Br J Haematol. 2017 Mar;176(5):728-742. doi: 10.1111/bjh.14492.

Investigation and management of IgM and Waldenström-associated peripheral neuropathies: recommendations from the IWWM-8 consensus panel.

D’Sa S1, Kersten MJ2, Castillo JJ3, Dimopoulos M4, Kastritis E4, Laane E5, Leblond V6, Merlini G7, Treon SP3, Vos JM2,8, Lunn MP9.

1 Waldenström Clinic, Cancer Division, University College London Hospitals NHS Foundation Trust, London, UK.
2 Department of Haematology, Academic Medical Centre, Amsterdam, the Netherlands.
3 Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
4 Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece.
5 Department of Haematology, North Estonia Medical Centre, Tallinn, Estonia.
6 AP-HP Hôpital Pitié Salpêtrière, UPMC Univ. Paris 6 GRC-11, Grechy, Paris, France.
7 Centre for Research and Treatment of Systemic Amyloidosis, University of Pavia, Pavia, Italy.
8 Cancer Centre, Sint Antonius Ziekenhuis, Nieuwegein, the Netherlands.
9 Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, London, UK.



Paraproteinaemic neuropathies are a heterogeneous group of disorders most frequently associated with IgM monoclonal gammopathies including Waldenström macroglobulinaemia (WM). Their consequences are significant for affected patients, and their management challenging for their physicians. The variability in clinical presentation and time course hamper classification and management. The indications for invasive investigations such as cerebrospinal fluid analysis, nerve conduction tests and sensory nerve biopsies are unclear, and the optimum way to measure clinical response to treatment unknown. When to intervene and and how to treat, also present challenges to physicians. As part of its latest deliberations at the International Workshops on WM (IWWM) in London, UK (August 2014), the IWWM8 panel have proposed a consensus approach to the diagnosis and management of peripheral neuropathies associated with IgM monoclonal gammopathies, including WM. Importantly, a consensus regarding the use of clinical outcome measures and recommended models of care for this group of patients is discussed, as well as appropriate treatment interventions. 2017 John Wiley & Sons Ltd.

KEYWORDS: IgM; Waldenstrom macroglobulinaemia; paraproteinaemic neuropathy

PMID: 28198999



Introduction: IgM paraprotein-associated neuropathies are a heterogeneous group of disorders whose exact prevalence is unknown. The prevalence of peripheral neuropathy (PN) in persons with monoclonal gammopathy of uncertain significance (MGUS) is up to 30-50% in the IgM setting. Peripheral neuropathy affects 2.4% of the general population, increasing to 8.0% with advancing age. When these two common conditions coexist, it is important to consider a causal association between the two conditions.

High quality evidence links at least 50% of the demyelinating neuropathies to a causal IgM paraprotein, including antibody transfer models, high titre IgM antibodies with a neural target (myelin associated glycoprotein (MAG)), site specific binding studies by light and immunoelectron microscopy, a unique pathological substrate (widely spaced myelin) and a response to treatment to reduce paraprotein levels. Alternative antibody targets include gangliosides GM1 and GD1b, and sulphatide.

In the setting of neural damage mediated by an IgM paraprotein, the presence of a neuropathy alone is not a justification for treatment, but steady progression with accumulating disability should prompt action.

Diagnosis and Investigation: A history and examination should delineate the important clinical features of the PN and are key to further appropriate testing and management. The nature of the PN symptoms, including speed of onset, clinical course, rate of change and effect on functional abilities, as well as the involvement of motor, sensory and autonomic systems assists the differential diagnosis and subsequent decision making.

Nerve conduction tests are advisable to define the neural pathology. Electrophysiological features associated with IgM-associated PN include symmetrical reduction of conduction velocities; more severe sensory than motor involvement; disproportionately prolonged distal motor latency (DML) and absent sural potentials. Atypical features should raise other possibilities.

MRI should ideally be performed prior to a diagnostic lumbar puncture (LP) for CSF analysis, as false-positive leptomeningeal enhancement may result from LP-related meningeal irritation.

Magnetic resonance imaging of the neuraxis with or without gadolinium enhancement is indicated in cases of suspected neural compression, leptomeningeal or radicular infiltration or where peripheral and central nervous system (CNS) features are present in the clinical examination. CNS involvement by WM (Bing Neel syndrome) is not addressed here. Brain involvement may appear as parenchymal lesions on MRI images. Nerve root or cranial nerve involvement may result in leptomeningeal or dural enhancement, or cranial nerve enlargement and enhancement. Spinal MRI can reveal enhancing intradural soft tissue, thickening and enhancement of nerve roots and leptomeningeal enhancement. Lymphomatous infiltration of individual nerves, spinal roots, cranial nerves or plexi is characterised by nodular or diffuse thickening of nerves which usually enhances with contrast.

CSF protein is significantly elevated (>1.0 g/L) in up to 80% of demyelinating paraproteinaemic neuropathies most likely due to humoral attack. Where relevant symptomatology is present, such as an asymmetrical pattern or mononeuritis multiplex, infiltration of the peripheral nerves may be the cause.

In suspected CNS disease, the presence of malignant cells in the CSF should be sought by immunocytology and/or flow cytometry. If a comprehensive clinical work up fails to identify a cause in the presence of a progressive and debilitating PN, and/or amyloidosis, vasculitis or direct nervous system invasion is suspected, a sensory nerve biopsy is may be required.

The following clinical scenarios are regularly encountered:

Waldenströms macroglobulinaemia (WM) -associated peripheral neuropathy:

Symptoms of PN are present in about 20% of patients with WM at diagnosis, and up to 50% are affected at some time in the course of their disease, most often a distal chronic symmetrical predominantly sensory polyneuropathy. Nerve conduction studies show evidence of demyelination with prolonged DML and reduced conduction velocities in the cases associated with MAG antibodies. Axonal neuropathies or mixed axonal and demyelinating neuropathies may also seen, especially when anti-MAG assay is negative.

When significant titres of anti-MAG antibodies are present, they are probably pathogenic in the WM setting. If atypical clinical or electrophysiological features are present, other pathologies including amyloidosis, cryoglobulinaemia, vasculitis or direct tumoural invasion of peripheral nerves may be instrumental and appropriate investigations should be performed.

There are no trial data specifically assessing the efficacy of treatment options in WM-associated PN. A variety of treatments have been used, including alkylating agents, purine analogues and Bortezomib with or without Rituximab, of which approximately half show symptomatic improvement in the PN. Such improvement is more likely with non-amyloid related PN, in patients who achieved a major haematological response, those who received therapy within 24 months of the onset and those who receive rituximab combination vs. any monotherapy vs. rituximab alone. A paradoxical increase in IgM levels following rituximab (‘flare’) occurs in 30% to 70% of patients immediately after completing the rituximab course and may be associated with a temporary worsening of PN symptoms. Newer agents such as Ibrutinib and Carfilzomib are showing promise regarding symptomatic improvement in PN associated with WM.

How to manage: Patients with slowly progressing WM or PN do not require immediate therapy. Where treatment is required, treatments such as Rituximab, Dexamethasone, Cyclophosphamide and Rituximab (DRC), Bendamustine-Rituximab (BR), Carfilzomib, Rituximab, Dexamethasone (CARD) or purine analogue combinations are possible options.  When indicated, treatment of appropriate intensity to remit both the systemic disease and the neurological component is required. Ibrutinib, where available could be considered in the setting of intolerance of chemotherapy-based therapies or if previous therapies have failed. Appropriate precautions should be taken in patients considered at high risk of a flare (IgM > 40 g/L), such as deferring rituximab until cycle 2 of combination chemotherapy or performing prior plasma exchange. Avoidance of neurotoxic agents is important; the vinca alkaloids have no place in the management of WM, particularly those with PN.  Plasmapheresis, corticosteroids and IVIG are of little or no value in the treatment of WM-associated neuropathies.

Peripheral neuropathy associated with anti-MAG antibodies: All patients with IgM-associated demyelinating PN should be tested for anti-myelin associated glycoprotein (MAG) antibodies. A clinically significant result is ‘strongly positive’ (for example > 70000 Bühlmann units (BTU)). ‘Weakly positive’ (1000 – 7000 BTU) or ‘positive’ (7000 – 70000 BTU) anti-MAG antibodies are less specific and may occur in the absence of a PN or alongside an unconnected neuropathy. If the anti-MAG assay is negative in the presence of an IgM-associated PN, testing for IgM antibodies against other neural targets including the gangliosides GM1, GD1a, GD1b, GT1b, GM2 and GM3 and the paragloboside SGPG should be undertaken. GM1 antibodies may be causally associated with a multifocal motor neuropathy, as can IgM GD1b antibodies. IgM disialosyl antibodies associate with CANOMAD (chronic ataxic neuropathy with ophthalmoplegia, M-protein, cold agglutinins and disialosyl ganglioside antibodies). Among IgM-related demyelinating neuropathies, 30-40% still have no identifiable antibody. The electrophysiological features associated with anti-MAG IgM demyelinating PN are readily recognisable with slowing of the main trunk velocity but disproportionate prolongation of the DML.

How to manage: Measurably progressive disease causing disability is an indication to consider definitive treatment given within 2 years from onset where possible for maximal benefit. Anti-MAG titres and levels of IgM paraprotein are neither related to the severity of neuropathy nor predictive of response to treatment.

There is moderate quality evidence that rituximab at a standard dose of 375mg/m2 administered weekly for 4 weeks is of benefit in the treatment of anti-MAG demyelinating neuropathy. Some studies report a worsening of the PN, possibly related to a Rituximab-induced flare of the IgM.

In patients with significant or progressive disability associated with a demyelinating anti- MAG associated IgM MGUS with a co-existent neuropathy, immunosuppressive or immunomodulatory treatment may be considered as an alternative to Rituximab depending on availability, comorbidity and patient preference.

IVIG may have some limited benefit in the short term but is of little clinical use. Corticosteroids alone are not effective but may be beneficial in combination with other agents such as cyclophosphamide. The purine analogues have demonstrated a modest improvement in some studies but toxicities are likely to be greater. For occasional patients with rapidly worsening neuropathy especially with signs of motor disability, sequentially administered active agents, combinations thereof or even high dose therapy have been attempted. 

IgM MGUS-associated peripheral neuropathy without antibodies: The typical clinical phenotype of antibody-negative PN seen in the setting of IgM monoclonal gammopathies is typically distal, chronic (>6 months), symmetrical and painless with a predominance of sensory symptoms, accompanied by imbalance or ataxia, tremor and mild or minimal weakness and demyelination on electrophysiological studies. The neuropathy is felt to be related to the monoclonal protein but the exact mechanism is unclear.

How to manage: The indication for therapeutic intervention depends on the patient’s needs. In patients without significant disability or haematological reason for treatment, there is no indication for immunosuppressive or immunomodulatory treatment, but ongoing surveillance is recommended to detect change that requires intervention. In patients with significant or progressive disability, immunosuppressive or immunomodulatory treatment may be effective. In patients who are unresponsive to measures such as IVIG, steroids or plasma exchange, agents such as Rituximab, in combination with alkylators, purine analogues or steroids could be considered. Symptomatic treatment for tremor may be helpful, and patients should remain under review to identify evidence for clinical evolution.

AL Amyloidosis associated with Waldenström’s macroglobulinaemia: AL amyloidosis should always be considered as a possible cause of a paraproteinaemic neuropathy. Common presentations include a progressive, painful small fibre predominant length-dependent PN which typically starts in the feet, accompanied by an autonomic neuropathy in about 65% of cases. Amyloid is most often a systemic disease; additional organ involvement is a strong pointer to an amyloidogenic PN. Such features may include cardiac insufficiency and arrhythmia, renal impairment with proteinuria, autonomic neuropathy, GI bleeding, macroglossia and bleeding diatheses. Early recognition is more likely to curtail irreversible organ damage and reduce mortality. Screening for AL amyloidosis can be performed using two biomarkers, serum NT-proBNP and urinary albumin that detect early amyloidosis in 97% of patients.

How to manage: Treatment of AL amyloidosis should be risk-adapted and response-tailored; neurotoxic agents should be used with caution. Rapidly-acting induction regimens followed by high dose therapy and autologous stem cell transplantation in first response is the treatment of choice in suitable patients. For transplant ineligible patients (75-80% cases), Bendamustine, purine analogue or Bortezomib-based combinations are effective. There is anecdotal experience of the benefit of maintenance Rituximab as a way to deepen the light chain response in treatment of amyloidosis in the WM (but not MGUS) setting.

Small fibre neuropathy associated with Waldenström’s macroglobulinaemia: Small fibre neuropathy typically presents with length-dependent burning pain beginning in the feet and may spread more proximally.

How to manage: Evidence-based justification for treating a WM or MGUS associated small fibre neuropathy is lacking. Treatment is usually symptomatic with tricyclic antidepressants, newer selective serotonin reuptake inhibitor/ serotonin norepinephrine reuptake inhibitor drugs, opioids and gabapentinoids.

Treatment response and clinical outcome measures: Assessing clinical response in the setting of treated IgM and WM-associated neuropathies is a multifaceted process, taking account of the haematological response criteria as well as the neurological response. The rate and degree of neurological response depends on the pre-treatment status of the patient. Patients with significant axonal damage may have limited neurological recovery. Historically, outcome measures have focused on assessment of impairment based on muscle strength and sensory testing and disability, using classical test theory derived scales. Instead, Rasch Theory-built scales linearly reflect patient function over a whole range of abilities and are designed and validated for individual diseases. They comprise a questionnaire that can be easily completed by the patient. The Inflammatory Rasch-Built Overall Disability Scale (I-RODS) is a valid disability scale for inflammatory neuropathies which captures meaningful changes over time and its use is recommended in this setting.

Models of care: In order to achieve meaningful clinical outcomes, joint working across disciplines is a recommended approach to enhance the likelihood of performing appropriate diagnostics and offering optimum therapeutic and supportive input. Physical and occupational therapists play a vital role in improving and maintaining functions that may be limited by PN including exercise intervention to help improve strength and balance, and coordination activities which can help decrease the risk of falling. Patient education can focus on improving safety, preventing injury and finding alternative ways to perform certain tasks. Provision of appropriate and well-fitting orthotic supports, can improve the efficiency of movement as well as harvesting energy from gait.

Conclusions: Paraproteinaemic neuropathies are a heterogeneous group of disorders most frequently associated with IgM monoclonal gammopathies including Waldenström’s  macroglobulinaemia (WM). Their consequences are significant for affected patients, and their management challenging for their physicians. Careful diagnostics can identify the underlying aetiology and if related to the underlying monoclonal gammopathy, judicious administration of appropriate therapies can improve outcomes for these patients.