POEMS syndrome, also known as Crow-fukase syndrome, Takatsuki disease, osteosclerotic myeloma, or PEP syndrome, is a multisystem plasma-cell disorder defined by the constellation of peripheral polyneuropathy (P), organomegaly (O), endocrinopathy (E), monoclonal protein (M), and skin changes (S). Not all features are present at initial presentation, and the syndrome remains frequently under-recognized or diagnosed late. Reported median delays from symptoms onset to diagnosis have ranged from 13 to 18 months [1], with misclassification as chronic inflammatory demyelinating polyneuropathy (CIDP), being the most common pitfall, given that neuropathy is typically the earliest and most disabling manifestation [2].

Current diagnostic criteria require both mandatory major criteria of demyelinating polyneuropathy and a clonal plasma-cell disorder along with at least one additional major criterion (sclerotic bone lesion, markedly elevated VEGF, or Castleman disease) and at least one minor criterion [3]. Recognition of this tiered framework is critical because POEMS responds to plasma-cell–directed therapies rather than the immunomodulatory agents used for CIDP. Practical tools including plasma VEGF measurement, skeletal imaging, and clonality assessment can substantially reduce diagnostic delay and redirect patients toward effective treatment [4].

Herein, we present the case of a patient with an extended course of progressive, IVIG-refractory neuropathy before POEMS syndrome was finally diagnosed few months after seeking medical advice. The case illustrates the clinical clues that should raise suspicion for POEMS, including poor IVIG response, thrombocytosis, thromboembolic events, a sclerotic bone lesion, lambda-restricted plasma-cell disease, and markedly elevated VEGF. We also provide a focused review of the literature on POEMS neuropathy, biomarker-based diagnosis, multisystem involvement, and treatment.

A 53-year-old morbidly obese woman, BMI 53.7 kg/m² (normal range 18.5-24.9 kg/ m²), with a past medical history of POEMS Syndrome, gastroesophageal reflux disease, hiatal hernia, irritable bowel syndrome, hypothyroidism, primary hyperparathyroidism status post parathyroidectomy, obstructive sleep apnea on auto-CPAP, deep-vein thrombosis, pulmonary embolism, Chronic hypoxic respiratory failure requiring 2 L of Oxygen, and stage I endometrial adenocarcinoma, status post hysterectomy, presented to clinic in a wheelchair for evaluation of progressive exertional dyspnea and longstanding bilateral extremity weakness. She denied any history of smoking, alcohol use, or illicit drug use. Her medications at the time of presentation included lenalidomide, amlodipine, aspirin 81 mg, carvedilol, furosemide, gabapentin, levothyroxine, potassium chloride, tramadol, warfarin, albuterol as needed, portable supplemental oxygen, and auto-CPAP nightly.

The patient reported that her illness began approximately 12 years prior when she noted mild weakness of the right upper extremity and an increased tendency to drop objects, attributed at the time to lateral epicondylitis and not initially investigated medically. Two years later she was hospitalized for menorrhagia of approximately one month’s duration, resulting in iron-deficiency anemia (iron 16 mg/dL [normal 60–170 mg/dL], ferritin 7 ng/mL [normal 12–50 ng/mL in women]) and marked thrombocytosis (platelet count 1.08 million/μL [normal 150,000–400,000/μL]) which was treated with iron infusion and maintained on oral iron supplement. She later developed progressive bilateral lower-extremity swelling, dyspnea, and increasing difficulty ambulating, requiring a walker. The patient was subsequently hospitalized again with deep-vein thrombosis, pulmonary embolism. Her lower extremities weakness has progressed and was unable to hold herself up on her feet.

On examination, the patient appeared in no acute distress and was wheelchair-bound. Cardiovascular, respiratory and abdominal examinations were unremarkable. Neurological examination revealed intact cranial nerves. Upper extremity strength was 5/5 proximally and in the forearms; grip was preserved. Lower extremity strength was 2/5 bilaterally with bilateral foot drop and absent ankle dorsiflexion. Sensation in lower extremities was diminished to light touch and vibration in a length-dependent distribution. Deep tendon reflexes were 1+ (out of 4+) in both upper extremities and absent in the lower extremities; plantar responses were downward bilaterally. Skin examination revealed residual hyperpigmentation without active rash. There were bilateral lower-extremity non-pitting edema and mild increased turgor of the bilateral hands with fixed flexion contractures of the fingers (claw-hand deformity) bilaterally (Figure 1).

Figure 1. Bilateral claw-hand contractures.

At the time of her initial presentation 10 years ago, hematologic evaluation revealed elevated both serum free light chain kappa and lambda with elevated kappa/lambda ratio and a normal serum protein electrophoresis. Hemoglobin was 9.8 g/dL (normal 12.0–16.0 g/dL). Peripheral blood smear showed microcytic, hypochromic red cells with innumerable platelets and no abnormal myeloid or lymphoid cells. Total serum immunoglobulins: IgG 1,147 mg/dL (normal 700–1,600 mg/dL), IgA 253 mg/dL (normal 70–400 mg/dL), IgM 47 mg/dL (normal 40–230 mg/dL). Serum free light chains: kappa 219.4 mg/L (normal 3.3–19.4 mg/L), lambda 66.9 mg/L (normal 5.7–26.3 mg/L), kappa/lambda ratio 3.28 (normal 0.26–1.65). Thyroid function tests confirmed hypothyroidism. Serum calcium was elevated 15.1 mg/dL (normal 8.5–10.5 mg/dL). CT of the neck identified a 2.3 cm parathyroid adenoma. Urinalysis showed no significant proteinuria. She was diagnosed with primary hyperparathyroidism requiring bisphosphonate therapy; parathyroidectomy was subsequently performed.

Initial serum protein electrophoresis (SPEP) was normal with no detectable M-spike. However, serum immunoelectrophoresis revealed an elevated serum kappa immunoglobulin of 1,640 mg/dL (normal 574–1,267 mg/dL) and elevated serum lambda immunoglobulin of 763 mg/dL (normal 269-638), and urine immunoelectrophoresis demonstrating elevated kappa light chains at 11.8 mg/dL (normal <1.9 mg/dL), while lambda was less than 5 mg/dL (normal <6.7 mg/dL). These results are summarized in Table 1.

CT of the thoracic spine, obtained following a fall, demonstrated a lucent lesion at the right posterior elements of T1, sclerotic lesions at the lower thoracic vertebral bodies and L1, and additional sclerotic foci in the pelvis and sacrum. MRI of the thoracic spine confirmed an enhancing lesion involving the T1 pedicle, facet, and lamina, which remained stable on serial imaging over approximately nine months. MRI of the lumbar spine showed inflammatory changes in the paraspinal musculature and nerve root enhancement. Bone scan was unremarkable. CT of the chest, abdomen and pelvis showed small left pleural effusion, moderate hepatosplenomegaly, a few mildly enlarged right axillary lymph nodes measuring 3´1.9 cm, and left inguinal lymphadenopathy. Diagnostic left thoracentesis with removal of 800 ml serous fluid demonstrated exudative pleural effusion and cytology was negative for malignancy.

Lumbar puncture (LP) demonstrated cytoalbuminologic dissociation consistent with a demyelinating or inflammatory process. Full CSF values with reference ranges are summarized in Table 2.

Nerve conduction studies (NCS) were technically limited by severe bilateral lower-extremity edema, precluding responses in the tibial, peroneal, sural, and superficial peroneal nerves on the left. Upper extremity NCS revealed markedly diminished conduction velocities of both ulnar and both median nerves with prolonged F-wave responses and diminished conduction of left radial nerve with prolonged F-wave responses. EMG, while was suboptimal study, demonstrated diffuse muscle membrane instability with sustained positive waves and fibrillation potentials, myopathic motor unit potentials in both upper and lower extremities, and markedly reduced recruitment of motor units on volitional activity along both upper extremities muscles while unable to do any volitional activity along both lower extremities. There were no fasciculations or joint potentials noted. The above findings are suggestive of severe peripheral neuropathy secondary to possible chronic inflammatory demyelinating polyneuropathy (CIDP) with associated myopathic changes and no evidence of motor neuron disease. IVIG was initiated at 2 g/kg over five days; the patient reported questionable and transient benefit. A second course of IVIG was administered without meaningful neurologic improvement.

Initial bone marrow biopsy was non-diagnostic (hemodiluted, hypocellular sample); flow cytometry was negative for lymphoproliferative disorder, though a reference laboratory report noted kappa light-chain restriction. Biopsy of the T1 lesion, performed after anticoagulation was held, demonstrated morphology consistent with a solitary plasmacytoma with lambda light-chain restriction on immunostaining. A left inguinal lymph node core biopsy showed few plasma cells present demonstrating kappa light chain predominance. Repeat bone marrow biopsy showed 7% plasma cells with a monoclonal population and flow cytometry immunophenotyping demonstrated kappa restriction. Plasma VEGF was subsequently measured and returned markedly elevated at greater than 12,000 pg/mL (reference range ≤200 pg/mL) (Table 3).

A diagnosis of POEMS syndrome was established at this time, four months after her hospital presentation, based on fulfillment of all current diagnostic criteria (Table 5, in the Discussion section): both mandatory major criteria (demyelinating polyneuropathy and clonal plasma-cell disorder), two additional major criteria (sclerotic bone lesion at T1 and markedly elevated plasma VEGF), and five minor criteria (thrombocytosis, extravascular volume overload, endocrinopathy (hypothyroidism, hyperparathyroidism), skin changes (hyperpigmentation). She also has thromboembolic events. This fulfillment is summarized in Table 5.

Treatment with lenalidomide and dexamethasone was initiated. Within weeks, the patient reported meaningful improvement in bilateral lower-extremity weakness. Follow-up plasma VEGF normalized rapidly (Table 1). Dexamethasone was gradually tapered. Peripheral stem cells were harvested and cryopreserved; autologous stem-cell transplantation (ASCT) was deferred pending recovery of activities of daily living. Maintenance lenalidomide was continued. Warfarin anticoagulation was maintained given restricted ambulation and persistent thrombotic risk.

Most recent plasma VEGF remains suppressed at 39.3 pg/mL (reference ≤96.2 pg/mL, Mayo Clinic Laboratories).

Progressive restrictive pulmonary dysfunction developed over the course of her illness. Serial pulmonary function testing (PFT) documented a progressive restrictive defect and reduction in diffusion capacity (DLCO) over six years. Recent NIF measurement was −36 cmH₂O (normal more negative than −60 to −70 cmH₂O), indicating severe respiratory muscle weakness. Upright versus supine spirometry revealed a significant positional fall in forced vital capacity (FVC), consistent with diaphragmatic weakness (Tables 4a and 4b). Flow volume loop demonstrated restrictive defect (Figure 2). Recent arterial blood gas analysis on 2 L of Oxygen demonstrated PH 7.41 (normal 7.35–7.45), PCO2 64.1 mmHg (normal 35–45 mmHg), PO2 75.6 mmHg (normal 80–100 mmHg on room air), consistent with chronic hypercapnic hypoxic ventilatory failure from neuromuscular respiratory dysfunction.

Figure 2. Flow volume loop.

Despite sustained biochemical control, the patient developed significant irreversible morbidity with persistent bilateral foot drop, bilateral claw-hand contractures (Figure 1), lower-extremity weakness and lymphedema managed with elevation and compression garments. She remains wheelchair-dependent for longer distances but ambulates short distances with a walker while continuing physical therapy.

Diagnostic criteria and delayed recognition

POEMS syndrome diagnosis follows a tiered framework requiring both mandatory major criteria (demyelinating polyneuropathy and a monoclonal plasma-cell disorder, most commonly lambda-restricted), at least one additional major criterion (sclerotic bone lesion, markedly elevated VEGF, or Castleman disease), and at least one minor criterion (organomegaly, extravascular volume overload, endocrinopathy, skin changes, papilledema, thrombocytosis, or polycythemia). The diagnostic criteria and their operationalization in the present case are summarized in Table 5.

Prior series have established that diagnosis anchored solely on the POEMS acronym can fail to identify nonclassical variants, and that an algorithmic approach centering on demyelinating polyneuropathy and clonal plasma-cell disease is more reliable. Diagnostic precision remains imperfect despite established criteria. One review of 629 patients found that only half of those initially meeting criteria went on to develop classical POEMS; lambda-restricted clones and sclerotic bone lesions were more common among true POEMS patients, whereas kappa light chains and vasculitic nerve changes were more common in false-positive cases [5]. Conversely, some patients with clinical POEMS features lack a detectable M-protein, particularly after corticosteroid use [6]. In patients with suspected CIDP presenting with systemic features or poor response to immunotherapy, POEMS-specific testing should be pursued early rather than treating POEMS as a diagnosis of exclusion.

POEMS neuropathy and differentiation from CIDP

POEMS polyneuropathy commonly resembles CIDP in its early stages, as both present with progressive, symmetric, length-dependent sensorimotor weakness. However, POEMS neuropathy tends to be more motor-predominant, more painful and disabling, and more frequently accompanied by systemic features. Approximately 60% of patients with POEMS are initially misdiagnosed with CIDP in large comparative series, delaying plasma-cell-directed treatment [7].

Progressive neuropathy refractory to IVIG, particularly when accompanied by thrombocytosis, thromboembolic disease, a sclerotic bone lesion, and lambda-restricted plasma-cell disease, should shift the diagnostic pathway toward plasma VEGF measurement, skeletal imaging, immunofixation, and bone marrow evaluation.

Electrodiagnostic studies can help distinguish POEMS from CIDP. POEMS neuropathy typically shows disproportionate reduction in compound muscle action potential (CMAP) amplitude relative to only mild distal latency prolongation, particularly in the lower extremities. In a retrospective comparison of 51 POEMS and 46 CIDP patients, absent tibial CMAPs and F-waves were present in 56% of POEMS cases versus 7% of CIDP cases, reflecting severe lower-limb axonal loss. POEMS is also characterized by proximal or trunk-predominant demyelination and a higher terminal latency index, whereas CIDP more often demonstrates distal accentuated slowing with multifocal conduction abnormalities. Conduction block and severe temporal dispersion, hallmarks of CIDP, are uncommon in POEMS [8]. Needle EMG may reveal fibrillation potentials and positive sharp waves consistent with active axonal degeneration, with direct implications for irreversibility of neurologic injury if treatment is delayed. While both POEMS and CIDP slow conduction, POEMS often shows a more uniform slowing across intermediated nerve segments. POEMS syndrome rarely exhibits sural sparing, leading to uniform and severe sensory amplitude reduction, while in CIDP, sural sensory nerve potentials (SNAPs) are often spared or preserved relative to other nerves [9].

Histopathologic findings correlate with these electrodiagnostic patterns. Sural nerve biopsies in POEMS show diffuse axonal degeneration with increased epineurial neovascularization, fewer onion bulbs, and less endoneurial inflammation compared with CIDP. Immunoelectron microscopy has demonstrated monoclonal IgG-lambda or IgA-lambda deposits within the endoneurium and subperineurial area without amyloid or vasculitis, distinguishing POEMS from amyloid neuropathy and vasculitic neuropathy [10].

VEGF and biomarker-based diagnosis

Plasma VEGF is the most diagnostically useful and clinically validated biomarker in POEMS syndrome. VEGF levels are typically 15 to 30 times greater than those in CIDP or Guillain-Barré syndrome and decrease with effective treatment [11]. Plasma rather than serum VEGF measurement is preferred, as platelet activation during clotting can falsely elevate serum values, especially in patients with thrombocytosis. A plasma VEGF cutoff of approximately 200 pg/mL has demonstrated approximately 95% specificity for POEMS . VEGF normalization is a key treatment endpoint and should be monitored serially, with a response defined as normalization below 200 pg/mL or a reduction of at least 50%.

Emerging biomarkers may complement VEGF. Procollagen type I N-terminal propeptide (P1NP) demonstrated 80% sensitivity and 91.5% specificity for POEMS at a threshold greater than 70 ng/mL, and may help distinguish POEMS from mimickers and track treatment response [12]. Interleukins 6 and 12 have been associated with vascular leak, overall disease activity, and neuropathogenesis, decreasing after effective treatment [13,14]. Matrix metalloproteinases and TIMP-1 may serve as markers of vascular remodeling and endothelial injury [15]. Until these biomarkers achieve widespread availability, plasma VEGF will remain the mainstay of diagnosis and monitoring.

Imaging, bone marrow, and pathology

Osteosclerotic lesions may be small, multifocal, or subtle and can be missed on limited skeletal surveys. Computed tomography is particularly effective at detecting lesions preferentially involving the vertebrae and pelvis [16]. PET/CT may identify metabolically active lesions amenable to biopsy when conventional imaging is unrevealing and has a potential role in monitoring treatment response and detecting early relapse [17–19]. Atypical osteolytic or mixed lytic-sclerotic lesions have been reported, and any suspicious lesion in the context of unexplained demyelinating neuropathy should be considered for biopsy [20].

Bone marrow findings in POEMS often differ from those in multiple myeloma. Plasma-cell burden may be low, serum free light-chain ratios can be normal despite lambda-restricted monoclonality, and standard myeloma screening algorithms may miss the clone [21]. Classic histologic findings include lambda-restricted plasma cells rimming lymphoid aggregates, megakaryocytic hyperplasia and atypia, and a JAK2 V617F-negative pattern distinguishing POEMS-related thrombocytosis from a true myeloproliferative neoplasm [22]. Sensitive testing with immunofixation, immunohistochemistry, in situ hybridization, and flow cytometry is necessary to detect small clones and should be interpreted alongside clinical and imaging findings [23].

Multisystem involvement

Endocrinopathy is present in over 80% of patients at diagnosis in large series, involving gonadal, thyroid, adrenal, and glucose metabolism [24]. Baseline assessment should include sex hormones with gonadotropins, thyroid function, morning cortisol, fasting glucose or hemoglobin A1c, prolactin, calcium, and parathyroid hormone, with longitudinal reassessment thereafter [25].

Thrombosis occurs in approximately one quarter of patients, with arterial events slightly more common than venous in some series; approximately 8% of patients develop ischemic stroke [26]. Risk factors include thrombocytosis, polycythemia, splenomegaly, effusions, prior thrombosis, and VEGF-mediated endothelial dysfunction [27]. Antiplatelet therapy is recommended for most patients, with anticoagulation added for those with additional risk factors.

Pulmonary complications represent an underappreciated source of morbidity. Recognized manifestations include restrictive ventilatory defects, impaired diffusing capacity, pulmonary hypertension, respiratory muscle weakness from severe polyneuropathy, and pleural effusions [28]. The pathophysiology involves increased vascular permeability from elevated VEGF, extravascular volume overload, and progressive neuromuscular impairment. Pulmonary hypertension has been shown to improve with effective disease treatment, with the degree of reversal correlating with disease severity at presentation and duration of endothelial dysfunction [29]. Serial pulmonary function testing—including upright and supine spirometry to evaluate for diaphragmatic weakness—diffusing capacity measurement, exertional oxygen assessment, and echocardiography are recommended at baseline and serially for all POEMS patients, even after biochemical remission [30]. Neuromuscular respiratory failure, evidenced by a positional FVC drop of 20% or more and a reduced MIP, should prompt evaluation for non-invasive ventilatory support.

Renal involvement includes glomerular changes resembling membranoproliferative glomerulonephritis with mesangial expansion and double-contoured capillary walls, driven predominantly by VEGF-mediated injury rather than immune complex deposition [31,32]. Baseline and longitudinal monitoring with urinalysis and serum creatinine is recommended.

Characteristic skin findings, including hyperpigmentation, hypertrichosis, sclerodermoid changes, and hemangiomas, can provide early diagnostic clues and may predate neuropathy [33]. Multiple cherry-red to violaceous hemangiomas in the context of CIDP-like symptoms should prompt VEGF measurement [34]. The AESOP syndrome (adenopathy and extensive skin patch overlying a plasmacytoma) may serve as an early diagnostic entry point in rare cases of POMES [35].

Treatment, response, and long-term monitoring

Treatment selection is guided by disease extent. Patients with an isolated plasmacytoma or limited discrete lesions without diffuse marrow involvement may be candidates for involved-field radiation alone, which can be curative in select cases [36]. Those with diffuse skeletal involvement, marrow infiltration, or progression following radiation require systemic plasma-cell-directed therapy.

High-dose melphalan followed by autologous stem-cell transplantation is the preferred approach for eligible patients with disseminated disease, associated with durable hematologic responses, VEGF reduction, neurologic improvement, and favorable long-term survival [37–40]. Melphalan with dexamethasone is a validated non-transplant option [41]. Lenalidomide with dexamethasone has demonstrated activity in newly diagnosed, relapsed, and refractory settings with multiple reports of rapid VEGF decline and organ-function improvement [42–44].

Other active agents include bortezomib, which offers rapid plasma-cell cytoreduction but must be used cautiously given its neuropathy risk; subcutaneous administration and dose reduction are often warranted [45–47]. Daratumumab has shown activity in refractory and selected newly diagnosed cases with emerging reports of VEGF improvement and neurologic benefit, though larger studies are needed [48–50]. Thalidomide reduces VEGF and improves symptoms but carries a significant neuropathy burden, limiting its use compared with newer immunomodulatory agents [51].

Response assessment in POEMS requires evaluation across multiple domains, as no single parameter captures overall disease activity. Hematologic response is assessed using IMWG-style criteria, though depth of marrow response does not necessarily predict longitudinal outcome. VEGF normalization to below 200 pg/mL or a decrease of 50% or more defines biomarker response. Neurologic response should be tracked with standardized scoring systems and nerve-conduction studies, as clinical improvement commonly lags behind biomarker response or may not occur at all. Organ-specific surveillance encompassing volume status, pulmonary function, papilledema, renal function, and endocrine parameters should be performed systematically.

Comparison with multiple myeloma

POEMS shares its plasma-cell dyscrasia underpinning with multiple myeloma yet differs substantially in presentation and diagnostic approach. Classic multiple myeloma is defined by CRAB criteria (hypercalcemia, renal insufficiency, anemia, lytic bone lesions), none of which are primary features of POEMS. POEMS features neuropathy as the central manifestation alongside osteosclerotic or mixed lesions, lambda-restricted clonality, thrombocytosis, endocrinopathy, edema, and skin changes. Standard myeloma screening algorithms are inadequate for POEMS detection, particularly in low-burden disease where cytokine-mediated organ effects substantially outpace quantitative tumor burden [52].

Future directions

Future treatment approaches should target the cytokine-angiogenic environment and underlying molecular features rather than simply reducing plasma-cell burden. Anti-VEGF therapy with bevacizumab has produced mixed results and symptomatic worsening in some patients, suggesting direct VEGF inhibition may be too far downstream of the primary pathogenic process.

Upstream cytokine inhibition is under early investigation; IL-6 inhibition has led to more rapid resolution of effusions and edema, and IL-12/23 blockade has been associated with concomitant reductions in IL-12 and VEGF with motor improvement in small case series.

Restricted lambda light-chain gene usage (IGLV1-40 and IGLV1-44) may enable minimal residual disease monitoring via next-generation sequencing [53]. Composite response criteria incorporating VEGF, P1NP, cytokines, and clonal biomarkers may eventually allow earlier relapse detection and safer treatment de-escalation in deep responders. Anti-CD38 agents such as daratumumab warrant prospective study across treatment lines, and response-adaptive treatment pathways that escalate or de-escalate therapy based on hematologic, cytokine, and neurologic trajectories merit future investigation.

While VEGF remains the standard diagnostic and monitoring biomarker for POEMS syndrome, recent clinical developments have highlighted interleukin-6 (IL-6), N-Terminal propeptide of type I collagen (P1NP) and Interlukin-12 (IL-12) as a potential new diagnostic and prognostic biomarkers [54,55].

This case highlights the diagnostic challenges of POEMS syndrome and emphasizes the importance of considering this condition in patients presenting with CIDP-like neuropathy who exhibit systemic features such as thrombocytosis, extravascular volume overload, endocrine abnormalities, skin changes, thromboembolic events, sclerotic bone lesions, or poor response to immunomodulatory therapy. Early recognition, early measurement of plasma VEGF levels, and evaluation for plasma-cell disorders with bone marrow assessment, skeletal imaging and immunofixation are critical to establishing the diagnosis and initiating effective plasma-cell–directed therapy to reduce irreversible neurologic and organ damage.