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• Refining diagnosis of early POEMS syndrome
  Nimish J Thakore, Yuebing Li
  Published on: 17 February 2019

• Published on: 17 February 2019

  Refining diagnosis of early POEMS syndrome

  • Nimish J Thakore, Neurologist Cleveland Clinic, Cleveland, Ohio, USA
  • Other Contributors:
    • Yuebing Li, Neurologist

  We applaud Suichi et al.[1] for proposing new diagnostic criteria for POEMS syndrome. There is clearly a need for simplified validated criteria that permit early diagnosis of this rare, elusive and devastating paraneoplastic disorder, especially because early local or systemic treatment of the underlying plasma cell malignancy can dramatically improve prognosis.[2] Our recent clinical experience[3] is in full agreement with the three proposed cardinal features of POEMS syndrome, namely polyneuropathy, vascular endothelial growth factor (VEGF) level elevation, and the presence of monoclonal protein. The authors argue that the triad alone may be insufficiently specific; therefore they propose the additional requirement of two of four secondary features, namely extravascular fluid accumulation, skin changes, organomegaly, and sclerotic bone lesion.

  We would like to draw attention to clinical and methodological aspects that could further enhance or refine the diagnosis of POEMS syndrome. First, the process of diagnosis starts with clinical suspicion. Polyneuropathy is usually the earliest symptom of POEMS syndrome. POEMS syndrome should be considered in any patient with a severely progressive polyneuropathy of acute to subacute onset that is not otherwise explained, and VEGF level measurement should be offered. Routine screening for monoclonal protein (with immunofixation) and skeletal survey may be negative initially, and could remain negative for a long duration into...

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  We applaud Suichi et al.[1] for proposing new diagnostic criteria for POEMS syndrome. There is clearly a need for simplified validated criteria that permit early diagnosis of this rare, elusive and devastating paraneoplastic disorder, especially because early local or systemic treatment of the underlying plasma cell malignancy can dramatically improve prognosis.[2] Our recent clinical experience[3] is in full agreement with the three proposed cardinal features of POEMS syndrome, namely polyneuropathy, vascular endothelial growth factor (VEGF) level elevation, and the presence of monoclonal protein. The authors argue that the triad alone may be insufficiently specific; therefore they propose the additional requirement of two of four secondary features, namely extravascular fluid accumulation, skin changes, organomegaly, and sclerotic bone lesion.

  We would like to draw attention to clinical and methodological aspects that could further enhance or refine the diagnosis of POEMS syndrome. First, the process of diagnosis starts with clinical suspicion. Polyneuropathy is usually the earliest symptom of POEMS syndrome. POEMS syndrome should be considered in any patient with a severely progressive polyneuropathy of acute to subacute onset that is not otherwise explained, and VEGF level measurement should be offered. Routine screening for monoclonal protein (with immunofixation) and skeletal survey may be negative initially, and could remain negative for a long duration into the disease course. In fact, in many patients with POEMS, the concentration of monoclonal protein in the serum or urine is conspicuously low. Lack of abnormality on one or these two tests is insufficient to exclude a diagnosis of POEMS syndrome.[3,4] It is important to emphasize that any patient with a severe polyneuropathy and a significantly elevated VEGF level (usually >200 pg/ml) should be subjected to an aggressive search for plasma cell malignancy with CT or CT-PET and possibly image-directed bone marrow biopsy. Second, searching for characteristics of the polyneuropathy may improve the specificity of the POEMS diagnosis and differentiate it from mimics, even in the absence of secondary features: sensorimotor polyneuropathy with mixed axonal and demyelinating features, notably a prior diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) refractory to intravenous immunoglobulin and corticosteroids, severe axon loss in distal leg muscles together with diffuse demyelinating features on nerve conduction studies of the upper extremity, and evidence of proximal involvement in the form of root enhancement on imaging and elevated cerebrospinal protein.[3,5] Third, secondary features of edema, skin changes, and organomegaly develop as the disease advances, and may not be manifest in the earliest stages. As it is desirable to make an early diagnosis and prevent accumulation of impairment from this treatable condition, there should not be a delay in diagnosing due to a lack of secondary features.

  Validation exercises of diagnostic criteria of clinical syndromes (that lack an objective diagnostic criterion) are by definition circular arguments that inflate the accuracy of criteria that match prevalent practice. It is possible that the reported 100% sensitivity and specificity are overestimates, and may be more applicable for patients in later stages.

  Therefore we propose a designation of "possible POEMS" for any progressive/severe or "red flags" polyneuropathy with elevated VEGF level. The probability of POEMS syndrome in this group is sufficiently high that a rapid and aggressive diagnostic evaluation for plasma cell malignancy is warranted. Only after completion of such an evaluation and careful neurological and hematological follow-up can POEMS syndrome be excluded.

  1 Suichi T, Misawa S, Sato Y, et al. Proposal of new clinical diagnostic criteria for POEMS syndrome. J Neurol Neurosurg Psychiatry 2019;90:133–7. doi:10.1136/jnnp-2018-318514
  2 Dispenzieri A. POEMS syndrome: 2017 Update on diagnosis, risk stratification, and management. Am J Hematol 2017;92:814–29. doi:10.1002/ajh.24802
  3 Li Y, Valent J, Soltanzadeh P, et al. Diagnostic challenges in POEMS syndrome presenting with polyneuropathy: A case series. J Neurol Sci 2017;378:170–4. doi:10.1016/j.jns.2017.05.019
  4 He T, Zhao A, Zhao H, et al. Clinical characteristics and the long-term outcome of patients with atypical POEMS syndrome variant with undetectable monoclonal gammopathy. Ann Hematol 2019;98:735–43. doi:10.1007/s00277-018-03589-4
  5 Mauermann ML, Sorenson EJ, Dispenzieri A, et al. Uniform demyelination and more severe axonal loss distinguish POEMS syndrome from CIDP. J Neurol Neurosurg Psychiatry 2012;83:480–6. doi:10.1136/jnnp-2011-301472

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  Conflict of Interest:
  None declared.

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