The levels of evidence (class I-IV) supporting the recommendations and ratings of recommendations (A-C, Good Practice Point [GPP]) are defined at the end of the "Major Recommendations" field.
Investigation and Classification of the Paraproteins
The Table below suggests investigations to be considered in all patients with a paraprotein. Serum immunofixation electrophoresis (SIFE) should be performed in all cases of known paraprotein to define the heavy- and light-chain types, in all acquired demyelinating neuropathies, and if a paraprotein is suspected but not detected by standard serum protein electrophoresis (SPEP).
| Table. Investigation of a Paraprotein |
The following should be considered in all patients with a paraprotein:
- Serum immunofixation electrophoresis
- Physical examination for peripheral lymphadenopathy, hepatosplenomegaly, macroglossia, and signs of polyneuropathy, organomegaly, endocrinopathy, M band, and skin changes (POEMS syndrome) (see section "Other neuropathy syndromes associated with paraproteinemia" in the original guideline document)
- Full blood count, renal and liver function, calcium, phosphate, erythrocyte sedimentation rate, C-reactive protein, uric acid, beta 2-microglobulin, lactate dehydrogenase, rheumatoid factor, serum cryoglobulins
- Total immunoglobulin G (IgG), IgA, IgM concentrations
- Random urine collection for the detection of Bence-Jones protein (free light chains), and, if positive, 24 h urine collection for protein quantification
- Radiographic x-ray skeletal survey, including skull, pelvis, spine, ribs, long bones (shoulder to wrist, and hip to ankle), to look for lytic or sclerotic lesions. If this is negative, then a Technetium-99 (Tc-99)m sesta-MIBI (2-methoxy-isobutyl-isonitrile) scan if high degree of suspicion of myeloma (IgA lambda and IgG lambda paraproteins are more frequently associated with osteosclerotic myeloma)
- Ultrasound or computed tomography of abdomen and chest (to detect lymphadenopathy, hepatosplenomegaly)
- Consultation with a hematologist and bone marrow examination (morphology, immunophenotype, and biopsy)
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Is the Paraprotein Causing the Neuropathy?
| Table. Causal Relationship between Paraprotein and Demyelinating Neuropathy |
- Highly probable if immunoglobulin M (IgM) paraprotein (monoclonal gammopathy of uncertain significance [MGUS] or Waldenstrom's) and:
- High titers of anti-myelin-associated glycoprotein (anti-MAG) or anti-GQ1b antibodies, or
- Nerve biopsy shows IgM or complement deposits on myelin, or widely spaced myelin on electron microscopy
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- Probable if either:
- IgM paraprotein (MGUS or Waldenström's) with high titers of IgM antibodies to other neural antigens (GM1, GD1a, GD1b, GM2, sulfatide, etc.), and slowly progressive predominantly distal symmetrical sensory neuropathy, or
- IgG or IgA paraprotein and nerve biopsy evidence (as in1b but with IgG or IgA deposits)
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- Less likely when any of the following are present in a patient with MGUS and without anti-MAG antibodies (diagnosis may be described as 'chronic inflammatory demyelinating polyradiculoneuropathy with coincidental paraprotein'):
- Time to peak of neuropathy <6 months
- Relapsing/remitting or monophasic course
- Cranial nerves involved (except chronic ataxic neuropathy with ophthalmoplegia, IgM monoclonal gammopathy, cold agglutinins, and disialoganglioside [CANOMAD])
- Asymmetry
- History of preceding infection
- Abnormal median with normal sural sensory action potential
- IgG or IgA paraprotein without biopsy features in 2b
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Cerebrospinal Fluid and Nerve Biopsy
Cerebrospinal fluid (CSF) examination and nerve biopsy may be helpful in selected circumstances (see Table, below, good practice points) but are not usually necessary if there is clearly demyelinating physiology with monoclonal gammopathy of uncertain significance (MGUS).
| Table. Cerebrospinal Fluid (CSF) Examination and Nerve Biopsy |
- CSF examination is most likely to be helpful in the following situations:
- In patients with borderline demyelinating or axonal electrophysiology or atypical phenotype, where the presence of raised CSF protein would help suggest that the neuropathy is immune mediated
- The presence of malignant cells would confirm lymphoproliferative infiltration
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- Nerve biopsy (usually sural nerve) is most likely to be helpful when the following conditions are being considered:
- Amyloidosis
- Vasculitis (e.g., due to cryoglobulinemia)
- Malignant lymphoproliferative infiltration of nerves, or
- Immunoglobulin M paraproteinemic demyelinating neuropathy (IgM PDN) with negative anti-myelin-associated glycoprotein antibodies, or IgG or IgA PDN with a chronic progressive course, where the discovery of widely spaced myelin on electron microscopy or deposits of immunoglobulin and/or complement bound to myelin would support a causal relationship between paraprotein and neuropathy. However, clinical decisions on treatment are often made without a biopsy.
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Treatment of Paraproteinemic Demyelinating Neuropathy (PDN)
Good Practice Points for Treatment of IgM PDN
- In patients without significant disability, consideration should be given to withholding immunosuppressive or immunomodulatory treatment, providing symptomatic treatment for tremor and paresthesiae, and giving reassurance that symptoms are unlikely to worsen significantly for several years.
- In patients with significant disability or rapid worsening, intravenous immunoglobulin (IVIg) or plasma exchange (PE) should be considered as initial treatment, although their efficacy is unproven.
- In patients with moderate or severe disability, immunosuppressive treatment should be considered, although its long-term efficacy remains unproven. Preliminary reports suggest that rituximab may be a promising therapy.
- More research is needed.
Good Practice Points for Treatment of IgG and IgA PDN
In patients with a chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)-like neuropathy, the detection of IgG or IgA MGUS does not justify a different therapeutic approach from CIDP without a paraprotein.
Good Practice Points for Treatment of POEMS (signs of polyneuropathy, organomegaly, endocrinopathy, M band, and skin changes)
- Patients should be managed in consultation with a hemato-oncologist.
- Local radiation or surgery should be considered as the initial treatment for isolated plasmacytoma.
- Melphalan (with or without corticosteroids) should be considered for patients with multiple or no detectable bone lesions.
Definitions:
Evidence Classification Scheme for a Diagnostic Measure
Class I: A prospective study in a broad spectrum of persons with the suspected condition, using a "gold standard" for case definition, where the test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy
Class II: A prospective study of a narrow spectrum of persons with the suspected condition, or a well-designed retrospective study of a broad spectrum of persons with an established condition (by "gold standard") compared to a broad spectrum of controls, where test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy
Class III: Evidence provided by a retrospective study where either persons with the established condition or controls are of a narrow spectrum, and where test is applied in a blinded evaluation
Class IV: Any design where test is not applied in blinded evaluation OR evidence provided by expert opinion alone or in descriptive case series (without controls)
Evidence Classification Scheme for a Therapeutic Intervention
Class I: An adequately powered prospective, randomized, controlled clinical trial with masked outcome assessment in a representative population or an adequately powered systematic review of prospective randomized controlled clinical trials with masked outcome assessment in representative populations. The following are required:
- Randomization concealment
- Primary outcome(s) is/are clearly defined
- Exclusion/inclusion criteria are clearly defined
- Adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias
- Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences
Class II: Prospective matched-group cohort study in a representative population with masked outcome assessment that meets a–e above or a randomized, controlled trial in a representative population that lacks one criteria a–e
Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome assessment is independent of patient treatment
Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion
Rating of Recommendations for a Diagnostic Measure
Level A rating (established as useful/predictive or not useful/predictive) requires at least one convincing class I study or at least two consistent, convincing class II studies.
Level B rating (established as probably useful/predictive or not useful/predictive) requires at least one convincing class II study or overwhelming class III evidence.
Level C rating (established as possibly useful/predictive or not useful/predictive) requires at least two convincing class III studies.
Rating of Recommendations for a Therapeutic Intervention
Level A rating (established as effective, ineffective, or harmful) requires at least one convincing class I study or at least two consistent, convincing class II studies.
Level B rating (probably effective, ineffective, or harmful) requires at least one convincing class II study or overwhelming class III evidence.
Level C rating (possibly effective, ineffective, or harmful) requires at least two convincing class III studies.
Good Practice Point (GPP) When only class IV evidence was available but consensus could be reached, the Task Force offered advice as good practice points.
