OBJECTIVE: To study, by literature review, the management of subclavian-axillary vein thrombosis (SAVT) and to make recommendations.
DATA SOURCES: The MEDLINE database and cross-referenced articles.
STUDY SELECTION: Key words subclavian-axillary vein thrombosis, venous thrombosis, Paget-Schroetter syndrome, anticoagulation, and thrombolysis were used to extract articles related to SAVT.
DATA EXTRACTION: Independent extraction of articles by 2 observers.
DATA SYNTHESIS: Although numerous studies are available in the literature, they vary widely in their patient selection, treatment methods, follow-up and conclusions. As such, the management of patients with SAVT remains controversial.
CONCLUSIONS: Anticoagulation remains the initial treatment of choice for acute SAVT although there is definitely a role for thrombolysis and surgery in selected cases. Surgical intervention should be reserved for patients in whom there is a specific indication. Since chronic symptoms depend largely on the etiology of the disease, treatment should be tailored to address the causative factors. A multicentre, prospective study is necessary to evaluate the optimum management strategies for patients with SAVT.
Subclavian-axillary vein thrombosis (SAVT) was first described independently by Paget and
Von Schroetter in the latter part of the nineteenth century. In 1949, Hughesl reviewed 320 cases of spontaneous upper limb venous thrombosis and named this condition Paget-Schroetter syndrome. Although the peer-review literature and standard surgical texts describe various treatment strategies for SAVT, there have been no randomized, controlled trials comparing treatments, and the majority of published series are small, retrospective ones. As a result, there is no consensus on the optimum management strategy for this condition.
In response to this problem we reviewed the literature on the management of SAVT, focussing on the role of thrombolysis in the treatment of this condition.
ETIOLOGY AND NOMENCLATURE
The descriptions "primary,"2"spontaneous,"&9 "idiopathic,"',l' "effort"912-18 and "traumatic"'9 have all been used inconsistently to describe Paget-Schroetter syndrome. However, several etiologic factors or events associated with SAVT are now recognized: strenuous upper body activity, resting arm position and positional activities;
an anatomic abnormality causing venous compression and possibly intimal damage to the vein"8 at the thoracic outlet (including abnormal anterior scalene, subclavius and pectoralis minor muscles, abnormal first rib or clavicle, congenital bands, scarring and congenital webs or malformed valves within the vein3);
local conditions, including damage due to a tumour or radiotherapy;
systemic disease, including malignant disease, cardiac failure and hematologic abnormalities;
local intravascular trauma, chemical irritation or flow disruption, including catheterization, dialysis fistula formation and intravenous drug use and abuse;
oral contraceptive use.
True Paget-Schroetter syndrome is "the more or less rapid onset of venous obstruction in an arm of an otherwise healthy person."' Sanders and Haug" pointed out that "most authors have regarded thoracic outlet syndromeassociated venous thrombosis as primary rather than secondary, because the anatomy is grossly normal and the mechanism speculative," and Lindblad, Tengborn and Bergqvist2' reported that up to 39% of cases of SAVT were secondary to an identifiable cause. It has also been suggested that the pathogenesis of the thrombosis determines outcome and chronic morbidity.2223 It is important to distinguish primary and secondary SAVT (Table I352136). Primary SAVT is idiopathic or related to physical activity or arm positioning with or without anatomic compression at the thoracic outlet ("true" Paget-Schroetter syndrome); secondary SAVT is related to such causes as cardiac failure, radiotherapy, instrumentation, catheterization, dialysis fistulae, intravenous drug abuse and tumour (including both local compression from a tumour mass and thrombosis secondary to the systemic hypercoagulable state often associated with neoplasia). Secondary causes can be further divided into those associated with local or systemic disease processes and those associated with catheterization and local irritants. Since abnormalities in the coagulation and fibrinolytic systems can be associated with both primary and secondary causes of SAVT,zl their presence should not be considered the main factor when classifying the thrombosis. Associations between SAVT and pregnancy24 and SAVT and Raynaud disease25 have also been described but are difficult to classify.
INCIDENCE
Between 1966 and 1986 SAVT accounted for less than 2% of all cases of deep venous thromboses (DVT)zl 16 and only 11 of 100 000 hospital admissions.26 However, more recently, the incidence has increased owing to greater use of central venous catheterization.37-39 Lindblad" summarized the resuits of 10 series (456 patients) in which mural or occlusive thrombus was identified in an average of 18.9% of patients who had a central venous catheter.
PRESENTATION
The characteristics of SAVT are swelling of the affected arm, venous engorgement, mild cyanosis and pain or discomfort.41 Other symptoms, including parasthesias and pruritus, have also been described,' and palpable, tender veins may be present..2..6
Patients often present within 2 to 3 days of the onset of symptoms, but the delay to presentation may be months, especially if there is a history of previous episodes of similar symptoms, which may be due to intermittent extrinsic venous compression rather than thrombosis per se.,43 In fact, Dunantl7 reported that up to 80% of patients who present with SAVT have had previous symptoms of intermittent venous obstruction. Since the timing of presentation has implications for management,26 patients who present within 7 days of the onset of symptoms should be considered to have acute SAVT, within 7 to 14 days subacute, and after more than 14 days chronic SAVT.4
SAVT occurs most commonly in young and middle-aged men,3 although both sexes and all age groups may be affected, and appears more often in the right arm,35 probably because this is the usual dominant limb and hence is involved most frequently in strenuous activity. The differential diagnosis includes superior vena caval occlusion, lymphedema,4s inflammatory carcinoma of the breast, lymphangitis, cellulitis,46 allergy, hematoma and gas gangrene.47
INVESTIGATION
After history-taking and clinical examination, the diagnosis of SAVT is confirmed by radiologic investigation, with venography being the technique of choice. Introduction of the contrast medium into the basilic vein is the optimum way to facilitate visualization of the deep venous system.48 Venography will clarify the location and extent of the thrombus as well as the extent of the collateral circulation and, when performed with the arm in the neutral and military positions, will also identify extrinsic compression.42 The disadvantages of venography are its invasive nature and potential to induce thrombosis, especially with repeated use,526 although this is unusual with modern, less irritant contrast media.
Doppler ultrasonography is also a useful investigation in the diagnosis of SAVT. It is safe and reliable,49 and its role in the repeated visualization of the upper limb veins has been emphasized,50 especially in patients with longterm indwelling venous catheters.51
Doppler ultrasonography also has its limitations. Acoustic shadowing from the clavicle can cause a "blind spot," resulting in nonvisualization of a short segment of the subclavian vein.52 Also, the presence of large collateral vessels can make interpretation of the scan difficult, leading to falsenegative results.6 Thus, Haire and associates"3 have suggested that although a positive Doppler ultrasound scan can preclude the need for venography, when there is a strong suggestion of SAVT but a negative scan, then venography is mandatory.
Plethysmography may be used to assess venous outflow.' Although Pollak and Walsh concluded that it had poor specificity for SAVT,46 in a more recent study" it was found to be highly accurate in identifying upper extremity DVT. However, as with Doppler ultrasonography, a negative result still requires confirmation by venography.
Other forms of investigation have been described, including intravascular ultrasonography,56 radionuclide venography," magnetic resonance imaging (MRI)52 and spiral computed tomography (CT);57 however, venography remains the standard.
If there is no obvious cause for a case of primary thombosis, then further investigation into its etiology is mandatory. Investigations that should be considered are radiologic examination of the chest and thoracic outlet and CT of the thoracic cavity. It has also been recommended that the more common thrombotic disorders (including antithrombin III, protein C and S deficiencies) should be sought, especially in patients under 40 years old"8 and in those who are considered to be candidates for long-term anticoagulation.59 Sundqvist and colleagues" found that 26 (49%) of 53 patients with confirmed SAVT had defective fibrinolytic capacity in excised sections of vein wall, and they recommended studies of fibrinolysis.
MANAGEMENT OPTIONS
The 2 important elements of the management of SAVT are treatment of the acute thrombosis, and investigation and treatment of any underlying disease. Effective treatment aims to reduce both acute morbidity (pain, swelling, venous gangrene and pulmonary embolism) and chronic morbidity (pain, swelling and limitation of movement).
Conservative management
In years past, acute SAVT has been managed with bed rest, limb elevation and warming of the limb. However, the results of this strategy have been poor, with significant long-term morbidity.' Gloviczki, Kazmier and Hotliers' found that anticoagulation was significantly better than conservative management at reducing chronic morbidity, and although Cohen and Dubin62 suggested that there was no difference between conservative management and anticoagulation, only 12 patients were studied and the cause of the thrombosis differed in the 2 groups. Currently, there is little to recommend such a conservative approach, with anticoagulation being the minimum intervention required for these patients.
Anticoagulation
Anticoagulation is the initial treatment for patients with acute SAVT and remains the standard by which all other treatments are judged. An intravenous heparin infusion is started as soon as the diagnosis (or presumptive diagnosis) is made and is titrated to gain an activated partial thromboplastin time of 2 to 3 times the control. The infusion is maintained for 5 to 7 days followed by conversion to anticoagulants taken orally, which are typically continued for about 3 months.61,63 Anticoagulation will not recanalize the vein, but it will prevent clot propagation, especially along venous collaterals, and helps to protect against pulmonary embolism.
A number of authors have emphasized the high incidence of chronic symptoms of arm swelling, pain and discomfort that occur after anticoagulation.26,65 However, Ameli and associates63 have shown that anticoagulation is effective in controlling early morbidity and preventing long-term symptoms; this work is supported by other authors.2,67
Surgery
Although early surgical thrombectomy for SAVT has had its advocates,",68 this procedure done in isolation now has little to recommend it. An approach consisting of thrombectomy with simultaneous correction of any underlying anatomic abnormality allows restoration of venous patency and theoretically reduces the risk of pulmonary embolism and chronic symptoms. However, surgery has the disadvantage of requiring general anesthesia and carries the risk of pneumothorax or arterial and brachial plexus damage with the possibility of disrupting venous collaterals. There are, unfortunately, no large trials comparing patients who have received early surgery and those treated by less invasive methods, and the reports that have been published are often anecdotal. Thus, the role of surgery in the treatment of SAVT remains unclear."
Balloon thrombectomy is also an option in these patients, but this procedure carries a risk of intimal damage and further thrombosis.69 Venous bypass has been used with some success in patients with chronic symptomatic SAVT,773 but this approach is not appropriate for acute thrombosis.
Thrombolysis
Why use thrombolysis?
Venous thrombosis can result in chronic venous occlusion. If recanalization occurs as a physiological phenomenon, it causes valvular damage leading to valvular insufficiency and may leave residual mural thrombus, which can organize, stenose the vessel and impair venous return, thus causing chronic symptoms in the arm. Acutely, venous gangrene has been reported but is rare; however, pulmonary embolization is more common than once thought. Visualization of a venous stenosis or an underlying compressive abnormality at the thoracic outlet may be impaired if clot remains in the vein, even if its propagation is reduced with the use of anticoagulants.
Considering these problems associated with SAVT, thrombolysis has theoretic advantages over both anticoagulation and surgery.
Venous patency, valvular integrity and chronic symptoms
Although heparin is protective against secondary thrombosis of collaterals and helps maintain venous return, some authors38,74 have reported better long-term results in patients treated with thrombolysis than with anticoagulation. Thrombolysis has the potential to restore deep venous patency early,7576 especially in the upper limb," and preserve valvular function.'9 In 14 studies of 69 patients undergoing thrombolytic therapy for SAVT, total or partial primary patency was seen in 61 (88%) of the patients.,74,80-84
This is an important finding because venous occlusion, whether complete or partial, compromises venous return and this, along with valvular destruction, may result in venous hypertension. However, this series of events has more impact in the lower limb, and the major postphlebitic changes often seen around the ankle are uncommon in the upper limb. There are 2 reasons for this. First, collateralization around the shoulder is very good, having 4 main pathways: shoulder to chest wall, shoulder to ipsilateral anterior neck, shoulder to ipsilateral posterior neck, and shoulder to contralateral neck.s A number of these collaterals, however, do traverse the costoclavicular space and are themselves prone to compression depending on the arm position. It has been shown that in the lower limb, major vein occlusion may be associated with a good clinical outcome as long as adequate venous collaterals are present.86 This appears to be true of the upper limb as well. Campbell and associates23 found that symptoms correlated better with venous outflow obstruction than with main channel patency per se, and Tilney, Griffiths and Edwards47 correlated chronic symptoms in the arm with venous hypertension rather than venography findings.
Second, in contrast to the upper limb, the lower limb venous valves protect against the pressure effects on the ankles of a long column of blood, especially during exercise.54 Although the role of venous valves in the upper limb is probably not as critical as in the lower limb, it remains important. Thus, treatment should aim to maintain the integrity of the valves where possible. It should be noted that some data regarding venous patency and collateralization after thrombolysis has to be viewed with caution, as patients may not be reassessed if they have become asymptomatic after SAVT. Also, since a number of authors perform some form of thoracic outlet decompression on all65 or some"7 of their patients, patency rates cannot be directly related to the use of thrombolysis alone.
Acute symptoms and embolization
In a few patients with acute SAVT, phlegmasia cerulea dolens will progress to frank venous gangrene.
This condition is rare but has important consequences. Smith and colleagues" described 3 patients with this complication, all of whom had an associated life-threatening systemic illness. One patient with bilateral SAVT was treated with streptokinase and showed definite improvement in both arms, suggesting that thrombolysis may have a role in this condition. However, all 3 patients eventually died of their systemic disease; hence, thrombolysis had no effect on the final outcome.
It was originally thought that SAVT-associated pulmonary embolism was rare, if indeed it existed at all.' However, this has been refuted by more recent work,19--9" and a rate of 14% has been suggested.3 The role of thrombolysis in the restoration of the pulmonary microcirculation after embolization has been stressed,7883 and is an action not observed with heparin. It is clear, therefore, that thrombolysis plays a dual role in patients with respect to pulomary embolism.
Visualization of compression
Venous patency immediately after thrombolysis averages 88%. The restoration of venous patency allows identification of intrinsic stenoses' and extrinsic compression.'4 By putting the arm through its range of movements, particularly hyperabduction,'2 visualization of any extrinsic compression is enhanced, allowing for the planning of further intervention, including surgery.
Method of administration
To achieve adequate lysis, the lyric agent has to be delivered effectively to the site of the clot. This can be done either by systemic infusion through a peripheral catheter placed in a vein in the dorsum of the hand or by local infusion directly into the clot through a long catheter introduced (usually) into the basilic vein. Both systemicb and local7,8,80sls' infusions of the thrombolytic agent have been described but have not been directly compared using large enough numbers of patients to clarify any advantage of one over the other.
In the analogous situation of peripheral arterial thrombosis, it is generally accepted that local infusion is the best method of delivering the agent directly to the thrombus in high concentration, although "burst therapy" utilizing intermittent peripheral infusions of the lytic agent for both arterial and venous thrombosis has been described with good results.92 Comerota and Aldridge* suggested that local thrombolysis is the delivery method of choice for lower limb DVT, and this probably holds true for venous thrombosis of the upper limb.
Most authors give a bolus dose of lytic agent initially and follow this with an infusion. The length of time of infusion depends on the degree of lysis observed on serial venography and on the infusion technique but is typically in the range of 6 to 48 hours.68087 Intravenous heparin is usually given simultaneously to prevent rethrombosis and thrombus cuff formation around the catheter. Actual doses and infusion regimens vary greatly between authors from a low dose of 10 000 IU (streptokinase) per houri4 to a high dose of 100 000 IU (streptokinase) per hour,86 with infusions up to 96 hours. There is probably little to recommend infusion for longer than 12 hours if clot lysis is not progressing.
Mechanical disruption of the clot may help its dissolution. The pulsespray technique has this effect and is now becoming more widely used in peripheral arterial and dialysis access graft thrombolysis.93-95 It can be employed if available. Which lytic agent? The 2 main thrombolytic agents used in the treatment of patients with SAVT are streptokinase and urokinase. Their method of action and administration have been previously described by Bell and Meek.96
There have been no controlled trials directly comparing the action of lyric agents in SAVT. However, Kunkel and Machleder found that urokinase was better than streptokinase in establishing early patency. Also, urokinase does not have the allergy problems associated with streptokinase. In a series of 4 patients treated with streptokinase for SAVT, all had to have their infusion terminated because of a combination of high antibody levels and fever. In all 4 cases, treatment was successfully completed using urokinase."
Ruckley, Boulton and Redhead82 described 6 cases of spontaneous SAVT treated with p-anisoylated streptokinase-plasminogen complex (APSAC) with partial or total lysis occurring in 5, and Pires and Jay97 described a similar case with a good result.
Tissue plasminogen activator (rtPA) does not appear to have been widely used in treating SAVT, although its use for lower limb venous thrombosis has been summarized.98
Regardless of which drug is used, the longer the history of the thrombosis the less likely it is that lytic therapy will be successful because of cellular infiltration and organization of the thrombus.99 Therefore, lyric therapy should be confined to acute cases of SAVT. The need for prompt treatment is emphasized by Coon and Willis.26 They found that 80% of patients who presented and were treated (with anticoagulation) within 7 days of the onset of symptoms had no residual symptoms.
Complications of thrombolysis
Morbidity associated with thrombolysis includes hemorrhage (intracranial, retroperitoneal, gastrointestinal, genitourinary, pulmonary and at sites of invasive procedures), fever, headaches and anaphylaxis. The allergic types of reactions are more common with streptokinase than with urokinase. There are few data on the incidence of these types of complications when thrombolysis is used for SAVT, although Machleder8 has described 2 episodes of allergic reaction and 1 minor hemorrhage in a series of 50 patients treated with catheter-directed streptokinase. In a review of streptokinase therapy for DVT of all types, Rogers and Lutcherl concluded that streptokinase is not only beneficial in DVT but that "when patients are carefully selected and invasive procedures minimized, major bleeding events including intracerebral haemorrhage are no more frequent with streptokinase than with conventional heparin therapy."
A number of authors have emphasized the importance of identifying and treating any underlying cause of primary SAVT,8,81,87,101-103 whether it is an intrinsic stenosis or an extrinsic compression. Otherwise, residual symptoms, with or without rethrombosis of the vein, will remain. Identification of a stenosis or area of extrinsic compression is facilitated by lysis of thrombus in that area.
Adjuvant surgical intervention for SAVT usually takes the form of first rib resection or some other thoracic outlet decompression procedure, with or without venoplasty. Balloon angioplasty of residual stenoses after the decompressive surgery has been found useful provided that any extrinsic compression has been relieved.' In contrast, if angioplasty is performed before such surgery it is associated with a high restenosis rates and may in fact be detrimental; Kunkel and Machleder' reported 4 out of 4 thrombotic occlusions in veins that were previously only stenotic. Balloon angioplasty has been applied to venous stenosis secondary to central venous catheterization in patients undergoing dialysis4 but results in low long-term patency (35% at 1 year and 6% at 2 years). However, the use of repeated angioplasty is recommended4,1 for patients who have limited access sites for dialysis.
The use of stents has been described and appears to have a better success rate in treating stenoses due to catheterization and those associated with arteriovenous dialysis fistulae than does angioplasty alone.l0Sl09 Stenting in primary SAVT is unlikely to be of benefit unless a short, localized intravenous lesion is identified.
Molina"13,44 and Urschel and Razzukt65 have proposed a protocol for the management of SAVT, involving a combination of thrombolysis and early surgery to remove the first rib in all patients with "effort" thrombosis. We do not find this a logical approach because not all patients with "effort" thrombosis have an identifiable extrinsic compression and because positional extrinsic compression does not necessarily cause venous thrombosis. This latter point is supported by Dunant,l' who found that venous obstruction could be demonstrated in up to 70% of healthy people when the shoulder was hyperabducted and retracted. Similar shoulder movement caused a significant rise in axillary vein pressure in 88% of healthy people. However, in a similar study, Stevenson and Parry"' found no evidence of venous compression in abduction and adduction venograms of healthy subjects, but only 10 subjects were included.
Rauwerda and colleagues"' reported on a series of patients who underwent thrombolysis followed, after a 3-month delay, by first rib resection. Venography and plethysmographic determination of venous outflow, venous capacity and impedance were performed postoperatively and showed good results, but no measurements were taken preoperatively for comparison. A similar approach was taken by Machleder,"4 who also suggests waiting 3 months to reassess symptoms, and by Pittam and Darke,"2 who advocated a 6-month delay.
When contemplating first rib resection, it must be remembered that this procedure may be associated with serious complications and that it is a potent source of litigation. Symptoms must be assessed very carefully and "lesser" procedures considered, if appropriate.
It must also be remembered that some patients with primary SAVT have thoracic outlet obstruction but with symptoms of neurologic origin.",80 Such symptoms can be confused with those of venous origin, and postoperative improvement may be due to relief of nerve compression rather than relief of venous obstruction.
Primary versus secondary
There is little hard evidence to indicate whether primary and secondary SAVT should be managed differently because patient numbers in series are small, and definitions and classifications of SAVT vary between authors. Donayre and associates22 suggested that patients with primary SAVT be treated aggressively with thrombolysis and surgery (if indicated) to prevent chronic disability, but that those with secondary causes of SAVT require only anticoagulation, as their longterm morbidity is low.'13 This latter point seems sensible when one considers the degree of comorbidity in patients with thrombosis secondary to cardiac failure, cancer and venous catheterization that is used in a variety of chronic illnesses. This comorbidity may preclude thrombolysis and surgery in many patients. Such an approach is supported by Campbell and associates,"3 who reported that none of their 8 patients who had secondary thrombosis complained of persistent symptoms whether or not they received anticoagulation.
Patients who require repeated central catheterization for dialysis access, total parenteral nutrition or chemotherapy may be an exception to this rule of minimal intervention because of the absolute necessity to maintain adequate venous access."
Long-term sequelae
Tables II to VI summarize the management and long-term sequelae of SAVT. Multiple publications and individual case reports have been excluded, as have those that lack adequate follow-up of symptomatology (less than 6 months) or adequate subclassification of the cause of thrombosis and its management.
CONCLUSIONS
The management of patients with SAVT remains controversial. A number of options are available, varying from the conservative heparinization followed by oral anticoagulation, through thrombolysis, to aggressive early surgical intervention. For patients with primary SAVT, the prevention of the chronic symptoms of pain, swelling and limitation of movement is of major importance, although the degree of long-term morbidity in published series varies greatly. For these patients, the only predictors of chronic symptoms appear to be the etiology of the thrombosis, the presence (or not) of extrinsic compression or venous stenosis and length of history. The acceptability of chronic symptoms depends on the activity level of the individual patient, which in turn is related to age, employment and recreational interests. Therefore, the type of treatment chosen for any particular patient should be tailored both to this and to the cause of the thrombosis.
Thrombolysis is becoming widely used in the management of SAVT. However, its side effects must be considered; problems with hemorrhage, allergy and catheter placement have all been recorded.99"4 When used correctly, thrombolytic drugs appear to be safe, but it must be remembered that local infusions require skilled catheter placement and that monitoring must be adequate and dosages carefully calculated. Financial implications must also be considered, as radiology time and equipment, beds in the intensive care unit and the drugs themselves are associated with significant cost. It has, however, to be compared with the overall cost to society of a young patient who cannot contribute economically over his or her lifetime because of chronic symptoms of arm swelling and pain.
Although the prevalence of SAVT is increasing, it remains uncommon. Becker, Philbrick and Walker6 have suggested that a multicentre trial would be justified to evaluate the management of SAVT. The purpose of such a trial should be specifically to define whether anticoagulation is adequate to prevent both the early and late sequelae of SAVT, whether thrombolysis should be more widely adopted or whether its use should be confined to specified groups of patients. The role of surgery would be more difficult to assess, partly because all patients should initially receive some form of pharmacologic intervention regardless of whether surgery is scheduled, and partly because of ethical considerations.
However, until such a trial is undertaken, on the basis of this review we propose the following management strategy and an algorithm (Fig. 1 ) similar to that suggested by Haire:lls
Anticoagulation remains the mainstay of treatment in the early stages and should be used in cases of acute thrombosis and continued for 3 months.
Chronic thromboses may require only conservative management; thrombolysis is not indicated.
Thrombolysis should be confined to specific categories of patients with primary SAVT: young patients, some patients with venous access requirements and older patients whose employment or recreational activity would be severely limited by chronic arm swelling or pain.
SAVT should be confirmed by venography even if Doppler ultrasonography is negative, and should be further investigated if no obvious cause is found.
Catheter-guided local administration of the lytic agent is the delivery method of choice. Urokinase has certain advantages over streptokinase.
After the acute episode, surgery should be considered if there is symptomatic extrinsic venous compression, and angioplasty of residual stenoses should only be performed postoperatively.
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[Author Affiliation]
From the Division of Vascular Surgery, The Wellesley Hospital, University of Toronto, Toronto, oronfor Ont. Presented at the International Multidisciplinary Vascular Disease Symposium, Winnipeg, Man., May 15. 1996 4ccepted for publication Feb. 17. 1997
Correspondence to: Dr. F. Michael Ameli, Suite 212, EK. ]ones Building. 160 Wetlesley St. E, Toronto ON M4Y 1J3; tel 416 926-7700; fax 416 926-7742
