Paraproteinemic Neuropathy: A Practical Review

Richard A. Rison; Said R. Beydoun

BMC Neurol. 2016;16(13)

Testing Strategy

A general and detailed neurological exam should be performed to characterize the neuropathic phenotype. Tests should include a hematology panel as well as serum and urine protein electrophoresis with immunofixation. Table 1 describes diagnostic tests, including urinalysis, imaging studies, electrodiagnostic tests, and biopsies.

For patients who are found to have a paraproteinemia, diagnostic testing leans towards investigations of possible hematologic neoplasms. If none are discovered, then other diseases should be considered, including primary (AL) amyloidosis and cryoglobulinemia.^[22,24] Monoclonal proteins should be characterized by protein electrophoresis and immunofixation of the serum and the urine. Detailed electrophysiology includes determination of DML (distal motor latency)/MNCV (motor nerve conduction velocity)/TLI (terminal latency index), assessment for CB (conduction block)/ATD (abnormal temporal dispersion). If results of the CBC and/or peripheral smear examination are abnormal, a bone marrow biopsy is recommended, in consult with a hematologist. Even if the results of the CBC and/or peripheral smear examination are normal, then a bone marrow biopsy is still considered and usually recommended based on consultation with a hematologist before the diagnosis of MGUS is made. A skeletal X-ray survey can detect the presence of lytic lesions.

Cerebrospinal fluid (CSF) analysis including cytology and neuroimaging studies (MR neurography) may exclude leptomeningeal infiltration, especially in the presence of lymphoma. Nerve and muscle biopsy are occasionally performed to exclude infiltrative neoplasms, paraproteinemic vasculitis, or AL. If vasculitis is suspected, biopsy of the sural nerve is indicated. Alternatively, biopsy of the superficial peroneal nerve and peroneus brevis muscle obtains both nerve and muscle with a single incision and may increase the yield of identifying vasculitic pathology by up to 10 %. In the work-up of possible AL, abdominal fat aspiration biopsy is preferred over nerve biopsy due to the more favorable safety profile of the former procedure, despite lower sensitivity. If small fiber neuropathy is suspected, epidermal nerve twig analysis via skin biopsy may be performed.

VEGF Testing for POEMS

In patients with M-protein, endocrine and skin changes, and demyelinating polyneuropathy, testing for elevated vascular endothelial growth factor (VEGF) may help diagnose POEMS. A retrospective study found that VEGF levels in patients with POEMS syndrome were markedly elevated compared with patients with other plasma cell dyscrasias (P < .001), peripheral neuropathy (P < .001), and connective tissue disease/vasculitis (P < .009). The best VEGF cut-off for POEMS diagnosis was 146 pg/mL; however, a cut-off of 200 pg/mL had a specificity of 95 % with a sensitivity of 68 % in support of a POEMS diagnosis (level of evidence: 3).^[37]

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Table 1. Diagnostic tests for PPN
Test	Description	Comments
Erythrocyte sedimentation rate (ESR)	Venous blood sample.	ESR elevation is primarily due to increased levels of Ig (clonal or polyclonal) or fibrinogen
Serum total protein and albumin	Venous blood sample.	Protein elevated in:
	Normal range:	Monoclonal gammopathy
	Serum total protein: 6 to 8 g/dL	Dehydration
	Serum albumin: 4 to 6 g/dL	Myeloma
		Waldenstrom macroglobulinemia
		Sarcoidosis
		Collagen vascular disease
Serum protein electrophoresis	Venous blood sample.	Indicated if serum protein and/or globulin is elevated or clinical findings raise suspicion of monoclonal gammopathy.
		M protein, if present, is a discrete spike in the γ, β or α2 region.
		MGUS, M peak: 0.5 to 3 g/dL, amount directly related to probability of progression to multiple myeloma or a related plasma cell malignancy.
		Serum M spike present in 80 % of patients with myeloma.
Immunofixation	Venous blood sample.	Indicated when an M spike is found on serum electrophoresis or when clinical findings present suspicion of multiple myeloma, other plasma cell malignancy, amyloidosis, or WM.
	Monoclonal immunoglobulin:
	MGUS: IgG (73 %), IgA (11 %), IgM (14 %), IgD, κ or λ light chains	Defines the heavy and light chain type of the abnormal serum protein, which can discriminate between MGUS, multiple myeloma, other plasma cell malignancies, WM, and amyloidosis.
	Multiple myeloma: IgG (50 %), IgA (20 %), IgD (few), free light chains (17 %)
	WM: IgM-κ
	Amyloidosis: IgG, IgA, IgD, IgM, κ or λ light chains; 30 % non-secretory
	Osteosclerotic myeloma: IgG-λ or IgA-λ
	Heavy-chain disease: IgG, IgA, IgM, no light chain
Serum light chain quantitation	Venous blood sample.	Provides a rapid, accurate, quantitative measurement of λ and κ light-chain in serum.
	κ free light chain: 3.3 to 19.4 mg/L	Increased light chain levels are seen in most plasma cell disorders, especially the more malignant disorders such as multiple myeloma.
	λ free light chain: 5.7 to 26.3 mg/L	Free light chain (FLC) ratio may be a risk factor for progression to malignancy [66].
		Unlike urine Bence-Jones protein assays, results are not affected by changes in renal function.
		The test is expensive and not widely available.
Autoantibody panels	Normal:	Measures presence and titer of antibodies.
	Absence of antibody	Anti-MAG antibody assesses distal demyelinating sensory neuropathy.
		Anti-GM1 antibody assesses multifocal motor neuropathy.
		Anti-GQ1b antibody assesses Miller-Fisher.
		Please note that absolute absence of autoantibodies is not required for a "normal" test for many antibodies at different labs.
Cryoglobulins	Normal:	Serum blood specimen collected and separated while warm for cryoprecipitation over a period of up to 7 days.
Cryoglobulins	Less than 80 μg/ml	At very high cryoglobulin titer states, cryoprecipitates during blood collection produce structures on peripheral blood smears that may be mistaken for leukocytes or platelets by automated cell differential analyzers.
24-h urine protein quantification and electrophoreses	Detects excretion of monoclonal immunoglobulin.	Dipstick test for proteinuria primarily detects albumin and often misses M protein.
	Normal:
	Urinary protein excretion less than 150 mg/day.	Recommended for patients with serum M spike or clinically-based suspicion of monoclonal gammopathy.
	Small amount of Bence-Jones protein not uncommon
Urine immunofixation	Characterizes urinary monoclonal immunoglobulin following test of 24-h urine and should be done if serum M spike is greater than 1.5 g/dL.	Indicated if multiple myeloma, WM, primary amyloidosis, or a related disorder is suspected, even if routine urinalysis is negative for protein, 24-h urine is within normal limits, or if no M spike is seen on electrophoresis of concentrated urine sample.
Electrodiagnostic (electro-myelogram and nerve conduction studies)	Determines whether symptoms are due to a muscle or nerve disorder by measuring conduction velocities and the presence or absence of conduction blocks.	Determines whether the polyneuropathy is axonal or demyelinating.
		Tests help to localize the anatomic site of a lesion that is causing pain, and determine the presence of active denervation.
Bone marrow aspiration and biopsy	A sample is taken usually from the posterior superior iliac crest region.	Required if a high M protein level is found to investigate the possibility of multiple myeloma or lymphoma.
	Normal result is age-appropriate cellularity and lineage distribution and < 10 % plasma cells.	May reveal clinically inapparent involvement.
		Requires local anesthesia and the assistance of an attendant.
		Risk of infection and bleeding.
Radiographic skeletal bone survey	Two dimensional radiographs of the entire skeleton.	Survey detects lytic and sclerotic lesions as well as fractures which may be pathologic.
Radiographic skeletal bone survey	Two dimensional radiographs of the entire skeleton.	There is a relatively high radiation exposure.
Cerebrospinal fluid analysis	Investigate CIDP and leptomeningeal lymphomatous infiltration.	Elevated protein level is common in PPN.
		Infiltration of the CNS by Non-Hodgkin's lymphoma will show clonal lymphocytes.
		Viral infection may result in increased CSF lymphocytes but will not be clonal.
		Autoantibodies can be tested within the CSF but the results may differ depending on the laboratory used. Absolute absence of autoantibodies is not required for a "normal" test for many antibodies at different labs.
Nerve biopsy	Biopsy of the superficial peroneal nerve is ideal so that a muscle biopsy of the peroneus brevis muscle may be done simultaneously; other choices include sural or superficial radial sensory nerves.	Identifies abnormal density of small and large axons and abnormal myelin sheaths.
		Reserved for cases in which it is difficult to identify whether the process is predominantly axon degeneration or demyelination, or for cases where there is patchy, asymmetric, or focal involvement.
	Evaluates suspected cases of infiltrative neoplasms, paraproteinemic vasculitis, or amyloidosis.	A negative nerve biopsy does not exclude amyloid neuropathy.
		Please note that as with serum and CSF autoantibody testing, results may differ depending on the laboratory used.
Muscle biopsy	See "Nerve biopsy" for best incision site.	The procedure helps distinguish between an atypical neurogenic disorder and a primary myopathic disorder.
Fat biopsy	A normal result is no amyloid protein.	The test is most often done when there is suspicion of amyloidosis.
Skin biopsy	Examines the degree of myelination of small fiber neurons.	Helps ascertain the presence or absence of small fiber neuropathy.
Skin biopsy	Examines the degree of myelination of small fiber neurons.	Epidermal nerve twig analysis via skin biopsy is sometimes done if small fiber neuropathy is suspected.
Whole-body computerized tomography scan	The scan can detect lymphadenopathy, hepatosplenomegaly, and ascites.	Intravenous contrast is usually required for better visualization of lymphoid structures.
Positron emission tomography scan	Functional images assess metabolic activity within various structures, including lymph nodes and may detect nodal, extranodal, and bone marrow involvement by lymphoma.	PET scan can be used concurrently with non-contrast CT scan to combine functional and anatomic imaging.
Positron emission tomography scan		Acute inflammation and infection can also result in increased uptake safety profile of the procedure, even though it is less sensitive than biopsy.

Table 2. Treatment for paraproteinemia
Treatment	Indication	Dose	Major contraindications
Intravenous immune globulin (IVIG)	First line treatment for CIDP associated with M protein (off-label use)	2 g/kg intravenously for 3–5 days, followed by maintenance dose of 1 g/kg every 3–4 weeks, followed by clinical reassessment	Hyperprolinemia
	First line treatment for multifocal motor neuropathy (off-label)		Hypersensitivity to albumin
	Alternative treatment for IgM/A/G-MGUS (after rituximab, off-label use)		Immunoglobulin A deficiency
	Treatment of CANOMAD (off label use)		Immunoglobulin A deficiency
Corticosteroids	First line treatment for CIDP associated with M protein (off-label use)	Prednisone:	Corticosteroid hypersensitivity
	An alternative treatment for IgM/A/G-MGUS (after rituximab or plasma exchange, off label use)	1 to 1.5 mg/kg/day orally	Fungal infection
		Several treatment dosing regimens are available and duration is not agreed upon.	Fungal infection
Azathioprine	Alternative immunosuppressive treatment (after IVIG or corticosteroids) for CIDP associated with M protein (off-label use)		Pregnancy (category D)
Azathioprine			Hypersensitivity to azathioprine
Rituximab	First line treatment for IgM-MGUS (off-label use)	Four weekly infusions of 375 mg/m2 rituximab [51]	Hypersensitivity to rituximab
Rituximab	Alternative therapy for multifocal motor neuropathy (after IVIG, off label use)	Four weekly infusions of 375 mg/m2 rituximab [51]	Hypersensitivity to rituximab
Chlorambucil	Alternative therapy for IgM-MGUS (off label use)	0.1 to 0.2 mg/kg orally daily for 3 to 6 weeks	Hypersensitivity to chlorambucil
Chlorambucil	Alternative therapy for IgM-MGUS (off label use)	0.1 to 0.2 mg/kg orally daily for 3 to 6 weeks	FDA pregnancy category D
Fludarabine	Alternative therapy for IgM-MGUS (off label use)	40 mg/m² for 5 days every 28 days	Hypersensitivity to fludarabine
Fludarabine	Alternative therapy for IgM-MGUS (off label use)	40 mg/m² for 5 days every 28 days	FDA pregnancy risk category D
Melphalan	Treatment for POEMS	For POEMS (high dose): 10 mg/m² for 4 days every 28 days [58]	Hypersensitivity to melphalan
Melphalan	In combination with prednisone as treatment for AL	For AL: 0.15 mg/kg once daily for 7 days every 6 weeks, increasing the dose by 2 mg in each 6 week course. Should be used in combination with prednisone.	Should not be used in patients whose disease has demonstrated prior melphalan resistance
Plasmapheresis (plasma exchange)	First line treatment of IgG/A MGUS	3 to 5 exchanges every other day	Risks associated with frequent vascular access
	May be helpful in severe cases of cryoglobulinemia.		Risk of transmission of infective agents if fresh plasma is used as replacement fluid
	May be helpful in severe cases of cryoglobulinemia.		Anaphylaxis and allergic reactions may occur with reinfusion of plasma substitute
Autologous peripheral stem cell transplant	First line treatment of POEMS syndrome	Myeloablative doses of chemotherapy and/or radiation therapy followed by infusion of peripheral blood stem cells	Patients who undergo HCT are at risk for bacterial, viral, and fungal infections
	Alternative treatment of AL, used in combination with melphalan		Early adverse effects include: nausea, vomiting, diarrhea, mouth sores
			Later adverse effects include: cataracts, sterility, increased risk of other neoplasias
Radiation therapy	First line treatment of dominant sclerotic plasmacytoma in POEMS syndrome	Radiation therapy delivered to osteosclerotic lesions in doses of 40–50 Gy	Adverse effects depend upon the location of the area irradiated
Radiation therapy			Increased risk of developing second malignancies in patients with Hodgkin's Lymphoma

Authors and Disclosures

Richard A. Rison¹* and Said R. Beydoun²

¹University of Southern California, Keck School of Medicine, Los Angeles County Medical Center, Medical Director PIH Health-Whittier Stroke Program, Neurology Consultants Medical Group, 12401 Washington Blvd., Whittier, CA 90602, USA. ²University of Southern California, Keck School of Medicine, Los Angeles County Medical Center, 1520 San Pablo Street Suite 3000, Los Angeles, CA 90033, USA.

*Correspondence
rison@usc.edu

Competing interests
SRB reports advisory, consulting, and speaking roles with Baxter and Grifols, and SRB has received research grants from Alexion, CSL, GSK, and Pfizer. RAR declares no competing interests.

Authors' contributions
RAR performed the initial literature search and wrote the original manuscript, revised and further edited the manuscript. SRB reviewed and further revised and edited the manuscript with additional citations. SRB and RAR were responsible for the intellectual content of the paper along with critical appraisals, and revisions. Both authors participated in and provided significant contributions in writing the manuscript. Both authors read and approved the final manuscript.

Authors' information
SRB is Director of the University of Southern California Neuromuscular Program, a Fellow of the American Academy of Neurology and the American Association of Neuromuscular and Electrodiagnostic Medicine, and is board certified by the American Board of Psychiatry and Neurology in Neurology, Clinical Neurophysiology, Pain Medicine, and Neuromuscular Medicine. SRB is also board certified by the American Board of Electrodiagnostic Medicine in Electrodiagnostic Medicine. SRB is a member of the advisory board and the scientific committee of the Myasthenia Gravis Foundation of California. RAR is a Deputy Editor for the Journal of Medical Case Reports, an Associate Neurology Editor for BMC Neurology, Grand Rounds and Webmed Central, and a Section Editor for BMC Research Notes. RAR practices general neurology at Neurology Consultants Medical Group, serves as Medical Director of the PIH Health Stroke Program, is a Clinical Assistant Professor of Neurology at the University of Southern California-Keck School of Medicine-Los Angeles County Medical Center, and is a Fellow of the American Association of Neuromuscular and Electrodiagnostic Medicine. RAR is board certified by the American Board of Psychiatry and Neurology in Neurology and Vascular Neurology, and Neurocritical care and Neuroimaging by the United Council of Neurologic Subspecialties. RAR is also board certified by the American Board of Electrodiagnostic Medicine in Electrodiagnostic Medicine. RAR is a former president of the Los Angeles Neurological Society and a Fellow of the American Academy of Neurology and the American Neurological Association.

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Testing Strategy

VEGF Testing for POEMS

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