DOI: https://doi.org/10.21203/rs.2.17758/v1
Background Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome is a rare paraneoplastic syndrome involving multisystem. Optic disc edema (ODE) is the most common ocular manifestation in patients with POEMS syndrome and serves as an independent prognostic factor. However, parameters previously used to estimate its severity were inconvenient and costly. This study was designed to bring forward a novel and practical parameter, optic disc edema area, to evaluate ODE in patients with this disease and applied it to assess effectiveness of lenalidomide and dexamethasone in respect of ODE.
Results Forty-one treatment-naive patients with POEMS syndrome were enrolled in this single-center prospective study and treated with lenalidomide and dexamethasone. They received ocular examination to determine optic disc edema (ODE) area and other optic manifestations. Meanwhile, serum VEGF was measured before and after treatment. Among 41 enrolled patients, 38 received complete ocular examinations, and 25 of which had ODE at initial visit. Binocular mean ODE area of patients with ODE was significantly related to ODE grade (r=0.620, p =0.003) and peripheral retinal thickness (r=0.760, p =0.000) before treatment. Serum VEGF was significantly higher in patients with ODE than their counterparts ( p =0.025) and positively correlated with binocular mean ODE area (r=0.460, p =0.036). After treatment, ODE area, along with serum VEGF, decreased markedly ( p =0.000).
Conclusion ODE area was a reliable index to evaluate ODE severity and could precisely reflect ODE improvement through systemic treatment. Additionally, it was related to serum VEGF, a key factor in disease pathogenesis, which suggests its potential capability of indicating the overall severity of this disease. Trial registration: Clinicaltrials, NCT01816620. Registered March 22 2013, https://clinicaltrials.gov/ct2/show/NCT01816620.
POEMS syndrome is a rare, chronic, multisystemic disease, characterized by acronym of a series of distinct features: polyneuropathy (P), organomegaly (O), endocrinopathy (E), monoclonal or M-protein band (M) and skin changes (S). Furthermore, some clinical signs beyond the extent of the definition of POEMS syndrome also contribute to the diagnosis of POEMS syndrome, of which papilledema is an important component. Among all the reported ocular symptoms in POEMS syndrome patients, papilledema is the most common one and serves as a negative prognostic factor.[1,2]
The pathogenesis of POEMS syndrome and its presentation of ODE is still under study. However, vascular endothelial growth factor (VEGF) is considered to be a pivotal factor in the progressing of many clinical features,[1] including papilledema. The connection between papilledema and serum VEGF has already been reported, both in our previous study and in studies of other ophthalmologists or hematologists, based on peripapillary retinal thickness (pRT) and subfoveal choroidal thickness.[3–6] But these two parameters were inconvenient and costly, thus impractical for routine ODE assessment.
Therefore, to bring forward a novel convenient evaluation index, optic disc edema (ODE) area, and determine its possibility in reflecting the treatment outcome of POEMS syndrome in terms of ocular manifestations and further confirm the relationship between papilledema and serum VEGF level, we conducted this prospective study of patients with POEMS syndrome diagnosed at Department of Hematology, Peking Union Medical College Hospital (PUMCH).
Patients
Forty-one newly-diagnosed patients with POEMS syndrome who met the diagnostic criteria defined by Dispenzeri were enrolled from April 2014 to November 2014.[7] Patients previously diagnosed with malignant tumor or treated with immunomodulatory drugs were excluded from the cohort. And patients with history in either eye of optic nerve diseases, glaucoma, diabetic retinopathy, retinal or choroidal vascular diseases, uveitis, high myopia no less than 6.00DS and who had undergone intraocular surgery were excluded either.
Treatment
Treatment with lenalidomide (Revlimid; Celgene Corporation, Summit, NJ, USA) was applied to all enrolled patients at a dose of 10 mg per day for 21 days of a 28-day cycle, accompanied by dexamethasone taken orally at 40 mg once per week. Besides, to prevent thrombosis, aspirin was prescribed at a dose of 100mg per day.
Ocular examination
All enrolled patients were supposed to receive complete ocular examination before treatment and every three months since treatment initiation until the completion of study, complete remission of papilledema or death of patients. Best-correct visual acuity (BCVA) measured by the International Standard Visual Acuity Chart, intraocular pressure (IOP), pupillary reflect, ocular motility, slit lamp examination and fundus examination were performed. In addition, fundus photography (TOPCON TRC.NW6S, Non-mydriatic retinal camera) and spectral domain optic coherence tomography (SD-OCT, Spectralis OCT; Heidelberg Engineering, Heidelberg, Germany) were also performed at each visit. Among them, we placed emphasis on fundus photography to determine the severity of papilledema.
Fundus photography measurement
Fundus photography was performed at every visit to grade the extent of ODE and obtain the area of optic disc edema. (1) ODE grade was determined by ophthalmologists according to Modified Frisén Scale, in which the severity of ODE was stratified into 5 categories and key features of each category were as follows: Grade 1 (minimal degree) is defined as the presence of a C-shaped halo of opacification of the RNFL at the region of the optic disc border; Grade 2 has a circumferential halo with decreased translucency, whereas each major retinal vessels were visible when coursing over optic disc and its border; Grade 3 is characterized by the loss of discontinuity along a segment of at least one major vessel when coursing over the optic disc margin; Grade 4 presents discontinuity due to opacification of at least one but not all major vessels on the optic disc; Grade 5 is characterized by obscuration of all major vessels on the optic disc.[8] Declination of the grade by one or more levels in either eye after treatment was considered as remission of ODE, while decreasing to zero in both eyes was considered as complete remission. (2) The border of edematous optic disc was decided by the margin of promontory optic disc as showed in fundus photography (Figure 1) and the area of it was measured automatically by the software of the machine used for examination.
Serum VEGF level measurement
Human Quantikine ELISA Kit (R&D Systems, Minneapolis, MN, USA) was used to measure serum VEGF levels at initial pretreatment examination and during follow-up through or after treatment. Normal range of VEGF was considered as below 600 pg/mL.[9]
Statistical analysis
SPSS statistics 17.0 (SPSS Inc., Chicago,IL, USA) was used to perform statistical analysis. The comparison between continuous variables including serum VEGF and ODE area was based on Student t test. The correlation between ODE area and ODE grade was determined by Spearman correlation coefficient, while correlations between ODE area and serum VEGF as well as between ODE area and peripheral retinal thickness (pRT, data extracted from our former study[6]) were performed using Pearson correlation coefficient. P value less than 0.05 was considered as statistically significant.
General information at baseline
At initial visit, all 41 newly-diagnosed patients had polyneuropathy, endocrinopathy, M-protein band and skin changes. Organomegaly manifested most commonly as lymphadenopathy (38/41, 92.7%). Besides, spleen (27/41, 65.9%) and liver (24/41, 58.5%) were two other common organs involved. Endocrinopathy included 71.8% (28/41) of increased ACTH, 41.5% (17/41) of hypothyroidism, 14.6% (6/41) of diabetes mellitus, and 75% (21/28) of male gynecomastia. Thirty-six patients completed 12 cycles of lenalidomide and dexamethasone therapy, while 3 patients died due to disease progression and 2 quitted the clinical trial midway. In this study, three patients who did not meet the basic requirement of ocular examination were excluded: one patient with incomplete initial ocular examination data, one with missed pre-treatment ODE area data, and another one with delayed first posttreatment measurement of optic disc at 12 months later. At diagnosis, average age of the enrolled 38 patients with complete data was 50.0±11.5 years (range 21–70). Among them, 26 were male and 12 were female. Mean serum VEGF level was 5655±3290 pg/mL (range 534–14328).
Ocular manifestations and ODE grading before and after treatment
At the first ocular examination before treatment, 25 (65.8%) patients were diagnosed with ODE, of which 24 (96%) were bilateral and only 1 (4%) was unilateral. ODE stratification was determined in these 25 patients: 1 eye (2%) was grade 0, 12 eyes (24%) were grade 1, 10 eyes (44%) were grade 2, 11 eyes (22%) were grade 3, 14 eyes (28%) were grade 4 and 2 eyes (32%) were grade 5. Among the 25 patients with ODE, except 8 (32%) did not show any ocular symptom, the other 17 patients (68%) had different symptoms mainly manifested as blurred vision, decreased vision and palpebral edema. Red eye, photophobia and photopsia also appeared in some patients. In contrast, all the other 13 patients (34.2%) without ODE did not show any ocular symptoms before treatment and during follow-up.
All enrolled patients received treatment with lenalidomide and dexamethasone after initial examination. Except 3 patients either died during treatment or showed very slight ODE and refused to receive following ocular examination, all the other 22 patients had ocular examination follow-up, with a mean duration of 8.6±3.3 months (range 3–13). Twenty-one patients received ocular examination 3 months after treatment. Remission rate was 83.3% (35/42) and complete remission rate was 14.3% (6/42), with only 7 eyes remained stable ODE grade. And at last visit, the remission rate was 90.9% (40/44) and complete remission rate was 54.5% (24/44). ODE grade was 0 in 24 eyes (54.2%), 1 in 14 eyes (33.3%) and 2 in 6 eyes (12.5%) (Figure 2, Figure 3). Ocular manifestations disappeared in almost all patients at last visit except one patient who still had blurred vision even with complete remission of his ODE.
ODE area measurement before and after treatment
ODE area was measured in 21 patients with ODE at initial examination. Except one patient died during treatment, all the other 20 patients had their ODE areas measured at follow-up ocular examinations.
The ODE area of right eye and left eye at initial examination was 2.0098±0.8050 mm2 (range 0.8064–3.2659) and 1.9310±0.7747 mm2 (range 0.8124–3.8495) respectively. There was no significant difference between ODE area of right and left eyes (p = 0.595) and binocular mean ODE area was 1.9704±0.7158 mm2 (range 0.8094–3.5577). The correlation between binocular mean ODE area and ODE grading before treatment was significant (r = 0.620, p = 0.003).
At last visit, ODE area of right and left eye of the 20 alive patients was 1.0501±0.2760 mm2 (range 0.6395–1.7315) and 1.1176±0.3265 mm2 (range 0.6690–1.9767) respectively, without significant difference (p = 0.230). Binocular mean ODE area was 1.0839±0.2768 mm2 (range 0.6646–1.7118), which was remarkably lower than the data at initial examination (p = 0.000). The declination in ODE area was noticeable through treatment (Figure 4, Figure 5).
Serum VEGF levels and ODE area
As stated above, mean serum VEGF level of all 38 POEMS patients with or without ODE at initial visit was 5655±3290 pg/mL (range 534–14328). And 3 months post-treatment, serum VEGF level of all 37 alive patients declined to 1979±2132 pg/mL (range 181–11179), significantly lower than VEGF before treatment (p = 0.000).
At initial visit, serum VEGF level of patients with and without ODE was 6564±3257 pg/mL (range 1553–14328) and 3907±740 pg/mL (range 534–8594), respectively. The difference in mean serum VEGF level between the two groups above was significant (p = 0.016).
Besides, binocular mean ODE area was significantly correlated with serum VEGF among patients with ODE before treatment (r = 0.460, p = 0.036, Figure 6). However, the correlation after treatment was not significant (r = 0.015, p = 0.937).
ODE area and peripheral retinal thickness
To confirm the consistency between ODE area and pRT, both were supposed to be capable of acting as indicators of ODE severity, we did correlation analysis between these two parameters among 20 patients with both two parameters measured before treatment and found significant correlation (r = 0.760, p = 0.000, Figure 7). The measurement of pRT in these patients was described in one of our former published articles.[6]
POEMS syndrome is a rare paraneoplastic syndrome involving multisystem due to underlying plasma cell disorder. According to previous studies, ocular signs and symptoms are common in POEMS syndrome, and ODE occurs most frequently, serving as an adverse prognostic feature for overall survival.[2] Consistent with existing reports, ODE was also the most common ocular finding in our trial, with an incidence of 65.8%, close to the upper bound of previous data (30-70%).[1,2,6,7,10,11] Analogous to the previous study,[11] 68% of patients with ODE showed variable associated symptoms at initial examination, including blurred vision, decreased vision, palpebral edema, red eye, photophobia and photopsia.
The pathogenesis of POEMS syndrome is complex and remains contested. However, VEGF, as a cytokine increasing vascular permeability reversibly and promoting angiogenesis, is considered as a potential contributor and correlated with disease activity, serving as an important prognostic factor.[12-15] It has also been suggested that elevated serum VEGF level might be a cause of ODE in POEMS syndrome.[3,4,6,10] The relationship between ODE and serum VEGF in this disease has already been proved in our recent studies based on binocular mean peripheral retinal thickness (pRT) and retinal nerve fiber layer (RNFL) thickness.[6] However, pRT and RNFL thickness are significantly affected by several factors such as myopia and optic disc size.[16-18] Besides, their measurements are costly and not universal enough to make them routine ocular tests for POEMS patients. Thus, as an extension, we chose ODE area as an evaluation parameter in this current study. In our study, ODE area was significantly correlated to ODE grade before treatment. We also compared ODE area with pRT data extracted from our previous study and found the correlation prominent.[6] These two parameters are consistent and efficacious in reflecting the severity of ODE. In addition, relationship between ODE area and serum VEGF before treatment was remarkable. This not only confirmed the relationship between VEGF and ODE in POEMS syndrome, but also indicate the possibility of ODE area to approximately represent patients’ serum VEGF level.
Besides ODE, edema also appeared elsewhere in our patient cohort, including lower extremities, abdomen and pleura. Thus, ODE was more like an ocular manifestation of systemic edema caused by circulating serum VEGF rather than a focal symptom caused by tissue-borne VEGF.[10,19] It has been reported that only binding to abluminal VEGFR2 rather than luminal receptor, can VEGFA increasing the permeability of a vessel.[20] Due to the caliber and flow volume differences between choroidal and retinal vessels, circulating VEGFA can only leak out from choroidal vessels and bind to abluminal VEGFR2 to improve permeability of surrounding vessels.[6,20-22] Also, previous study reported that subfoveal choroidal thickness was positively related to serum VEGF level in POEMS syndrome.[4] These findings together suggested that circulating VEGF triggered ODE in patients with POEMS syndrome through choroid, which could only be relieved through systemic treatment. The outcome of systemic treatment using lenalidomide and dexamethasone was satisfactory in our study: ODE was relieved in 90.9% and completely resolved in 54.2% of patients at last visit, accompanied by significantly reduction of ODE area and serum VEGF level. Beyond that, we also found choroidal thickness around optic disc decreasing in several patients through the treatment, which again verified the hypothesis stated above (Table 1, Figure 8 ).
Table 1. Choroidal thickness (μm) change of a POEMS syndrome patient (70/F) through treatment.
|
|
Right eye |
Left eye |
||||
|
Treatment cycle→ Location↓ |
C3 |
C6 |
C12 |
C3 |
C6 |
C12 |
|
T |
154 |
139 |
120 |
161 |
144 |
128 |
|
TS |
151 |
135 |
111 |
186 |
186 |
171 |
|
NS |
140 |
119 |
110 |
189 |
169 |
159 |
|
N |
119 |
105 |
90 |
161 |
146 |
123 |
|
NI |
108 |
100 |
89 |
137 |
111 |
92 |
|
TI |
135 |
121 |
103 |
129 |
120 |
112 |
|
Mean |
134.5 |
119.8 |
103.8 |
160.5 |
146 |
130.8 |
*T: temporal, TS: superior-temporal, NS: superior-nasal, N: nasal, NI: inferior-nasal, TI: inferior-temporal. The data was obtained from SD-OCT at each visit, showing the declination of choroidal thickness at all locations around optic discs in both eyes after 3, 6 and 12 cycles of treatment. This declination is accompanied by the reduction of VEGF and ODE area (VEGF from 8275 to 151 pg/mL, binocular ODE area from 2.8687 to 0.8742 mm2).
Although correlation between VEGF and ODE area before treatment was significant, the correlation coefficient was 0.460, indicating other factors might contribute to ODE. Elevated intracranial pressure (ICP), vasculitis and nerve infiltration were three other reported causes,[10,11] among which elevated ICP received most attention. However, relevant results were controversial: some studies affirmed the correlation between elevated ICP and ODE,[2,23] while some others repudiated it.[3,24] Unfortunately, ICP were recorded in only seldom patients in our cohort thus it was unpractical to include it in our study. Another limitation was incomplete measurement of choroidal thickness due to obscurity of choroid borders in many patients with ODE. In addition, optic disc area changes in different ethnic groups, axial length and myopic refractive error,[25,26] yet we cannot avoid this bias since it was hard to determine original disc area in patients with ODE. Despite these limitations, this is still a valuable work. On the one hand, we brought forward ODE area as an evaluation index to estimate the severity of ODE in a relatively large cohort of POEMS patients, and outcomes proved its reliability. Besides, ODE area was significantly correlated to serum VEGF. Since fundus photography is more universal than SD-OCT and ODE area measurement is more convenient and less expensive than pRT and RNFL thickness measurement, ODE area could act as a feasible parameter evaluating the change of ODE as well as VEGF level in patients with POEMS syndrome. On the other hand, we confirmed the effectiveness of lenalidomide in terms of ocular involvement.
ODE area was an intuitive and effective index in ODE evaluation which is expected to put into clinical practice in patients with POEMS syndrome. Besides, we confirmed that ODE, related to serum VEGF level, could be resolved successfully through systemic treatment with lenalidomide.
POEMS syndrome: Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes syndrome
ODE: optic disc edema
ODE area: optic disc edema area/edematous optic disc area
VEGF: vascular endothelial growth factor
pRT: peripapillary retinal thickness
RNFL: retinal nerve fiber layer
BCVA: best-correct visual acuity
IOP: intraocular pressure
SD-OCT: spectral domain optic coherence tomography
ICP: intracranial pressure
The protocol of this study was approved by the Institutional Review Board of Peking Union Medical College Hospital. All the patients were informed about the purpose and treatment procedure, and written informed consents were obtained. All procedures conformed to the tenets of the Declaration of Helsinki.
Consents for publication of patients’ individual fundus photography and SD-OCT outcomes (displayed in Figure 3 and Figure 8) were all obtained from them.
The dataset supporting the conclusions of this article is included within the article.
All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/coi_disclosure.pdf and declared: supports from organizations for the submitted work were stated in Funding part; no financial relationships with any organization that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work.
This study was supported by grants from the National Natural Science Foundation of China (grant no. 81570195), the Beijing Natural Science Foundation (grant no. 7142130), the Specialized Research Fund for the Doctoral Program of Higher Education (grant no. 2013110611000), and the Peking Union Medical College New Star (2011, for J. Li).
LLS is first author. LJ obtained funding. DRP and LJ designed the study. ZX, ZH, GXM, DRP, LJ and ZDB did the measurement and collected the data at initial visit and follow-up. LLS, ZX, ZH and GXM were involved in data cleaning and verification. LLS analyzed the data, interpreted the results and drafted the manuscript. DRP contributed to the critical revision of the manuscript approved the final version of the manuscript. All authors have read and approved the final manuscript. DRP and LJ are the study guarantors.
Not applicable.
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