Table 1 Diagnostic tests for PPN

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.

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.

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.

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.

Acute inflammation and infection can also result in increased uptake safety profile of the procedure, even though it is less sensitive than biopsy.