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Primary amyloidosis presenting as dilated veins
Letters to the Editor
disease, although a renal biopsy was done in only 4 patients and only in a resected ischemic kidney. Only two types of glomerulonephritis would have been identified by the serologic evaluation done by the authors (diffuse proliferative glomerulonephritis with cryoglobulinemia and membranoproliferative glomerulonephritis). In addition, renovascular disease has been found in 30% of patients with focal segmental glomerulonephritis (2). As they did not rule out other causes of nephrotic syndrome, they cannot conclude that renovascular disease is a common cause of proteinuria among patients aged 50 years or older. Second, the authors imply that the difference in outcome between the groups can be explained by the presence of proteinuria. The authors compare patients with renovascular disease, most of whom had advanced atherosclerosis (strokes and coronary artery disease), with patients with glomerulonephritis. It is obvious that patients with advanced vascular disease will have worse outcomes, including cerebrovascular disease, myocardial infarction, or death, regardless of proteinuria. Patients with renovascular disease have a more rapid decrease in renal function and progression to end-stage renal disease than patients with chronic glomerulonephritis, which can take 10 to 30 years to progress. Their conclusion that “patients with nephrotic-range proteinuria resulting from renovascular disease have distinct characteristics and poor prognosis” may be true, but is not proven. If their aim was to prove that the proteinuria was responsible for the poor prognosis, the authors should have compared two groups with renovascular disease, one with and one without proteinuria. Causality between renovascular disease and nephrotic syndrome is inferred but not demonstrated. It would be important to know what proportion of the authors’ patients with renovascular disease develop nephrotic-range 174
August 1, 2000
proteinuria. The authors state that 19% of their patients with nephroticrange proteinuria have renovascular disease. Are they certain that the proteinuria did not come first, leading to hyperlipidemia, which then led to arteriosclerosis? Abdullah Hamad, MD Donald Feinfeld, MD Laurie Ward, MD Nassau County Medical Center East Meadow, New York 1. Halimi JM, Ribstein J, Du Cailar G, Mimran A. Nephrotic-range proteinuria in patients with renovascular disease. Am J Med. 2000; 108:120 –126. 2. Thadani R, Pascual M, Neckeleit V, et al. Preliminary description of focal segmental glomerulosclerosis in patients with renovascular disease. Lancet. 1996;347:231–233.
The Reply: Renovascular disease may have many clinical presentations, including proteinuria. However, in most textbooks of medicine, renovascular disease is not listed as a cause of massive proteinuria, despite several case reports. It is therefore crucial to understand this condition better. Only 4 of our patients had a renal biopsy, and it was therefore not possible to rule out superimposed glomerulonephritis. Many factors, however, suggest that the cause of proteinuria was the renal artery lesion. This point was discussed extensively in our paper. Focal segmental glomerulonephritis was not found in the 4 patients who did undergo renal biopsy. In addition, the patients with renovascular disease had similar presentations and renal hemodynamic measurements and function. These characteristics were all substantially different from those in patients with glomerular disorders. Proteinuria was markedly reduced by revascularization in our patients. Similar reductions in proteinuria have been described in similar patients following the use of angiotensin-converting enzyme inhibitors (but not calcium antagonists), nephrectomy, or revascularization.
THE AMERICAN JOURNAL OF MEDICINE威
Volume 108
We did not imply that the difference in outcome between the two groups was explained by the presence of proteinuria. Indeed, proteinuria at baseline was similar in the two groups. Only 2 of 14 patients with renovascular disease had a history of proteinuria, suggesting no previous glomerular disease in those patients. Finally, the prognosis of these patients was indeed poor: 2 died and 3 required dialysis during follow-up. Jean-Michel Halimi, MD Jean Ribstein, MD Guilhem Du Cailar, MD Albert Mimran, MD Department of Medicine and Hypertension Hoˆpital Lapeyronie Centre Hospitalier Universitaire Montpellier, France
PRIMARY AMYLOIDOSIS PRESENTING AS DILATED VEINS To the Editor: A 72-year-old woman was admitted with a 6-month history of pain in the wrists, knees, and shoulders, paresthesia of the fingers, and swollen areas on the inner forearms, popliteal fossae, and legs. The swollen areas on her arms were oval, 3 to 4 cm in diameter, pitting, and moderately painful. They decreased when she raised her arms. There were extensive varicose veins in her legs. Doppler ultrasonography confirmed that the swellings were venous. All of the deep and superficial venous trees of all four limbs showed marked thickening of the walls, particularly in the outer layers. The venous lumina were patent. Doppler arteriography showed diffuse thickening of the walls of the femoral, iliac, and popliteal arteries, and distal pulses were palpable. A biopsy specimen of an arm vein revealed extensive amyloid deposits in the media. A biopsy specimen of the synovial membrane of the wrist flexors during neu-
Letters to the Editor
Figure. Extensive varicose veins of the right leg.
rolysis of the median nerve (for treatment of carpal tunnel syndrome) also revealed amyloidosis. However, the tongue and the skin were normal, as was ultrasonography of the heart, liver, and spleen. Protein electrophoresis showed hypogammaglobulinemia (5.6 g/L). Immunobinding of serum and urine revealed monoclonal kappa light chains. Proteinuria was absent, and the serum creatinine level was normal. The 2-microglobulin level was 2.30 mg (normal range 1 to 2.5 mg). Examination of the bone marrow showed 21% dystrophic plasma cells. No bone lesions of myeloma were seen on radiographs. Treatment with melphalan (2 mg/kg per day) and dexamethasone (40 mg per day for 4 days every 6 weeks) was instituted. The swelling receded and the quantity of light chains decreased. Eighteen months later, after 12 cycles of treatment, only a few varicose veins persisted in the legs. Doppler ultrasonography showed a marked decrease in the thickness of the venous and arterial walls. Immunobinding of serum and urine showed an absence of light chains, and a bone marrow study showed 1% residual plasmacytosis. A year and a half after discontinuation of treatment, the patient’s clinical and biologic condition was unchanged.
Amyloidosis is usually discovered at autopsy after hemorrhage (1), thrombotic events (2), or coronary insufficiency (3). It is rare for amyloidosis to present as venous swelling (4); there is a similar report of a patient with scalp nodules due to vascular amyloidosis (5). In our patient, amyloidosis involved only the vascular walls and the synovial membranes, and she showed marked improvement after treatment with melphalan and dexamethasone. Michel Laroche, MD Arnaud Constantin, MD Bernard Mazie`res, MD Service de Rhumatologie Center Hospitalier Universitaire de Ranguell Toulouse, France 1. Rapoport M, Yona R, Kaufman S, et al. Unusual bleeding manifestations of amyloidosis in patients with multiple myeloma. Clin Lab Hemat. 1994;16:349 –353. 2. Cools FJ, Kockx MM, Boeckxstaens GE, et al. Primary systemic amyloidosis complicated by massive thrombosis. Chest. 1996; 110:282–284. 3. Jennette JC, Sheps DS, McNeill DD. Exclusively vascular systemic amyloidosis with visceral ischemia. Arch Pathol Lab Med. 1982;106:323–327. 4. Gertz MA, Kyle RA. Amyloidosis: prognosis and treatment. Semin Arthritis Rheum. 1994;24:124 –138. 5. Henry RB, Fisher GB, Cooper PH. Vascular amyloid in a patient with multiple myeloma. J Am Acad Dermatol. 1986;15:379 – 382.
NEISSERIA SICCA MENINGITIS IN A WOMAN WITH NASCENT PERNICIOUS ANEMIA To the Editor: Neisseria sicca is a commensal parasite found in the mucous membranes of the human respiratory tract. It rarely causes infection in normal hosts. We report a previously healthy woman who was hospitalized with N. sicca meningitis and sepsis. Six months after recovery, she developed acute pernicious anemia that initially resembled a lymphoma. August 1, 2000
A 39-year-old African-American woman presented with fever, mental obtundation, nucchal rigidity, and hypotension. Laboratory tests showed moderate pancytopenia. Examination of the cerebrospinal fluid was consistent with acute bacterial meningitis, and both cerebrospinal fluid and blood cultures showed evidence of N. sicca, identified by Microscan (Dade-Behring, Deerfield, Illinois). She recovered after 14 days of therapy with a third-generation cephalosporin. One month after admission, a complete blood count, hemoglobin electrophoresis, serum folate level, and C3 and C4 complement levels were all within normal limits. The serum vitamin B12 level was 314 pg/ mL. She had no antibodies for the human immunodeficiency virus (HIV). Approximately 6 months later, she presented with weakness, left upper quadrant abdominal pain, night sweats, and daily fevers and rigors. Physical examination revealed diffuse moderate lymphadenopathy and marked hepatosplenomegaly. The hemoglobin level was 6.1 g/dL, the white blood cell count was 3.2 ⫻ 103/ L, and the platelet count was 69 ⫻ 103/L. The mean corpuscular volume was 115 fL, with marked macrocytosis and anisocytosis of the red blood cells. The serum lactate dehydrogenase level was elevated at 10,483 U/L. Initial examination of a bone marrow aspirate and biopsy suggested a myelodysplastic process. Laboratory evaluation revealed a vitamin B12 level of 39 pg/mL. Antiparietal cell antibodies were present, but the patient declined a Schilling test. She was given cyanocobalamin by intramuscular injection at 1,000 g per day for 7 days; by approximately day 4, immature red blood cells appeared and the cytopenias resolved. The patient’s fevers and hepatosplenomegaly resolved slowly. She was treated with 1,000 g cyanocobalamin intramuscularly every month, and all follow-up blood counts were normal. This patient manifested two extraordinary illnesses in short succes-
THE AMERICAN JOURNAL OF MEDICINE威
Volume 109 175
disease, although a renal biopsy was done in only 4 patients and only in a resected ischemic kidney. Only two types of glomerulonephritis would have been identified by the serologic evaluation done by the authors (diffuse proliferative glomerulonephritis with cryoglobulinemia and membranoproliferative glomerulonephritis). In addition, renovascular disease has been found in 30% of patients with focal segmental glomerulonephritis (2). As they did not rule out other causes of nephrotic syndrome, they cannot conclude that renovascular disease is a common cause of proteinuria among patients aged 50 years or older. Second, the authors imply that the difference in outcome between the groups can be explained by the presence of proteinuria. The authors compare patients with renovascular disease, most of whom had advanced atherosclerosis (strokes and coronary artery disease), with patients with glomerulonephritis. It is obvious that patients with advanced vascular disease will have worse outcomes, including cerebrovascular disease, myocardial infarction, or death, regardless of proteinuria. Patients with renovascular disease have a more rapid decrease in renal function and progression to end-stage renal disease than patients with chronic glomerulonephritis, which can take 10 to 30 years to progress. Their conclusion that “patients with nephrotic-range proteinuria resulting from renovascular disease have distinct characteristics and poor prognosis” may be true, but is not proven. If their aim was to prove that the proteinuria was responsible for the poor prognosis, the authors should have compared two groups with renovascular disease, one with and one without proteinuria. Causality between renovascular disease and nephrotic syndrome is inferred but not demonstrated. It would be important to know what proportion of the authors’ patients with renovascular disease develop nephrotic-range 174
August 1, 2000
proteinuria. The authors state that 19% of their patients with nephroticrange proteinuria have renovascular disease. Are they certain that the proteinuria did not come first, leading to hyperlipidemia, which then led to arteriosclerosis? Abdullah Hamad, MD Donald Feinfeld, MD Laurie Ward, MD Nassau County Medical Center East Meadow, New York 1. Halimi JM, Ribstein J, Du Cailar G, Mimran A. Nephrotic-range proteinuria in patients with renovascular disease. Am J Med. 2000; 108:120 –126. 2. Thadani R, Pascual M, Neckeleit V, et al. Preliminary description of focal segmental glomerulosclerosis in patients with renovascular disease. Lancet. 1996;347:231–233.
The Reply: Renovascular disease may have many clinical presentations, including proteinuria. However, in most textbooks of medicine, renovascular disease is not listed as a cause of massive proteinuria, despite several case reports. It is therefore crucial to understand this condition better. Only 4 of our patients had a renal biopsy, and it was therefore not possible to rule out superimposed glomerulonephritis. Many factors, however, suggest that the cause of proteinuria was the renal artery lesion. This point was discussed extensively in our paper. Focal segmental glomerulonephritis was not found in the 4 patients who did undergo renal biopsy. In addition, the patients with renovascular disease had similar presentations and renal hemodynamic measurements and function. These characteristics were all substantially different from those in patients with glomerular disorders. Proteinuria was markedly reduced by revascularization in our patients. Similar reductions in proteinuria have been described in similar patients following the use of angiotensin-converting enzyme inhibitors (but not calcium antagonists), nephrectomy, or revascularization.
THE AMERICAN JOURNAL OF MEDICINE威
Volume 108
We did not imply that the difference in outcome between the two groups was explained by the presence of proteinuria. Indeed, proteinuria at baseline was similar in the two groups. Only 2 of 14 patients with renovascular disease had a history of proteinuria, suggesting no previous glomerular disease in those patients. Finally, the prognosis of these patients was indeed poor: 2 died and 3 required dialysis during follow-up. Jean-Michel Halimi, MD Jean Ribstein, MD Guilhem Du Cailar, MD Albert Mimran, MD Department of Medicine and Hypertension Hoˆpital Lapeyronie Centre Hospitalier Universitaire Montpellier, France
PRIMARY AMYLOIDOSIS PRESENTING AS DILATED VEINS To the Editor: A 72-year-old woman was admitted with a 6-month history of pain in the wrists, knees, and shoulders, paresthesia of the fingers, and swollen areas on the inner forearms, popliteal fossae, and legs. The swollen areas on her arms were oval, 3 to 4 cm in diameter, pitting, and moderately painful. They decreased when she raised her arms. There were extensive varicose veins in her legs. Doppler ultrasonography confirmed that the swellings were venous. All of the deep and superficial venous trees of all four limbs showed marked thickening of the walls, particularly in the outer layers. The venous lumina were patent. Doppler arteriography showed diffuse thickening of the walls of the femoral, iliac, and popliteal arteries, and distal pulses were palpable. A biopsy specimen of an arm vein revealed extensive amyloid deposits in the media. A biopsy specimen of the synovial membrane of the wrist flexors during neu-
Letters to the Editor
Figure. Extensive varicose veins of the right leg.
rolysis of the median nerve (for treatment of carpal tunnel syndrome) also revealed amyloidosis. However, the tongue and the skin were normal, as was ultrasonography of the heart, liver, and spleen. Protein electrophoresis showed hypogammaglobulinemia (5.6 g/L). Immunobinding of serum and urine revealed monoclonal kappa light chains. Proteinuria was absent, and the serum creatinine level was normal. The 2-microglobulin level was 2.30 mg (normal range 1 to 2.5 mg). Examination of the bone marrow showed 21% dystrophic plasma cells. No bone lesions of myeloma were seen on radiographs. Treatment with melphalan (2 mg/kg per day) and dexamethasone (40 mg per day for 4 days every 6 weeks) was instituted. The swelling receded and the quantity of light chains decreased. Eighteen months later, after 12 cycles of treatment, only a few varicose veins persisted in the legs. Doppler ultrasonography showed a marked decrease in the thickness of the venous and arterial walls. Immunobinding of serum and urine showed an absence of light chains, and a bone marrow study showed 1% residual plasmacytosis. A year and a half after discontinuation of treatment, the patient’s clinical and biologic condition was unchanged.
Amyloidosis is usually discovered at autopsy after hemorrhage (1), thrombotic events (2), or coronary insufficiency (3). It is rare for amyloidosis to present as venous swelling (4); there is a similar report of a patient with scalp nodules due to vascular amyloidosis (5). In our patient, amyloidosis involved only the vascular walls and the synovial membranes, and she showed marked improvement after treatment with melphalan and dexamethasone. Michel Laroche, MD Arnaud Constantin, MD Bernard Mazie`res, MD Service de Rhumatologie Center Hospitalier Universitaire de Ranguell Toulouse, France 1. Rapoport M, Yona R, Kaufman S, et al. Unusual bleeding manifestations of amyloidosis in patients with multiple myeloma. Clin Lab Hemat. 1994;16:349 –353. 2. Cools FJ, Kockx MM, Boeckxstaens GE, et al. Primary systemic amyloidosis complicated by massive thrombosis. Chest. 1996; 110:282–284. 3. Jennette JC, Sheps DS, McNeill DD. Exclusively vascular systemic amyloidosis with visceral ischemia. Arch Pathol Lab Med. 1982;106:323–327. 4. Gertz MA, Kyle RA. Amyloidosis: prognosis and treatment. Semin Arthritis Rheum. 1994;24:124 –138. 5. Henry RB, Fisher GB, Cooper PH. Vascular amyloid in a patient with multiple myeloma. J Am Acad Dermatol. 1986;15:379 – 382.
NEISSERIA SICCA MENINGITIS IN A WOMAN WITH NASCENT PERNICIOUS ANEMIA To the Editor: Neisseria sicca is a commensal parasite found in the mucous membranes of the human respiratory tract. It rarely causes infection in normal hosts. We report a previously healthy woman who was hospitalized with N. sicca meningitis and sepsis. Six months after recovery, she developed acute pernicious anemia that initially resembled a lymphoma. August 1, 2000
A 39-year-old African-American woman presented with fever, mental obtundation, nucchal rigidity, and hypotension. Laboratory tests showed moderate pancytopenia. Examination of the cerebrospinal fluid was consistent with acute bacterial meningitis, and both cerebrospinal fluid and blood cultures showed evidence of N. sicca, identified by Microscan (Dade-Behring, Deerfield, Illinois). She recovered after 14 days of therapy with a third-generation cephalosporin. One month after admission, a complete blood count, hemoglobin electrophoresis, serum folate level, and C3 and C4 complement levels were all within normal limits. The serum vitamin B12 level was 314 pg/ mL. She had no antibodies for the human immunodeficiency virus (HIV). Approximately 6 months later, she presented with weakness, left upper quadrant abdominal pain, night sweats, and daily fevers and rigors. Physical examination revealed diffuse moderate lymphadenopathy and marked hepatosplenomegaly. The hemoglobin level was 6.1 g/dL, the white blood cell count was 3.2 ⫻ 103/ L, and the platelet count was 69 ⫻ 103/L. The mean corpuscular volume was 115 fL, with marked macrocytosis and anisocytosis of the red blood cells. The serum lactate dehydrogenase level was elevated at 10,483 U/L. Initial examination of a bone marrow aspirate and biopsy suggested a myelodysplastic process. Laboratory evaluation revealed a vitamin B12 level of 39 pg/mL. Antiparietal cell antibodies were present, but the patient declined a Schilling test. She was given cyanocobalamin by intramuscular injection at 1,000 g per day for 7 days; by approximately day 4, immature red blood cells appeared and the cytopenias resolved. The patient’s fevers and hepatosplenomegaly resolved slowly. She was treated with 1,000 g cyanocobalamin intramuscularly every month, and all follow-up blood counts were normal. This patient manifested two extraordinary illnesses in short succes-
THE AMERICAN JOURNAL OF MEDICINE威
Volume 109 175