It is quite specific in POEMS and Castleman's disease.  Others including amyloidosis, multiple myeloma have low VEGF levels.  VEGF levels can come down if patient is treated with corticosteroids and can be falsely normalized upto 3 months.  VEGF is expressed in osteoblasts, macrophages, plasma cells, platelets.  It is not the only driving force of the disease, however, as studies using anti-VEGF as treatment have not been a success, so there are other factors that also drive the disease and these are not known.  Plasma VEGF level of 200 pg/mL had a specificity of 95% with a sensitivity of 68% in support of a diagnosis of POEMS syndrome. Other diseases with high VEGF include connective tissue disease and vasculitis.

N-terminal propeptide type I collagen has been identified as a novel marker for the diagnosis of patients with POEMS syndrome.

CSF in POEMS also has elevated protein and so is not a big differentiator from CIDP.  

Electrophysiologically both POEMS and CIDP are demyelinating polyneuropathies or polyradiculopneuropathies, so they both show reduction in CV, prolongation of DL, secondary axonal involvement which is reflected as low CMAPs, SNAPs, and often F waves are prolonged in both cases.  Distinguishing characteristics relate to the fact that in POEMS the demyelination is uniform, unlike CIDP.  So, in POEMS one sees less CB, less temporal dispersion than CIDP.  The typical sural sparing pattern which is sometimes seen in CIDP is not seen in POEMS.  Less prolongation of the motor DL in POEMS and greater slowing of the motor CV.  POEMS has greater axonal loss, so in patients with POEMS, the lower extremities NCS is usually unobtainable. Reduced sensory and motor amplitudes, fibrillation potentials, neurogenic MUPs distal > proximal. Terminal latency index which is a measure of distal segment slowing shows less distal slowing in POEMS syndrome.  Blink reflex: prolonged R1 blink response.

Nerve biopsy differences between CIDP and POEMS:  Axonal degeneration is more in POEMS.  More epineural blood vessels (neovascularization) in POEMS due to VEGF.  POEMS unlike CIDP is not an inflammatory demyelinating polyneuropathy.  CIDP biopsies have a lot of endoneurial inflammation than POEMS patients do. POEMS patients have some epineural inflammation and not endoneurial inflammation.  Onion bulb formation (evidence of chronic demyelination and remyelination) does not occur in POEMS and is seen in CIDP.  Nerve biopsy in POEMS syndrome reveals signs of demyelination with uncompacted myelin on electron microscopy in the absence of macrophage-associated demyelination.

Nerve ultrasound studies of 34 patients with POEMS syndrome demonstrated a larger upper limb nerve cross-sectional area in those patients compared with unaffected patients, and the enlargement was more prominent proximally.

Nerve biopsy in POEMS:

Bone marrow biopsy: lymphoid aggregates, plasma cell rimming, megakaryocyte hyperplasia and clusters.

Pathophysiology:  POEMS is thought to be a paraneoplastic vasculopathy and exactly how it damages axons is not known.  

Diagnostic criteria for POEMS syndrome requires the two mandatory criteria PLUS ≥ 1 major AND ≥ 1 minor criterion:

Other symptoms: Clubbing, weight loss, hyperhidrosis, pulmonary hypertension/restrictive lung disease, thrombotic diatheses, diarrhea, low vitamin B12 values.

Treatment of POEMS: Done by hematologist and not neurologist. 

The neuropathy in POEMS syndrome often begins distally in the lower limbs with weakness and sensory loss and can progress rapidly to a polyradiculoneuropathy with proximal and distal weakness and areflexia.  The distal weakness is often severe, with bilateral foot-drop and distal leg atrophy. Pain is often present and is a helpful feature to distinguish POEMS from CIDP.  Nerve conduction studies often support a primarily demyelinating length-dependent sensorimotor peripheral neuropathy or diffuse polyradiculoneuropathy.  The demyelination is often uniform throughout the nerve; conduction block and temporal dispersion are less common but can occur.  Autonomic involvement is uncommon, apart from erectile dysfunction, which may be related to hypogonadism.  Nerve biopsy demonstrates demyelination and axonal degeneration and an increase in epineurial microvessels.   

The monoclonal protein in POEMS syndrome is lambda light chain–restricted in more than 95% of patients.  An elevated platelet count is present in more than half of patients with POEMS, compared to in 1% to 2% of patients with CIDP.  VEGF levels greater than 200 pg/mL in plasma and greater than 1920 pg/mL in serum are helpful markers for POEMS syndrome.  As patients with POEMS commonly have an endocrinopathy (hypogonadism, hyperprolactinemia, hypothyroidism, glucose intolerance, or adrenal insufficiency), screening via a comprehensive laboratory workup is warranted and should include the following tests: total and bioavailable testosterone, follicle-stimulating hormone, luteinizing hormone, estradiol (in women), prolactin, thyroid-stimulating hormone (TSH), free thyroxine, fasting glucose, cortisol, and adrenocorticotropic hormone (ACTH).  Osteosclerotic lesions occur in approximately 95% of patients but can be confused with benign bone lesions. They can also be lytic rather than sclerotic in appearance.  Whole-body low-dose CT is more sensitive than plain x-ray in detecting small sclerotic lesions and can also show other features of the disease, such as hepatosplenomegaly, adenopathy, or effusions, including ascites. Treatment for POEMS syndrome is directed at the underlying clonal plasma cell disorder and is based on the extent of plasma cell infiltration. The neuropathy is reported to stabilize or improve with various systemic therapies, including autologous stem cell transplantation.

Clinical Vignette - POEMS

A 60-year-old man was referred by his primary neurologist for a neuromuscular opinion regarding a diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with a 17-month history of progressive neurologic symptoms. His initial symptoms were a painful tingling and burning sensation in the soles of his feet. This was followed by progressive weakness in his bilateral lower extremities and frequent falls. Within 10 months, he was using a wheelchair exclusively. He then noted progressive weakness and sensory symptoms in his hands. At that time, he was admitted to the hospital. CSF examination demonstrated albuminocytologic dissociation with an elevated protein of 114 mg/dL. He underwent five sessions of plasma exchange with an equivocal response. Subsequently, he was treated with IV immunoglobulin (IVIg) and additional plasma exchanges with no effect. On initial evaluation with the neuromuscular neurologist, he reported unintentional weight loss of 18 kg (40 pounds). He was not able to write or feed himself. He confirmed progressive darkening of his skin; a vascular papule was noted on the right side of his forehead. 

Neurologic examination demonstrated severe distal worse than proximal upper and lower limb weakness, muscle atrophy, areflexia, and length-dependent sensory loss to all modalities. Electrodiagnostic studies were abnormal, revealing absent compound muscle and sensory nerve action potentials with recording at distal sites. However, compound muscle action potentials of the axillary and musculocutaneous nerves were present and revealed severely prolonged latencies. A complete blood cell count revealed an elevated platelet count of 603,000 cells/mm3 . Serum protein electrophoresis was normal, but immunofixation demonstrated IgA lambda monoclonal protein. The quantitative IgA level was within the normal range. The vascular endothelial growth factor (VEGF) level was elevated at 360 pg/mL (normal range, 9 to 86 pg/mL). A bone marrow biopsy demonstrated 5% to 10% lambda light chain–restricted plasma cells. A skeletal bone survey was unremarkable. Positron emission tomography (PET)-CT of his chest, abdomen, and pelvis demonstrated hepatosplenomegaly and multiple prominent lymph nodes . His testosterone level was 44 ng/dL (normal range, 250 to 1100 ng/dL). His forehead lesion biopsy was consistent with capillary hemangioma. 

He was diagnosed with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes) syndrome and started on lenalidomide and dexamethasone. His VEGF level and the immunofixation normalized. However, neurologic improvement at a 9-month follow-up was still lacking. 

COMMENT:  This case illustrates the significance of early diagnosis and treatment to mitigate the disability seen with neurologic progression in patients with POEMS syndrome. Key factors in recognizing the diagnosis are CIDP refractory to conventional therapy, electrodiagnostic findings of a demyelinating neuropathy with axonal loss, neuropathic pain, presence of thrombocytosis, and other systemic signs. 

Multiple myeloma

Mechanisms of Nerve Damage in Paraproteinemia 

The clinical approach to peripheral neuropathies associated with monoclonal gammopathy  

Amyloidosis 

Amyloidosis refers to an etiologically heterogeneous group of protein misfolding diseases, pathologically characterized by extracellular amyloid fibrils producing congophillic amorphous deposits in organs and tissues, which may lead to severe organ dysfunction and mortality. Clinical presentations vary and are often nonspecific, depending on what organs or tissues are affected. In systemic amyloidosis, the peripheral nervous system is commonly affected, whereas the skeletal muscles are only rarely involved. Immunoglobulin light chain (AL) amyloidosis and hereditary transthyretin (ATTRv) amyloidosis are the most frequent types of systemic amyloidosis involving the neuromuscular system. Localized amyloidosis can occur in skeletal muscle, so-called isolated amyloid myopathy. Amyloid neuropathy typically involves small myelinated and unmyelinated sensory and autonomic nerve fibers early in the course of the disease, followed by large myelinated fiber sensory and motor deficits. The relentlessly progressive nature with motor, painful sensory and severe autonomic dysfunction, profound weight loss, and systemic features are distinct characteristics of amyloid neuropathy. Amyloid myopathy presentation differs between systemic amyloidosis and isolated amyloid myopathy. Long-standing symptoms, distal predominant myopathy, markedly elevated creatine kinase level, and lack of peripheral neuropathy or systemic features are highly suggestive of isolated amyloid myopathy. In ATTR and AL amyloidosis, early treatment correlates with favorable outcomes. Therefore, awareness of these disorders and active screening for amyloidosis in patients with neuropathy or myopathy are crucial in detecting these patients in the everyday practice of neuromuscular medicine.  


The diagnosis requires tissue confirmation of amyloid deposits.  All amyloid proteins are characterized by misfolding from the native α-helical configuration to β-pleated sheets.  The amyloid fibrils may deposit at the location where they were produced, resulting in localized amyloidosis (eg, Alzheimer dis-

ease), or may deposit in other tissues or organs distant from where they originated, resulting in systemic amyloidosis (eg, transthyretin, or ATTR amyloidosis).


Clinical presentation of Amyloidosis



Red flags for amyloidosis when found in association with a neuromuscular syndrome:


Amyloid Specific ROS:



Peripheral nervous system involvement in amyloidosis 

Sensorimotor peripheral neuropathy:  Amyloid neuropathy typically starts by involving the small myelinated and unmyelinated sensory and autonomic nerve fibers, presenting with pain and paresthesias in the feet and autonomic symptoms.  In the early stages, upon neurological examination, a dissociated pattern of sensory abnormalities is usually found in the distal lower extremities, with prominent involvement of pain and temperature sensory modalities and relatively preserved touch, vibration and proprioception.  With progression of the neuropathy, large sensory and motor fibers are also involved.  Importantly, when patients present at more advanced stages of the disease or age of symptom onset after the 6th decade, they may have pan-modality sensory loss and distal weakness on examination that makes it difficult to distinguish amyloidosis from other causes of peripheral neuropathy.  Careful attention to symptoms of autonomic disturbance, therefore, is important in the routine evaluation of patients with peripheral neuropathy.  Such symptoms include dry eyes and/or mouth, constipation, diarrhea, early satiety, erectile dysfunction, urinary or bowel incontinence, and orthostatic intolerance.  When amyloidosis affects motor nerve fibers, falls, gait impairment, and dependence on walking aids are common.  It is also helpful to routinely inquire about symptoms of extra-neuromuscular amyloidosis, including heart failure (dyspnea on exertion, orthopnea, and peripheral edema), cardiac arrhythmias (palpitation and syncope), renal disease (foamy urine and diffuse edema), weight loss, fever, and night sweats.

On neurological examination, sensory findings predominate, with pain and thermal sensation being usually more affected than touch, vibration, and proprioception.  Sensory loss and weakness usually follow a length-dependent fashion.  One important characteristic of amyloid neuropathy is its relentlessly progressive nature.  Progressive polyneuropathy of uncertain etiology should highly suggest amyloidosis.   Almost all patients develop weakness within 2 years of symptom onset.  Patients with monoclonal gammopathy of uncertain significance (MGUS) and peripheral neuropathy can convert to AL amyloidosis years after symptom onset.  If left untreated, amyloid neuropathy will usually progress to severe weakness, inability to walk, cachexia, and death.   In amyloid neuropathy, nerve conduction studies (NCS) and electromyography (EMG) usually show a primary length-dependent axonal peripheral neuropathy.  However, amyloid neuropathy can also present as polyradiculoneuropathy, multiple mononeuropathies, or focal neuropathy.  The pattern of multiple mononeuropathies has been described in both AL and ATTR amyloid and needs to be recognized as presentation of amyloidosis as it may be confused with vasculitic neuropathy. 

Amyloid Neuropathy

Primary amyloid or Amyloid light-chain

ATTR amyloidosis


Light Chain–Associated Disorders


Amyloid neuropathy and CIDP confusion

Even though a common misdiagnosis of amyloid neuropathy is chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), the presentation of CIDP and amyloid neuropathy are quite different.  Amyloid neuropathy is usually a small greater than large fiber predominant length dependent peripheral neuropathy, whereas CIDP is a large myelinated fiber predominant polyradiculoneuropathy (involvement of proximal and distal segments).  Pain and autonomic dysfunction are clinical hallmarks of amyloid neuropathy; although they can occur in CIDP, they do so less frequently and are milder.  Pain occurs in 27%-74% of patients with amyloid neuropathy and approximately one-third of those with CIDP, whereas autonomic symptoms occur in 65%-94% of patients with amyloid neuropathy and 23% of patients with CIDP.  In CIDP, NCS usually show findings indicative of an acquired demyelinating neuropathy and EMG commonly shows diffuse chronic neurogenic changes and active denervation affecting both proximal and distal muscles (polyradiculoneuropathy).   Amyloid neuropathy is typically a length-dependent axonal neuropathy but very rarely demonstrates demyelinating features fulfilling the European Federation of Neurological Societies/ Peripheral Nerve Society criteria for CIDP.   In contrast to Europe, CIDP is not the most common misdiagnosis of ATTRv-peripheral neuropathy in the United States.  In a single center study, the most common misdiagnosis of ATTRv peripheral neuropathy was idiopathic peripheral neuropathy.  The differential diagnosis of amyloid neuropathy includes vasculitis, diabetes, connective tissue disorders, toxic neuropathy, and paraneoplastic neuropathies.  Similar to Sjogren's syndrome, amyloid neuropathy can present as a non-length dependent small fiber neuropathy.  In our practice, we usually pursue Congo red staining of fat pad aspirate, skin biopsy, and/or sensory nerve biopsy when there is a suspicion of amyloid neuropathy.   In the peripheral nerves, amyloid deposits of variable sizes occur extracellularly in the epineurium, perineurium or endoneurium, often around blood vessels. The primary pathologic process is usually that of axonal degeneration that affects primarily the small myelinated and unmyelinated fibers, causing an alteration in nerve fiber size distribution towards more large myelinated fibers remaining.

Differential diagnosis of autonomic failure, peripheral neuropathy with autonomic neuropathy and neuromyopathy

Autonomic neuropathy in amyloidosis

Autonomic neuropathy is a common manifestation of amyloid neuropathy.  It occurs in as many as 65% to 75% of patients with AL amyloid neuropathy and in 10% to 82% of patients with ATTRv polyneuropathy, depending on genotype and geographic location.  It can also occur in beta2-microglobulin amyloidosis, gelsolin (AGel) amyloidosis, and the advanced stage of amyloid A (AA) amyloidosis.  Importantly, the presence of prominent autonomic dysfunction narrows significantly the differential diagnosis of autonomic failure with and without peripheral neuropathy.  The most common symptoms in amyloid autonomic neuropathy are orthostatic intolerance (74%), gastrointestinal (71%) and erectile dysfunction (67% of males).  Gastrointestinal symptoms are diverse, including diarrhea,  steatorrhea, constipation, abdominal pain, early satiety, and bowel pseudo-obstruction.  There are multiple mechanisms that may explain gastrointestinal dysfunction in amyloidosis, but it is mainly caused by amyloid deposition in the mucosa, submucosa, muscularis propria and the enteric autonomic nervous system of the gastrointestinal tract.  Gastrointestinal manifestations may mimic inflammatory bowel disease or irritable bowel syndrome. On physical exam, measurement of heart rate and blood pressure supine and 3 min after standing are extremely important.  Orthostatic hypotension is defined by a decrease in 20 mmHg in the systolic or 10 mmHg in the diastolic blood pressure.  Orthostatic hypotension can be secondary to hypovolemia, medication effect, heart failure or have a neurogenic origin.  As a general rule, in true neurogenic orthostatic hypotension the heart rate does not increase more than 10 beats per minute (bpm) upon standing for 3 min.  In patients with neurogenic orthostatic hypotension, there is a far lower increase of heart rate than expected due to reduced sympathetic innervation, considering the magnitude of the blood pressure drop.  A ratio between the increase in heart rate and the fall in systolic blood pressure upon standing or head-up tilt (delta heart rate/delta systolic blood pressure ratio) < 0.5 bpm/mmHg has been validated as a diagnosis of neurogenic orthostatic hypotension.  Conversely, a delta heart rate/delta systolic blood pressure ratio ≥ 0.5 bpm/mmHg suggests a non-neurogenic etiology. However, this should be interpreted with caution in patients taking beta-blockers or who have a paced rhythm on ECG.  Neurogenic orthostatic hypotension occurs in autonomic peripheral neuropathies and neurodegenerative α-synucleinopathies.

Autonomic nervous system testing evaluates sudomotor, cardiovagal, and adrenergic functions and may help with diagnosis and monitoring response to treatment in autonomic neuropathies.  In autonomic laboratory, measure the severity of the autonomic impairment using the Composite Autonomic Severity Scale (CASS).  Patients with true autonomic neuropathies usually have moderate/severe autonomic dysfunction (CASS > 3), whereas patients with other peripheral neuropathies (including CIDP) have no or only mild autonomic dysfunction (CASS ≤ 3).  Generalized autonomic failure shortens the time to diagnosis in amyloid neuropathy.  The severity of autonomic findings in ATTRv and AL amyloid neuropathy is similar.  Autonomic neuropathy is an independent poor prognostic factor in AL amyloidosis.

Focal neuropathy or mononeuropathy and amyloid

The most common focal neuropathy (mononeuropathy) in systemic amyloidosis is bilateral median neuropathies at the wrists or carpal tunnel syndromes.  This occurs in up to 21% of AL, 74% of ATTRv polyneuropathy and in 48% of wild-type ATTR (ATTRwt) amyloidosis patients.  It can also occur in AGel47 and Beta-2-microglobulin amyloidosis.  A recent prospective study showed that 10 of 98 patients (10.2%) (men >50 and women >60 y old) with idiopathic bilateral carpal tunnel syndrome, who underwent carpal tunnel release, had tenosynovium amyloid deposits (5 ATTRwt, 2 ATTRv, 2 AL, and 1 uncharacterized amyloidosis).  In our practice, we have been recommending tenosynovium biopsy with Congo red staining in any patient with carpal tunnel syndrome who undergoes carpal tunnel release surgery.  In addition, the astute neurologist should be suspicious of amyloidosis in patients with bilateral carpal tunnel syndrome and progressive peripheral neuropathy, although this co-occurrence can also happen in other conditions such as diabetes mellitus and rheumatoid arthritis.  Progression or recurrence of carpal tunnel syndrome after release should also be a red flag for amyloidosis.  Rarely amyloid can accumulate on peripheral nerve tissues, usually originating from vertebral bodies or Gasserian ganglion, single peripheral nerves or lumbosacral or brachial plexus, forming a tumor-like deposit, so-called amyloidoma.  Amyloidoma may occur as a localized form of amyloidosis without systemic amyloid deposition.  All except one case of peripheral nerve amyloidomas reported to date have been of AL amyloidosis subtype.  MRI typically shows enlargement of peripheral nerve, sometimes with a mass-like appearance, featuring T2 hyperintensity but no contrast enhancement.  Ultimately, these patients usually need an MRI targeted fascicular nerve biopsy to establish a diagnosis.

Cranial neuropathy in amyloidosis

Apart from bilateral facial neuropathy as a clinical hallmark of AGel amyloidosis, cranial neuropathies are very rare in other types of systemic amyloidosis.  One peculiar feature of AGel amyloidosis is that the facial neuropathy predominantly affecting temporal and zygomatic branches.  Multiple cranial neuropathies can also occur in AL amyloidosis.

Non-neurological manifestations of amyloidosis

Screening for non-neurological systemic symptoms is important in every patient with a neuromuscular disorder.  Many of the clinical features of systemic amyloidosis are nonspecific, such as lower extremity edema, dyspnea on exertion, orthopnea, easy bruising, and weight loss.  In patients with neuromuscular disorders that carry a diagnosis of proteinuria >500 mg/24 h without known diabetes or hypertension, heart failure with preserved ejection fraction without hypertension, hepatomegaly without an obvious cause, MGUS, or family history of neuropathy and/or cardiomyopathy, the possibility of amyloidosis should be carefully considered.  Macroglossia and periorbital purpura (“racoon eyes”) occur in approximately 15% of patients with AL amyloidosis but are highly specific of this disorder.  In AL amyloidosis, purpuric macules and ecchymoses develop with minor trauma due to fragility of cutaneous blood vessels from amyloid deposition.  Corneal lattice dystrophy and cutis laxa are highly sensitive and specific for AGel amyloidosis.  Corneal lattice dystrophy is caused by gelsolin amyloid deposition in the eye, causing impaired vision.  Cutis laxa is characterized by loose and sagging skin with reduced elasticity and resilience.  These skin features in conjunction with the bilateral facial weakness often give the face a drooping, mask-like appearance.  In addition to cranial neve or extraocular muscle involvement, ocular findings such as conjunctivitis, vitreous opacities, pupillary abnormalities, and occlusive vascular diseases may occur in systemic amyloidosis, especially AL and ATTR amyloidosis.

Cardiac amyloidosis is a progressive and life-threatening disorder.  The most common cause of amyloid cardiomyopathy is ATTRwt, which may affect up to 25% of the general population older than 85 years.  The hallmark of the disease is a low voltage QRS on ECG and increased left ventricle wall thickness on echocardiogram.  An interventricular septal thickness of >12 mm in the absence of aortic valve disease or substantial systemic hypertension strongly suggests cardiac amyloidosis, especially if there is discordance between wall thickness on echocardiogram and QRS voltage on ECG.  The global longitudinal strain of −15.1% or greater has a sensitivity of 87% and a specificity of 72% for the diagnosis of amyloid cardiomyopathy.  Diffuse subendocardial late gadolinium enhancement on cardiac magnetic resonance imaging has 80% sensitivity and 94% specificity for the diagnosis of cardiac amyloidosis.  Radionuclide bone scintigraphy (PYP and DPD tracers) revolutionized the diagnosis of ATTR amyloid cardiomyopathy.  The sensitivity of bone scintigraphy for ATTR cardiomyopathy was initially considered to be close to 100% with specificity of 82% as mild tracer uptake can also occur in AL amyloidosis.  However, the specificity of grade 2 or 3 cardiac uptake on bone scintigraphy reaches 100% if patients do not have monoclonal gammopathy.  Patients with a positive bone scintigraphy should undergo TTR gene sequencing.  In such cases, the lack of TTR mutations is considered to be diagnostic of ATTRwt and a tissue biopsy showing amyloidosis is not necessary.  This is in contrast to nerve and muscle presentations of amyloidosis in which the authors believe tissue confirmation is still required.  Recently, a study showed that sensitivity of bone scintigraphy in patients with ATTRv cardiomyopathy with Phe64Leu mutation is only 10.5%. Therefore, a negative bone scintigraphy does not entirely exclude the possibility of ATTRv cardiomyopathy.  The prognosis of AL amyloid cardiomyopathy is very poor with a median survival of <6 months.  ATTRv and ATTRwt cardiomyopathy is associated with better a prognosis, with a median survival of 57 months.

Diagnostic approach for amyloidosis

The early diagnosis of amyloidosis is crucial because there are now treatments available for common amyloidosis subtypes.  Order a monoclonal gammopathy screen in almost every patient that presents with peripheral neuropathy and/or myopathy of undetermined etiology.  This screen encompasses serum protein electrophoresis and immunofixation, free light chains assay, and 24 hr urine protein electrophoresis and immunofixation.  If this screen is negative, AL amyloidosis is likely ruled out (with the exception of the rare focal amyloidoma).  If suspicion for other types of amyloidosis is high, the patient should undergo a tissue biopsy with Congo red stain.  If the monoclonal gammopathy screen is positive, the patients may have monoclonal gammopathy of uncertain significance (MGUS) or less commonly malignant plasma cell disorders.  MGUS is defined by a serum M protein less than 3 g/dL, bone marrow plasma cells less than 10%, and the absence of anemia, hypercalcemia, lytic bone lesions, or renal failure.  MGUS occurs in 3% of the population ≥ 50 yr old, 5% in ≥70 yr old but only 0.3% of those <50 yr of age.

Regardless of the characteristics of the monoclonal protein, refer the patients with a monoclonal gammopathy to a hematologist, as the monoclonal protein may be secondary to multiple myeloma, AL amyloidosis or Waldenström macroglobulinemia.  Even if the patient is ultimately diagnosed with a MGUS, he or she will need a follow-up monoclonal protein study and follow-up visit with hematologist on a yearly basis given the risk of malignant transformation (on average 1%/yr).  It is noteworthy that when the amount of the monoclonal protein is <1.5 g/dL, the isotype of the monoclonal protein is IgG and the free light chain ratio is normal, the MGUS is of low risk of malignant transformation, and lifetime risk of progression to malignancy is only 2%.  In a recent study of 1384 MGUS patients from Southern Minnesota, United States, with a median follow-up time of 34.1 years, only 14 MGUS patients (0.01%) developed AL amyloidosis over time.  It is important to note that a combination of monoclonal gammopathy and amyloid neuropathy does not always indicate AL amyloidosis.  Amyloid subtyping remains vital given up to 40%-50% of patients with ATTR amyloidosis may have MGUS.

In patients suspected to have amyloid neuropathy, if the free light chain ratio is abnormal, monoclonal protein size >1.5 g/dL, or the monoclonal gammopathy screen is negative but suspicion for amyloid neuropathy is still high, the patients should undergo abdominal fat pad aspirate or lower limb skin biopsy with Congo red stain.  If amyloidis present, it is imperative to perform amyloid subtyping, ideally with mass spectrometry based proteomic analysis, which is the gold standard test to identify specific amyloidosis subtype, with >90% sensitivity and nearly 100% specificity.  If fat pad aspirate or skin biopsy is negative for amyloid or if they are positive but there is not enough amyloid present to do subtype analysis, we perform a sensory nerve biopsy, usually of the sural nerve.  The sensitivity of the nerve biopsy is high (up to 93%), but a nerve biopsy that is negative for amyloid does not rule out amyloid neuropathy.  When nerve biopsy is negative for amyloid deposits but clinical suspicion for amyloid neuropathy remains high (eg, progressive polyneuropathy with prominent autonomic dysfunction, heart failure, proteinuria, concomitant myopathy, or monoclonal gammopathy), we usually consult with hematology and cardiology to identify the best suitable alternative targets for a biopsy (rectum, salivary gland, skeletal muscle, stomach, intestine, or endomyocardium) and perform a bone scintigraphy in patients with cardiac involvement.  In patients with a negative nerve biopsy, we sometimes perform MRI of peripheral nerves to search for a potential site for an MRI-targeted fascicular nerve biopsy or biopsy a different sensory nerve.

Whole body 18F-florbetapir PET/MRI imaging is a novel and promising diagnostic tool for a potential nerve biopsy target when conventional imaging and tissue biopsies are persistently negative but clinical suspicion is still high.  If a concomitant myopathy is present, we perform a muscle biopsy.  Our position on the role of genetic testing for ATTRv has evolved.  Given its easy access and speed of testing, we advocate early ATTRv genetic testing in patients whose clinical history is highly suggestive of ATTRv amyloidosis.  These features include a rapidly worsening neuropathy with weakness, pain, sensory loss and autonomic involvement, co-existing carpal tunnel syndrome, lumbar spinal stenosis or cardiomyopathy.  However, due to a variable penetrance of TTR mutations and the potential serious adverse reactions of ATTRv disease modifying therapies, a tissue diagnosis remains important.

In patients with a proximal myopathy of undetermined etiology, we usually pursue a muscle biopsy.  Congo red stain is routinely performed in our muscle laboratory.  If muscle biopsy is negative for amyloid and monoclonal gammopathy screen is negative, the possibility of amyloid myopathy is ruled out.  When amyloid myopathy is suspected, it is important to communicate this to the muscle biopsy laboratory to save specimen for potential paraffin embedding as amyloid subtyping can only be done on paraffin-embedded tissue.  As mentioned above, in dysferlinopathy and anoctaminopathy with amyloidosis, the amyloid subtyping generally identifies amyloid-associated proteins, but not the known amyloidogenic proteins associated with systemic amyloidosis.