Ocular Manifestations of Polyneuropathy, Organomegaly, Endocrinopathy, Myeloma Protein, and Skin Changes (POEMS) Syndrome
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Disease Entity
Disease
POEMS Syndrome, also known as osteosclerotic myeloma, Crow-Fukase syndrome, or Takatsuki syndrome[1] is a paraneoplastic hematologic condition that is characterized by aberrant production of plasma cells[2]. The acronym POEMS stands for Polyneuropathy, Organomegaly, Endocrinopathy, Myeloma (M) protein, and Skin changes (POEMS),[2] but the acronym does not address all important features of the disease, e.g. papilledema and extravascular volume overload[3]. The pathogenesis is not fully understood but is thought to be due to an imbalance between multiple proinflammatory, angiogenic, and anti-inflammatory cytokines[1] that can lead to severe progressive decline in function in multiple organ systems[2]. POEMS Syndrome has potential ocular manifestations, including papilledema, retinal detachment, and central retinal artery occlusion (CRAO)[4].
Pathophysiology
The pathogenesis of POEMS syndrome remains incompletely understood, but excess proinflammatory and angiogenic cytokines (e.g. Interleukin-1β [IL-1β], interleukin-6 [IL-6], interleukin-12 [IL-12], fibroblast growth factor, hepatocyte growth factor, vascular endothelial growth factor [VEGF]), an underproduction of anti-inflammatory cytokines, especially transcription growth factor β1, and an expansion of clonal and polyclonal plasma cells are thought to contribute to this condition. While VEGF levels correlate to disease activity, they may not be the principal driving force since anti-VEGF therapies produce mixed responses[1].
The main ocular manifestation of POEMS syndrome are papilledema[4] and macular edema[5]. Papilledema occurs in nearly 50% of known POEMS cases[4], and optic disc edema occurs in 29-64% of known POEMS cases[5]. The reason for disc swelling is unclear, however, increased vascular permeability is hypothesized[6]. Higher levels of VEGF are thought to increase macula and optic nerve vessel permeability, and osmotic gradients cause high molecular weight immunoglobulin deposition that leads to cystic macular edema and potentially macular detachment[5]. Many experts believe that increased CSF proteins, due to increased concentration of immunoglobulin in the plasma, leads to a type of communicating hydrocephalus[4].
Etiology
The incidence and prevalence of POEMS syndrome are not as clear as it is a rare condition[2]. In Japan, the alleged country of origin, the prevalence is approximately 0.3 per 100,000 people[2]. Many cases have also been reported in France, China, India, and the USA[3]. A Japanese survey in 2015 indicated a slight male:female ratio of 1.5 with a median age of onset at 54 years of age (range of 21-84)[7]. This differs from multiple myeloma, which peaks in the 7th and 8th decades[8]. With an unclear pathogenesis, risk factors for the disease are also largely unknown[2].
Signs
Patients with POEMS may have asymptomatic ocular findings, but many have concerns for blurred vision, transient obscurations of vision, or diplopia. Optic disc edema, papilledema, serous macular detachment, and visual field defects may occur[5].
Patient Exam[9]
- Signs of Elevated Intracranial Pressure:
- Headache
- Nausea and Vomiting
- Diplopia
- Ataxia
- Altered Consciousness
Possible Fundus Findings[9]:
- Elevation and blurring of optic disc
- Venous congestion
- Retinal Hard Exudates
- Splinter Hemorrhages and Infarcts
| Finding | Presenting Symptoms and signs | Imaging / Tests |
|---|---|---|
| Cystoid Macular Edema[9] | Symptoms: Central visual loss.
Fundoscopy: Intraretinal cystoid macular edema and thickening[10] |
Test of Choice: Lens-aided slit-lamp biomicroscopy of the posterior pole
Ophthalmoscopic and optical coherence tomography (OCT) findings: Macular thickening, exudates, and cystoid changes[11] |
| Serous Macular Detachment[9] | Painless Loss of Vision, Blurry Vision[12] | Test of Choice: Binocular ophthalmoscopy and OCT[12]
Findings: Loss of foveal fundus reflex, elevation of the retina by subretinal fluid seen on OCT[12] |
| Venous Sinus Thrombosis[9] | Papilledema, Headache (Thunderclap, migraine, cluster), Cranial Nerve Involvement including non-localizing sixth nerve palsy, Altered Consciousness[13] | Test of Choice: Computed tomography (CT) or CT venography or Magnetic Resonance Imaging (MRI) and MR Venography (MRV). May require catheter angiography.[14]
Radiographic findings: Occlusion/thrombus in cerebral veins and sinuses [14] |
| Central Retinal Artery Occlusion (CRAO)[9] | Acute, monocular painless of vision[15] | Tests of Choice: Fundus examination, fluorescein angiography, OCT[16]
Findings in descending order of prevalence[16]:
|
| Uveitis[9] | Pain, redness, photophobia, anterior or posterior chamber cells, loss of vision[17] | Test of Choice: Slit lamp biomicroscopy, dilated Fundus Examination and OCT may show inflammatory signs (e.g., anterior chamber cell and flare), CME or serous detachments as above[18]
Findings: Anterior uveitis, vitreitis, retinitis, exudative retinal detachment, disc atrophy or edema, and chorioretinal scarring[18] |
Diagnosis
POEMS Syndrome[2]:
A patient with POEMS may have a variable initial presentation, but the four most common symptoms and signs, based on a large series of retrospective studies, include polyneuropathy, organomegaly, volume overload, and endocrine abnormalities[2]. Not all features need to be present to make the diagnosis.
The diagnosis of POEM syndrome may include the following tests[2]:
- Physical Examination evaluating for lymphadenopathy, organomegaly, and edema
- Complete neurological exam
- EMG condition tests
- Detailed neurological history
- Sural Nerve Biopsy
- Endocrine Profile, including sexual and menstrual function
- Serum Protein Electrophoresis (SPEP) and immunofixation
Diagnostic Criteria for POEMS Syndrome[2]:
Mandatory Major Criteria (Both are required)
- demyelinating polyneuropathy
- Monoclonal plasma cell proliferative disorder
Other major criteria (At least one is required)[2]:
- Castleman Disease
- Sclerotic Bone Lesions
- VEGF elevation
Minor Criteria (At least One is required)
- Organomegaly (Splenomegaly, Hepatomegaly, or Lymphadenopathy)
- Extravascular Volume Overload
- Endocrinopathy
- Skin changes
- Papilledema
- Thrombocytosis or Polycythemia
Note: This is a condition related to excessive B-cell and plasma cell proliferation in lymphatic tissue. The findings range from asymptomatic discrete lymphadenopathy to major hematologic systemic effects with lymphadenopathy[19].
Differential diagnosis
The differential diagnosis of POEMS syndrome includes the following conditions[20]:
- Multiple Myeloma
- Chronic Inflammatory Demyelinating Polyneuropathy
- Monoclonal gammopathy of undetermined significance (MGUS)
- Solitary Plasmacytomas
- Plasma Cell Leukemia
- AL Amyloidosis
These other diseases must be carefully considered and evaluated before diagnosing a patient with POEMS syndrome.
Management
General treatment
The treatment for POEMS syndrome is collaborative with hematology and oncology[21]. Most strategies are based on retrospective case studies and lack clear evidence based guidelines. Treatments should target both the symptomatic manifestations and the clonal plasma cell origin with anti-plasma cell directed therapy[22]. Differentiating patients with POEMS and concomitant Castleman Disease (POEMS-CD) is useful as POEMS-CD patients respond better to thalidomide plus dexamethasone[23].
Generally, the first step in therapy is to determine the level of systemic involvement using systemic markers, including symptoms and bone health[21]. Studies have shown that optic disc edema[24], VEGF, and IL-12 levels positively relate to disease activity and may be useful in monitoring the disease[25]. For non-metastatic disease, radiotherapy is first-line[21] with or without corticosteroids for systemic control[22]. For those determined to have more systemic disease, a combination of chemotherapy and autologous stem cell transplantation has been considered[21]. Most drug agents are either alkylating agents, such as melphalan or cyclophosphamide, or anti-cytokine agents, such as thalidomide and bevacizumab[21]. Melphalan plus dexamethasone combination has improved neurological symptoms, however with the challenge related to treating young patients due to stem cell toxicity and no clear long-term results. Autologous hematopoietic stem cell transplantation (ASCT) showed promising hematologic response and long-term survival[6].
![Figure 1: general algorithm for treating POEMS syndrome [26]](https://eyewiki-images.s3.us-east-va.perf.cloud.ovh.us/thumb/c/c3/Jcm-11-07011-g002.png/120px-Jcm-11-07011-g002.png)
Figure 1: general algorithm for treating POEMS syndrome [26]
![Figure 1: general algorithm for treating POEMS syndrome [26]](/File:Jcm-11-07011-g002.png)
In the treatment of the patient’s papilledema, the first line therapy is to address the underlying cause in POEMS[27]. Standard medical and surgical treatments of papilledema may be necessary however[27].
Prognosis
The median time of onset of disease to diagnosis of POEMS syndrome is nearly 13-18 months[20]. The median survival with therapy is approximately 14 years[20]. Common causes of death include cardiorespiratory failure, progressive inanition, infection, capillary leak-like syndrome, and renal failure[20]. POEMS with Castleman Disease has milder neuropathy, more frequent systemic inflammation, and better response to certain therapies[23].
References
- ↑ 1.0 1.1 1.2 Khouri J, Nakashima M, Wong S. Update on the Diagnosis and Treatment of POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, and Skin Changes) Syndrome: A Review. JAMA Oncol. 2021;7(9):1383–1391. doi:10.1001/jamaoncol.2021.0586.
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 Dispenzieri, A. (2019). POEMS Syndrome: 2019 Update on diagnosis, risk-stratification, and management. American Journal of Hematology, 94(7), https://doi.org/10.1002/ajh.25495.
- ↑ 3.0 3.1 Dispenzieri A. POEMS syndrome: 2021 Update on diagnosis, risk-stratification, and management. Am J Hematol. 2021; 96: 872–888. https://doi.org/10.1002/ajh.26240.
- ↑ 4.0 4.1 4.2 4.3 Lam, C, & Margolin, E. (2016). A case of POEMS and chronic papilledema with preserved optic nerve function. Canadian Journal of Ophthalmology, 51, 6-8.
- ↑ 5.0 5.1 5.2 5.3 Sarkar, P., Mehtani, A., Gandhi, H.C. et al. Paraneoplastic ocular syndrome: a pandora’s box of underlying malignancies. Eye 36, 1355–1367 (2022). https://doi.org/10.1038/s41433-021-01676-x.
- ↑ 6.0 6.1 Yu Ri Kim.Update on the POEMS syndrome.Blood Research. Review. Vol 57 Number S1. 2022 Apr 30;57(S1):27-31.doi: 10.5045/br.2022.2022001.PMID: 35483922 PMCID: PMC9057663.
- ↑ Suichi T, Misawa S, Beppu M, Takahashi S, Sekiguchi Y, Shibuya K, Amino H, Tsuneyama A, Suzuki YI, Nakamura K, Sato Y, Kuwabara S. Prevalence, clinical profiles, and prognosis of POEMS syndrome in Japanese nationwide survey. Neurology. 2019 Sep 3;93(10):e975-e983. doi: 10.1212/WNL.0000000000008062. Epub 2019 Aug 1.
- ↑ Dispenzieri A. POEMS syndrome. Blood Rev. 2007 Nov;21(6):285-99. doi: 10.1016/j.blre.2007.07.004. Epub 2007 Sep 11.
- ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 Jindahra, P., Dejthevaporn, C., Niparuck, P. et al. Atypical central retinal artery occlusion as the first presentation of POEMS syndrome: a case report. BMC Neurol 18, 64 (2018). https://doi.org/10.1186/s12883-018-1071-y.
- ↑ Musat, O., Cernat, C., Labib, M., Gheorghe, A., Toma, O., Zamfir, M., & Boureanu, A. M. (2015). DIABETIC MACULAR EDEMA. Romanian journal of ophthalmology, 59(3), 133–136.
- ↑ Gundogan, F. C., Yolcu, U., Akay, F., Ilhan, A., Ozge, G., & Uzun, S. (2016). Diabetic Macular Edema. Pakistan journal of medical sciences, 32(2), 505–510. https://doi.org/10.12669/pjms.322.8496.
- ↑ 12.0 12.1 12.2 Jalali S. (2003). Retinal detachment. Community eye health, 16(46), 25–26.
- ↑ Luo, Y., Tian, X., & Wang, X. (2018). Diagnosis and Treatment of Cerebral Venous Thrombosis: A Review. Frontiers in aging neuroscience, 10, 2. https://doi.org/10.3389/fnagi.2018.00002.
- ↑ 14.0 14.1 Ferro, J.M., Canhão, P. Cerebral Venous Sinus Thrombosis: Update on Diagnosis and Management. Curr Cardiol Rep 16, 523 (2014). https://doi.org/10.1007/s11886-014-0523-2.
- ↑ Hayreh S. S. (2018). Central retinal artery occlusion. Indian journal of ophthalmology, 66(12), 1684–1694. https://doi.org/10.4103/ijo.IJO_1446_18.
- ↑ 16.0 16.1 16.2 Varma, D. D., Cugati, S., Lee, A. W., & Chen, C. S. (2013). A review of central retinal artery occlusion: clinical presentation and management. Eye (London, England), 27(6), 688–697. https://doi.org/10.1038/eye.2013.25.
- ↑ Rathinam, S. R., & Babu, M. (2013). Algorithmic approach in the diagnosis of uveitis. Indian journal of ophthalmology, 61(6), 255–262. https://doi.org/10.4103/0301-4738.114092.
- ↑ 18.0 18.1 Al-Dhibi, H. A., Al-Mahmood, A. M., & Arevalo, J. F. (2014). A systematic approach to emergencies in uveitis. Middle East African journal of ophthalmology, 21(3), 251–258. https://doi.org/10.4103/0974-9233.134687
- ↑ Saeed-Abdul-Rahman, I., & Al-Amri, A. M. (2012). Castleman disease. The Korean journal of hematology, 47(3), 163–177. https://doi.org/10.5045/kjh.2012.47.3.163.
- ↑ 20.0 20.1 20.2 20.3 Nozza, A. (2017) POEMS syndrome: an update. Mediterranean journal of hematology and infectious diseases, 9(1), e2017051. https://doi.org/10.4084/MJHID.2017.051.
- ↑ 21.0 21.1 21.2 21.3 21.4 Dispenzieri, A. How I treat POEMS syndrome. Blood. 2012; 119(24): 5650-5658. Doi: 10.1182/blood-2012-03-378992.
- ↑ 22.0 22.1 Bou Zerdan M, George TI, Bunting ST, Chaulagain CP. Recent Advances in the Treatment and Supportive Care of POEMS Syndrome. Journal of Clinical Medicine. 2022; 11(23):7011. https://doi.org/10.3390/jcm11237011.
- ↑ 23.0 23.1 Suichi T, Misawa S, Sekiguchi Y, Shibuya K, Tsuneyama A, Suzuki YI, Nakamura K, Kano H, Kuwabara S. Treatment response and prognosis of POEMS syndrome coexisting with Castleman disease. J Neurol Sci. 2020 Jun 15;413:116771. doi: 10.1016/j.jns.2020.116771. Epub 2020 Mar 6.
- ↑ Liu LS, Zhang X, Zhao H, Gao XM, Zhou DB, Dai RP, Li J. Reliability of optic disc edema area in estimating the severity of papilledema in patients with POEMS syndrome. Orphanet J Rare Dis. 2020 May 19;15(1):116. doi: 10.1186/s13023-020-01392-x.
- ↑ Yokouchi H, Nagasato D, Mitamura Y, Egawa M, Tabuchi H, Misawa S, Kuwabara S, Baba T. Alterations in choroidal vascular structures due to serum levels of vascular endothelial growth factor in patients with POEMS syndrome. Sci Rep. 2023 Jun 30;13(1):10650. doi: 10.1038/s41598-023-37727-4.
- ↑ Bou Zerdan M, George TI, Bunting ST, Chaulagain CP. Recent Advances in the Treatment and Supportive Care of POEMS Syndrome. Journal of Clinical Medicine. 2022; 11(23):7011. https://doi.org/10.3390/jcm11237011.
- ↑ 27.0 27.1 Rigi, M., Almarzouqi, S.J., Morgan, M.L., Lee, A. G. (2015). Papilledema: epidemiology, etiology, and clinical management. Eye and brain, 7, 47-57. https://doi.org/10.2147/EB.S69174.
