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A Protean Protein

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A Protean Protein CLINICAL CARE CONUNDRUM A Protean Protein Mariam T Nawas, MD1*; Evan J Walker, MD2; Megan B Richie, MD3; Andrew A White, MD4; Gerald Hsu, MD, PhD2 This icon represents the patient’s case. Each paragraph that follows represents the discussant’s thoughts. 1Medical Oncology Fellowship Program, Memorial Sloan-Kettering Cancer Center, New York, New York; 2Department of Medicine, University of California, San Francisco Medical Center, San Francisco, California; 3Department of Neurology, University of California, San Francisco Medical Center, San Francisco, California; 4Department of Medicine, University of Washington Medical Center, Seattle, Washington. A 39-year-old man presented to a neurologist with three Electromyography and nerve conduction studies re- weeks of progressive leg weakness associated with vealed a sensorimotor mixed axonal/demyelinating numbness in his feet and fingertips. His medical history in- polyneuropathy in all extremities. CSF analysis found one cluded hypertriglyceridemia, hypogonadism, and gout. He white cell per mm3, glucose of 93 mg/dL, and protein of 313 was taking fenofibrate and colchicine as needed. There was mg/dL. Magnetic resonance imaging (MRI) of the spine with- no family history of neurologic issues. He did not smoke or out contrast showed normal cord parenchyma. The vitamin drink alcohol. B12 level was 441 pg/mL (normal >200 pg/mL). Antibodies to The patient appeared well with a heart rate of 76 beats per HIV-1, HIV-2, hepatitis C virus, and Borrelia burgdorferi were minute, blood pressure 133/72 mm Hg, temperature 36.6°C, negative. Serum protein electrophoresis (SPEP) and immuno- respiratory rate 16 breaths per minute, and oxygen satura- fixation were normal. tion 100% on room air. His cardiopulmonary and abdomi- The patient received two courses of intravenous immuno- nal examinations were normal. His skin was warm and dry globulin (IVIG) for suspected AIDP. His weakness progressed without rashes. On neurologic examination, upper extremity over the next several weeks to the point that he required a strength and sensation was normal. Bilateral hip flexion, knee wheelchair. flexion, and knee extension strength was 4/5; bilateral ankle dorsiflexion and plantar flexion strength was 3/5. Reflexes Progression of symptoms beyond three weeks and lack of re- were trace in the arms and absent at the patellae and ankles. sponse to IVIG are atypical for AIDP. Alternate diagnoses for a He had symmetric, length-dependent reduction in vibration, sensorimotor polyneuropathy should be considered. Causes pinprick, and light touch sensation in his legs. of subacute or chronic demyelinating polyneuropathy include inflammatory conditions (chronic inflammatory demyelinating Peripheral neuropathy presenting with ascending symmetric polyneuropathy [CIDP], connective-tissue disorders), parapro- motor and sensory deficits progressing over three weeks raises tein disorders (myeloma, amyloidosis, lymphoplasmacytic lym- the suspicion of an acquired inflammatory demyelinating poly- phoma), paraneoplastic syndromes, infectious diseases (HIV, neuropathy (AIDP), a variant of Guillain-Barre Syndrome. Alter- Lyme disease), infiltrative disorders (sarcoidosis), medications native causes of acute polyneuropathy include thiamine (B1) or toxins, and hereditary disorders. Of these etiologies, the first deficiency, vasculitis, sarcoidosis, or malignancy, particularly three seem the most likely given the history and clinical course, lymphoma and multiple myeloma. Further evaluation should the negative HIV and Lyme testing, and the absence of expo- include electromyography, nerve conduction studies, lumbar sures and family history. Normal SPEP and immunofixation make puncture with cerebrospinal fluid (CSF) protein, glucose, and paraprotein disorders less likely, but sFLC testing should be sent cell count differential. Follow-up laboratory testing based on to evaluate for a light chain-only paraprotein. A paraneoplas- results of the above may include serum protein electrophore- tic antibody panel and a CT of the chest, abdomen, and pelvis sis (SPEP), serum free light chains (sFLC), vitamin B12, human should be ordered to evaluate for sarcoidosis, lymphoma, or immunodeficiency virus (HIV), hepatitis B and C testing, antinu- other malignancies. Although a peripheral nerve biopsy would clear antibody, and erythrocyte sedimentation rate. further classify the polyneuropathy, it is of low diagnostic yield in patients with subacute and chronic distal symmetric poly- neuropathies and is associated with significant morbidity. In the *Corresponding Author: Mariam T. Nawas, MD, E-mail: [email protected]; absence of history or physical exam findings to narrow the differ- Twitter: @mariamtn89 ential diagnosis for polyneuropathy, testing for paraneoplastic Published online first November 28, 2018. antibodies and imaging is appropriate. Received: May 30, 2018; Revised: September 24, 2018; Accepted: October 2, 2018 The patient tested negative for antiganglioside GM1 © 2019 Society of Hospital Medicine DOI 10.12788/jhm.3102 and antimyelin-associated glycoprotein antibodies. An Official Publication of the Society of Hospital Medicine Journal of Hospital Medicine Vol 14 | No 2 | February 2019 117 Nawas et al | Protean Protein Urine arsenic, lead, and mercury levels were normal. Tests for region, but urine immunofixation demonstrated polyclonal serum antinuclear antibody, rapid plasmin reagin, and a para- light chains. The plasma vascular endothelial growth factor neoplastic neuropathy panel including amphiphysin antibody, (VEGF) level was 612 pg/mL (reference range, 31-86 pg/mL). CV2 antibody, and Hu auto-antibody were negative. Repeat CT imaging of the chest, abdomen, and pelvis with con- electrodiagnostic testing was consistent with CIDP. The pa- trast demonstrated an enlarged liver and spleen and possible tient received prednisone 60 mg daily for six weeks and was splenic infarcts. A skeletal survey and whole-body FGD-PET then tapered to 30 mg daily over six weeks. Concurrently, he scan were normal. The patient declined bone marrow biopsy. underwent twelve cycles of plasma exchange. His strength improved, and he could walk with a cane; however, weakness Polyneuropathy secondary to a monoclonal protein was previ- recurred when steroids were further tapered. ously considered, and an SPEP was normal. Full evaluation for He was maintained on prednisone 50 mg daily. Over the a monoclonal protein additionally requires sFLC testing. If clini- next year, the patient’s lower extremities became flaccid and cal suspicion remains high after a negative result, 24-hour UPEP severely atrophied. He developed hyperpigmented patches and urine immunofixation should be obtained. Normal results on his trunk, severe gastroesophageal reflux disease (GERD), in this case argue against the presence of a monoclonal protein. dysphonia, and gynecomastia. He had lost 60 pounds since The presence of a monoclonal protein and polyneuropathy symptom onset. He was prescribed levothyroxine for subclin- are mandatory diagnostic criteria for POEMS syndrome (poly- ical hypothyroidism (thyroid stimulating hormone 12.63 µIU/ neuropathy, organomegaly, endocrinopathy, monoclonal pro- mL [normal 0.10-5.50 µIU/mL], free thyroxine 0.8 ng/dL [0.8- tein, and skin changes), a plasma cell proliferative disorder. Major 1.7 ng/dL]). diagnostic criteria include osteosclerotic bone lesions, Castle- man’s disease, and markedly elevated VEGF levels. Castleman’s At this point, the diagnosis of CIDP should be questioned, and disease is a lymphoproliferative disorder characterized by angio- additional investigation is warranted. Although improvement follicular lymphoid hyperplasia that results in lymphadenopathy was initially observed with plasma exchange and steroids, sub- in one or multiple lymph node regions. Imaging studies reveal sequent progression of symptoms despite prednisone sug- organomegaly, one of many minor criteria, but not bone lesions gests a nonimmune-mediated etiology, such as a neoplastic or or lymphadenopathy. A diagnosis of POEMS syndrome requires infiltrative process. Conversely, negative serologic testing for the presence of both mandatory, one major, and one minor crite- paraneoplastic antibodies may be due to an antibody that has ria. Since only one of two of the mandatory criteria are met at this not been well characterized. point, a diagnosis of POEMS syndrome cannot be made. While prednisone could explain GERD and gynecomastia, the weight loss, dysphonia, and subclinical hypothyroidism Eighteen months after symptom onset, the patient pre- may offer clues to the diagnosis underlying the neurological sented to the emergency department with dyspnea, or- symptoms. Weight loss raises suspicion of a hypercatabolic thopnea, and lower extremity edema. B-type natriuretic pep- process such as cancer, cachexia, systemic inflammation, heart tide was 1564 pg/mL. Transthoracic echocardiography failure, or chronic obstructive pulmonary disease. Causes of showed a severely dilated and hypertrophied left ventricle. dysphonia relevant to this presentation include neurologic Left ventricular ejection fraction was 20%. A furosemide infu- dysfunction related to malignant invasion of the vagus nerve sion was initiated. Angiography of the coronary vessels was or demyelinating disease. Subclinical hypothyroidism due to not performed. Congo red stain of an abdominal adipose bi- chronic autoimmune thyroiditis seems most likely in the ab- opsy was negative for amyloid. sence of a medication effect
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