CLINICAL STUDY: ENDOCARDIAL FIBROELASTOSIS
Endocardial fibroelastosis associated with maternal anti-Ro and anti-La antibodies in the absence of atrioventricular block
Lynne E. Nield, MD*,
Earl D. Silverman, MD ,
Jeffrey F. Smallhorn, MD*,
Glenn P. Taylor, MD ,
J. Brendan,
M. Mullen, MD ,
Leland N. Benson, MD* and
Lisa K. Hornberger, MD*,*
* Division of Cardiology, Department of Pediatrics, The Hospital for Sick Children and the Research Institute, Toronto, Canada
Division of Rheumatology, Department of Pediatrics, The Hospital for Sick Children and the Research Institute, Toronto, Canada
Division of Pathology, Department of Pediatrics, The Hospital for Sick Children and the Research Institute, Toronto, Canada
Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, the University of Toronto Faculty of Medicine, Toronto, Canada
Manuscript received April 26, 2001;
revised manuscript received April 15, 2002,
accepted May 15, 2002.
* Reprint requests and correspondence: Dr. Lisa K. Hornberger, The Hospital for Sick Children, Division of Cardiology, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
hornberg{at}sickkids.on.ca
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Abstract
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OBJECTIVES: This study was designed to document the association of endocardial fibroelastosis (EFE) and maternal autoantibodies.
BACKGROUND: Neonatal lupus erythematosus is associated with the transplacental passage of maternal anti-Ro and anti-La antibodies, leading to complete atrioventricular block (CAVB). In some cases, CAVB is associated with EFE. Isolated EFE may be independently related to maternal anti-Ro and anti-La antibodies.
METHODS: We identified three cases (one fetus and two infants, all female) of isolated EFE in infants born to autoantibody-positive mothers in the absence of CAVB. Demographics, echocardiograms, and pathology were reviewed. Immunohistochemical analyses for immunoglobulin (Ig)G, IgM, IgA, T-cell, B-cell, and terminal deoxynucleoleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) (test for cell apoptosis) staining were performed on multiple sections of the heart in each case and compared with negative controls.
RESULTS: Two cases died and one received a cardiac transplant. All three cases had histologically confirmed EFE. All cases demonstrated significant diffuse IgG infiltration. To a lesser extent, myocardial tissue was also positive for IgM, CD43, and Granzyme B. None of the specimens were TUNEL positive.
CONCLUSIONS: These are the first reported cases of isolated EFE associated with maternal anti-Ro and anti-La antibodies in the absence of CAVB. The diffuse deposition of IgG and the presence of a T-cell infiltrate throughout the myocardium suggest that the transplacental passage of maternal autoantibodies induces an immune reaction within the myocardium, leading to isolated EFE. Autoantibody-mediated EFE may be an etiologic factor in cases of fetal and neonatal "idiopathic" dilated cardiomyopathy.
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Abbreviations and Acronyms
| | CAVB | | complete atrioventricular block | | CHF | | congestive heart failure | | EFE | | endocardial fibroelastosis | | Ig | | immunoglobulin | | LV | | left ventricular | | NLE | | neonatal lupus erythematosus | | RV | | right ventricular | | TUNEL | | terminal deoxynucleoleotidyl transferase-mediated dUTP-biotin nick end-labeling |
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Neonatal lupus erythematosus (NLE) is an illness of the fetus and neonate associated with the transplacental passage of maternal anti-Ro and anti-La antibodies (1). The most significant disease manifestations are related to cardiac involvement, including complete congenital atrioventricular block (CAVB) and first- and second-degree atrioventricular block. When CAVB is associated with endocardial fibroelastosis (EFE), there is a very high mortality rate (2). The link between maternal autoantibodies and CAVB was originally suggested from a single case report published in 1966 (3).
Endocardial fibroelastosis is a rare and poorly understood disease of the endomyocardium that often progresses to end-stage heart failure and death. Patients present in the fetal or infant period with the clinical signs of congestive heart failure (CHF) (4–6). The etiology of EFE remains unclear, but it may be the result of an autoimmune process (7). Endocardial fibroelastosis has been described in isolated cases of CAVB (8–10) and has been attributed to long-standing CAVB and bradycardia, leading to progressive CHF (3). This hypothesis does not explain the finding that not all patients with CAVB develop EFE. Furthermore, some patients with anti-Ro and anti-La antibody-associated CAVB have developed EFE despite adequate pacing at physiologic heart rates, implying that perhaps EFE and CAVB are two separate disease manifestations of NLE (11).
We describe one fetal case and two infant cases with EFE and cardiomyopathy with clinically normal conduction systems conceived by mothers positive for anti-Ro and/or anti-La antibodies. Immunohistochemical studies demonstrated for the first time that the fetal immune system played a role in the evolution of myocardial damage seen in these patients.
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Methods
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Demographic data collected on the three patients were obtained from hospital records at the Hospital for Sick Children, Toronto, Canada. All available fetal and postnatal echocardiograms were reviewed by two investigators (L. E. N. and L. K. H.). Echocardiographic parameters examined included: the left ventricular (LV) ejection fraction, severity of mitral regurgitation, measurements of the LV end-diastolic and posterior wall, interventricular septal, right ventricular (RV) end-diastolic dimensions from M-mode tracings, or two-dimensional images in centimeters. The presence or absence of endocardial fibrosis was identified as areas of echogenicity on the endocardial surface of the heart. The echogenicity was defined as bright, white-appearing endocardium with clearly defined margins and was graded as mild, moderate, or severe, depending on the thickness and extent of myocardial involvement.
Pathology.
The fetal and postnatal pathology reports and slides from either autopsy specimens or explanted hearts following cardiac transplantation were reviewed by one of two pathologists who were blind to clinical data (G. P. T. and J. B. M. M.) for: weight and shape of heart; severity of endocardial fibrosis graded as mild, moderate, or severe; extent of EFE defined as diffuse or focal; thickness of EFE defined as thin or thick; and depth of EFE measured in millimeters (7).
Immunohistochemical analysis.
In all three cases, 5 µm formalin-fixed, paraffin-embedded tissue sections were mounted on positively charged microscopic slides. Tissue sections were then baked overnight at 60°C dewaxed in xylene and hydrated to distilled water through decreasing concentrations of alcohol. All immunohistochemical procedures were performed on the Ventana Gen II auto-immuno in-situ stainer (Ventana Medical Systems, Tucson, Arizona), a closed system using the avidin biotin complex (ABC), employing "DAB (3-3'-Diaminobenzidine) Ventana Detection System," as outlined by the manufacturer. Briefly, tissue sections were incubated with biotinylated antibodies against human IgG, IgM, IgA, CD20, CD43, CD4, CD8, and Granzyme B. Following automated washings, the tissue sections were incubated with the ABC detection system which contains perioxidase labeled streptavidin and DAB chromagen, substrate, and copper enhancer. Tissue sections were treated for endogenous peroxidase and biotin and counterstained with haematoxylin for nuclear detail. For the IgG, IgM, IgA staining, rabbit polyclonal antihuman specific antibody was used (DAKO, Carpinteria, California). Monoclonal mouse antihuman specific antibody was used for CD20, CD43, and CD8 (DAKO), using mouse IgG1 kappa isotypes. Monoclonal mouse anti-human antibodies were used against CD4 (NovoCastra, Newcastle upon Tyne, UK) and Granzyme B (Serotec, Oxford, UK). The omission of the primary antibody from the serial section was used as the negative control.
Deoxyribonucleic acid damaged cells were detected by the terminal deoxynucleoleotidyl transferase (TdT)-mediated dUTP-biotin nick end-labelling (TUNEL) technique, on 5 µm formalin-fixed, paraffin-embedded tissue sections (12). This technique tests for the presence of apoptosis, or cell-mediated death. The procedure was adapted to an automated in situ hybridization instrument (GEN II, Ventana Medical Systems, Inc.). All tissue sections were treated for endogenous peroxidase with 3% hydrogen peroxide methanol solution and endogenous biotin (Vector Avidin Biotin Blocking Kit, Vector Laboratories, Inc., Burlingame, California). The protocol involved Protease I (Ventana Medical Systems) enzyme digestion for 8 min at 37°C of the TUNEL reaction mixture, comprising of recombinant TdT in TdT buffer (Gibco BRL, Gaithersburg, Maryland), for adding homo-polymer tails to the 3' ends of deoxyribonucleic acid. Biotinylated-16-dUTP (Boehringer Mannheim, Mannheim, Germany) was the label used for terminal transferase in this reaction. Negative controls were obtained by omitting the recombinant TdT. Colormetric detection was performed using a mouse anti-biotin (Jackson ImmunoResearch Laboratories, West Grove, Pennsylvania) at 37°C for 32 min followed by the DAB(3-3'-Diaminobenzidine) Ventana ABC Detection System. The counterstain of preference was haematoxylin, for nuclear detail.
A 20-week gestation fetus, a one-month-old infant and a six-month-old infant were used as negative case controls. The 20-week fetus died secondary to therapeutic abortion, the one-month-old was a sudden infant death syndrome related death who had no evidence of infection and the six-month-old died of asphyxia. All cases were stained for IgG, IgA, IgM, CD20, CD43, CD8, Granzyme B, and TUNEL staining using the identical methods outlined above.
All slides were reviewed by E. D. S. and L. E. N. who were blinded to clinical data and compared with positive and negative controls for both the fetal and postnatal specimens. Each marker was recorded as either positive or negative. If positive, the strength of the reaction was graded as +, ++, and +++, depending on the extent of infiltration (diffuse or focal) and location (global, central, or peripheral).
Case presentations.
Case 1
This six-month-old female presented with a history of progressive tachypnea, diaphoresis and poor oral intake over several months. She was born at term to a 25-year-old G2P1 mother with systemic lupus erythematosus. The mother was anti-Ro, but not anti-La, antibody positive. The mother was treated with hydroxychloroquine sulfate but did not receive corticosteroids during the pregnancy. Because of her diagnosis of systemic lupus erythematosus, the mother had had two screening fetal echocardiograms at 20 and 28 weeks gestation. Both studies showed an anatomically normal heart with normal cardiac function and normal sinus rhythm with occasional premature atrial contractions.
At presentation, the baby was diagnosed with severe CHF. The echocardiogram at the time of admission revealed an anatomically normal heart with LV and RV dilation, severely reduced ventricular function (ejection fraction 25% by M-mode), and moderate mitral regurgitation. There were areas of echogenicity consistent with EFE, predominately seen in the left ventricle along the interventricular septum and the mitral valve papillary muscles (Fig. 1). Medical management failed the child and it was listed for cardiac transplantation. An echocardiogram on the day before cardiac transplantation revealed persistent LV dilation and ventricular dysfunction (ejection fraction 27% by Simpson’s rule). The areas of increased echogenicity were noted to be more severe when compared with the initial study, and involved the interventricular septum and free wall of the left ventricle and papillary muscles of the mitral valve. The electrocardiogram showed sinus rhythm (PR interval 0.08 ms) with a nonspecific intraventricular conduction block at a rate of 120 beats/min. The patient is currently alive, five years after cardiac transplantation.
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Figure 1 Transthoracic echocardiogram at the time of hospital admission for congestive heart failure demonstrating a dilated left ventricle (LV) with areas of endocardial fibroelastosis along the endocardial surface of the LV, mitral valve, and papillary muscles. LA = left atrium.
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Case 2.
This female fetus presented at 22 weeks gestation with supraventricular tachycardia and hydrops fetalis. The mother was a 31-year-old G5P3 healthy woman, known to be positive for anti-La but negative for anti-Ro antibody. She had a previous miscarriage at 22 weeks of a fetus with oligohydramnios, which had prompted autoantibody screening for this pregnancy. A fetal echocardiogram was performed during this pregnancy to rule out supraventricular tachycardia suspected on routine obstetrical ultrasound examination. The initial echocardiogram at 22 weeks gestation revealed hydrops fetalis with a structurally normal heart, moderate ascites, and severely reduced ventricular function. The heart rate was predominately in normal sinus rhythm at a rate of 140 to 195 beats/min with occasional premature atrial contractions. The LV end-diastolic and posterior wall dimensions were within normal limits, whereas the right ventricular end-diastolic dimension was at the upper limit of normal for gestational age (13). The myocardium was echogenic, with predominant RV involvement and mild LV wall echogenicity.
The mother was treated with oral digoxin and dexamethasone. The fetus was followed clinically and by echocardiography. Follow-up studies at 25 weeks gestation revealed severe fetal sinus bradycardia at a rate of 40 to 95 beats/min with 1:1 atrioventricular conduction and severe bilateral ventricular dysfunction. The right ventricle, left ventricle, and LV free wall dimensions were at the upper limit of normal for gestational age. The echogenicity of the right and left ventricles was unchanged from the initial study and also involved both the right and left atria. Both echocardiographic studies demonstrated moderate tricuspid regurgitation, but no mitral regurgitation. The fetus died in utero one week later.
Case 3.
This patient was a three-month-old, previously healthy girl, who presented to a peripheral hospital emergency department with a two-day history of vomiting. She was noted to be in severe CHF with sinus tachycardia and could not be resuscitated. She was transferred moribund to the Hospital for Sick Children. There were no echocardiograms available for review. The mother was a 21-year-old G3P3 healthy woman, found to be anti-Ro positive and anti-La antibody negative as part of a research study (tested four years after the child’s demise).
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Results
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Pathologic findings.
Case 1
The explanted heart was globular in shape, with severe EFE (Fig. 2), predominately in the left ventricle, where it was diffuse and thick (1 mm depth). There was evidence of focal mild EFE in the right ventricle. The right and left atria were unaffected. There was a nonobstructive mural thrombus in the LV outflow tract.
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Figure 2 Pathologic specimen of the explanted heart illustrating diffuse, severe endocardial fibroelastosis in the left ventricle, mitral valve and papillary muscles, and the globular-shaped heart.
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Case 2.
At postmortem, the heart had a normal shape and weight. There was mild focal EFE affecting multiple areas of the heart including the right atrium, LV outflow tract, and mitral valve papillary muscles. The EFE was predominately present in the left side of the heart, with a maximal depth of 0.5 mm. The mitral valve papillary muscles were dystrophic and calcified. The sinus node and atrioventricular node were calcified. The right atrium was dilated.
Case 3.
The heart was globular in shape, with mild, diffuse EFE. The EFE predominately involved the left ventricle at a depth of 0.3 to 0.5 mm, but was also present in focal areas in the right ventricle. The mitral valve papillary muscles were not available for review. There was no EFE in either the left or right atria. Of note, on histology there were five mitotic figures with evidence of myocyte hyperplasia.
Immunohistochemical findings.
Case 1
Immunohistochemical staining of LV tissue was strongly and diffusely positive for immunoglobulin (Ig)G, moderately positive for IgM and mildly positive for IgA deposition (Table 1) . Although less striking, the tissue also contained areas that had an infiltrate of anti-CD43+, anti-CD8+ mononuclear cells and areas that stained positive for Granzyme B. The TUNEL staining was negative and we did not detect anti-CD20+ or anti-CD4+ cells (Fig. 3).
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Figure 3 Paraffin sections of case 1 using alkaline phosphatase-conjugated antibodies directed against (staining methods as outlined in Methods section): (A) human immunoglobulin (Ig)G demonstrating diffuse deposition of IgG; (B) human IgM demonstrating focal areas of deposition; (C) negative terminal deoxynucleoleotidyl transferase-mediated dUTP-biotin nick end-labeling staining for apoptosis; (D) negative staining for pan B cell marker (CD 20); (E) focal areas of pan T cell marker (CD 43); and (F) focal area of Granzyme B positive staining (magnification 25 x 10 x 1.25).
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Case 2.
Immunohistochemical staining was similar to case 1, with diffuse areas of IgG deposition and a milder degree of IgM deposition in the myocardium (Table 1). However, only right atrial and atrioventricular nodal tissue, not LV or RV tissue, were available for analysis. In addition, there were some areas that had foci of anti-CD20+ cells and others with foci of anti-CD43+ cells. The TUNEL staining was negative, as was staining with other antibodies.
Case 3.
Immunologic staining of LV tissue showed strong, diffuse areas with evidence of IgG and IgM but not IgA deposition (Table 1). We did not detect any areas of anti-CD20+ cells. There were diffuse areas that contained large numbers of anti-CD43+ cells with some focal areas showing an infiltrate with CD8+ cells and evidence of Granzyme B, but no evidence of CD4+ cells. As with the other two cases, TUNEL staining was negative.
Control cases.
All immunohistochemical stains were negative in the one-month and six-month-old infant hearts tested. The 20-week fetal heart demonstrated diffuse staining with IgG but not IgM or IgA, as seen in the cases. The intensity of the IgG staining was less than that generally seen in the three cases (Fig. 4). Staining for CD20, CD43, CD8, and Granzyme B were all negative.
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Figure 4 Paraffin sections of case 1 and normal control case using alkaline phosphatase conjugated antibodies directed against (staining methods as outlined in Methods section): (A) human immunoglobulin (Ig)G demonstrating dense, diffuse deposition of IgG with loss of nuclei and myocardial disarray; (B) human IgM demonstrating focal areas of deposition; (C) human IgG in control case demonstrating mild, diffuse IgG deposition with a normal myocardial muscle pattern with normal, multiple nuclei; (D) human IgM in control case showing normal myocardial muscle pattern with normal, multiple without deposition of IgM (magnification 20 x 0.5).
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Discussion
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Neonatal lupus erythematosus represents a spectrum of disease involving the heart, skin, and liver in patients born to anti-Ro and anti-La antibody-positive mothers (1). The most common cardiac manifestation is isolated CAVB. Although CAVB may be associated with the development of EFE (2), to our knowledge, the cases reported here are the first cases of isolated EFE associated with maternal anti-Ro and anti-La antibodies in the absence of CAVB. All three of our cases presented with severe congestive heart failure or fetal hydrops, resulting in death in two patients and cardiac transplantation in one patient. Given that myocarditis in infants with NLE has been described (1), we suggest that our cases illustrate that EFE may be the most severe consequence of fetal or neonatal lupus myocarditis, and may, in fact, be a separate cardiac manifestation of NLE.
Maternal anti-Ro and anti-La antibodies are known to cross the transplacental barrier in utero, deposit in the myocardium, and result in inflammation, fibrosis, and ultimately irreversible myocardial damage (14–18). In addition to the effect these antibodies have on the atrioventricular node, they can also deposit directly onto fetal myocardium, leading to myocardial fibrosis (19,20). In most cases, the transplacental passage of maternal autoantibodies leads to damage to the conduction system of the heart, with or without an associated EFE. Endocardial fibroelastosis, a specific form of myocardial fibrosis, consists of collagen and elastin hyperplasia and diffuse endocardial thickening (21). Our small series suggests that there exists a subgroup of fetuses and infants in whom maternal autoantibodies may damage the developing myocardium, resulting in EFE without concomitant CAVB.
We confirmed that there was diffuse deposition of IgG throughout the myocardium of all three cases. Previous investigators have been able to demonstrate IgG, anti-Ro, and anti-La antibodies on the hearts of fetuses who died of CAVB (15,17,19,22). Taken together, these findings suggest that anti-Ro and anti-La antibodies deposit throughout the myocardium, and not just within the conduction system. More importantly, we demonstrate for the first time that there is IgM and occasionally IgA deposition, a T-cell and, to a lesser degree, a B-cell myocardial infiltrate. The finding of IgM and the occasional B-cell in fetal cardiac tissue suggests that there is an active fetal B-cell response in addition to the passive deposition of transplacentally passed maternal immunoglobulin. Furthermore, the presence of a T-cell infiltrate in the myocardium, and in particular CD8+ cells and their effector molecules Granzyme B (as evidence of T-cell activation) also support the likelihood of a true autoimmune reaction mounted by the fetus. Although it is possible that the T-cells are of maternal origin, it is very unlikely. Maternal T-cells are found relatively infrequently in the fetus, and can only be detected using the polymerase chain reaction technique (23,24). Finally, we excluded programmed cell death or apoptosis as a mechanism of development of the myocardial pathology. The fetal and neonatal autoimmune reaction in response to the maternal autoantibody deposition may explain the observed progression of EFE throughout fetal life and early infancy. Therefore, we suggest that, although the initial myocardial damage in utero is likely secondary to the passive deposition of maternal anti-Ro and anti-La antibodies, the progression of EFE may be the result of an ongoing fetal and postnatal autoimmune reaction.
Incidence of EFE.
The true incidence of maternal autoantibody-induced EFE is unclear. We identified a total of three cases of EFE with normal conduction systems at the Hospital for Sick Children. During that same time period (1981 to 2001), we have found 11% of 46 patients with autoantibody-induced CAVB to have clinically significant and echocardiographically detectable EFE (2). Although this incidence is relatively low, the EFE accounted for over 80% of the deaths in these patients. As nearly half of the deaths associated with EFE occurred before birth, it is likely that some cases of autoantibody-mediated EFE with or without conduction disturbances may go undiagnosed where there is fetal demise. In addition, a less severe spectrum of the disease may go unrecognized. In our experience, echocardiographic assessment is very subjective and often identifies only the most severe degree of EFE. Finally, on the basis of our observations in the present study, there is likely a subgroup of "idiopathic" dilated cardiomyopathies identified prenatally and postnatally that represent unrecognized maternal autoantibody-induced EFE. Given that at least 70% of mothers with anti-Ro and anti-La antibodies with affected offspring are clinically asymptomatic (that is, no autoimmune disease), screening mothers, and perhaps the affected fetus or infant, for autoantibodies would be the only method of identifying such cases (25,26). Still, the majority of patients with autoantibody-induced CAVB do not develop severe and clinically manifested EFE and, from the present case series, there are other patients that develop only EFE without clinically manifested conduction abnormalities.
Anti-Ro and anti-La antibodies are present in at least 0.1% to 0.2% of the general population (27,28), yet CAVB occurs in 1/14,000 live births (29). As well, CAVB occurs only in 1% to 6% of pregnancies with anti-Ro and anti-La antibodies (30,31), suggesting further that there must be additional maternal and/or fetal factors that influence disease development and manifestation. The maternal factors may be related to the autoantibody profile of mothers of children with NLE, which differs from that of mothers with connective tissue disorders and unaffected children (32–34). We and others have also found that certain peptides derived from the La and Ro proteins to be recognized by sera from mothers with affected children, but not from mothers of unaffected children (32–34). The development of severe EFE may require a secondary "trigger" such as viral infection or genetic predisposition, leading to a more global inflammatory reaction within the myocardium. Finally, the responsiveness of the fetal immune system may also contribute to autoantibody-mediated cardiac disease development and severity. We suggest that CAVB may be secondary to differences in maternal autoantibody repertoire and offspring susceptibility or predisposition.
Clinical implications.
Irrespective of its true etiology and epidemiology, recognition of maternal autoantibody-induced EFE may be important for the clinical management of the affected child. Immunosuppressive agents such as corticosteroids, intravenous gamma globulin, and plasmapheresis may improve the outcome of these patients. Both prenatal maternal and postnatal infant corticosteroid therapy in the context of autoantibody-induced CAVB with cardiomyopathy have been shown to improve ventricular function in some cases (35–37). In addition, anti-inflammatory agents have been used in the management of children and adults diagnosed with acute myocarditis with some success (38,39). Given that the current management of EFE and CHF is essentially limited to supportive care and antifailure medications, the use of anti-inflammatory agents might have a tremendous impact on the clinical outcome of these patients.
Recognition of maternal autoantibodies as a cause of isolated EFE and cardiomyopathy also has important implications for the mother and offspring. We and others have shown that many mothers who are asymptomatic at the time of diagnosis of NLE in their child will develop clinical signs and symptoms later in life (40). In addition, the presence of maternal autoantibodies places subsequent offspring at risk of NLE, and therefore future pregnancies should be followed closely for the development of CAVB, EFE, or other manifestations of NLE.
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Conclusions
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In this paper we have reported for the first time the association of isolated EFE in the absence of CAVB and maternal autoantibodies. We have demonstrated that there is likely a fetal autoimmune component to NLE, as suggested by the presence of a T-cell infiltrate and IgM deposition. Further studies are necessary to determine the true incidence of autoantibody-induced EFE in fetal and infant cases of idiopathic dilated cardiomyopathy and to determine if other manifestations of NLE may have an autoimmune component. We are currently prospectively measuring anti-Ro and anti-La antibodies in infants under 12 months of age presenting with dilated cardiomyopathy or myocarditis, and in their mothers, to determine the incidence of anti-Ro/anti-La antibody associated cardiomyopathy.
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Acknowledgments
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We would like to thank Michael Ho, MLT, who performed the immunohistochemical analyses of the specimens, for his contribution to the manuscript.
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Footnotes
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This work was supported in part by a grant from the March of Dimes to Drs. Hornberger and Silverman and a grant from the Medical Research Council of Canada to Dr. Silverman.
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