Paraproteinemic neuropathy

So Young Pyun; Byung-Jo Kim

doi:10.14253/acn.2017.19.2.79

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Pyun and Kim: Paraproteinemic neuropathy

Review

J Rheum Dis 2017;19(2):79-92.

Published online: 5 January 2017

DOI: https://doi.org/10.14253/acn.2017.19.2.79

Paraproteinemic neuropathy

So Young Pyun¹, Byung-Jo Kim²

¹Department of Neurology, National Police Hospital, Seoul, Korea

²Department of Neurology, Korea University College of Medicine, Seoul, Korea

Correspondence to Byung-Jo Kim Department of Neurology, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea Tel: +82-2-920-6619 Fax: +82-2-925-2472 E-mail: nukbj@korea.ac.kr

Received 25 October 201619 March 2017 Accepted 12 May 2017

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

초록

Paraproteinemia is caused by a proliferation of monoclonal plasma cells or B lymphocytes. Approximately 10% of idiopathic neuropathies are associated with paraproteinemia, where a certain paraprotein acts like an antibody targeted at constituents of myelin or axolemma in peripheral nerves. The relationship between paraproteinemia and peripheral neuropathy remains unclear despite this being of interest for a long time. Neurologists frequently find paraproteinemia during laboratory examinations of patients presenting with peripheral neuropathy, especially in the elderly. The possibility of a relationship with paraproteinemia should be considered in cases without an explainable cause. We review the causal association between paraproteinemia and neuropathy as well as clinical, laboratory, and electrophysiologic features, and the treatment options for paraproteinemic neuropathy.

Keywords: Monoclonal gammopathy, Paraproteins, Peripheral neuropathy, POEMS Syn-drome, Multiple myeloma, Waldenstrom macroglobulinemia

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Table 1.

Examinations for patients with suspected paraproteinemic neuropathy

Routine workup
Clinically neurologic examination at baseline, and follow-up checks at regular intervals
Electrophysiologic test determines whether the polyneuropathy has an axonal (CMAP/SNAP) or a demyelinating (DML/MNCV/TLI and CB/TD) pattern
Serum protein electrophoresis (with the presence or absence of an M-protein), immunoelectrophoresis, or immunofixation (to demarcate the heavy- and light-chain types of the paraprotein)
Quantitative Ig levels
Serum light-chain quantification, and the detection of Bence-Jones protein (free light chains) in a random urine sample; if positive, 24-h urine collection for urine protein quantification
Full blood cell count with differential, kidney and liver function tests, calcium and phosphate levels, and erythrocyte sedimentation rate
Physical examination for involvement of systemic organs such as lymphadenopathy, hepatosplenomegaly, ascites, edema, or macroglossia
Radiographic X-ray skeletal survey (including the skull, pelvic, spine, and ribs) to look for lytic or sclerotic lesions. If lytic or sclerotic lesions are strongly suspected, CT and/or MRI of the spine, pelvis, or whole body may be considered
Ultrasonography or CT of the chest, abdomen, and pelvis (to detect organomegaly or malignancy)
Bone-marrow aspiration and biopsy (required if the M-protein level is >15 g/L or the free-light-chain ratio is abnormal)
CSF analysis involving cellularity, cytospin, and protein level
Advanced workup
Serum VEGF levels if POEMS syndrome is suspected
Anti-MAG antibody ^a
MRI of nerve roots and brachial plexus, as for CIDP
Nerve biopsy ^b
Fat biopsy, most often when there is suspicion of amyloidosis

General ideas were derived from “Rajabally²²" and "Rison et al.⁹⁹".

CMAP, compound motor action potential; SNAP, sensory nerve action potential; DML, distal motor latency; MNCV, motor nerve conduction velocity; TLI, terminal latency index; CB, conduction block; TD, temporal dispersion; Ig, immunoglobulin; CT, computed tomography; MRI, magnetic resonance imaging; CSF, cerebrospinal fluid; VEGF, vascular endothelial growth factor; POEMS syndrome, polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes; MAG, myelin-associated glycoprotein; CIDP, chronic inflammatory demyelinating polyneuropathy.

^a Half of patients with IgM paraproteinemic neuropathy have anti-MAG antibodies.

^b The following conditions are suspected: (1) IgM paraproteinemic demyelinating neuropathy with negativity for anti-MAG antibodies, or IgG or IgA paraproteinemic demyelinating neuropathy with a chronic progressive course, and with the discovery of widely spaced myelin on electron microscopy or deposits of Ig and/or complement bound to myelin; (2) amyloidosis; and (3) malignant lymphoproliferative infiltration of nerves.

Table 2.

Summary of incidence rates, clinical, laboratory, electrophysiologic, and pathologic findings, and treatment options for patients with paraproteinemic neuropathies

Disease	Prevalence of peripheral neuropathy	Clinical	Laboratory	Electrophysiology	Pathology	Treatment
MGUS	30%	Slowly progressive, distal sensory ataxia (IgM);	M-protein <30 g/L	Demyelinating with remarkably prolonged distal latencies	Widening of myelin lamellae	IgM MGUS (especially anti-MAG neuropathy) IVIg
			Increased IgM, IgG, or IgA level
		Distal and proximal sensorimotor neuropathy as in CIDP-like neuropathy (IgG/IgA)			IgM antibodies against MAG, gangliosides (anti-GM1, -GD1a, -GD1b, or -GM2), sulfatide, chondroitin sulfate C
			Anti-MAG antibodies detection in half (IgM)			Interferon alfa-2a
				Reduced TLI (IgM) CIDP-like or axonal (IgG/IgA)		Plasma exchange
						Rituximab + Cyclophosphamide
						+ steroid
					Endoneurial Ig deposits	IgG/IgA MGUS
						IVIg
						Corticosteroid
						Cyclophosphamide + steroid
						Plasma exchange
Multiple myeloma	10–75%	Length-dependent sensory or	M-protein >30 g/L	Almost always axonal	Axonal degeneration	No intervention reverses neuropathy;
	(throughout	sensorimotor neuropathy	Bence-Jones proteinuria		with or without amyloid	treating myeloma can cause or
	disease course)		>10% plasma cells in		deposition	exacerbate existing neuropathy
			bone marrow
			IgG (50%) or IgA (20%)
			kappa
			Anemia, hypercalcemia
POEMS syndrome	50–85%	Ascending symmetric proximal	l IgG or IgA lambda	Mixed demyelinating	Axonal degeneration	Isolated bone lesion without clonal
	(throughout	and distal sensorimotor	Elevated VEGF	and axonal	Loss of myelinated fibers	plasma cells
	disease course)	symptoms (CIDP-like	Sclerotic bone lesions	No conduction	Inflammation in endoneu-	Radiation
		neuropathy)		block or temporal	rium, and uncompacted	Disseminated bone-marrow
		Weakness eventually		dispersion	myelin lamellae	involvement
		predominant		Normal TLI		Corticosteroids
						Melphalan + dexamethasone
						Cyclophosphamide +
						dexamethasone
						Auto-PBSCT
						Thalidomide or
						lenalidomide +
						dexamethasone
						Bortezomib
						Bevacizumab
Waldenström	10–47%	Slowly progressive symmetric	c IgM kappa	Similar to IgM MGUS	Similar to IgM MGUS	Primary
macroglobulin-	(throughout	distal sensory, or	Anti-MAG antibodies in			Rituximab +
emia	disease course)	sensorimotor (CIDP-like	some cases			cyclophosphamide +
		neuropathy) symptoms				dexamethasone + fludarabine
						Refractory
						Bortezomib, rituximab,
						autologous stem-cell
						transplantation
						Weekly plasma exchange
Amyloidosis	Presenting	Painful progressive symmetric	c, IgG or IgA lambda	Axonal sensorimotor	Endoneurial amyloid	If eligible, autologous stem-cell
	symptom is	distal sensorimotor with or	Occurs alone or with	neuropathy	deposition on	transplantation
	neuropathy in	without dysautonomia	other plasma-cell	Carpal tunnel	Congo-red staining	If not eligible,
	15–30%	Carpal tunnel syndrome in 25	% disorders	syndrome	Light chains on	melphalan, corticosteroid
					immunochemistry	thalidomide, lenalidomide, and
					Axonal degeneration	bortezomib

General ideas were derived from “Raheja et al. 8" and “Rison et al. 99”.

MGUS, monoclonal gammopathy of undetermined significance; IgM, immunoglobulin M; IgG, immunoglobulin G; IgA, immunoglobulin A; MAG, myelin-associated glycoprotein; TLI, terminal latency index; GM, ganglioside M; GD, ganglioside D; IVIg, intravenous immunoglobulin; CIDP, chronic inflammatory demyelinating polyneuropathy; POEMS syndrome, polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes; VEGF, vascular endothelial growth factor; Auto-PBSCT, autologous peripheral-blood stem-cell transplantation.

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