A 52-year-old Thai man presented with sudden painless visual loss in his left eye upon awakening 5 days prior to presentation. He had no visual complaints regarding his right eye. He reported no fever, jaw claudication, general malaise, anorexia, hearing of a whooshing sound, or new-onset headache. His ocular history was significant for bilateral hyperopia. His medical history was notable for 18.5-kg body weight loss in the past 2 years. He was not taking any medications and was a nonsmoker.
Ocular examination revealed visual acuity of 20/20 and no light perception in the right eye and left eye, respectively. The presence of a grade 4+ relative afferent pupillary defect of the left eye was noted. The intraocular pressure was 15 mmHg bilaterally. Slit-lamp examination showed a mild cortical cataract without signs of ocular inflammation bilaterally. Fundoscopic examination of the left eye showed that the entire retina was opaque and edematous, particularly in the posterior pole, and pallid “chalky white” generalized optic disc swelling was noted (Fig. 1b). Neither emboli nor cotton-wool spots were detected. Fundoscopic examination of the right eye was significant only for hyperemic generalized optic disc swelling; no hemorrhage, cotton-wool spots, or exudates were present (Fig. 1a).
A color vision test (Lanthony desaturated 15-hue test) of the right eye was unremarkable. The Humphrey 24-2 automated static perimetry program of the right eye showed blind spot enlargement. The average retinal nerve fiber layer thickness of the optic nerve head measured by spectral-domain optical coherence tomography (Cirrus HD-OCT, software version 6.0.0.599; Carl Zeiss Meditec, Inc., Dublin, CA, USA) was 554 and 187 μm in the right and left eye, respectively. Fundus fluorescein angiography (FFA) revealed profound leakage of the bilateral optic nerve heads, and filling defects were observed in multiple arterioles, predominantly in the macular area of the left eye, along with leakage of small retinal arterioles in the left eye (Fig. 1c, d). No filling defect or retinal vessel leakage was noted in the right eye. Indocyanine green angiography (ICG) demonstrated a choroidal filling defect in the left eye only. Partial occlusion of both retinal and choroidal circulation in the left eye was suspected. An electroretinogram (ERG) was evaluated according to the International Society for Clinical Electrophysiology of Vision standard (MonColor; Metrovision, Perenchies, France). A full-field ERG of the left eye showed a significant reduction of both the a-wave and b-wave amplitude, along with a decreased b:a ratio with a normal implicit time in the photopic and maximal combined responses, confirming both retinal and choroidal circulation in the left eye was affected. An ERG of the right eye was normal. Both sides of the superficial temporal artery were pulsatile and painless. The patient’s blood pressure was 130/80 mmHg. A provisional diagnosis of atypical central retinal artery occlusion (CRAO) with anterior ischemic optic neuropathy (AION) in the left eye in conjunction with generalized right optic disc swelling was made. Treatment was started with intravenous methylprednisolone at 1 g once daily for 5 days.
A complete blood count showed 5.7 × 109/L white blood cells with 76% neutrophils; the platelet count was 595× 109/L, and the hemoglobin level was 17.3 g/dL. The erythrocyte sedimentation rate was 9 mm/h, and the C-reactive protein level was 1.14 mg/L. The results of a comprehensive vasculitis panel, including measurement of antinuclear antibody, cytoplasmic antineutrophil cytoplasmic antibodies, perinuclear antineutrophil cytoplasmic antibodies, and anti-double-stranded DNA, were within normal limits. The results of the serum Venereal Disease Research Laboratory (VDRL) test, Treponema pallidum hemagglutination (TPHA) test, and anti-human immunodeficiency virus antibody test were negative. A metabolic panel, including liver function tests, the fasting blood sugar level, and a lipid profile, was unremarkable. Antiphospholipid antibodies were negative. The results of a coagulation panel were within normal limits.
Magnetic resonance imaging (MRI) of the brain with gadolinium injection revealed early subacute left anterior cerebral artery/middle cerebral artery watershed infarction, early subacute left middle cerebral artery/posterior cerebral artery watershed infarction, and marked pachymeningeal thickening with enhancement of the bilateral cerebral convexities (Fig. 2d). Diffusion weighted imaging (DWI) of the brain showed restricted diffusion involving gray-white matter of the left parietal lobe and centrum semiovale. Moreover, enhancement and luminal narrowing of the petrous and supraclinoid left internal carotid artery (ICA) were observed (Fig. 2a–c). The bilateral optic nerves showed a normal size and signal intensity. Magnetic resonance angiography (MRA) revealed luminal narrowing from the distal cervical left ICA extending to the supraclinoid left ICA. The patient was treated with aspirin. Echocardiography and electrocardiography showed normal results.
A lumbar puncture was then performed, and 6 mL of clear cerebrospinal fluid (CSF) was obtained with an opening pressure of 19 cmH2O. CSF analysis revealed a significantly high protein level (234.6 mg/dL), normal glucose concentration (61 mg/dL), and white cell count of 4 cells/mm3 (100% mononuclear cells). The VDRL test, TPHA test, polymerase chain reaction (PCR), and cultures for microorganisms were all negative in the CSF.
No clinical improvement was demonstrated during the 5-day course of methylprednisolone, and patient developed numbness in both feet.
Serum protein electrophoresis revealed no hypergammaglobulinemia, whereas, an IgGλ monoclonal gammopathy was detected by serum immunofixation electrophoresis (Fig. 3a). In addition, computed tomography (CT) of the whole spine showed multiple mixed lytic osteosclerotic bone lesions involving the T8 and L1 bodies (Fig. 3b), bilateral 8th ribs, right ilium, and right sacrum.
A more comprehensive systemic examination showed a symmetrical decrease in the motor power of the bilateral extensor hallucis longus and a symmetrical decrease in sensation (including proprioception, vibration, pain, and temperature) of both feet. The Achilles and patellar reflexes were absent bilaterally. A nerve conduction study also revealed sensory and motor demyelinating polyneuropathy. The Romberg sign was positive and steppage gait was noted. Moreover, hepatomegaly was observed on a CT scan of the whole abdomen, and localized hypertrichosis associated with hyperpigmentation involving the dorsal aspect of both feet was noted (Fig. 3c).
A diagnosis of POEMS syndrome was made. The levels of hormones, plasma interleukin-6, and plasma vascular endothelial growth factor (VEGF) were measured and PCR for human herpesvirus type 8 in serum was performed to support this diagnosis. The interleukin-6 level was < 1.5 pg/mL (reference range, 0–7 pg/mL), and the plasma VEGF level was 1828 pg/mL (reference range, 0–860 pg/mL). PCR for human herpesvirus type 8 in serum was negative. The levels of hormones, including testosterone, free T3, free T4, thyroid-stimulating hormone, and cortisol, were normal.
A bone marrow biopsy demonstrated normocellular bone marrow; adequate red cells, white cells, and platelets; and scattered plasma cells. CD138 immunohistochemistry showed only 5% plasma cells.
Sural nerve biopsy was also undertaken and demonstrated neuropathy through slightly decreased myelinated fibers density (Fig. 3d). Mild to moderately increased small vessels in epineurium led to the diagnosis of POEMS syndrome, which confirmed by a positive VEGF (Fig. 3e). There was no evidence of vasculitis or amyloidosis. The patient was treated with eight cycles of bortezomib, cyclophosphamide, and dexamethasone (BorCyDex). After the 2nd cycle of BorCyDex, the polyneuropathy had remarkably improved and the platelet count returned to normal; however, the visual loss in the left eye was still present. Disease assessment was performed after the 4th and 8th cycles of BorCyDex. CSF was obtained and showed high protein levels (200 and 150 mg/dL after the 4th and 8th cycle of treatment, respectively). Hepatomegaly was significantly reduced based on CT. After eight cycles of BorCyDex, the patient finally underwent autologous hematopoietic stem cell transplantation with high-dose melphalan.
