J Neurol (2014) 261:60–65 DOI 10.1007/s00415-013-7143-4
ORIGINAL COMMUNICATION
Papilloedema is an independent prognostic factor for POEMS syndrome RongTai Cui • ShengYuan Yu • XuSheng Huang • JiaTang Zhang • ChengLin Tian • ChuanQiang Pu
Received: 30 July 2013 / Revised: 1 October 2013 / Accepted: 3 October 2013 / Published online: 20 October 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract POEMS syndrome is a potentially fatal disease, and prediction of prognostic factors for POEMS syndrome is important for clinicians. Papilloedema is an early sign of the syndrome. The present study was carried out to evaluate whether papilloedema is a prognostic factor for POEMS syndrome. Between January 2003 and December 2012, 94 patients with POEMS syndrome were enrolled in this study. The patients were divided into groups with and without papilloedema. Logistic regression was performed to identify risk factors related to papilloedema. Prognostic factors were analysed with Cox proportional hazard regressions for POEMS syndrome-related prognoses, and survival curves were plotted using the Kaplan–Meier method and compared by the log-rank test. Papilloedema was found in 52.1 % of the patients with POEMS syndrome. Raised intracranial pressure [hazard ratio (HR) 3.06, 95 % confidence interval (CI) 1.24–7.41; P = 0.011] and elevated cerebrospinal fluid protein levels (HR 2.03, 95 % CI 1.07–4.51; P = 0.043) were independently associated with papilloedema. Papilloedema, decreased diffusing capacity of the lung for carbon monoxide (DLCO) and treatment with corticosteroids alone were related to poor prognosis in POEMS syndrome. In multivariate analysis, papilloedema (HR 1.58, 95 % CI 1.05–2.46; p = 0.027) and decreased DLCO (HR 2.17, 95 % CI 1.12–3.39; p = 0.023) were independent factors for POEMS syndrome-related death. Papilloedema and decreased DLCO are important prognostic factors for patients with POEMS syndrome, which can help clinicians
R. Cui S. Yu X. Huang J. Zhang C. Tian C. Pu (&) Department of Neurology, Chinese PLA General Hospital, 28 FuXing Road, Beijing 100853, China e-mail: [email protected]
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predict the risk of mortality and provide better medical care for these patients. Keywords POEMS syndrome Prognostic factor Cox model Papilloedema
Introduction POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome is a rare cause of demyelinating and axonal mixed neuropathy with multiorgan involvement and monoclonal plasma cell-proliferative disorder [1–3]. Other common manifestations are sclerotic bone lesions, Castleman’s disease, thrombocytosis, extravascular fluid overload (peripheral edema, pleural effusion, ascites, and pericardial effusion) [4]. POEMS syndrome is a potentially fatal disease, and patients’ quality of life deteriorates because of progressive neuropathy, massive pleural effusion or ascites, or thromboembolic events [3, 5]. Prediction of prognostic factors for POEMS syndrome is important for clinicians. With investigation of the mechanism of POEMS syndrome, many parameters such as respiratory symptoms, patients with coexisting Castleman’s disease and patients who had thrombocytosis have been approved as prognostic factors for POEMS syndrome [4, 5]. Several studies have shown that swelling of the optic disks is an early sign of the syndrome [6–8]. But there are limited data on the incidence of papilloedema associated with POEMS syndrome, and whether papilloedema can be used to indicate poor prognosis for POEMS syndrome has not been reported. Therefore, we divided patients into with/ without papilloedema to identify the risk factors for papilloedema and to evaluate the prognostic role of
J Neurol (2014) 261:60–65
papilloedema on POEMS syndrome, in an attempt to further define new prognostic factors in patients with POEMS syndrome.
Materials and methods The medical records of consecutive patients admitted to the Chinese PLA General Hospital with a diagnosis of POEMS syndrome between January 2003 and December 2012 were retrospectively reviewed. The diagnosis of POEMS syndrome was based on the standard criteria applied by Dispenzieri [4, 9]. At the time of admission, a complete physical examination was performed. Funduscopy (under mydriasis with tropicamide 1 %) was conducted by one experienced neuroophthalmologist using a 90-diopter lens [10]. Papilloedema was considered in the presence of either of the following: hyperemia of the disc, disc blurring or absent spontaneous venous pulsation [11]. Patients without at least one complete ophthalmologic examination were excluded from the study. In patients who had undergone an ocular examination, the following data were recorded: age, gender, lumbar puncture (LP) opening pressure, cerebrospinal fluid (CSF) protein levels, pulmonary function tests [diffusing capacity of the lung for carbon monoxide (DLCO) measured by means of the single-breath test], other laboratory data, such as serum levels of albumin, lactate dehydrogenase (LDH), C-reactive protein (CRP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), thyroid-stimulating hormone (TSH), complement component 3 (C3), complement component 4 (C4), kappa light chain (KAP), lambda light chain (LAM), tumor necrosis factor a (TNF-a), interleukin 6 (IL-6), b2-microglobulin (b2-MG), complete blood counts, as well as treatment and survival. Only measurements within 1 month of the first ophthalmic examination were taken into consideration. The values for these parameters were compared with normal ranges delineated by laboratories used by the Chinese PLA General Hospital. Initial therapies for the treatment of POEMS syndrome in this study, including corticosteroid therapy, radiation therapy, alkylator-based chemotherapy or different combinations, were provided. All patients received at least one method of treatment. Overall survival was calculated from the date of disease diagnosis to date of death by any cause, or the date on which the patient was last evaluated. POEMS syndromerelated death was calculated from the date of the POEMS syndrome diagnosis to the date of death or the date on which the patient was last evaluated. This investigation was reviewed and approved by the local ethical committee.
61 Table 1 Basic characteristics of 94 patients with POEMS syndrome Variables
Patients with papilloedema* (n = 49)
Patients without papilloedema (n = 45)
p value
Age, mean ± SD (years)
52.5 ± 15.8
49.4 ± 14.5
0.33
Gender, male
34/49 (70.0)
32/45 (72.7)
0.86
Serum marker at diagnosis WBC (9l09/L) [10
7/49 (14.3)
6/45 (13.3)
0.89
PLT (9l09/L) [400
12/49 (24.5)
10/45 (22.2)
0.80
Hb (g/dl) \11.0 Albumin (g/L) \35
7/49 (14.3) 18/49 (36.7)
7/45 (15.6) 15/45 (33.3)
0.86 0.73
AST (U/L) [40
10/49 (20.4)
9/45 (20.0)
0.96
Urea (mmol/L) [7.5
10/49 (20.4)
11/45 (24.4)
0.64
Creatinine (lmol/L) [110
11/49 (22.4)
9/45 (20.0)
0.77
LDH (U/L) [249
19/49 (38.8)
16/45 (35.6)
0.75
C3 (mg/dL) [180
30/43 (69.8)
28/45 (62.2)
0.46
C4 (mg/dL) [40
30/41 (73.2)
22/44 (50.0)
0.029
KAP (mg/dL) [370
16/45 (35.6)
15/40 (37.5)
0.85
LAM (mg/dL) [210
29/45 (64.4)
27/41 (65.9)
0.89
8/49 (16.0)
7/45 (15.6)
0.92
TNF-a (ng/L) [18
31/40 (77.5)
20/42 (47.6)
0.005
IL-6 (pg/mL) [7
32/41(78.1)
22/40 (55.0)
0.028
b2-MG (mg/ L) [ 2.5
20/42 (47.6)
16/38 (42.1)
0.62
27/49 (55.1)
23/45 (51.1)
0.86
19/45 (42.2)
0.95
CRP (mg/L) [15
Bone lesions
Extravascular volume overload Peripheral edema
21/49 (42.9)
Ascites
17/49 (34.7)
12/45 (26.7)
0.40
Pleural effusion
15/49 (30.6)
11/45 (24.4)
0.50
Pericardial 11/49 (22.4) effusion Pulmonary function tests
10/45 (22.2)
0.98
12/34 (35.3)
6/25 (24.0)
0.35
41/49 (83.7)
9/45 (20.0)
0.000
Decreased DLCO Lumbar puncture Opening pressure (mmH2O), [200
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Table 1 continued Variables
CSF protein levels (mg/L), [450
Patients with papilloedema* (n = 49)
Patients without papilloedema (n = 45)
p value
35/49 (71.40)
5/45 (11.1)
0.000
Corticosteroids alone
21/49 (42.9)
20/45 (44.4)
0.88
Chemotherapy alone
11/49 (20.4)
9/45 (20.0)
0.96
Radiotherapy alone
0
0
18/49 (36.7)
16/45 (35.6)
Treatment
Combined treatment
0.91
CSF cerebrospinal fluid, WBC white blood cells, PLT platelet, Hb hemoglobin, AST aspartate aminotransferase, ALT alanine aminotransferase, LDH lactate dehydrogenase, TSH thyroid-stimulating hormone, C3 complement component 3, KAP kappa light chain, LAM lambda light chain, CRP C-reactive protein, TNF-a tumor necrosis factor a, IL-6 interleukin 6, b2-MG b2-microglobulin, DLCO diffusing capacity of the lung for carbon dioxide, CSF cerebrospinal fluid * Values indicate the number of patients with the findings/number of patients detected (percent), unless otherwise noted
Statistical analysis Data analysis was performed using a statistical software package (SPSS 20.0 software, SPSS, Chicago, IL, USA). Data were summarized using mean ± SD for continuous or numeric variables and percentages and counts for categoric variables. Quantitative data were evaluated using the Chisquare and Fisher’s exact tests. Continuous variables were compared using the Student’s t test. Univariate logistic regression analyses were performed in an attempt to identify factors related to papilloedema. Multivariate logistic regression analyses were used to identify independent variables related to papilloedema. Survival data were evaluated by univariate and multivariate Cox regression analyses. Survival curves were plotted using the Kaplan–Meier method and compared by the log-rank test. Differences were considered significant at P \ 0.05.
Results Patients’ characteristics One hundred and twelve patients with POEMS syndrome were identified and treated at our institute during the 10-year study period. Fifty of these patients have been reported in part previously. Ninety-four (83.9 %) patients who had undergone at least one ophthalmological
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examination were enrolled in this study and completed follow-up. There were 66 men (70.2 %) and 28 women (29.8 %) with a mean age of 50.2 ± 13.6 years (range 29–76 years). They were divided into groups of patients with papilloedema and those without. The characteristics of the patients are given in Table 1. With the exception of elevated serum TNF-a (p = 0.005), IL-6 levels (p = 0.028), raised intracranial pressure and elevated CSF protein levels (both p = 0.000), both groups were similar in the median age, gender, performance status and treatment programs and other serum markers. Intracranial hypertension was more common in the group with papilloedema. The incidence and clinical findings of papilloedema in POEMS syndrome Papilloedema was found in 49 (52.1 %) of the patients. Of them, 31 (63.3 %) patients had blurred vision, 12 patients (24.5 %) reported diplopia, one patient with progressive loss of vision (2.0 %) and five patients (10.2 %) were asymptomatic at the time of the initial examination. No subsequent development of optic atrophy was seen. Factors related to papilloedema in patients with POEMS syndrome On univariate analysis, clinical factors associated with papilloedema in POEMS syndrome were elevated: serum TNF-a (p = 0.039), IL-6 levels (p = 0.044), C4 (p = 0.047), raised intracranial pressure (p = 0.042) and elevated CSF protein levels (p = 0.020). Multivariate analyses indicated that only raised intracranial pressure [hazard ratio (HR) 3.06; 95 % confidence interval (CI) 1.24–7.41; P = 0.011] and elevated CSF protein levels (HR 2.03; 95 % CI 1.07–4.51; P = 0.043) were independent factors (Table 2). Prognostic factors for POEMS syndrome Of the 94 patients studied, 14 patients have died. Median follow-up for surviving patients was 5.6 years and the overall mortality rate was 14.9 %. Univariate analysis of POEMS syndrome-related death revealed that papilloedema (p = 0.016), decreased DLCO (p = 0.012), and treatment with corticosteroids (p = 0.043) were important factors. On multivariate analysis, papilloedema (HR 1.58; 95 % CI 1.05–2.46; p = 0.027) and decreased DLCO (HR 2.17; 95 % CI 1.12–3.39; p = 0.023) were independent prognostic factors for POEMS syndrome-related death (Table 3). Kaplan–Meier plots revealed that the patients with papilloedema or decreased DLCO had significantly higher incidence of death compared to those without
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Table 2 Univariate and multivariate logistic regression analysis of the factors associated with papilledema in POEMS syndrome Variable
Univariate *
Multivariate
P
HR
95 % CI
P
HR
95 % CI
Male
0.36
0.83
0.56–1.24
Age C60 years
0.90
0.93
0.64–1.45
C3
0.45
0.75
0.63–1.48
C4
0.047
2.24
1.48–4.37
0.076
3.40
0.88–5.17
IL-6
0.044
2.36
1.23–11.59
0.55
1.00
0.89–2.05
LAM
0.18
0.75
0.25–2.31
b2-MG TNF-a
0.41 0.039
0.92 0.76
0.66–1.38 0.12–0.91
0.083
4.86
0.74–7.86
Raised intracranial pressure
0.042
2.66
1.03–6.08
0.011
3.06
1.24–7.41
Elevated CSF protein levels
0.020
2.18
1.09–3.04
0.043
2.03
1.07–4.51
HR hazard ratio, CI confidence interval * We considered variables that had a P value \0.10 in univariate logistic regression analyses as independent variables for multivariate logistic regression analyses
Table 3 Univariate and multivariate Cox regression analysis of the prognostic factors for POEMS syndrome-related death Variable
Univariate *
Multivariate
P
HR
95 % CI
Male
0.86
0.79
0.54–1.26
Age [60 years C4
0.44 0.45
0.81 1.17
0.66–1.47 0.62–1.78
IL-6
0.17
0.94
0.55–1.88
LAM
0.72
0.68
0.46–1.21
b2-MG
0.95
1.22
0.76–1.99
P
HR
95 % CI
TNF-a
0.78
1.38
0.95–2.63
Papilledema
0.016
2.01
1.01–7.09
0.027
1.58
1.05–2.46
Decreased DLCO
0.012
1.47
1.03–2.49
0.023
2.17
1.12–3.39
Corticosteroids alone
0.043
1.73
1.31–3.04
0.084
3.71
0.98–5.45
HR hazard ratio, CI confidence interval * The factors with P \ 0.05 in univariate analysis were enrolled into the forward stepwise multivariate Cox hazard regression
papilloedema or decreased DLCO (p = 0.033 and p = 0.012, respectively), which indicated these clinical factors were useful prognostic factors (Fig. 1).
Discussion POEMS syndrome is a multisystem disorder related to a plasma-cell dyscrasia [9, 12]. Previous studies have shown that papilloedema is a common finding in patients with POEMS syndrome [6–8]. However, there are only a small number of single case reports and small case series that examine the ocular manifestations of the POEMS disorder, and data regarding papilloedema were often incomplete, particularly about the association between papilloedema and the prognosis of patients with POEMS syndrome.
Herein, we reported, to our knowledge, the largest singlecenter series of POEMS syndrome with papilloedema, and evaluated the prognostic role of papilloedema in these patients. Consistent with the studies reported in the literature [6, 7], the most common ocular manifestation in POEMS syndrome in our series is papilloedema, which occurred in 52.1 % of the patients with POEMS syndrome. Other signs and symptoms include diplopia, blurred vision and vision loss. It suggested that papilloedema is an important feature in patients with POEMS syndrome. The pathogeny and physiopathology for papilloedema in POEMS syndrome remains contested. Some small series have found no relationship between papilloedema and raised ICP [13, 14]. In the current study, however, raised intracranial and CSF protein levels are still independently
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Fig. 1 Kaplan-Meier curves show that patients with papilledema (a) and decreased DLCO (b) have poor overall survival (p = 0.033 and 0.012, respectively)
associated with papilloedema. The authors propose that the presence of intracranial hypertension also may be a contributing factor to ocular manifestations in POEMS syndrome. Raised intracranial pressure provides a mechanical explanation for the development of papilloedema in POEMS syndrome, because the pressure can transmit to the orbit, causing papilloedema [6]. Increased vascular endothelial growth factor (VEGF) levels were reported to be involved in the cause for papilloedema [6, 7]. Also, serum C4, TNF-a and IL-6 levels were correlated with papilloedema on univariate analysis in our study. It was suggested that cytokines and an inflammatory pathophysiologic process may also be responsible for papilloedema in POEMS syndrome [15–19]; however, only raised intracranial pressure and elevated CSF protein levels were independent risk factors on multivariate analysis. Further studies are required to confirm these findings. POEMS syndrome results from an underlying plasma cell proliferative disorder and, if untreated, may have a lethal outcome, e.g., due to cardiorespiratory failure or
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progressive inanition [20]. Earlier studies focused on prognostic factors of POEMS syndrome on those parameters such as elevated serum VEGF, fingernail clubbing, extravascular volume overload and patients who received radiation therapy [5, 9]. Interestingly, the strong association of papilloedema with poor outcome was observed in our study. The possible reasons for papilloedema being a significantly poor prognostic factor for patients with POEMS syndrome may be the intracranial hypertension and the presence of an inflammatory pathophysiologic process [21–23]. This data may be helpful for clinicians to predict the risk of papilloedema and provide improved medical care for these patients. The pulmonary manifestations in POEMS syndrome are protean, including pulmonary hypertension, restrictive lung disease and impaired neuromuscular respiratory function [24, 25]. The function of the alveolar-capillary membrane is assessed by the diffusing capacity of DLCO, which is shown to be impaired in POEMS syndrome patients. DLCO is a measure of the ease of transfer for pulmonary
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gas exchange; therefore, alterations in DLCO are likely to affect plant gain and influence the stability of the ventilatory control system [26]. Moreover, abnormalities in ventilation and gas exchange result in hypoxia, hypercapnia, and respiratory acidosis, and these, in turn, interfere with cerebral metabolism, increase cerebral blood flow, and may lead to secondary cerebral vasodilatation with elevated intracranial pressure and consecutive papilloedema [27]. Thus, we hypothesized that ventilatory control instability plays a key pathophysiologic role in patients with POEMS syndrome, and reductions in DLCO would be associated with more severe respiratory and neurologic disturbance. In the current study, we provide evidence that a decreased DLCO is an important prognostic factor for patients with POEMS syndrome. This observation was not emphasized in other earlier studies. Other clinical factors such as treatment with corticosteroids alone was also important for POEMS syndrome-related prognosis. The major limitations of this study are the incomplete testing and reporting inherent in a retrospective study. For various reasons, modern treatments like peripheral blood stem cell transplantation were not widely used in those patients with POEMS syndrome. Despite these limitations, this is a valuable work and several important observations have been found which may lay the groundwork for future prospective studies. In conclusion, papilloedema and decreased DLCO at presentation are the most important prognostic factors of patients with POEMS syndrome. Our results may help clinicians predict the risk of mortality in POEMS syndrome and provide better medical care for these patients. Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
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8. 9. 10.
11. 12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
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ORIGINAL COMMUNICATION
Papilloedema is an independent prognostic factor for POEMS syndrome RongTai Cui • ShengYuan Yu • XuSheng Huang • JiaTang Zhang • ChengLin Tian • ChuanQiang Pu
Received: 30 July 2013 / Revised: 1 October 2013 / Accepted: 3 October 2013 / Published online: 20 October 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract POEMS syndrome is a potentially fatal disease, and prediction of prognostic factors for POEMS syndrome is important for clinicians. Papilloedema is an early sign of the syndrome. The present study was carried out to evaluate whether papilloedema is a prognostic factor for POEMS syndrome. Between January 2003 and December 2012, 94 patients with POEMS syndrome were enrolled in this study. The patients were divided into groups with and without papilloedema. Logistic regression was performed to identify risk factors related to papilloedema. Prognostic factors were analysed with Cox proportional hazard regressions for POEMS syndrome-related prognoses, and survival curves were plotted using the Kaplan–Meier method and compared by the log-rank test. Papilloedema was found in 52.1 % of the patients with POEMS syndrome. Raised intracranial pressure [hazard ratio (HR) 3.06, 95 % confidence interval (CI) 1.24–7.41; P = 0.011] and elevated cerebrospinal fluid protein levels (HR 2.03, 95 % CI 1.07–4.51; P = 0.043) were independently associated with papilloedema. Papilloedema, decreased diffusing capacity of the lung for carbon monoxide (DLCO) and treatment with corticosteroids alone were related to poor prognosis in POEMS syndrome. In multivariate analysis, papilloedema (HR 1.58, 95 % CI 1.05–2.46; p = 0.027) and decreased DLCO (HR 2.17, 95 % CI 1.12–3.39; p = 0.023) were independent factors for POEMS syndrome-related death. Papilloedema and decreased DLCO are important prognostic factors for patients with POEMS syndrome, which can help clinicians
R. Cui S. Yu X. Huang J. Zhang C. Tian C. Pu (&) Department of Neurology, Chinese PLA General Hospital, 28 FuXing Road, Beijing 100853, China e-mail: [email protected]
123
predict the risk of mortality and provide better medical care for these patients. Keywords POEMS syndrome Prognostic factor Cox model Papilloedema
Introduction POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome is a rare cause of demyelinating and axonal mixed neuropathy with multiorgan involvement and monoclonal plasma cell-proliferative disorder [1–3]. Other common manifestations are sclerotic bone lesions, Castleman’s disease, thrombocytosis, extravascular fluid overload (peripheral edema, pleural effusion, ascites, and pericardial effusion) [4]. POEMS syndrome is a potentially fatal disease, and patients’ quality of life deteriorates because of progressive neuropathy, massive pleural effusion or ascites, or thromboembolic events [3, 5]. Prediction of prognostic factors for POEMS syndrome is important for clinicians. With investigation of the mechanism of POEMS syndrome, many parameters such as respiratory symptoms, patients with coexisting Castleman’s disease and patients who had thrombocytosis have been approved as prognostic factors for POEMS syndrome [4, 5]. Several studies have shown that swelling of the optic disks is an early sign of the syndrome [6–8]. But there are limited data on the incidence of papilloedema associated with POEMS syndrome, and whether papilloedema can be used to indicate poor prognosis for POEMS syndrome has not been reported. Therefore, we divided patients into with/ without papilloedema to identify the risk factors for papilloedema and to evaluate the prognostic role of
J Neurol (2014) 261:60–65
papilloedema on POEMS syndrome, in an attempt to further define new prognostic factors in patients with POEMS syndrome.
Materials and methods The medical records of consecutive patients admitted to the Chinese PLA General Hospital with a diagnosis of POEMS syndrome between January 2003 and December 2012 were retrospectively reviewed. The diagnosis of POEMS syndrome was based on the standard criteria applied by Dispenzieri [4, 9]. At the time of admission, a complete physical examination was performed. Funduscopy (under mydriasis with tropicamide 1 %) was conducted by one experienced neuroophthalmologist using a 90-diopter lens [10]. Papilloedema was considered in the presence of either of the following: hyperemia of the disc, disc blurring or absent spontaneous venous pulsation [11]. Patients without at least one complete ophthalmologic examination were excluded from the study. In patients who had undergone an ocular examination, the following data were recorded: age, gender, lumbar puncture (LP) opening pressure, cerebrospinal fluid (CSF) protein levels, pulmonary function tests [diffusing capacity of the lung for carbon monoxide (DLCO) measured by means of the single-breath test], other laboratory data, such as serum levels of albumin, lactate dehydrogenase (LDH), C-reactive protein (CRP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), thyroid-stimulating hormone (TSH), complement component 3 (C3), complement component 4 (C4), kappa light chain (KAP), lambda light chain (LAM), tumor necrosis factor a (TNF-a), interleukin 6 (IL-6), b2-microglobulin (b2-MG), complete blood counts, as well as treatment and survival. Only measurements within 1 month of the first ophthalmic examination were taken into consideration. The values for these parameters were compared with normal ranges delineated by laboratories used by the Chinese PLA General Hospital. Initial therapies for the treatment of POEMS syndrome in this study, including corticosteroid therapy, radiation therapy, alkylator-based chemotherapy or different combinations, were provided. All patients received at least one method of treatment. Overall survival was calculated from the date of disease diagnosis to date of death by any cause, or the date on which the patient was last evaluated. POEMS syndromerelated death was calculated from the date of the POEMS syndrome diagnosis to the date of death or the date on which the patient was last evaluated. This investigation was reviewed and approved by the local ethical committee.
61 Table 1 Basic characteristics of 94 patients with POEMS syndrome Variables
Patients with papilloedema* (n = 49)
Patients without papilloedema (n = 45)
p value
Age, mean ± SD (years)
52.5 ± 15.8
49.4 ± 14.5
0.33
Gender, male
34/49 (70.0)
32/45 (72.7)
0.86
Serum marker at diagnosis WBC (9l09/L) [10
7/49 (14.3)
6/45 (13.3)
0.89
PLT (9l09/L) [400
12/49 (24.5)
10/45 (22.2)
0.80
Hb (g/dl) \11.0 Albumin (g/L) \35
7/49 (14.3) 18/49 (36.7)
7/45 (15.6) 15/45 (33.3)
0.86 0.73
AST (U/L) [40
10/49 (20.4)
9/45 (20.0)
0.96
Urea (mmol/L) [7.5
10/49 (20.4)
11/45 (24.4)
0.64
Creatinine (lmol/L) [110
11/49 (22.4)
9/45 (20.0)
0.77
LDH (U/L) [249
19/49 (38.8)
16/45 (35.6)
0.75
C3 (mg/dL) [180
30/43 (69.8)
28/45 (62.2)
0.46
C4 (mg/dL) [40
30/41 (73.2)
22/44 (50.0)
0.029
KAP (mg/dL) [370
16/45 (35.6)
15/40 (37.5)
0.85
LAM (mg/dL) [210
29/45 (64.4)
27/41 (65.9)
0.89
8/49 (16.0)
7/45 (15.6)
0.92
TNF-a (ng/L) [18
31/40 (77.5)
20/42 (47.6)
0.005
IL-6 (pg/mL) [7
32/41(78.1)
22/40 (55.0)
0.028
b2-MG (mg/ L) [ 2.5
20/42 (47.6)
16/38 (42.1)
0.62
27/49 (55.1)
23/45 (51.1)
0.86
19/45 (42.2)
0.95
CRP (mg/L) [15
Bone lesions
Extravascular volume overload Peripheral edema
21/49 (42.9)
Ascites
17/49 (34.7)
12/45 (26.7)
0.40
Pleural effusion
15/49 (30.6)
11/45 (24.4)
0.50
Pericardial 11/49 (22.4) effusion Pulmonary function tests
10/45 (22.2)
0.98
12/34 (35.3)
6/25 (24.0)
0.35
41/49 (83.7)
9/45 (20.0)
0.000
Decreased DLCO Lumbar puncture Opening pressure (mmH2O), [200
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Table 1 continued Variables
CSF protein levels (mg/L), [450
Patients with papilloedema* (n = 49)
Patients without papilloedema (n = 45)
p value
35/49 (71.40)
5/45 (11.1)
0.000
Corticosteroids alone
21/49 (42.9)
20/45 (44.4)
0.88
Chemotherapy alone
11/49 (20.4)
9/45 (20.0)
0.96
Radiotherapy alone
0
0
18/49 (36.7)
16/45 (35.6)
Treatment
Combined treatment
0.91
CSF cerebrospinal fluid, WBC white blood cells, PLT platelet, Hb hemoglobin, AST aspartate aminotransferase, ALT alanine aminotransferase, LDH lactate dehydrogenase, TSH thyroid-stimulating hormone, C3 complement component 3, KAP kappa light chain, LAM lambda light chain, CRP C-reactive protein, TNF-a tumor necrosis factor a, IL-6 interleukin 6, b2-MG b2-microglobulin, DLCO diffusing capacity of the lung for carbon dioxide, CSF cerebrospinal fluid * Values indicate the number of patients with the findings/number of patients detected (percent), unless otherwise noted
Statistical analysis Data analysis was performed using a statistical software package (SPSS 20.0 software, SPSS, Chicago, IL, USA). Data were summarized using mean ± SD for continuous or numeric variables and percentages and counts for categoric variables. Quantitative data were evaluated using the Chisquare and Fisher’s exact tests. Continuous variables were compared using the Student’s t test. Univariate logistic regression analyses were performed in an attempt to identify factors related to papilloedema. Multivariate logistic regression analyses were used to identify independent variables related to papilloedema. Survival data were evaluated by univariate and multivariate Cox regression analyses. Survival curves were plotted using the Kaplan–Meier method and compared by the log-rank test. Differences were considered significant at P \ 0.05.
Results Patients’ characteristics One hundred and twelve patients with POEMS syndrome were identified and treated at our institute during the 10-year study period. Fifty of these patients have been reported in part previously. Ninety-four (83.9 %) patients who had undergone at least one ophthalmological
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examination were enrolled in this study and completed follow-up. There were 66 men (70.2 %) and 28 women (29.8 %) with a mean age of 50.2 ± 13.6 years (range 29–76 years). They were divided into groups of patients with papilloedema and those without. The characteristics of the patients are given in Table 1. With the exception of elevated serum TNF-a (p = 0.005), IL-6 levels (p = 0.028), raised intracranial pressure and elevated CSF protein levels (both p = 0.000), both groups were similar in the median age, gender, performance status and treatment programs and other serum markers. Intracranial hypertension was more common in the group with papilloedema. The incidence and clinical findings of papilloedema in POEMS syndrome Papilloedema was found in 49 (52.1 %) of the patients. Of them, 31 (63.3 %) patients had blurred vision, 12 patients (24.5 %) reported diplopia, one patient with progressive loss of vision (2.0 %) and five patients (10.2 %) were asymptomatic at the time of the initial examination. No subsequent development of optic atrophy was seen. Factors related to papilloedema in patients with POEMS syndrome On univariate analysis, clinical factors associated with papilloedema in POEMS syndrome were elevated: serum TNF-a (p = 0.039), IL-6 levels (p = 0.044), C4 (p = 0.047), raised intracranial pressure (p = 0.042) and elevated CSF protein levels (p = 0.020). Multivariate analyses indicated that only raised intracranial pressure [hazard ratio (HR) 3.06; 95 % confidence interval (CI) 1.24–7.41; P = 0.011] and elevated CSF protein levels (HR 2.03; 95 % CI 1.07–4.51; P = 0.043) were independent factors (Table 2). Prognostic factors for POEMS syndrome Of the 94 patients studied, 14 patients have died. Median follow-up for surviving patients was 5.6 years and the overall mortality rate was 14.9 %. Univariate analysis of POEMS syndrome-related death revealed that papilloedema (p = 0.016), decreased DLCO (p = 0.012), and treatment with corticosteroids (p = 0.043) were important factors. On multivariate analysis, papilloedema (HR 1.58; 95 % CI 1.05–2.46; p = 0.027) and decreased DLCO (HR 2.17; 95 % CI 1.12–3.39; p = 0.023) were independent prognostic factors for POEMS syndrome-related death (Table 3). Kaplan–Meier plots revealed that the patients with papilloedema or decreased DLCO had significantly higher incidence of death compared to those without
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Table 2 Univariate and multivariate logistic regression analysis of the factors associated with papilledema in POEMS syndrome Variable
Univariate *
Multivariate
P
HR
95 % CI
P
HR
95 % CI
Male
0.36
0.83
0.56–1.24
Age C60 years
0.90
0.93
0.64–1.45
C3
0.45
0.75
0.63–1.48
C4
0.047
2.24
1.48–4.37
0.076
3.40
0.88–5.17
IL-6
0.044
2.36
1.23–11.59
0.55
1.00
0.89–2.05
LAM
0.18
0.75
0.25–2.31
b2-MG TNF-a
0.41 0.039
0.92 0.76
0.66–1.38 0.12–0.91
0.083
4.86
0.74–7.86
Raised intracranial pressure
0.042
2.66
1.03–6.08
0.011
3.06
1.24–7.41
Elevated CSF protein levels
0.020
2.18
1.09–3.04
0.043
2.03
1.07–4.51
HR hazard ratio, CI confidence interval * We considered variables that had a P value \0.10 in univariate logistic regression analyses as independent variables for multivariate logistic regression analyses
Table 3 Univariate and multivariate Cox regression analysis of the prognostic factors for POEMS syndrome-related death Variable
Univariate *
Multivariate
P
HR
95 % CI
Male
0.86
0.79
0.54–1.26
Age [60 years C4
0.44 0.45
0.81 1.17
0.66–1.47 0.62–1.78
IL-6
0.17
0.94
0.55–1.88
LAM
0.72
0.68
0.46–1.21
b2-MG
0.95
1.22
0.76–1.99
P
HR
95 % CI
TNF-a
0.78
1.38
0.95–2.63
Papilledema
0.016
2.01
1.01–7.09
0.027
1.58
1.05–2.46
Decreased DLCO
0.012
1.47
1.03–2.49
0.023
2.17
1.12–3.39
Corticosteroids alone
0.043
1.73
1.31–3.04
0.084
3.71
0.98–5.45
HR hazard ratio, CI confidence interval * The factors with P \ 0.05 in univariate analysis were enrolled into the forward stepwise multivariate Cox hazard regression
papilloedema or decreased DLCO (p = 0.033 and p = 0.012, respectively), which indicated these clinical factors were useful prognostic factors (Fig. 1).
Discussion POEMS syndrome is a multisystem disorder related to a plasma-cell dyscrasia [9, 12]. Previous studies have shown that papilloedema is a common finding in patients with POEMS syndrome [6–8]. However, there are only a small number of single case reports and small case series that examine the ocular manifestations of the POEMS disorder, and data regarding papilloedema were often incomplete, particularly about the association between papilloedema and the prognosis of patients with POEMS syndrome.
Herein, we reported, to our knowledge, the largest singlecenter series of POEMS syndrome with papilloedema, and evaluated the prognostic role of papilloedema in these patients. Consistent with the studies reported in the literature [6, 7], the most common ocular manifestation in POEMS syndrome in our series is papilloedema, which occurred in 52.1 % of the patients with POEMS syndrome. Other signs and symptoms include diplopia, blurred vision and vision loss. It suggested that papilloedema is an important feature in patients with POEMS syndrome. The pathogeny and physiopathology for papilloedema in POEMS syndrome remains contested. Some small series have found no relationship between papilloedema and raised ICP [13, 14]. In the current study, however, raised intracranial and CSF protein levels are still independently
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Fig. 1 Kaplan-Meier curves show that patients with papilledema (a) and decreased DLCO (b) have poor overall survival (p = 0.033 and 0.012, respectively)
associated with papilloedema. The authors propose that the presence of intracranial hypertension also may be a contributing factor to ocular manifestations in POEMS syndrome. Raised intracranial pressure provides a mechanical explanation for the development of papilloedema in POEMS syndrome, because the pressure can transmit to the orbit, causing papilloedema [6]. Increased vascular endothelial growth factor (VEGF) levels were reported to be involved in the cause for papilloedema [6, 7]. Also, serum C4, TNF-a and IL-6 levels were correlated with papilloedema on univariate analysis in our study. It was suggested that cytokines and an inflammatory pathophysiologic process may also be responsible for papilloedema in POEMS syndrome [15–19]; however, only raised intracranial pressure and elevated CSF protein levels were independent risk factors on multivariate analysis. Further studies are required to confirm these findings. POEMS syndrome results from an underlying plasma cell proliferative disorder and, if untreated, may have a lethal outcome, e.g., due to cardiorespiratory failure or
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progressive inanition [20]. Earlier studies focused on prognostic factors of POEMS syndrome on those parameters such as elevated serum VEGF, fingernail clubbing, extravascular volume overload and patients who received radiation therapy [5, 9]. Interestingly, the strong association of papilloedema with poor outcome was observed in our study. The possible reasons for papilloedema being a significantly poor prognostic factor for patients with POEMS syndrome may be the intracranial hypertension and the presence of an inflammatory pathophysiologic process [21–23]. This data may be helpful for clinicians to predict the risk of papilloedema and provide improved medical care for these patients. The pulmonary manifestations in POEMS syndrome are protean, including pulmonary hypertension, restrictive lung disease and impaired neuromuscular respiratory function [24, 25]. The function of the alveolar-capillary membrane is assessed by the diffusing capacity of DLCO, which is shown to be impaired in POEMS syndrome patients. DLCO is a measure of the ease of transfer for pulmonary
J Neurol (2014) 261:60–65
gas exchange; therefore, alterations in DLCO are likely to affect plant gain and influence the stability of the ventilatory control system [26]. Moreover, abnormalities in ventilation and gas exchange result in hypoxia, hypercapnia, and respiratory acidosis, and these, in turn, interfere with cerebral metabolism, increase cerebral blood flow, and may lead to secondary cerebral vasodilatation with elevated intracranial pressure and consecutive papilloedema [27]. Thus, we hypothesized that ventilatory control instability plays a key pathophysiologic role in patients with POEMS syndrome, and reductions in DLCO would be associated with more severe respiratory and neurologic disturbance. In the current study, we provide evidence that a decreased DLCO is an important prognostic factor for patients with POEMS syndrome. This observation was not emphasized in other earlier studies. Other clinical factors such as treatment with corticosteroids alone was also important for POEMS syndrome-related prognosis. The major limitations of this study are the incomplete testing and reporting inherent in a retrospective study. For various reasons, modern treatments like peripheral blood stem cell transplantation were not widely used in those patients with POEMS syndrome. Despite these limitations, this is a valuable work and several important observations have been found which may lay the groundwork for future prospective studies. In conclusion, papilloedema and decreased DLCO at presentation are the most important prognostic factors of patients with POEMS syndrome. Our results may help clinicians predict the risk of mortality in POEMS syndrome and provide better medical care for these patients. Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
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8. 9. 10.
11. 12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
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