Introduction:
POEMS syndrome [peripheral neuropathy (P), organomegaly (O), endocrinopathy (E) monoclonal plasma-cells proliferative disorder (M) and skin changes (S)]is a rare paraneoplastic syndrome associated with an underlying plasma cell disorder. [1,2] However, the POEMS syndrome does not warrant the presence of all the features present in the acronym. Further, there are several other clinical and laboratory findings associated with POEMS that are not included in the acronym. Though rare, cases of POEMS syndrome have been reported in India [3] and the United States of America[1] However, the prevalence and incidence of POEMS worldwide is largely unknown. The pathophysiology in POEMS is attributed to vascular endothelial growth factor (VEGF) produced by the plasma cells. [1] The present case reports an unusual association with POEMS syndrome.
Case Report:
A 75-year-old lady, with no pre-existing morbidities presented with complaints of progressive quadriparesis since 5 days which was preceded by generalized tonic-clonic seizures and several episodes of diarrhea. There was no associated fever during this period. There was also no reported sensory disturbance or cranial nerve involvement. Following the seizures, the patient had lost control over her bladder and bowel and was catheterized at a local clinic before being brought to our hospital. There was no history of trauma prior to onset of symptoms. The patient had no history of alcohol, tobacco or drug abuse.
On examination, she was found to be in altered sensorium (GCS-E2V5M6). Vital parameters recorded were normal. General physical examination showed blood pressure of 130/70mm of Hg. It revealed pallor and pitting edema over the lower limbs (Figure 1). There was on hepatosplenomegaly or obvious skin lesions on examination. On neurological examination, she was found to have areflexic quadriparesis, with lower limb weakness more than upper limb weakness. There was decreased tone over all limbs, power over bilateral upper limbs was grade 3/5 while lower limbs exhibited a power of Grade 1/5. Bilateral plantar reflexes were absent. Sensory system could not be evaluated as patient was in altered sensorium. Bilateral pupils were equal and reactive, gag reflex was present with normal palatal movements. Other cranial nerves could not be examined in view of the altered sensorium. Bedside fundus examination was normal.
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Figure 1: Pitting edema seen on the shin of the patient |
Figure 2: MRI spine showing osteosclerotic lesions in the vertebrae at level T1 and T4 as indicated by the red arrows. |
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Figure 3: Immunofixation light chain assay |
Following the history and examination, a provisional diagnosis of Guillain-Barre syndrome was made in view of the pattern of presentation of quadriparesis (following diarrhea) and the presence of areflexia. The features that did not typically fit into the diagnosis of Guillain-Barre syndrome were loss of bowel and bladder control at the onset on illness, seizures and altered sensorium. This suggested an alternative etiology. The possibility of a cerebrovascular accident was remote as the presentation was a paraparesis with no cranial nerve involvement. However, compressive myelopathies in a background of metabolic encephalopathy were considered (keeping in view the preceding loss of electrolytes due to diarrhea).
Lab investigations (Table 1) suggested anemia with leukocytosis and thrombocytosis. Metabolic alkalosis is associated with normal renal parameters (serum urea and creatinine). However, urine calcium is high with low serum magnesium levels. There were atypical lymphocytes noted on the peripheral smear and an elevated ESR in the background, provoked consideration of a possible hematological etiology to the disease spectrum.
| Table 1: Laboratory findings suggestive of POEMS |
Lab parameters |
Values |
Normal values |
Hemoglobin |
7gm/dl |
12- 15 gm/dl |
Total leucocyte count |
23x 103 /microlitre |
4-10x 103/ microlitre |
Neutrophils |
88% |
<60 -70% |
Peripheral smear |
Atypical lymphocytes noted |
- |
Erythrocyte sedimentation rate |
89 mm/hr |
0-20mm/hr |
Platelet count |
4.75 x 105/microlitre |
1.4 -4x 105/microliter |
Serum Urea |
44 mg/dl |
15-50mg/dl |
Serum Creatinine |
0.5 mg/dl |
0.5-0.9mg/dl |
Serum Sodium |
134 mmol/litre |
135-145 mmol/litre |
Serum Potassium |
3.5 mmol/litre |
3.5-5.5 mmol/litre |
Serum Magnesium |
1.2mg/dl |
1.7-2.2 mg/dl |
Urine calcium |
150 mg/day |
100-250mg/day |
Serum bicarbonate |
40mEq/L |
22-32 mEq/L |
Blood pH |
7.5 |
7.35-7.45 |
Total bilirubin |
0.5 mg/dl |
0.3-1.2 mg/dl |
Aspartate amino transferase |
32 IU/L |
<32 IU/L |
Alanine transaminase |
19 IU/L |
<32 IU/L |
Alkaline phosphatase |
110 IU/L |
35-105 IU/L |
Vitamin B12 |
220 pg/ml |
160-950 pg/ml |
CSF analysis |
Normal |
- |
In view of the altered sensorium on presentation, lumbar puncture with CSF analysis was done (to rule out an infective etiology and to look for albumin-cytological dissociation) which was also normal.
Nerve conduction studies were done for the evaluation of the quadriparesis (to rule out Guillain-Barre syndrome) and was reported as an axonopathy. MRI spine (Figure 2) was also done to rule out compressive myelopathy at the cervical level and osteosclerotic lesions were noted at the T1 vertebra with evidence of marrow infiltrative disease. The marrow infiltration further strengthened the suspicion of a hematological etiology. The osteosclerotic lesions on the MRI also triggered the possibility of POEMS in this patient. Bone marrow aspiration and biopsy confirmed the diagnosis of Plasma cell myeloma. Serum protein electrophoresis showed decreased albumin, increased alpha 1 globulin and decreased gamma globulin, with no M band. Serum light chain assay (as shown in Figure 3) showed elevated free lambda chain (950 g/dl) with preserved Kappa: lambda chain ratio. We also evaluated the heavy chains IgM, IgA, IgD and IgE and found elevated IgA values (748 g/dl).
The combined presentation of plasma cell myeloma with peripheral neuropathy aroused the possibility of POEMS syndrome i.e. Polyneuropathy, Organomegaly, Endocrinopathy, M proteins, and Skin changes. A diagnosis of POEMS was made according to the 2014 update on diagnosis, risk-stratification and management by Dispenzieri et al1. The major criteria of polyneuropathy with monoclonal plasma proliferative disorder was satisfied along with minor criteria of osteosclerotic bone lesions and edema. The associated features corroborating the POEMS diagnosis were thrombocytosis, diarrhea and low vitamin B12 values.
Interestingly, this patient did not have any skin changes or endocrinopathies that contributed to the diagnostic criteria. Along the course of hospital admission, she developed persistent hypokalemia with metabolic alkalosis and preserved renal functions. Urine routine also showed no casts. On evaluation, hypomagnesemia with normocalciuria were noted. This could have been a consequence of osmotic diuresis causing hypokalemia and metabolic alkalosis by contraction alkalosis or it could be a manifestation of acquired Gitelman Syndrome. However, this differential diagnosis could not be confirmed as the patient was unwilling for further evaluation. Patient was treated with oral potassium supplements and the dose of diuretics were also decreased.
The patient was scheduled for skeletal radiograph survey with PET scan and cytogenetic testing for further evaluation. However, in view of the patient's advanced age and poor prognosis of the primary disease and cost of treatment, they opted for palliative care.
During the period of her hospital stay, she developed aspiration pneumonia and was treated with intravenous Piperacillin and tazobactam. She also received a course of steroids (methylprednisolone). As the patient refused any disease directed therapy, she was given conservative treatment (hydration for diarrhea, anti-epileptics, prophylaxis for deep vein thrombosis and limb physiotherapy) to alleviate her symptoms. On discharge from our care, she was conscious and oriented with marginal improvement in her limb weakness. Weakness improved in both the upper limbs from grade 3/5 to grade 4/5. The weakness over both the lower limbs improved from grade 1/5 to grade 2/5.
Discussion:
POEMS was first described as early as 1938 in Scheinker's autopsy case, where a young man was found to have solitary plasmacytoma with peripheral neuropathy and skin changes. It has been described as Crow-Fukase syndrome or PEP syndrome (plasma cell dyscrasia, endocrinopathy, and polyneuropathy).[1] In 1980, Bardwick et al coined the interesting acronym POEMS syndrome for the first time. Following this, POEMS has been diagnosed on finding a constellation of clinical and laboratory features. In 2003, Dispenzieri et al [1] presented the first diagnostic criteria (as shown in Table 2) for POEMS, which was later updated in 2011.[2]
| Table 2: Diagnostic criteria for POEMS* syndrome |
Mandatory criteria
|
Major criteria |
Minor criteria
|
|
|
|
-
Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy)
-
Extravascular volume overload (edema, pleural effusion, or ascites)
-
Endocrinopathy (adrenal, pituitary, gonadal, parathyroid, thyroid and pancreatic)
-
Skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora, acrocyanosis, flushing, and white nails)
-
Papilledema
-
Thrombocytosis/polycythemia
|
| Diagnosis of POEMS syndrome-The two mandatory criteria PLUS ≥ 1 major AND ≥ 1 minor criterion. |
| *POEMS- peripheral neuropathy (P), organomegaly (O), endocrinopathy (E) monoclonal plasma-cells proliferative disorder (M) and skin changes (S); †VEGF- Vascular endothelial growth factor |
The pathophysiology in POEMS involves an interplay of pro-inflammatory cytokines, with VEGF having the most correlation with disease activity. VEGF causes increased vascular permeability and angiogenesis thereby mediating several clinical manifestations of this disease.[4,5] Often, VEGF levels are used along the course of the treatment to assess response to treatment and prognosis. However, we did not perform VEGF levels during the treatment of our patient.
Peripheral neuropathy was the most common presenting complaint in patients with POEMS and it is also a major criteria required in the diagnosis.[1] A Chinese study done on 1946 patients with POEMS showed that polyneuropathy was the first symptom noted in POEMS.[6] It is interesting to note that our patient presented with diarrhea prior to polyneuropathy, thus making the initial diagnosis of Guillain-Barre more plausible. However, the plasma cell dyscrasia found on bone marrow biopsy with the polyneuropathy aroused the suspicion of POEMS in this case. Though organomegaly and skin changes are also frequently noted in cases of POEMS [2], they were not found in our case.
MRI spine showed degenerative changes with osteosclerotic lesions in the T1 vertebra as shown in Figure 2. The serum protein electrophoresis was normal, without an M band but the immunofixation light chain assay (as seen in Figure 3) showed increased lambda chains. The monoclonal protein is typically small and will be missed on serum protein electrophoresis if immunofixation is not done. [1] Therefore, immunofixation study gains significance in this setting as it can conclusively detect the light chain abnormality.
The other associated features noted were extravascular volume overload that presented as pedal edema as shown in Figure 1. There was also evidence of diarrhea on history, thrombocytosis and vitamin B12 deficiency on laboratory investigations which contributed to the diagnosis of POEMS.
Although it is not included in the diagnostic criteria, renal involvement is frequently seen in POEMS.[6]According to data from a large Chinese study, renal involvement in POEMS was noted in 22.4%..[7] An interesting feature noted in our case was the presence of persistent hypokalemia with metabolic alkalosis with normal renal functions. Light chain deposition is known to occur in POEMS.[8,9] Deposition of light chains in the distal tubule of the nephron can cause metabolic alkalosis with hypokalemia presenting a Gitelman-like syndrome. This hypothesis was further strengthened by the presence of hypomagnesemia and normocalciuria in this patient. However, as there is no case report of POEMS with Gitelman-like renal involvement in published literature and in the absence of a renal biopsy in this patient, we can only hypothesize the possibility of Gitelman-like syndrome associated with our case of POEMS syndrome.
Corticosteroids are frequently used in POEMS, but they only alleviate symptoms and do not affect disease progression.[6] However, due to advanced age, progression of disease and financial constraints the patient and her relatives refused definitive therapy and she was treated with a course of intravenous steroids. The median survival time in this disease was noted to be 165 months as per the Mayo clinic database.[1]
Conclusion:
In our case report, the presenting symptom of quadriparesis can be explained by several more common conditions like compressive myelopathy, Guillain-Barre syndrome, multiple sclerosis, amyotrophic lateral sclerosis and transverse myelitis. Therefore, the diagnosis of POEMS can be made only with a high index of suspicion owing to its rarity. This case report seeks to familiarize clinicians with the presentation spectrum in POEMS to facilitate early diagnosis and treatment in this debilitating and potentially fatal disease syndrome.
References:
- Dispenzieri A, Kyle RA, Lacy MQ, Rajkumar SV, Therneau TM, Larson DR et al: POEMS syndrome: Definitions and long-term outcome. Blood 2003;101:2496-2506.
- Dispenzier A. POEMS syndrome: 2011 update on diagnosis, risk-stratification and management. Am J Hematol 2011;86: 592-601.
- Kulkarni GB, Mahadevan A, Taly AB, Yasha TC, Seshagiri KS, Nalini A et al. Clinicopathological profile of polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes (POEMS) syndrome. J Clin Neurosci 2011;18: 356-60.
- Wang C, Huang XF, Cai QQ, Cao XX, Cai H, Zhou D, et al. Remarkable expression of vascular endothelial growth factor in bone marrow plasma cells of patients with POEMS syndrome. Leuk Res 2016; 50:78-84.
- Sakuta K, Mukai T, Suzuki K, Nishiwaki K, Yaguchi H. Irreversible Vasculopathy Proceeds Rapidly in POEMS Syndrome. Intern Med. 2019 Dec 15;58(24):3573-5.
- Dispenzieri A. POEMS Syndrome: 2019 Update on diagnosis, risk-stratification, and management. Am J Hematol 2019; 94:812-27.
- Ye W, Wang C, Cai QQ, Cai H, Duan MH, Li H et al. Renal impairment in patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes syndrome: incidence, treatment and outcome. Nephrol Dial Transplant 2016; 31:275-83.
- Lambotte O, Dürrbach A, Ammor M, Paradis V, Djeffal R, Machover D et al. Association of a POEMS syndrome and light chain deposit disease: first case report. Clin Nephrol 2001; 55:482.
- Pulivarthi S, Gurram MK. An atypical presentation of POEMS syndrome with IgG kappa type M protein and normal VEGF level: Case report and review of literature. J Can Res Ther 2018; 14:679-81.
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