With optimal approaches still evolving for the diagnosis and management of peripheral neuropathies associated with Waldenström macroglobulinemia and other IgM paraproteinemias, new consensus recommendations from a multidisciplinary panel were recently published in the British Journal of Haematology.
Up to half of patients with IgM monoclonal gammopathies develop peripheral neuropathy, according to the 11-member panel (Br J Haematol. 2017 Mar;176[5]:728-42). The panel began deliberations at the eighth International Workshop on Waldenström Macroglobulinemia in London and was led by Shirley D’Sa, MD, of the Waldenström Clinic, Cancer Division, University College London Hospitals NHS Foundation Trust.
• Diagnostic evaluation: “The indications for invasive investigations such as cerebrospinal fluid analysis, nerve conduction tests, and sensory nerve biopsies are unclear,” according to the panelists.
When clinical examination identifies a neuropathy, neurophysiologic testing can ascertain its nature and inform additional work-up. Cerebrospinal fluid examination is not mandatory in cases of demyelinating neuropathy, but it is indicated when clinical evaluation is inconclusive and malignancy or CNS invasion is suspected.
Nerve biopsy carries substantial risk and is rarely indicated. It may be warranted when a comprehensive systemic work-up has not identified a cause and clinicians still suspect amyloid, vasculitis, or direct cellular invasion; in atypical cases not responding to treatment; or when the neuropathy is progressive and debilitating.
When it comes to imaging, “MRI of the neuraxis should be performed prior to lumbar puncture to avoid false positive meningeal enhancement,” they advised. “Prior discussion of likely sites of involvement with an experienced neuroradiologist will ensure that the correct sequences of the correct anatomical area are performed with appropriate gadolinium enhancement.”
• Clinical phenotypes and their treatment: IgM-associated neuropathies vary with respect to specific antibodies present and the likelihood that they are causally associated with the neuropathy, Dr. D’Sa and her colleagues noted. They provided a decision tree to help guide the work-up to determine the specific etiology.
“The presence of a neuropathy alone is not a justification for treatment, but steady progression with accumulating disability should prompt action,” they maintained.
Patients with antibody-negative peripheral neuropathy associated with IgM monoclonal gammopathies of undetermined significance who have mild disease and no hematologic reason for treatment can be managed with surveillance, according to the panelists.
However, immunosuppressive or immunomodulatory treatment should be considered when there is substantial or progressive disability associated with demyelination.
Patients with anti-MAG (myelin-associated glycoprotein) demyelinating neuropathy may benefit from rituximab (Rituxan). In those with more advanced disease, clinicians should consider immunosuppressive or immunomodulatory treatment instead.
Surveillance is also an option for Waldenström macroglobulinemia–associated peripheral neuropathy that is progressing slowly. When used, treatment should be tailored to severity of both systemic and neurologic disease.
• Treatment response assessment: “The optimum way to measure clinical response to treatment unknown,” Dr. D’Sa and her fellow panelists noted. A variety of measures of muscle strength, sensory function, and disability are used.
“The I-RODS [Inflammatory Rasch-Built Overall Disability Scale] more often captures clinically meaningful changes over time, with a greater magnitude of change, compared with the INCAT-ONLS [Inflammatory Neuropathy Cause and Treatment–Overall Neuropathy Limitation Scale] disability scale and its use is therefore suggested in future trials involving patients with inflammatory neuropathies,” they wrote.
• Model of care: Management of patients with IgM-associated neuropathies requires multidisciplinary care with good collaboration to optimize patient outcomes, the consensus panel said.
“A suggested model of care is a combined neurological and hematological clinic, in which patients are seen jointly by a specialist neurologist and hematologist and a decision can be made about the sequence of investigations, interventions, and the formulation of a treatment plan,” they proposed. “Appropriate and timely referral to physical, occupational, and orthotic professionals is recommended in order to maximize safety and function.”
• Future perspectives: “There is much to be done to improve outcomes for patients with IgM and [Waldenström macroglobulinemia]-associated peripheral neuropathies,” the panelists concluded.
Key areas of focus are “early recognition of the problem, appropriate causal attribution achieved through sensitive diagnostics that are not overly invasive, timely therapeutic intervention with effective and nonneurotoxic therapies, achievement of an appropriate degree of clonal reduction for optimum clinical outcomes, and the use of reproducible and readily applicable tools to measure outcomes.”
Dr. D’Sa disclosed that she receives honoraria from Janssen.