primary amyloidosis (AL), the fibrillar precursors are frag- ments of free light chains produced in the setting of a plasma cell dyscrasia or in MGUS. In contrast, in ...
LETTERS TO THE EDITOR CASE REPORTS NEPHROTIC SYNDROME AND LAMBDA LIGHT-CHAIN MONOCLONAL GAMMOPATHY SUGGESTIVE OF PRIMARY AMYLOIDOSIS WITH POSITIVE STAINING FOR AA AMYLOID To the Editor: Monoclonal gammopathy of undetermined significance (MGUS) is a common finding in elderly adults. More than 3% of individuals aged 50 and older have an M-protein in their serum.1,2 The risk of MGUS progressing to multiple myeloma or other lymphoproliferative disorders is approximately 1% per year.2 Amyloidosis results from the extracellular deposition of a fibrillar amyloid protein in addition to glycosaminoglycans and the serum amyloid P component. Regarding primary amyloidosis (AL), the fibrillar precursors are fragments of free light chains produced in the setting of a plasma cell dyscrasia or in MGUS. In contrast, in secondary (or AA) amyloidosis, the precursor is the serum amyloid A protein (SAA), an acute-phase reactant that is high in inflammatory and chronic infectious conditions. Clinical manifestations of amyloidosis include restrictive cardiomyopathy (75% of patients), nephrotic syndrome (30% of patients), dysautonomia, arrhythmias, peripheral neuropathy, and hepatomegaly.3–5 A diagnosis of amyloidosis requires histological demonstration of amyloid deposits. Herein is reported the case of an elderly woman who presented with edema of unknown origin; amyloidosis was diagnosed according to kidney biopsy. An 82-year-old woman was seen at Vall d’Hebron General Hospital (Barcelona, Spain) for worsening edema in the lower extremities. Her medical history included arterial hypertension, diabetes mellitus, and chronic infection with hepatitis C virus (HCV). She reported progressive edema in the lower extremities for the past 5 months with functional disability. Urgent abdominopelvic Doppler revealed correct permeability of the lower cava and iliac veins and normal-size kidneys without evidence of ascites. Analytical tests were significant for high protein measurement of 4.6 g in 24-hour urine and a beta monoclonal peak on serum protein electrophoresis. Immunofixation revealed a monoclonal component formed by lambda light chains. Free light chains quantification showed high lambda chain level of 273 mg/dL (normal range 5.71–26.30 mg/dL), with normal kappa chain level and a kappa:lambda ratio of 0. Other analytical parameters were normal, except for dissociated cholestasis. An echocardiogram revealed nonobstructive hypertrophic cardiomyopathy with minus diastolic dysfunction. Neurophysiological findings were indicative of heart autonomic malfunction with a pathologic heart rate variability index. A mature B polyclonal population, with 3% of plasma cells with aberrant immuno-
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phenotype (CD38+CD19 CD56+) was detected in bone marrow aspirate. Primary amyloidosis was suspected because of the coexistence of nephrotic syndrome, autonomic dysfunction, and serum monoclonal peak; thus, subcutaneous fat and hepatic biopsies were performed, without evidence of amyloid material. Finally, Congo Red staining in a kidney sample demonstrated amyloid deposits. Immunohistochemical technique was positive for AA amyloid, showing direct immunofluorescence lambda light chain deposits at the glomeruli. Although histochemical positivity for SAA is characteristic of secondary amyloidosis, deposits of SAA can be demonstrated in up to 20% cases of primary amyloidosis.6–8 These SAA deposits would be responsible for fake positivity on the immunohistochemical tests. The patient was positive for HCV, but no clinical symptoms of cirrhosis had been reported in her medical history. In the literature HCV has not been reported to occur with AA amyloidosis, except those cases associated with another predisposing disease (e.g., immunodeficiency).9 Chronic inflammatory or infectious disease was excluded in this patient, and the presence of an abnormal kappa:lambda ratio, as well as the presence of lambda light chain deposits at the glomeruli on direct immunofluorescence led to the diagnosis of primary amyloidosis. Finally, Congo Red staining was performed, and the apple-green birefringence remained after the administration of potassic permanganate. This result supported the diagnosis of AL. Clinicians should be aware that, in elderly adults with suspected amyloidosis and monoclonal gammopathy, if AA amyloid is documented, AL and AA amyloidosis must be excluded given the high prevalence of gammopathy in elderly adults and the possibility of false positivity with histochemical staining. In case of doubt, another test should be performed to confirm the type of amyloidosis, including, if it is available, proteomic analysis. Mar Riveiro-Barciela, MD Fernando Martı´nez-Valle, MD, PhD Miquel Vilardell-Tarre´s, MD, PhD Systemic Autoimmune Diseases Unit, Department of Internal Medicine, Vall d’Hebron General Hospital Barcelona, Spain
ACKNOWLEDGMENTS Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: Conception, design, analysis: Martinez-Valle. Design, acquisition of data, analysis:
0002-8614/12/$15.00
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Riveiro-Barciela. Analysis and final revision: VilardellTarres. Final approval: all authors. Sponsor’s Role: No sponsor’s role in the design, methods, subject recruitment, data collections, analysis, and preparation of paper.
REFERENCES 1. Kyle RA, Therneau TM, Rajkumar SV et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med 2006;354:1362– 1369. 2. Mollee P. Current trends in the diagnosis, therapy and monitoring of the monoclonal gammophathies. Clin Biochem Rev 2009;30:93–103. 3. Rajkumar SV, Dispenzieri A, Kyle RA. Monoclonal gammopathy of undetermined significance, Waldestro¨m macroglobulinemia, AL amylidosis, and related plasma cell disorders: Diagnosis and treatment. Mayo Clin Proc 2006;81:693–703. 4. Rajkumar SV, Kyle RA, Therneau TM et al. Presence of monoclonal free lights chains in the serum predicts risk of progression in monoclonal gammopathy of undetermined significance. Br J Haematol 2004;127:308– 310. 5. Picken MM, Pelton K, Frangione B et al. Primary amyloidosis A. Inmunohistochemical and biochemical characterization. Am J Pathol 1987;129:536– 542. 6. Falck HM, Westermark P. Protein AA in primary and mieloma associated amyloidosis. Clin Exp Immunol 1983;54:259–264. 7. Husby G, Sletten K, Michaelsen TE et al. Amyloid fibril protein subunit, “protein AS”: Distribution in tissue and serum in different clinical types of amyloidosis including the associated with myelomatosis and Waldenstro¨m′s macroglobulinemia. Scand J Immunol 1973;2:395. 8. Pras M, Zaretzky J, Frangione B et al. AA protein in a case of “primary” or “idiopathic” amyloidosis. Am J Med 1980;68:291–294. 9. Turkmen K, Anil M, Solak Y et al. A hepatitis C-positive patient with new onset of nephrotic syndrome and systemic amyloidosis secondary to common variable immunodeficiency. Ann Saudi Med 2010;30:401–403.
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daily living and instrumental activities of daily living independently. His previous medical history was benign, with the exception of a documented Zenker’s diverticulum that had not caused dysphagia before admission, according to a family member. He was reported to be eating a regular diet before hospital admission. His cognitive status was characterized by fluctuating consciousness, poor attention, and disordered sleeping patterns. He was unable to ambulate independently. Spontaneous speech was limited, with markedly poor intelligibility related to severe mixed hypokinetic, flaccid dysarthria. Severe oropharyngeal dysphagia was noted. Cranial magnetic resonance imaging (MRI) revealed no evidence of infarcts or intracranial abnormality. Neuroleptic medications were administered at admission, and haloperidol and lorazepam were given at various points throughout the hospital stay, but no improvement in cognitive function was observed. Modified barium swallow (MBS) studies revealed persistent, severe oral preparatory-stage swallowing deficits, including poor oral bolus control, preparation, and transport; repetitive tongue pumping; posterior tongue residue; and limited tongue base retraction. This swallowing pattern resulted in significant pharyngeal residue after swallowing. The Zenker’s diverticulum was noted to lead to the eventual entry of material into the airway. His risk of developing aspiration pneumonia secondary to prandial aspiration was judged to be too high for him to continue eating and drinking orally.
CASE 2 DYSPHAGIA IN DELIRIUM: TWO CASES To the Editor: Delirium is a debilitating disorder involving cognitive and functional disturbances.1 Delirium is associated with greater mortality, poor functional status, limited rehabilitation, more hospital acquired complications, longer hospital stay, greater risk of institutionalization, and higher healthcare expenditures.2 The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,1 includes dysarthria and aphasia as communication deficits that may occur in the context of delirium. In contrast, swallowing impairment, or dysphagia, is not included. Nevertheless, dysphagia has been reported in a small number of case studies.3–5 Dysphagia has been identified as one of the most important risk factors for aspiration pneumonia,6 which accounts for more than 15,000 deaths per year in the United States.7,8 The purpose of this report is to describe the presence of severe dysphagia in two older adults with delirium.
CASE 1 A 96-year-old man was admitted to the hospital with acute, community–acquired pneumonia and concurrent delirium, based on the Confusion Assessment Method (CAM).9 He had multiple episodes of pneumonia. His delirium did not resolve during his hospital stay. Before hospital admission, he had lived alone, ambulated without a gait aid, and performed all activities of
A 78-year-old man was admitted to the hospital with confusion and a fractured wrist after a fall. Before hospital admission, he had lived at home alone. His previous medical history included significant alcohol intake, upper gastrointestinal bleeding from esophagitis, hypertension, chronic obstructive pulmonary disease, osteoarthritis, an old lacunar infarct identified on cranial computed tomography, and cognitive impairment. On postadmission day 3, the attending geriatrician diagnosed the patient with delirium, based on the CAM.9 He was reported to demonstrate severe behavioral, cognitive, and functional deficits throughout the acute episode of disease. On that same day, prandial aspiration was observed, and he became hypoxic and later developed aspiration pneumonia. Clinical swallowing assessments and a MBS documented severe oropharyngeal dysphagia characterized by prolonged mastication, decreased hyolaryngeal excursion, incomplete epiglottic deflection and airway protection, incomplete pharyngeal clearance, and silent aspiration with a delayed cough that was not sufficient to clear the airway of residual material. Medications including lorazepam, acetaminophen with tramadol, trazodone, and diazepam were administered throughout the course of delirium, with no improvement in cognitive function. There was considerable improvement of the delirium by postadmission day 28, marked by improved cognitive and physical functioning. A follow-up MBS documented improved swallowing, characterized by lower frequency and volume of tracheal aspiration.
