References 1. BEESON PB, MCDERMOTT W (eds): Textbook of Medicine, 14th ed, Philadelphia, Saunders, 1975, pp 65-6 2. ZINGO W: The management of accidental hypothermia. Can Med Assoc J 96: 214, 1967 3. MERIWEATHER WD, GOODMAN RM: Severe accidental hypothermia with survival after rapid rewarming. Case report, pathophysiology and review of the literature. Am J Med
53: 505, 1972
4. FERNANDEZ JP, O'RoultKa RA, Ewy GA: Rapid active external rewarming in accidental hypothermia. JAMA 212: 153, 1970
loxication - a report of rapid "core" rewarming by periloneal dialysis. JAMA 201: 123, 1967 10. SEVERINCHAUS 1W: Blood gas conccnlrations. in Hao.Ibook oj Piyxiologi', section 3: ReSpiration, vol 2, FENN WO, RAHN H (eds).
5. HUDSON LD, CONN RD: Accidental hypothermia - associated diagnoses and prognosis in a common problem. JAMA 227: 37, 1974 6. WICKSTROM P. Ruxz E, LILJA GP. et al: Accidental hypothermia - core rewarming with partial bypass. Am J Surg 131: 622. 1976 7. LINTON AL. LEDINOHAM IM: Severe hypothermia with barbiturate inloxication. Lance: 1: 24. 1966 8. THORN GW. ADAMS RD, BRAUNWALD E, et al (eds): Harrison's Principles of Inernal
Washington. Am Physiol Soc. 1965, pp 1475-87 II. PAtToN JF. DOOLITILE WH: Core rewarming by peritoneal dialysis following induced hypothermia in the dog. J App) Physiol 33: 800, 1972
Medicine, 8th ed, New York, McGraw. 1977.
12. HARDY I D, BAR!) P: Body temperature regula-
9. LASH RF, BURDETTE JA, OzDIL T: Accidental profound hypothermia and barbiturate in-
MOUNUCASTLE VB (ed), St Louis, Moshy,
tion, in Medical Physiology. 14th ed, vol 2.
pp 57-8
1974, p 1312
Coichicine therapy for nephrotic syndrome due to familial Mediterranean fever G. SKRINSKAS, MD; R.A. BEAR, MD, FRCP[C], FACP
Familial Mediterranean fever is a genetic disorder that occurs in certain ethnic groups (in descending order of frequency: Sephardic Jews, Armenians, Arabs, Ashkenazic Jews and others). It is marked by the sporadic appearance of acute attacks of fever and polyserositis and by the insidious onset of amyloidosis. Coichicine administration has been described as being effective in preventing acute attacks.'8 However, virtually no information exists regarding the effects of colchicine therapy on the associated amyloidosis. In this report we describe a patient with familial Mediterranean fever in whom the nephrotic syndrome developed secondary to biopsy-proven renal amyloidosis. Improvement in both clinical features and proteinuria occurred with coichicine therapy.
A. MAGIL, MD, FRCP[C]; K.Y. LEE, MD, FRCP[C]
pretibial edema the results of physical examination were normal. Urinalysis revealed proteinuria (4+) and many hyaline and granular casts. The 24-hour urinary protein excretion was 16 and 18 g on two occasions. Serum concentrations were as follows: total protein, 4.8 g/dL; albumin, 1.6 g/dL; creatinine, 0.9 mg/dL; and cholesterol, 304 mg/dL. Additional extensive laboratory evaluation, including measurement of fasting and postprandial blood glucose concentrations and serum complement (C3 and C4) concentrations, and assessments for underlying collagen vascular disease, yielded normal results. Bilateral renal vein venography also yielded normal findings, thereby ruling out renal vein thrombosis as a cause of the nephrotic syndrome. A renal biopsy specimen disclosed diffuse expansion of glomerular mesangial areas by homogeneous eosinophilic ma-
terial that stained orange-red with Congored dye and exhibited the characteristic birefringence of amyloid (Fig. 1). Segments of glomerular basement membrane were thickened by the same material and the walls of small arteries contained amybid. Electron microscopy revealed typical amyloid fibrils in the mesangium and in some segments of the glomerular basement membrane adjacent to the mesangium. Epithelial cell foot processes were effaced. Direct immunofluorescent examination of the specimen revealed diffuse deposits of C3 in the capillary walls and mesangium of glomeruli. There was no localization of immunoglobulins A, G or M or of fibrin. The findings were diagnostic of renal amyloidosis. A diagnosis of familial Mediterranean fever with nephrotic syndrome secondary to renal amvloidosis was made and oral therapy with colchicine, 0.6 mg tid, was
Case report A 42-year-old Italian woman presented for assessment of abdominal pain and peripheral edema. The pain had been present for approximately 20 years, occurring once or twice a month, lasting 4 to 5 days and usually being preceded by fever. The pain began in the epigastrium, rapidly spread throughout the abdomen and was associated with nausea and vomiting. Bilateral leg edema had been noticed by the patient for 2 months in association with facial puffiness and swelling of the hands. Findings from systems review were otherwise unremarkable. Past medical history was negative except for appendectomy and hysterectomy at the ages of 15 and 22 years, respectively. The patient's brother had died at the age of 40 years of renal insufficiency of unknown origin. Apart from moderate obesity and mild From the departments of medicine (division of nephrology) and pathology, St. Michae.l's Hospital, Toronto, and the University of Toronto Reprint requests to: Dr. RA. Bear, Department of medicine, St. Michael's Hospital, 30 Bond St., Toronto, Ont. M5B 1W8
p FIG 1 Glomerular mesangium widened by amyloid deposits (periodic acid-Schiff; original magnification, X160, reduced 20%).
1416 CMA JOURNAL/DECEMBER 17, 1977/VOL. 117
instituted. Over a 20-month follow-up
period the patient had no further attacks of abdominal pain or fever. The serum creatinine concentration during this interval remained stable at 0.9 to 1.1 mg/dL. The 24-hour urinary protein excretion was 2.4, 1.7 and 1.3 g 9, 14 and 20 months, respectively, after institution of therapy. The total serum protein concentration after 14 months was 6.5 g/dL and the serum albumin concentration was 4.2 g/dL. Because of religious convictions the patient was unwilling to accept blood transfusions; it was not considered appropriate, therefore, to perform another renal biopsy.
Discussion In this case the family history, clinical features, renal biopsy findings and response to therapy supported the diagnosis of familial Mediterranean fever with secondary renal amyloidosis. Although improvement in the clinical symptoms of this disorder (fever, abdominal pain and polyserositis) may occur with colchicine therapy,1. there is little detailed information regarding the effect of this medication on the complicating renal amyloidosis. In 1976 a group of Israeli investigators described improvement in proteinuria in patients with familial Mediterranean fever treated with colchicine; however, clinical and renal biopsy data were not
given.5 In a recent review of the use of coichicine therapy in this disease the effects of therapy on renal amyloidosis and urinary protein excretion were not mentioned.' As detailed in a recent issue of this journal7 there are two major types of amyloid fibril proteins, one related to immunoglobulins and the other unrelated. In familial Mediterranean fever the major component of the amyloid fibrils is a nonimmunoglobulin protein, designated AA, consisting of 76 amino acids and having a molecular weight of 7000 to 9000 daltons. Although rare reports have described resolution of primary amyloidosis during chemotherapy,t there is no known therapy for the type of amyloidosis that complicates familial Mediterranean fever. Long-term colchicine therapy is not totally free of side effects. Azoospermia may occur9 and chromosomal nondysjunction leading to Down's syndrome in offspring of patients receiving colchicine therapy has been described.10 In a serious and disabling disease such as familial Mediterranean fever, however, these risks appear justified. The precise mechanisms involved in human amyloidogenesis are unknown. Although studies have suggested inhibition of amyloid formation by colchicine in animals,""2 the mechanism of the
apparent beneficial effects of this medication on the renal amyloidosis in our case remain speculative and await better understanding of the nature of amyloid. References 1. WRIGHT DG, WOLFF SM, FAucI AS, et al: Efficacy of intermittent coichicine therapy in familial Mediterranean fever. Ann Intern Med 86: 162. 1977 2. ZEMER D, REVACH M, PEAS M, et al: A
controlled trial of coichicine in preventing
attacks of familial Mediterranean fever. N
Engi I Med 291: 932, 1974
3. DINARELLO CA, WOLFF SM, GOLDFINOER SE,
et al: Coichicine therapy in familial Mediterranean fever: a double-blind trial. Ibid, p 934 4. ELIAKIN M, LICHT A: Colchicine-aspirin for recurrent polyserositis (familial Mediterranean fever). Lancet 2: 1333, 1973 5. ZEMER D, PRAS M, SOHAR E, et al: Colchicine in familial Mediterranean fever (C). N Engi I Med 294: 170, 1976 6. HASSAN A, IsAansI B, FARID Z: Colchicine for familial Mediterranean fever. N Engi I Med 290: 973, 1974 7. KATZ A, PRUZANSKI W: Newer concepts in
amyloidogenesis (E). Can Med Assoc 1 114: 872, 1976 8. CoHEN HJ, LEssIN LS, HALLAL 3, et al: Resolution of primary amyloidosis during chemotherapy. Ann Intern Med 82: 466, 1975 9. MERLIN HE: Azoospermia caused by colchicine: a case report. Fertil Steril 23: 180, 1972 10. FERREIRA NR, BuoNicown A: Trisomy after colchicine therapy. Lancet 2: 1304, 1968 11. KEDAR I, ROvID M, SOHAR E: Coichicine inhibition of casein-induced amyloidosis in mice. Isr I Med Sci 10: 787, 1974 12. SHIRAHAMA T, COHEN AS: Blockage of amyloid induction by coichicine in an animal model. I Exp Med 140: 1102, 1974
Congenital infection with cytomegalovirus and Epstein-Barr virus J.H. JONCAS, MD, PH D; A. WILLS, M Sc; B. MCLAUGHLIN, MD
Congenital infection with cytomegalovirus (CMV) is a well established entity. The occurrence of congenital infection with Epstein-Barr virus (EBV) has never been demonstrated conclusively and must be rare. EBVpositive lymphoblastoid cell lines have been established from the cord blood leukocytes of two infants. Serologic tests for EBV yielded negative results in the first 2 years of life of one of the infants.1 In the other case serologic testing for EBV was not done.2 In a third case virus was detected in the saliva of an infant aged 16 days and serologic testing was done only at age 2 months and later.2 This paper reports a case in which congenital infection with CMV was From the pediatric research centre and the department of microbiology, H8pital SainteJustine, Montr6al Reprint requests to: Dr. J.H. Joncas, Department of microbiology, H8pital Sainte-Justine, 3175 chemin C8te Sainte-Catherine, Montreal, PQ H3T iCS
associated with congenital or very early neonatal infection with EBV.
Case report A boy was born weighing 2.027 kg after an uneventful delivery. His 28-yearold mother had had two previous pregnancies, the first ending in abortion, and the second with the birth of a healthy boy now 5 years old. Shortly after birth of the second child a petechial rash over the face and trunk and hepatosplenomegaly were noted. There were no other significant clinical findings except that the head circumference of 29 cm was small for the gestational age of 36 weeks. A roentgenogram of the skull revealed numerous periventricular calcifications. Abnormal laboratory findings included thrombocytopenia and a total serum 1gM concentration of 84 mg/dL at birth, increasing to 160 mg/dL at the age of 5 months. Characteristic intranuclear inclusion bodies were observed in the cells of the urinary sediment, and with negativestaining electron microscopy herpesvirus
particles were seen in the urine on the 1st day of life. CMV was subsequently isolated from the five urine specimens collected between birth and age 30 months. A fourfold or greater increase in titre of IgG antibodies to CMV and EBV was demonstrated in paired sera from blood samples taken at birth and at age 3 months (Table I). EBV 1gM antibodies in the serum at a titre of 1:20 at birth were detected in our laboratory by a method previously reported.3 CMV and EBV 1gM antibodies were also found in the serum from the blood samples taken at 3 and 9 months of age and the titres were confirmed in another laboratory. There was an insufficient amount of serum from the first collection of blood to test for CMV 1gM antibodies in addition to EBY 1gM antibodies. Neither peripheral blood nor cord blood could be obtained from this infant at birth to try to establish a permanent EVB-positive lymphoblastoid cell line. However, permanent EBV-positive lymphoblastoid cell lines were subsequently established spontaneously each time 10
CMA JOURNAL/DECEMBER 17, 1977/VOL. 117 1417
53: 505, 1972
4. FERNANDEZ JP, O'RoultKa RA, Ewy GA: Rapid active external rewarming in accidental hypothermia. JAMA 212: 153, 1970
loxication - a report of rapid "core" rewarming by periloneal dialysis. JAMA 201: 123, 1967 10. SEVERINCHAUS 1W: Blood gas conccnlrations. in Hao.Ibook oj Piyxiologi', section 3: ReSpiration, vol 2, FENN WO, RAHN H (eds).
5. HUDSON LD, CONN RD: Accidental hypothermia - associated diagnoses and prognosis in a common problem. JAMA 227: 37, 1974 6. WICKSTROM P. Ruxz E, LILJA GP. et al: Accidental hypothermia - core rewarming with partial bypass. Am J Surg 131: 622. 1976 7. LINTON AL. LEDINOHAM IM: Severe hypothermia with barbiturate inloxication. Lance: 1: 24. 1966 8. THORN GW. ADAMS RD, BRAUNWALD E, et al (eds): Harrison's Principles of Inernal
Washington. Am Physiol Soc. 1965, pp 1475-87 II. PAtToN JF. DOOLITILE WH: Core rewarming by peritoneal dialysis following induced hypothermia in the dog. J App) Physiol 33: 800, 1972
Medicine, 8th ed, New York, McGraw. 1977.
12. HARDY I D, BAR!) P: Body temperature regula-
9. LASH RF, BURDETTE JA, OzDIL T: Accidental profound hypothermia and barbiturate in-
MOUNUCASTLE VB (ed), St Louis, Moshy,
tion, in Medical Physiology. 14th ed, vol 2.
pp 57-8
1974, p 1312
Coichicine therapy for nephrotic syndrome due to familial Mediterranean fever G. SKRINSKAS, MD; R.A. BEAR, MD, FRCP[C], FACP
Familial Mediterranean fever is a genetic disorder that occurs in certain ethnic groups (in descending order of frequency: Sephardic Jews, Armenians, Arabs, Ashkenazic Jews and others). It is marked by the sporadic appearance of acute attacks of fever and polyserositis and by the insidious onset of amyloidosis. Coichicine administration has been described as being effective in preventing acute attacks.'8 However, virtually no information exists regarding the effects of colchicine therapy on the associated amyloidosis. In this report we describe a patient with familial Mediterranean fever in whom the nephrotic syndrome developed secondary to biopsy-proven renal amyloidosis. Improvement in both clinical features and proteinuria occurred with coichicine therapy.
A. MAGIL, MD, FRCP[C]; K.Y. LEE, MD, FRCP[C]
pretibial edema the results of physical examination were normal. Urinalysis revealed proteinuria (4+) and many hyaline and granular casts. The 24-hour urinary protein excretion was 16 and 18 g on two occasions. Serum concentrations were as follows: total protein, 4.8 g/dL; albumin, 1.6 g/dL; creatinine, 0.9 mg/dL; and cholesterol, 304 mg/dL. Additional extensive laboratory evaluation, including measurement of fasting and postprandial blood glucose concentrations and serum complement (C3 and C4) concentrations, and assessments for underlying collagen vascular disease, yielded normal results. Bilateral renal vein venography also yielded normal findings, thereby ruling out renal vein thrombosis as a cause of the nephrotic syndrome. A renal biopsy specimen disclosed diffuse expansion of glomerular mesangial areas by homogeneous eosinophilic ma-
terial that stained orange-red with Congored dye and exhibited the characteristic birefringence of amyloid (Fig. 1). Segments of glomerular basement membrane were thickened by the same material and the walls of small arteries contained amybid. Electron microscopy revealed typical amyloid fibrils in the mesangium and in some segments of the glomerular basement membrane adjacent to the mesangium. Epithelial cell foot processes were effaced. Direct immunofluorescent examination of the specimen revealed diffuse deposits of C3 in the capillary walls and mesangium of glomeruli. There was no localization of immunoglobulins A, G or M or of fibrin. The findings were diagnostic of renal amyloidosis. A diagnosis of familial Mediterranean fever with nephrotic syndrome secondary to renal amvloidosis was made and oral therapy with colchicine, 0.6 mg tid, was
Case report A 42-year-old Italian woman presented for assessment of abdominal pain and peripheral edema. The pain had been present for approximately 20 years, occurring once or twice a month, lasting 4 to 5 days and usually being preceded by fever. The pain began in the epigastrium, rapidly spread throughout the abdomen and was associated with nausea and vomiting. Bilateral leg edema had been noticed by the patient for 2 months in association with facial puffiness and swelling of the hands. Findings from systems review were otherwise unremarkable. Past medical history was negative except for appendectomy and hysterectomy at the ages of 15 and 22 years, respectively. The patient's brother had died at the age of 40 years of renal insufficiency of unknown origin. Apart from moderate obesity and mild From the departments of medicine (division of nephrology) and pathology, St. Michae.l's Hospital, Toronto, and the University of Toronto Reprint requests to: Dr. RA. Bear, Department of medicine, St. Michael's Hospital, 30 Bond St., Toronto, Ont. M5B 1W8
p FIG 1 Glomerular mesangium widened by amyloid deposits (periodic acid-Schiff; original magnification, X160, reduced 20%).
1416 CMA JOURNAL/DECEMBER 17, 1977/VOL. 117
instituted. Over a 20-month follow-up
period the patient had no further attacks of abdominal pain or fever. The serum creatinine concentration during this interval remained stable at 0.9 to 1.1 mg/dL. The 24-hour urinary protein excretion was 2.4, 1.7 and 1.3 g 9, 14 and 20 months, respectively, after institution of therapy. The total serum protein concentration after 14 months was 6.5 g/dL and the serum albumin concentration was 4.2 g/dL. Because of religious convictions the patient was unwilling to accept blood transfusions; it was not considered appropriate, therefore, to perform another renal biopsy.
Discussion In this case the family history, clinical features, renal biopsy findings and response to therapy supported the diagnosis of familial Mediterranean fever with secondary renal amyloidosis. Although improvement in the clinical symptoms of this disorder (fever, abdominal pain and polyserositis) may occur with colchicine therapy,1. there is little detailed information regarding the effect of this medication on the complicating renal amyloidosis. In 1976 a group of Israeli investigators described improvement in proteinuria in patients with familial Mediterranean fever treated with colchicine; however, clinical and renal biopsy data were not
given.5 In a recent review of the use of coichicine therapy in this disease the effects of therapy on renal amyloidosis and urinary protein excretion were not mentioned.' As detailed in a recent issue of this journal7 there are two major types of amyloid fibril proteins, one related to immunoglobulins and the other unrelated. In familial Mediterranean fever the major component of the amyloid fibrils is a nonimmunoglobulin protein, designated AA, consisting of 76 amino acids and having a molecular weight of 7000 to 9000 daltons. Although rare reports have described resolution of primary amyloidosis during chemotherapy,t there is no known therapy for the type of amyloidosis that complicates familial Mediterranean fever. Long-term colchicine therapy is not totally free of side effects. Azoospermia may occur9 and chromosomal nondysjunction leading to Down's syndrome in offspring of patients receiving colchicine therapy has been described.10 In a serious and disabling disease such as familial Mediterranean fever, however, these risks appear justified. The precise mechanisms involved in human amyloidogenesis are unknown. Although studies have suggested inhibition of amyloid formation by colchicine in animals,""2 the mechanism of the
apparent beneficial effects of this medication on the renal amyloidosis in our case remain speculative and await better understanding of the nature of amyloid. References 1. WRIGHT DG, WOLFF SM, FAucI AS, et al: Efficacy of intermittent coichicine therapy in familial Mediterranean fever. Ann Intern Med 86: 162. 1977 2. ZEMER D, REVACH M, PEAS M, et al: A
controlled trial of coichicine in preventing
attacks of familial Mediterranean fever. N
Engi I Med 291: 932, 1974
3. DINARELLO CA, WOLFF SM, GOLDFINOER SE,
et al: Coichicine therapy in familial Mediterranean fever: a double-blind trial. Ibid, p 934 4. ELIAKIN M, LICHT A: Colchicine-aspirin for recurrent polyserositis (familial Mediterranean fever). Lancet 2: 1333, 1973 5. ZEMER D, PRAS M, SOHAR E, et al: Colchicine in familial Mediterranean fever (C). N Engi I Med 294: 170, 1976 6. HASSAN A, IsAansI B, FARID Z: Colchicine for familial Mediterranean fever. N Engi I Med 290: 973, 1974 7. KATZ A, PRUZANSKI W: Newer concepts in
amyloidogenesis (E). Can Med Assoc 1 114: 872, 1976 8. CoHEN HJ, LEssIN LS, HALLAL 3, et al: Resolution of primary amyloidosis during chemotherapy. Ann Intern Med 82: 466, 1975 9. MERLIN HE: Azoospermia caused by colchicine: a case report. Fertil Steril 23: 180, 1972 10. FERREIRA NR, BuoNicown A: Trisomy after colchicine therapy. Lancet 2: 1304, 1968 11. KEDAR I, ROvID M, SOHAR E: Coichicine inhibition of casein-induced amyloidosis in mice. Isr I Med Sci 10: 787, 1974 12. SHIRAHAMA T, COHEN AS: Blockage of amyloid induction by coichicine in an animal model. I Exp Med 140: 1102, 1974
Congenital infection with cytomegalovirus and Epstein-Barr virus J.H. JONCAS, MD, PH D; A. WILLS, M Sc; B. MCLAUGHLIN, MD
Congenital infection with cytomegalovirus (CMV) is a well established entity. The occurrence of congenital infection with Epstein-Barr virus (EBV) has never been demonstrated conclusively and must be rare. EBVpositive lymphoblastoid cell lines have been established from the cord blood leukocytes of two infants. Serologic tests for EBV yielded negative results in the first 2 years of life of one of the infants.1 In the other case serologic testing for EBV was not done.2 In a third case virus was detected in the saliva of an infant aged 16 days and serologic testing was done only at age 2 months and later.2 This paper reports a case in which congenital infection with CMV was From the pediatric research centre and the department of microbiology, H8pital SainteJustine, Montr6al Reprint requests to: Dr. J.H. Joncas, Department of microbiology, H8pital Sainte-Justine, 3175 chemin C8te Sainte-Catherine, Montreal, PQ H3T iCS
associated with congenital or very early neonatal infection with EBV.
Case report A boy was born weighing 2.027 kg after an uneventful delivery. His 28-yearold mother had had two previous pregnancies, the first ending in abortion, and the second with the birth of a healthy boy now 5 years old. Shortly after birth of the second child a petechial rash over the face and trunk and hepatosplenomegaly were noted. There were no other significant clinical findings except that the head circumference of 29 cm was small for the gestational age of 36 weeks. A roentgenogram of the skull revealed numerous periventricular calcifications. Abnormal laboratory findings included thrombocytopenia and a total serum 1gM concentration of 84 mg/dL at birth, increasing to 160 mg/dL at the age of 5 months. Characteristic intranuclear inclusion bodies were observed in the cells of the urinary sediment, and with negativestaining electron microscopy herpesvirus
particles were seen in the urine on the 1st day of life. CMV was subsequently isolated from the five urine specimens collected between birth and age 30 months. A fourfold or greater increase in titre of IgG antibodies to CMV and EBV was demonstrated in paired sera from blood samples taken at birth and at age 3 months (Table I). EBV 1gM antibodies in the serum at a titre of 1:20 at birth were detected in our laboratory by a method previously reported.3 CMV and EBV 1gM antibodies were also found in the serum from the blood samples taken at 3 and 9 months of age and the titres were confirmed in another laboratory. There was an insufficient amount of serum from the first collection of blood to test for CMV 1gM antibodies in addition to EBY 1gM antibodies. Neither peripheral blood nor cord blood could be obtained from this infant at birth to try to establish a permanent EVB-positive lymphoblastoid cell line. However, permanent EBV-positive lymphoblastoid cell lines were subsequently established spontaneously each time 10
CMA JOURNAL/DECEMBER 17, 1977/VOL. 117 1417
