Cerebral large artery stenosis and occlusion in POEMS syndrome.

BACKGROUND: This study aimed to investigate the frequency and risk factors for cerebral artery stenosis and occlusion in patients with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome. METHODS: We reviewed results of magnetic resonance angiography (MRA) or computed tomography angiography (CTA) in 61 patients with POEMS syndrome seen between 2010 and 2017. Stenosis or occlusion was assessed in the initial MRA/CTA. Multivariate analysis was used to identify risk factors for artery stenosis/occlusion. In an autopsy case, pathologic examination was conducted of the occluded middle cerebral arteries. RESULTS: Stenosis (> 50 %) or occlusion of the major cerebral arteries was found in 29 (47.5 %) patients on the initial MRA/CTA. The internal carotid artery was involved most frequently (32.8 %), followed by the anterior (21.3 %) and middle (16.4 %) cerebral arteries. The basilar (1.3 %) and vertebral (3.6 %) arteries were rarely affected. Cerebral infarction developed in eight (13.1 %) patients. The serum vascular endothelial growth factor (VEGF) level was an independent predictor for stenosis/occlusion (odds ratio, 1.228; 95 % confidence interval, 1.042-1.447; P = 0.014). An autopsy study showed occluded middle cerebral arteries by fibrous and myxomatous thickening of intima with splitting of the internal elastic lamina. Follow-up MRA in 23 patients showed improved, worsened, and unchanged stenosis in 20.7 %, 8.7 %, and 69.6 %, respectively. CONCLUSIONS: Cerebral large-vessel stenosis or occlusion is frequently seen in approximately half of patients with POEMS syndrome. Vasculopathy was related to serum VEGF levels and thereby disease activity. Assessment of cerebral vessels is recommended in these patients to improve management.

POEMS syndrome: 2021 Update on diagnosis, risk-stratification, and management.

DISEASE OVERVIEW: POEMS syndrome is a paraneoplastic syndrome due to an underlying plasma cell neoplasm. The major criteria for the syndrome are polyradiculoneuropathy, clonal plasma cell disorder (PCD), sclerotic bone lesions, elevated vascular endothelial growth factor, and the presence of Castleman disease. Minor features include organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis. DIAGNOSIS: The diagnosis of POEMS syndrome is made with three of the major criteria, two of which must include polyradiculoneuropathy and clonal plasma cell disorder, and at least one of the minor criteria. RISK STRATIFICATION: Because the pathogenesis of the syndrome is not well understood, risk stratification is limited to clinical phenotype rather than specific molecular markers. Risk factors include low serum albumin, age, pleural effusion, pulmonary hypertension, and reduced eGFR. RISK-ADAPTED THERAPY: For those patients with a dominant plasmacytoma, first line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated bone marrow involvement and for those who have progression of their disease 3-6 months after completing radiation therapy should receive systemic therapy. Corticosteroids are temporizing, but alkylators are the mainstay of treatment, either in the form of low dose conventional therapy or high dose with stem cell transplantation. Lenalidomide shows promise with manageable toxicity. Thalidomide and bortezomib also have activity, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy. Prompt recognition and institution of both supportive care measures and therapy directed against the plasma cell result in the best outcomes.

POEMS syndrome: A multisystem clonal disorder.

Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS) syndrome is a rare condition defined by monoclonal plasma cell disorder, peripheral neuropathy, and other systemic symptoms. The pathophysiology of POEMS syndrome is unknown, but the overproduction of vascular endothelial growth factor (VEGF) appears to be an important contributory element. The diagnosis of POEMS syndrome requires the presence of both mandatory criteria (ie, polyneuropathy and a monoclonal plasma cell disorder), at least one major criterion (ie, osteosclerotic bone lesions, Castleman disease, or elevated serum or plasma levels of vascular endothelial growth factor), and at least one of the six minor criteria. POEMS syndrome lacks a standard treatment, but patients with limited sclerotic bone lesions are typically treated with radiation therapy. In contrast, those with widespread lesions receive chemotherapy and hematopoietic stem cell transplantation.

Ischemic stroke in patients with POEMS syndrome.

Polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes (POEMS) syndrome is associated with increased risk for ischemic stroke (IS). Because POEMS syndrome is rare, little is known regarding the underlying mechanism and prognosis for IS in patients in whom it occurs. The medical records of patients with POEMS syndrome were screened between January 2018 and January 2000 at Peking Union Medical College Hospital to identify those with IS. The baseline characteristics, IS features, and patient outcomes were analyzed. Forty-one (8.0%) of 510 POEMS patients were documented to have IS. Patients with IS were older, had a higher percentage of Overall Neuropathy Limitation Scale score >4, and had a higher level of fibrinogen compared with those who did not have IS. Ninety-three percent of IS events occurred before or within 3 months after a diagnosis of POEMS. Of 41 occurrences of IS, 29 (46.3%) were multifocal. Recurrent IS was observed in 13 (31.7%) of 41 patients, but not in patients with successful anti-plasma cell therapy. The 3-year overall survival rate in patients with IS was 71.0% and for those without IS, it was 88.5% (P = .002). We showed that 8.0% of POEMS patients had IS, and most IS events occurred in POEMS patients not being treated effectively. Having IS was a predictor of unfavorable prognosis. Early diagnosis, immediate initiation of treatment for POEMS, and control of POEMS syndrome is key to reducing the occurrence of IS, improving survival, and preventing recurrence of IS.

Diagnosis of paraproteinemic neuropathy: Room for improvement.

OBJECTIVE: To report our institutional experience with paraproteinemic neuropathy. METHODS: We reviewed the charts of patients evaluated at our tertiary, academic neuromuscular clinic for neuropathy between 2017 and 2019 and selected those with a serum monoclonal protein. We collected patients' characteristics and reviewed their initial diagnoses and eventual outcomes. RESULTS: Fifty-four of 410 patients with neuropathy (13%) had a monoclonal protein. Of these patients, 25% had not had SPEP or IFE checked prior to referral. FLC was not checked in any of the patients prior to referral. The neuropathy was felt to be related to the monoclonal protein in 24 patients (44%). Ten patients (19%), had been misdiagnosed either because they were not screened for monoclonal protein or the monoclonal protein was considered a MGUS. AL amyloid and POEMS syndrome were the most frequently missed diagnoses. CONCLUSION: The diagnosis of paraproteinemic neuropathy was missed in nearly one in five patients in our cohort. Failure to accurately characterize a paraproteinemic neuropathy can have devastating effect on patients as some have underlying malignancies. We propose that testing serum free light chains in patients with peripheral neuropathy of unknow etiology, when SPEP/IFE are normal, may reduce the rate of misdiagnosis. Furthermore, patients with refractory CIDP should be carefully screened for POEMS syndrome.

High rates of venous and arterial thrombotic events in patients with POEMS syndrome: results from the UCLH (UK) POEMS Registry.

Arterial and venous thromboses occur in patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein level, and skin changes) syndrome at a previously reported rate of 20%. We reviewed the University College London Hospitals (UCLH) POEMS Registry to determine the rate of venous thromboembolism (VTE), arterial events, and risk factors. This registry, established in 1999 and comprising 103 patients at the time of this study, is the largest single-center cohort in Europe. Of the 83 assessable patients, median age at presentation was 52 years (range, 31-84). Twenty-five patients experienced clinically apparent arterial or venous events, and 2 had concurrent arterial and venous thromboses. Eleven patients had VTEs, including deep vein thrombosis (DVT; 3 of 11), pulmonary embolism (4 of 11), and peripherally inserted central catheter-associated DVT, which occurred during autologous stem cell transplantation (3 of 11). Sixteen patients experienced arterial events: stroke (7 of 16), peripheral arterial occlusion (5 of 16), myocardial infarction (3 of 16), and microvascular disease (1 of 16), with no discernible relationship with thrombocytosis or polycythemia. Thirty percent of POEMS patients have arterial and venous thromboses, higher than previously reported. There were more arterial than venous events, and most occurred during active disease, before the start of chemotherapy, indicating the need for a preemptive approach to thromboprophylaxis.

Prevalence, clinical profiles, and prognosis of POEMS syndrome in Japanese nationwide survey.

OBJECTIVE: To elucidate current epidemiological, clinical profiles, and treatment of polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome. METHODS: We conducted a nationwide survey in 2015 using an established epidemiologic method. Data processing sheets were sent to all neurology and hematology specialist departments throughout Japan to identify patients with POEMS who were seen between April 2012 and March 2015. RESULTS: The estimated number of patients with POEMS was 392 (95% confidence interval [CI] 320-464), and the prevalence was 0.3 per 100,000. Detailed clinical profiles were available for 167 patients. Median age at onset was 54 years (range, 21-84 years), and the ratio of male to female was 1.5. All patients showed polyneuropathy; 89% had monoclonal plasma cell proliferation; and 84% had elevated vascular endothelial growth factor level in whom pretreatment serum or plasma was available (n = 87). Other common features were skin changes (84%), edema/effusion (81%), and organomegaly (76%). A total of 160 patients were treated with any of the following: radiation, corticosteroids, melphalan, thalidomide, lenalidomide, bortezomib, or autologous stem cell transplantation. Primary therapeutic options were thalidomide (n = 86) and autologous stem cell transplantation (n = 71). Thirty-nine patients (24%) were initially treated with corticosteroid alone. The 10-year overall survival was 93% (95% CI 86%-96%). DISCUSSION: This study showed current epidemiologic and clinical status of POEMS syndrome in Japan. A quarter of patients were still inadequately treated with corticosteroid alone, whereas either autologous stem cell transplantation or immunomodulatory drugs improved the prognosis.

Characteristics of 1946 Cases of POEMS Syndrome in Chinese Subjects: A Literature-Based Study.

POEMS syndrome is a rare paraneoplastic disorder characterized secondary to a rare plasma cell dyscrasia. Here, we aimed to analyze the clinical characteristics of large sample cases of POEMS in Chinese subjects through making a review of the Chinese literature. Four databases were electronically searched from inception until October 2016. Case reports and case series were identified. Six hundred studies with 1946 participants were identified. The first case was reported in 1986, and the number of reported cases peaked in 2009 and 2010. The top seven provinces on the number of reported cases were in the south-east area of China. The top three departments on the number of published papers and reported cases were ordinally department of Neurology, Hematology, and Endocrinology. The ratio of male to female was about 2.23. The range of age onset was from 10 to 81 years with the mean age of 46.39 (SD, 12.10 years). The initial symptoms of POEMS with peripheral neuropathy, edema and effusions, endocrinopathy, skin changes, and organomegaly accounted for 60.44, 15.72, 9.87, 8.05, and 2.13%, respectively, and subsequently acquired above symptoms as the prevalence was 99.49, 81.91, 75.56, 77.08, and 83.09%, respectively. The present study would help to understand the clinical presentations of POEMS syndrome in the Chinese population.

Clinical characteristics and the long-term outcome of patients with atypical POEMS syndrome variant with undetectable monoclonal gammopathy.

The diagnosis of polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome requires polyneuropathy and monoclonal plasma cell proliferation as two mandatory criteria. Our aim was to summarize clinical manifestations and treatment responses of POEMS variants with no evidence of monoclonal gammopathy. We queried all medical documentation of patients referred to Peking Union Medical College Hospital from August 2012 to July 2017, and reviewed the clinical and laboratory features of 13 patients with atypical POEMS syndrome with undetectable monoclonal gammopathy, and compared to prototypes published. The prevalence of polyneuropathy, organomegaly, skin changes, and extravascular fluid overload were 100%, 100%, 92%, and 100%, respectively. Other clinical manifestations, such as endocrinopathy, pulmonary hypertension, papilledema, thrombocytosis, and polycythemia affected similar percentages of patients as seen in prototypes. POEMS variants enrolled had a median serum vascular endothelial growth factor (VEGF) level of 4998 pg/ml (range 2155-11,029 pg/ml). Long-term follow-up found that all 12 patients received autologous stem cell transplant, melphalan-based therapy or lenalidomide/thalidomide-based therapy obtained clinical improvement, of which eight experienced decreased levels of VEGF by 50% or back to normal. The median progression-free survival was 101.5 months. Our findings raised a variant of POEMS syndrome variants with featured clinical manifestations, elevated VEGF levels, and good response to therapies targeting plasma cell.

Thrombotic microangiopathy associated with monoclonal gammopathy.

Thrombotic microangiopathy (TMA) is a rare disease comprising of a diverse set of disorders linked by a common histologic finding of endothelial injury. Monoclonal immunoglobulins may act as a potential trigger in the pathogenesis of TMA. To determine the prevalence of monoclonal gammopathy and clinicopathological features of TMA associated with monoclonal immunoglobulin, we performed a retrospective study in adults (18 and older) with a clinical diagnosis of TMA. Of 146 patients with TMA, we detected monoclonal immunoglobulin in 20 patients (13.7%). Among patients 50 and older, the prevalence of monoclonal gammopathy was 21%, which is approximately five-fold higher than the 4.2% expected rate in this population. Fifteen patients had monoclonal gammopathy of undetermined significance, one had multiple myeloma, one with smoldering myeloma, two had POEMS syndrome, and one had T-cell lymphocytic leukemia. Renal biopsy was performed in 15 cases, of which six showed thrombi, 11 showed mesangiolysis, and all showed double contours along glomerular capillary walls. Acute tubular injury was present in 12 cases. Treatment options were varied and included therapeutic plasma exchange in 11 patients. Ten patients progressed to end-stage renal disease, of which two received kidney transplant. Thus, our study shows an unexpectedly high prevalence of monoclonal gammopathy in patients with TMA, suggesting a potential pathogenetic mechanism. This study underscores the importance of evaluating for a monoclonal gammopathy in patients with TMA as well as the potential for targeting the underlying hematologic disorder as an approach to treating TMA.

XXXII Reunión Anual de la Sociedad Valenciana de Neurología. Comunicaciones: Alicante, 6-7 de Marzo de 2015 / XXXII Reunión Anual de la Sociedad Valenciana de Neurología. Communications

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Prevalence and risk factors for depression in newly diagnosed patients with POEMS syndrome.

This prospective study delineated the prevalence and risk factors for clinical depression in patients with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes). Using a PHQ-9 (Patient Health Questionnaire scale-9, which evaluates the severity of depressive symptoms) score cut-off ≥ 10, the prevalence of pretreatment depression was 38.0%. Based on multivariate logistic regression, higher ONLS (Overall Neuropathy Limitation Scale, which assesses the severity of neuropathy) upper limb scores (hazard ratio [HR] 1.75; 95% confidence interval [CI] 1.09-2.81; p = 0.02) and ascites (HR 4.30; 95% CI 1.03-17.9; p = 0.04) were significant and independent predictors for depression. The incidence of post-treatment depression was 1.53% by the end of follow-up, while no patients received antidepressants. A preliminary logistic regression suggested depression to be a risk factor for early death (within 3 months after diagnosis) (HR 9.77; 95% CI, 1.08-88.9; p = 0.04).

[Pitfalls of monoclonal gammopathy]. / Les pièges des gammapathies monoclonales.

Monoclonal gammopathy of undetermined significance (MGUS) is a frequent condition affecting at least 3% of the general population over 50 years. Usually, the diagnosis of MGUS is made accidentally during a biological assessment for other conditions. Although MGUS is most frequently a benign and asymptomatic disorder, it has well been described that MGUS could be a premalignant status and that the risk of transformation into myeloma or other lymphoproliferative disorders is estimated at 1% per year. MGUS can also be associated with other diseases than malignant disorders such as Infections, autoimmune diseases. In some case it could reflect rare but severe disorders that will be crucial not to miss the diagnosis.

The characteristics of ascites in patients with POEMS syndrome.

The characteristics of ascites in patients with POEMS syndrome, which comprise polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes, are unknown. We described the frequency of ascites at presentation of POEMS syndrome and further evaluated for the pathogenesis and nature of the ascites. One hundred and six consecutive patients with POEMS syndrome in Chinese PLA General Hospital were evaluated for the presence of ascites, and the cellular and biochemical characteristics of the ascitic fluids were assessed. Serum levels of complement, cytokines, and clinical chemistry parameters were analyzed in peripheral blood samples of the patients with POEMS syndrome. Ascites was observed in 42 of 106 (39.6 %) patients with POEMS syndrome. Patients with ascites had significantly high serum levels of C3 and C4 complement components and TNF-α (all p < 0.01). In 31 (73.8 %) patients who underwent paracentesis, the ascitic fluids had low serum ascites albumin gradients (SAAG), indicating non-portal hypertension. Spontaneous bacterial peritonitis was not observed. Ascites is a common complication of POEMS syndrome and has characteristics of non-portal hypertension, based on low SAAG. Increased immune activation and inflammatory status could contribute to the pathogenesis of ascites in POEMS syndrome.

Preserved autonomic function in patients with POEMS syndrome.

AIM: We systematically performed autonomic testing on patients with polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes syndrome (POEMS) to determine whether autonomic function is preserved in such patients. METHODS: We studied 17 POEMS patients, 17 diabetic neuropathy (DN) patients and 17 age-matched normal subjects. Blood pressure responses to the head-up tilt test and heart rate variability were used to evaluate cardiovascular autonomic function. Sweat responses and cutaneous vasoconstriction to several stimuli were recorded via the finger tips to estimate cutaneous sympathetic function. In addition, motor nerve conduction studies were performed. RESULTS: Although the results of the autonomic testing were normal in POEMS patients, motor disability was severe, and motor nerve conduction studies provided evidence of extensive axonal loss. The DN patients showed significantly impaired autonomic responses despite mild motor dysfunction. CONCLUSIONS: Autonomic function was normal in POEMS patients, indicating the preservation of autonomic fibers and selective involvement of large fibers.

Combination of melphalan and dexamethasone for patients with newly diagnosed POEMS syndrome.

POEMS syndrome is a rare clonal plasma cell disorder without standard treatment. Based on the efficacy and low toxicity of a combination of melphalan and dexamethasone (MDex) for light chain amyloidosis, we conducted a prospective study of MDex treatment for patients with newly diagnosed POEMS syndrome. Thirty-one patients (19 men) were enrolled and the median age at the time of diagnosis was 44 years (range, 32-68 years). All patients received 12 cycles of MDex treatment. Twenty-five patients (80.6%) achieved hematologic response including 12 (38.7%) complete remission and 13 (41.9%) partial remission. Of all 31 patients, the neurologic response rate was 100%, assessed by overall neuropathy limitation scale (ONLS). The initial neurologic response was observed in 24 patients (77.4%) at 3 months after treatment and the median time to maximal neurologic response was 12 months (range, 3-15 months). Moreover, MDex substantially improved the level of serum vascular endothelial growth factor and relieved organomegaly, extravascular volume overload, and pulmonary hypertension. Only 6 patients (19.3%) suffered from grade 3 adverse events during treatment. All patients are alive and free of neurologic relapse after the median follow-up time of 21 months. Therefore, MDex is an effective and well-tolerated treatment option for patients with newly diagnosed POEMS syndrome.

[Clinical analysis of 22 cases of POEMS syndrome].

This study was purposed to investigate the clinical characteristics of POEMS syndrome in China, the clinical data of 22 patients with POEMS syndrome admitted in Chinese PLA general hospital from April 1993 to April 2008 were analyzed retrospectively. The results showed that the average age of patients was 47.7 years old, and the male:female ratio was 2.67. Weakness was the most frequent initial symptom. Nervous system lesions were found in all cases, weakness and numbness were predominant. Electromyogram showed neurogenic damage. Cerebrospinal fluid pressure and protein level were often elevated. Monoclonal band could be seen in electrophoresis of cerebrospinal fluid. Enlargement of liver, spleen and lymph nodes were common. Endocrine diseases accounted for 95.5%, in which gonadal dysfunction was most common. The sensitive test in M protein examination was immunofixation electrophoresis with positive rate 92.9%. IgA level was higher than IgG, and λ-type light chain was the majority, but κ-type light chain appeared in a small number of patients. Changes in skin included hyperpigmentation, hirsutism and sweating. In conclusion, clinical characteristics of patients in this group were basically similar to that reported in home, but were some different from that reported in abroad including following indicators: cerebrospinal fluid protein level, incidence of hepatomegaly and splenomegaly, serum protein level, light chain κ and λ level, incidence of peripheral edema, ascites, pleural effusion and platelet count.