Serum protein electrophoresis

Serum proteins are separated through agarose gel by molecular weight, shape and charge, and visualised as coalescent bands (figure 1D). Stained bands (figure 1D) can be quantified by densitometry (figure 1C). Normal (figure 1C Blue) or abnormal serum protein electrophoresis patterns (figure 1C, D Red) are obvious. A sharp, well-demarcated matched heavy and light chain band identifies a complete M-protein (figure 1D) as long as it is present in sufficient quantity to visualise it above background. As the serum protein electrophoresis provides a quantification of the paraprotein, it can be used for diagnosis and monitoring. Serum protein electrophoresis alone is not sensitive enough as a screening test in neurology (lower limit of gamma region detection >0.5 g/L9). In low-burden diseases such as MGUS and many relevant low-grade lymphomas serum protein electrophoresis often cannot detect the paraprotein.

Immunofixation

After electrophoresis, antibody fixation with anti-heavy and anti-light chain antibodies increases sensitivity (lower limit of detection ~0.1 g/L9) and types the M-protein (figure 1D). The addition of immunofixation to serum protein electrophoresis improves detection rates from 87.6% to 94.4% in multiple myeloma and 65.9% to 73.8% in AL amyloidosis.10 Immunofixation is qualitative and can be used for diagnosis and assessment of complete remission but not for monitoring. Biochemistry or immunology laboratories often need assistance to understand why the sensitivity of the immunofixation is required as they may be unaware of the low-level pathological paraproteins that are not detected by serum protein electrophoresis but which are crucial to diagnosis and treatment.

Urine protein electrophoresis and immunofixation

Urinary protein electrophoresis is performed in the same way as in serum and has the same benefits and limitations. Urine free light chains (Bence Jones proteins) can occur with or without a detectible serum paraprotein. The urinary protein electrophoresis has only 37.7% sensitivity for paraprotein screening,11 but can help in prognostication and in monitoring treatment response.

Serum free light chains

In this assay, free light chains are detected using antibodies to light chain epitopes hidden when immunoglobulins are intact. This assay does not demonstrate monoclonality; however monoclonality is inferred when there is an abnormal ratio (normal 0.26–1.65) between the kappa and lambda free light chains. The serum free light chains assay plays a useful role in prognostication, disease monitoring and measuring treatment response. However, great care must be taken if using serum free light chains assays as they do not distinguish between polyclonal or monoclonal light chains and can be abnormal in renal impairment and autoimmune disease. Furthermore, false negatives can occur where there is a low-level paraprotein, in biclonal disorders and in disease where there is both monoclonal and polyclonal immunoglobulin (eg, in POEMS syndrome).

Bone marrow aspirate and trephine

A bone marrow aspirate and trephine is a marrow fluid aspirate and a core trephine of bone and marrow (figure 1F). It can establish the cytological features of a clonal population of cells and evaluate the cellular architecture and spatial relationships of the marrow. The marrow can be stained with Congo red for amyloid. Cytogenic and molecular testing can identify chromosomal (eg, t14:16 in multiple myeloma) or somatic mutations (eg, MYD88 L256P mutation in Waldenström macroglobulinaemia) providing important prognostic and treatment information. Bone marrow aspirate and trephine may be necessary to distinguish MGUS from symptomatic disease. However, if a patient is asymptomatic and has a low risk profile (eg, a stable IgG paraprotein <15 g/L and normal serum free light chains ratio, the 20-year risk of progression is <5%12), bone marrow aspirate and trephine may be deferred to limit morbidity and healthcare costs.13

Body imaging–CT skeletal survey, CT scans of neck, chest, abdomen and pelvis or fluorodeoxyglucose-positron-emission tomography-CT (FDG-PET-CT)

Patients may need imaging assessing for nodal or extranodal disease, lytic or sclerotic bony lesions or hypermetabolic ‘hot’ spots to further define the type and extent of disease, and to inform treatment making decisions.

Cerebrospinal fluid (CSF)

CSF analysis, while not necessary for making a diagnosis of a paraproteinaemic neuropathy, can help to exclude direct infiltration of the proximal peripheral nervous system or central nervous system (CNS). Elevated CSF protein levels >1 g/L occur in 80% of demyelinating paraproteinaemic neuropathies.14 If the clinical phenotype suggests neurolymphomatosis, or there are central signs suggesting Bing–Neel syndrome, flow cytometry, immunocytology and molecular studies of CSF cells can be useful. If flow cytometry identifies an abnormal population (figure 1E), PCR for heavy chain (IgH) rearrangements can demonstrate neoplastic proliferation.15 Furthermore, detection of the MYD88 L256P mutation in CSF can help in the diagnosis of Bing–Neel syndrome. If there is blood contamination of the CSF, false positives can occur.

Tissue biopsy

Occasionally multiple biopsies may be required to make a diagnosis. The location of a tissue biopsy (eg, node or bony lesion) should be clinically or imaging targeted. In suspected AL amyloidosis, a fat pad, skin, rectum, gut, salivary gland or flexor retinaculum biopsy might be considered based on the phenotype. A sensory nerve biopsy can be considered if amyloidosis, vasculitis or neurolymphomatosis is suspected but not identified in other biopsies. As well as normal staining, nerves should be visualised with Congo red for amyloid, tinctural markers of vasculitis (eg, haemosiderin) and immunohistochemistry for infiltration with B-cells and T-cells. If amyloid is found, the constituent proteins can be further differentiated.

Anti-MAG paraproteinaemic demyelinating peripheral neuropathy

Anti-MAG antibodies occur in approximately 50% of IgM-associated demyelinating neuropathies, and are most commonly kappa.16 All patients with an IgM paraprotein and demyelinating neuropathy should be tested for anti-MAG antibodies.

Anti-MAG paraproteinaemic demyelinating peripheral neuropathy is the most common in men in their seventh decade. The typical clinical phenotype is an insidious, distal, sensory predominant, sensorimotor neuropathy with unsteadiness and tremor. The key clinical features of an anti-MAG neuropathy are the high vibratory loss, the small fibre sensory loss only in the feet and the almost normal joint position sense despite ataxia and tremor. Typical neurophysiology has prolonged distal motor latencies in the setting of conduction slowing, but without other demyelinating features such as conduction block or temporal dispersion, as seen in chronic inflammatory demyelinating peripheral neuropathy (CIDP). The terminal latency index (TLi=distal conduction distance (mm)/(Conduction velocity (m/s)×distal motor latency (ms))) provides a quantifiable measure of this finding and a TLi of <0.25 suggests anti-MAG paraproteinaemic demyelinating peripheral neuropathy rather than CIDP or demyelinating Charcot-Marie-Tooth disease.17 18

Anti-MAG antibodies are most commonly assayed by a commercial ELISA giving results in ‘Bühlmann units’ (BTU). The assay is non-linear with a positive skew, with low and high cut-offs of 1000 and 70 000 BTU. A titre of >70 000 BTU (‘strong positive’) is likely causally related to the neuropathy. However, 7000–70 000 BTU (‘positive’) or 1000–7000 BTU (‘weakly positive’) titres are less specific and can occur in asymptomatic people or with other neuropathies. Neither the anti-MAG titre nor the level of IgM paraprotein predicts the disease severity or treatment response19 and titres changing by 1000s of BTU have no clinical utility.

The prognosis of anti-MAG paraproteinaemic demyelinating peripheral neuropathy is generally favourable.20 Given the usual slow, insidious progression, many patients do not require treatment. Motor involvement or rapid progression is an indication for treatment, best started within 5 years of diagnosis. Despite a single randomised controlled trial of short-term intravenous immunoglobulin suggesting benefit, any effect diminishes rapidly. Corticosteroids with cyclophosphamide are sometimes useful.20 21 Trials of rituximab (375 mg/m² weekly for 4 weeks) provide low-to-moderate certainty evidence of improvement. Thus, when treatment is indicated, rituximab is the current recommended treatment.21 Stabilisation of the neuropathy is most likely, although significant improvements have been reported. Ibrutinib, a Bruton’s tyrosine kinase inhibitor, looks promising in early studies.22

IgM demyelinating paraproteinaemic neuropathy without MAG antibodies

About 35% of patients with an IgM paraprotein and a neuropathy have no identifiable nerve target.16 IgM-associated anti-MAG antibody-negative neuropathies can have a similar distal acquired demyelinating sensory neuropathy phenotype to anti-MAG paraproteinaemic demyelinating peripheral neuropathy.23 Underlying haematological conditions include IgM MGUS, Waldenström macroglobulinaemia, chronic lymphocytic lymphoma or B lymphoproliferative disorders. There may be conduction velocity slowing, without temporal dispersion or conduction block. The presence of atypical features, such as rapid progression, prominent early motor involvement, early axonal damage and autonomic or other organ involvement, should prompt assessment for AL amyloidosis or cryoglobulinaemic vasculitis. Uncomplicated slowly progressive IgM-paraprotein/distal acquired demyelinating sensory neuropathy alone can be monitored for unexpected progression of either the neuropathy or haematological disease, to initiate treatment.23 Treatment should be directed at the haematological diagnosis if appropriate and required.19

Multifocal motor neuropathy with conduction block

Occasionally a multifocal motor neuropathy with conduction block phenotype occurs in conjunction with an IgM paraprotein with antiganglioside GM1 or GD1b antibodies.19 When the antiganglioside titre is very high, the paraprotein is likely to harbour the GM1/GD1b activity. Although there are no data to support treatment in this situation, where intravenous immunoglobulin is ineffective, treatment might be directed at the gammopathy. Multifocal motor neuropathy with conduction block typically presents as an asymmetric, pure motor, upper limb predominant multiple mononeuropathy with a male preponderance. The key feature is the anatomically identifiable individual motor nerve involvements with the only sensory deficit being mild vibration loss at the toes. More information can be found in Yeh et al.24

Chronic ataxic neuropathy with ophthalmoplegia, M-protein, cold agglutinins and disialosyl ganglioside antibodies (CANOMAD)

CANOMAD is a very rare chronic neuropathy, characterised by sensory neuropathy with ataxia, ophthalmoplegia and occasionally other cranial neuropathies, typically bulbar.25 26 A slowly progressive course is common but a there may be a relapsing–remitting phenotype.25 The IgM paraprotein has one or more anti-disialylated ganglioside activities.25 An acellular CSF with raised protein is expected25 and occasionally the only abnormalities in neurophysiology are in the evoked potentials. The underlying gammopathy may be IgM MGUS, B-lymphoproliferative disorder or Waldenström macroglobulinaemia.25 In some cases, intravenous immunoglobulin is effective, but others need rituximab or chemotherapy directed to the clonal population.25

IgM deposition disease

IgM deposition-associated neuropathy is an extremely rare form of paraproteinaemic neuropathy, mimicking amyloidosis and requiring nerve biopsy (figure 5C,D), often using electron microscopic features for diagnosis.27 28 The clinical phenotype is an asymmetric, painful, distal, sensory neuropathy, sometimes with cranial nerve involvement with onset in the seventh and eighth decades.29–31 Motor neuropathy and wasting appear late27–34 but autonomic involvement does not occur.28 Neurophysiological changes are axonal. The long-term prognosis is more favourable than amyloid, with survival of up to 13 years.28

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Figure 5

Typical nerve biopsy and MRI findings in paraproteinaemic neuropathy. (A)–(B) AL amyloidosis. (A) Amyloid deposit in an endoneurial blood vessel wall in a Congo red stained nerve biopsy section. (B) Immunohistochemical staining of endoneurial vessel walls showing lambda light chain staining. (C)–(D) IgM deposition disease. (C) Large deposits of amorphous eosinophilic material in the subperineurial space on toluidine blue stain, inset negative Congo red staining. (D) Positive immunohistochemical IgM staining of the amorphous subperineurial deposits. (E)–(F) Neurolymphomatosis. (E) Perivascular, inflammatory cell infiltrate surrounding epineurial, subperineurial and endoneurial blood vessels on toluidine blue stain. (F) Immunohistochemical CD20 staining demonstrates the inflammatory infiltrate is positive for CD20. (G)–(H) MR scan of brain in POEMS syndrome. (G) T1-weighted gadolinium enhanced image demonstrating diffuse enhancement of intracranial pachymeninges (red arrow). (H) T1-weighted gadolinium enhanced image of the cervical spine demonstrating intradural leptomeningeal enhancement of cervical nerve roots. G–H images modified with permission from Ziff et al. Frequent central nervous system, pachymeningeal and plexus MRI changes in POEMS syndrome. J Neurol 266, 1067–1072 (2019).

Bing–Neel syndrome

Bing–Neel syndrome is a rare complication of Waldenström macroglobulinaemia, caused by the infiltration of lymphoplasmacytic cells into the CSF, meninges or cerebral parenchyma as well as the proximal nerve roots and peripheral nerves. As a result, the presentation is diverse and should always be considered in lymphoplasmacytic lymphoma. Raised intracranial pressure headaches, cognitive and psychiatric dysfunction, seizures, cranial and peripheral neuropathies and gait disorders may occur.35 Bing–Neel syndrome can be an initial lymphoplasmacytic lymphoma manifestation but usually presents in Waldenström macroglobulinaemia relapse, with a gradually progressive course over weeks to months. It can arise with other pre-existing Waldenström macroglobulinaemia-associated diseases (eg, anti-MAG paraproteinaemic demyelinating peripheral neuropathy); thus, Bing–Neel syndrome should be considered if central or atypical features develop.35

The diagnosis is made by MR scan of brain with gadolinium followed by a clean CSF analysis to prevent false positive results. MRI abnormalities are seen in 80%, most commonly leptomeningeal enhancement, and less frequently parenchymal lesions.35 CSF analysis should always include flow cytometry with molecular testing to confirm the diagnosis with the surface immunohistochemical signature,35 immunoglobulin heavy chain rearrangement for clonality and identification of the somatic MYD88 L256P mutation (positive in 94%–100%).

Treatment of Bing–Neel syndrome follows published guidelines36 but is changing rapidly. Corticosteroids, CNS-penetrating chemotherapy and radiotherapy are all used with the goal of reversing clinical symptoms and providing protracted progression-free survival. Ibrutinib is very effective35 and next-generation Bruton’s tyrosine kinase inhibitors (zanubrutinib), proteasome inhibitors (marizomib) and B-cell lymphoma-2 (BCL2) antagonists (venetoclax) all hold promise.35

Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin lesions—POEMS syndrome

POEMS syndrome is a rare paraneoplastic condition characterised by a monoclonal proliferation of plasma cells, producing an M-protein, almost always with a lambda light chain, a disabling inflammatory peripheral neuropathy and additional widespread multisystem features. POEMS is frequently misdiagnosed as CIDP, Guillain–Barré syndrome or another neuropathy, with the correct diagnosis delayed by an average of 15 months.37 This delay in diagnosis has significant morbidity implications with 76% of patients losing independent mobility and 36% being bed or wheelchair users at diagnosis.37

CIDP is the most common misdiagnosis but POEMS very seldom has proximal weakness at presentation, has early axonal loss on neurophysiology and nearly always has obvious multisystem involvement; by the time of diagnosis patients have a median of seven features.37 This symphony of features makes diagnosis easy (see table 1).

The neuropathy in POEMS is easily identifiable. It is subacute with progressive, ascending, length-dependent positive and negative sensory symptoms. Almost every patient describes aching calf pain at onset, which later develops into a more typical dysaesthetic neuropathic pain. Distal weakness with a sharp demarcation of weakness at the ankles and then wrists are the norm. Proximal weakness, typical of CIDP, occurs only in severely progressed disease. The Castleman’s (lymphadenopathy with typical histopathological features) variant of POEMS syndrome has a much milder, often pure sensory neuropathy. A length-dependent, sensorimotor neuropathy, with upper limb conduction slowing (no conduction block or temporal dispersion) and lower limb axonal loss is typical of the neurophysiology37; lower limb sensory and motor responses are usually absent.37 CSF protein is elevated (often very high) in 96%–100%.37–40 Brachial and lumbosacral plexus thickening, with appearances undifferentiated from CIDP, develops in 59%.37 Patients with POEMS occasionally present with large or small vessel ischaemic infarcts or subarachnoid haemorrhage. Diffuse asymptomatic pachymeningeal thickening (figure 5G), dural fluid collections and white matter lesions develop in more than 70% of cases, and can help to distinguish POEMS from CIDP.37

Identifying the diagnostic criteria for POEMS makes the diagnosis (table 1). Serum VEGF is elevated in 94% of cases, typically >1000 pg/mL, and is a diagnostic, therapeutic and relapse biomarker.37 Failure of VEGF suppression with treatment portends a poor prognosis.37 The VEGF cannot be interpreted without a lambda light chain monoclonal disorder, which occurs in 98%.37 The serum free light chains can be misleading as the ratio is frequently normal with polyclonal kappa and lambda stimulation.37 If serum and urine investigations do not identify an M-protein, patients need a bone marrow aspirate and trephine, targeted bony lesion or plasmacytoma biopsy. The bone marrow aspirate and trephine typically contains a low volume (1%–5%) of CD138 positive and light chain restricted clonal plasma cells with megakaryocyte hyperplasia.37

Optimal treatment for systemic disease is autologous stem cell transplantation; however, it is not appropriate for all. Chemotherapy (lenalidomide, melphalan, bortezomib or cyclophosphamide and dexamethasone) can de-bulk disease, to allow a future autologous stem cell transplantation (but note that the use of melphalan is not compatible with later stem cell harvest), or may also be used as a long-term treatment in those unfit for this procedure. Radiotherapy is preferred for those with two or fewer bony lesions. The overall treated 5-year survival is 90%, and 82% at 10 years (progression-free survival 65% and 53%).37 Improvement of the neuropathy typically starts 2 years after disease suppression in severely affected patients. Rehabilitation strategies to promote mobility and to reduce contractures are essential.

Myeloma

Peripheral neuropathy develops as a consequence of myeloma in fewer than 3% of cases. The mechanisms are usually a result of cryoglobulinaemia, amyloidosis or treatments, or more commonly bony or extranodal lesions causing neural compression.

Light chain (AL) amyloidosis

AL amyloidosis should be considered in any paraproteinaemic neuropathy. As with POEMS, if the diagnosis is delayed there are significant effects on morbidity and mortality.

AL amyloidosis is the deposition of monoclonal light chains, usually lambda, in tissues and organs. AL amyloid neuropathy presents as a rapidly and relentlessly progressive, (usually) painful, length-dependent, small-fibre and autonomic neuropathy, with sequential development of length-dependent sensory and then motor nerve involvement.41 Carpal tunnel syndrome from flexor retinaculum amyloid deposition is common. Plexus, brachial and lumbar radiculopathies, and cranial neuropathies may occur.41 42 Autonomic neuropathy causing postural hypotension, erectile dysfunction, gastroparesis, changed bowel habit, sweating and pupillary abnormalities occur in up to 65%.41

The neurophysiology identifies a symmetrical, length-dependent, axonal, sensory predominant, sensorimotor neuropathy but not infrequently conduction slowing, and asymmetric and patchy alterations promote electrophysiological diagnostic uncertainty. Frequently the clinical picture is so clear as to not need formal assessment of autonomic function beyond bedside assessments.

As with POEMS, the co-occurrence of a typical neuropathy with additional organ involvement is the key to diagnosis of AL amyloidosis. Autonomic involvement, in a patient without diabetes but with an acquired neuropathy, suggests amyloid until proven otherwise. Carpal tunnel syndrome, or cardiac arrhythmia, and an appropriate neuropathy should also stimulate investigation. ‘Textbook’ systemic features of amyloid (macroglossia), periorbital ecchymoses (’racoon eyes’), renal dysfunction with proteinuria and gastrointestinal bleeding (figure 2) are much less common but give valuable clues. Genetics for hereditary transthyretin amyloidosis (ATTRv) should be performed in parallel as 10%–20% of patients with ATTRv have a concurrent paraprotein.43

Tissue biopsies from accessible sites are recommended; quoted diagnostic yields are good from periumbilical subcutaneous fat (75%), rectum (81%) or salivary gland (86%).44–46 A concurrent bone marrow aspirate and trephine can improve the sensitivity to 90%.19 Targeted flexor retinaculum, skin, gastrointestinal, endomyocardial, nerve or muscle biopsies can be performed and may increase yield. The sensitivity of nerve biopsy varies widely in studies (30%–100%), limited by both disease and investigational expertise.44 47 Amyloid has an easily recognisable microscopic appearance (figure 5A,B). Genetics, and laser microdissection and mass spectrometry on biopsies have been used, when immunohistochemical staining is negative, to identify amyloid subtype.48 49

Suppression of the clonal process can slow progressive morbidity. In general, in low risk patients an autologous stem cell transplantation with or without bortezomib induction and conditioning provides best long-term outcomes.50 If ineligible for transplantation, a bortezomib containing regimen is preferred.50 Greatly improved treatment-related neurotoxicity is achieved if bortezomib is administered subcutaneously, weekly.19

Neurolymphomatosis

Neurolymphomatosis is the direct infiltration of individual peripheral nerves, plexus or nerve roots by a clonal population of lymphoma, or rarely leukaemic cells, occurring in 5% of all lymphomas.51 The clinical phenotype is usually a progressive, painful, asymmetric, mononeuritis multiplex pattern, with an acute or sub-acute onset.52 However, a symmetric polyneuropathy with both distal and proximal weakness, mimicking CIDP, has been described.53–55 The proximal blood–nerve barrier is deficient, and infiltration of the proximal nerve trunks is common, resulting in proximal conduction slowing mimicking demyelination, with secondary distal axonal degeneration.55 Neurophysiology can show partial (pseudo-) conduction block, which as a stage before axonotmesis can respond more favourably to early treatment.53 55 56 In some series up to 34% of patients with pathologically confirmed neurolymphomatosis fulfil the 2010 EFNS/PNS criteria for CIDP55; hence in patients with treatment resistant CIDP, neurolymphomatosis should be considered. Eventually the conduction slowing and block transform into clear axonal degeneration.52 55 56

A nerve biopsy is required for diagnosis (figure 5E,F). Unfortunately, disease is often proximal, and biopsy risks morbidity. However, with MRI or PET-CT guidance the sensitivity of nerve biopsy increases to 88%.57 Where biopsy is not possible CSF combined with contrast-enhanced MRI imaging or FDG-PET CT can help.52 55 58 The diagnostic yield of MRI is estimated at 80% and PET at 88% (ensure the PET goes to the toes when lower limb involvement is present) to identify peripheral nerve infiltration.57 The CSF protein is frequently raised, and an abnormal population of cells can be identified using flow cytometry, immunohistochemistry and clonality studies. Because the peripheral nervous system is sequestered behind the blood–nerve barrier it is a common site for lymphoma recurrence.55 59 CSF and blood-nerve penetrating chemotherapeutic regimens are required to optimally manage neurolymphomatosis.54 55

Cryoglobulinaemia and cryoglobulinaemic vasculitis

Cryoglobulins are either mono- or polyclonal immunoglobulins that precipitate in blood and tissues at temperatures below 37°C, and dissolve with rewarming. Cryoglobulinaemias are classified into three types60 61:

• Type I: monoclonal immunoglobulin (IgM>IgG>IgA>light chain) only, and occurring in monoclonal gammopathies (MGUS: 40%, multiple myeloma, Waldenström macroglobulinaemia or chronic lymphocytic lymphoma: 60%).

• Type II: monoclonal IgM and polyclonal IgG, occurring in infections (hepatitis C: 90%, HIV, hepatitis B), connective tissue diseases or lymphoproliferative diseases (B-cell lymphomas or Waldenström macroglobulinaemia).

• Type III: polyclonal IgM and polyclonal IgG, occurring in connective tissue disease or infection (hepatitis C).

Cryoglobulinaemia associated with haematological malignancy makes up less than 25% of all cases.61 Cryoglobulinaemia may be asymptomatic, and incidentally identified, or symptomatic, where it results in cryoglobulinaemic vasculitis.61 The pathogenesis of monoclonal and mixed cryoglobulinaemia differs, and this accounts for different disease manifestations. Type I cryoglobulins undergo temperature and concentration dependent crystallisation and aggregation leading to small vessel occlusion with the occasional development of small vessel vasculitis. This causes predominant distal extremity and renal dysfunction.61 Mixed cryoglobulinaemias form immune complexes leading to cryoprecipitation with rheumatoid factor activity, complement fixation and vasculitis.61 As a result, rheumatoid factor levels are often high and complement C4 consumed, resulting in diagnostic confusion with rheumatoid vasculitis.61

In type I cryoglobulinaemia, skin manifestations occur in 86%, predominantly involving distal limbs, nose and ears.61 Livedo reticularis, purpura, acrocyanosis, Raynaud’s phenomenon, skin ulcers, necrosis and gangrene are frequent and amputations not uncommon.61 Nerve involvement occurs in 19%–44% of type I cryoglobulinaemia.61 The neuropathy is typical of other confluent vasculitides with predominant small fibre sensory change in 25% and no autonomic involvement62; mononeuritis multiplex is uncommon.62

In mixed cryoglobulinaemias (type II and III) systemic symptoms, including fever, lethargy, myalgia, arthralgia and anorexia occur secondary to immune complex formation.61 A relapsing–remitting course is typical. Skin biopsy specimens can identify widespread leukocytoclastic vasculitis with fibrinoid necrosis.61

Limiting cold exposure of extremities is an essential part of management. Reduction of the underlying clonal disease and plasmapheresis with body temperature replacement fluid to avoid precipitation, and corticosteroids can be useful.61

Hyperviscosity syndromes

Hyperviscosity syndromes occur with very high paraprotein or cryocrit levels causing capillary viscosity to be greater than 4.0 centipoise (normal <1.5)63; these can be life-threatening. Build-up of paraproteins in disease, or flares after rituximab treatment of gammopathies can precipitate hyperviscosity.64 Common symptoms of hyperviscosity include nasal or gingival bleeding, blurred vision, retinal haemorrhage, acute deafness, headache, ataxia, confusion and stroke, and fluid overload due to volume expansion. Hyperviscosity is most often IgM associated disease because of the pentameric IgM structure (figure 1B).63 Hyperviscous patients require immediate plasma exchange (which can also be used as rituximab pre-treatment), and then treatment of the clonal disorder.

CIDP with a paraprotein

Extensive discussion of CIDP is beyond the scope of this review, however some key points should be emphasised. Raised CSF protein is frequently found in both paraproteinaemic neuropathies and typical CIDP and hence is not useful as a distinguishing factor. Neurophysiology can help to distinguish CIDP and paraproteinaemic neuropathies, as conduction block and temporal dispersion occur in CIDP, but not anti-MAG or POEMS neuropathy.14 37 IgG and IgA associated ‘typical CIDP’ is nearly always CIDP with a coincidental paraprotein. Lastly, paraproteinaemic neuropathies are commonly misdiagnosed as CIDP for extended periods leading to accrued disability and increased mortality. Clinicians should be aware of the extra-neural features of POEMS or AL amyloid, and reconsider a CIDP diagnosis in every treatment-resistant patient.