2
1405 retrospective and the prospective studies is disquieting. The prospective studies may be better, but again few details are available. Are the mothers with epilepsy representative of all such mothers? Are all pregnancy outcomes, including therapeutic abortions, recorded? In both types of study, there is little information on the severity of the underlying epilepsy in women who have used valproate, and on other treatments given concomitantly or in the recent past. Prospective studies are also needed to measure the total risk of severe congenital abnormalities of any type associated with different severities of epilepsy and modes of therapy, since this information is essential for clinical management. Congenital malformation registries have been established in many parts of the world for the purpose of detecting new teratogens and local epidemics, often in response to the thalidomide tragedy. These results may show the success of the registries in identifying an important new teratogen. However, those concerned have failed to present the thorough, detailed, and convincing data that are necessary for optimum practical action, and have not adequately explored the biological and teratological questions that arise. DIURNAL VARIATION IN PLATELET AGGREGATION RESPONSES NUMEROUS studies have shown enhanced platelet aggregation to various agonists, including ADP, adrenaline, and collagen, in thromboembolic conditions. In particular, enhanced aggregation responses and other alterations of platelet function have been recorded in patients with acute myocardial infarction.1-3 Changes include raised plasma levels of platelet factor 4 and beta-thromboglobulin, increases in thromboxane B2 production and platelet sensitivity to arachidonic acid and ADP, and decreased platelet sensitivity to prostacyclin. These fmdings suggest that in-vivo platelet activation and aggregation may be involved in the initiation and extension of myocardial infarction. Increased circulating levels of thromboxane A2 in the local microarterial environment will also cause vasoconstriction and activate platelets directly, thereby increasing the threshold of the second phase of ADP- induced aggregation. The suggestion that platelets help to initiate myocardial infarction has led to widespread interest in the use of antiplatelet drugs, particularly aspirin and dipyridamole, in the primary prevention of myocardial infarction and in secondary prevention programmes.4 Data from the MILIS study in the USA showed a pronounced circadian periodicity in the time of onset of myocardial infarction, with a peak incidence in the morning.’ This periodicity was observed by both timing of pain onset and increase of plasma creatine kinase MB activity. Peak onset of pain was between 0800 and 1100 h, with a peak to trough ratio of approximately 2:1 in a study 1. Szcteklik A, Serwanska M, Lukasiewicz W, et al. Arachidonate versus ADP-induced platelet aggregation in acute myocardial infarction. Thrombos Haemostas 1979; 42: 822-30. 2. Salky N, Dugdale M. Platelet abnormalities in ischaemic heart disease. Am J Cardiol 1973; 32: 612-18. 3 Handin RI, McDonough M, Lesch M. Evaluation of platelet factor four in acute myocardial infarction. J Lab Clin Med 1978; 91: 340-47. 4. Callus AS. The use of antithrombotic drugs in artery disease. Clin Haematol 1985, 15: 509-59. 5. Muller JE, Stone PH, Ture ZG, et al. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med 1985; 313: 1315-22. group of 8900 patients. Such circadian variation had previously been recorded in several other studies of acute myocardial infarction, including two from the UK.6-8 A similar diurnal variation has been reported for sudden cardiac death and for cerebral infarction, with peak onset of thrombotic strokes in the early morning.9,10 Several daily rhythm patterns could contribute to the early morning peak, including those related to the haemostatic control mechanism of which platelet function plays an important role. As a follow-up to the MILIS study, Brezinski and colleagues," using the turbidometric technique, have now shown a morning increase in platelet aggregability to threshold concentrations of ADP and adrenaline in a group of healthy young male volunteers. These results confirm an earlier report by Tofler et al, who found increased aggregation responses during the morning, when people began to awake and start their daily routine activities, that were specifically increased upon assuming an upright posture.12 These changes were associated with the maximum increase in the striking daily variations of plasma adrenaline and noradrenaline levels. The increased hormone levels are not sufficient to stimulate in-vitro platelet aggregation directly, but they may have a synergistic effect on other platelet agonists, including ADP. The clinical relevance of observations of enhanced platelet aggregation and their relation to thrombotic events is uncertain. Reduced platelet reactivity and aggregation is often directly related to impaired haemostasis in vivo and to clinical haemorrhagic episodes. Conversely, there is no conclusive evidence that increased platelet aggregation in vitro is pathologically important in thrombosis. Many clinical and laboratory variables may affect the degree of platelet aggregability-eg, high fibrinogen levels are associated with increased ADP-induced aggregation responses, particularly in men.13 Increased aggregation responses are also noted in association with hyperlipidaemia (particularly hypercholesterolaemia), cigarette smoking, exercise, and emotional stress,14-16 all of which are proven factors for arterial thrombotic events and vary considerably during normal daily activities. The degree of aggregation measured in vitro will also be influenced by laboratory conditions such as platelet concentration, pH, temperature, speed of stirring, and concentration of agonist. 17 To this list one must now add the time of day and whether the subject has lately assumed an upright posture. For large 6. Reinberg A, Smolensky MH. Biological rhythms and medicine: cellular, metabolic, physiopathologic and pharmacological aspects. New York: Springer-Verlag, 1983. 7. Myers A, Dewar HA. Circumstances attending 100 sudden deaths from coronary artery disease with coroner’s necropsies. Br Heart J 1975; 37: 1133-43. 8. Tunstall Pedoe H, Clayton D, Moms JN, Bngden W, McDonald L. Coronary heart-attacks in East London. Lancet 1975; ii: 833-38. 9. Muller JE, Ludmer PL, Willich SN, et al Circadian variation in the frequency of sudden cardiac death. Circulation 1987; 75: 131-38. 10. Marshall J. Diurnal variation in occurrence of stokes. Stroke 1977; 8: 20-21. 11. Brezinski DA, Tolfer GH, Muller JE, et al. Morning increase in platelet aggregability: association with assumption of the upright posture Circulation 1988; 78: 35-40. 12. Tolfer GH, Brezinski DA, Schafer AI, et al. Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med 1987; 316: 1514-18. 13. Meade TW, Vickers MV, Thompson SG, et al. Epidemiological characteristics of platelet aggregability. Br Med J 1985; 290: 428-32. 14. McDonald JWD, Dupre J, Rodger NW, et al. Comparison of platelet thromboxane synthesis in diabetic patients on conventional insulin therapy and continuous insulin infusion. Thrombosis Res 1982; 28: 705-12. 15. Pittilo RM, Clarke JMF, Harris D, et al. Cigarette smoking and platelet adhesion. Br J Haematol 1985; 58: 627-32. 16. Levine SP, Towell BL, Suarez AM, et al. Platelet activation and secretion associated with emotional stress. Circulation 1985; 71: 1129-34. 17. Yardumian DA, Mackie IJ, Machin SJ. Laboratory investigation of platelet function—a review of methodology. J Clin Pathol 1986; 39: 701-12.

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Page 1: DIURNAL VARIATION IN PLATELET AGGREGATION RESPONSES

1405

retrospective and the prospective studies is disquieting. Theprospective studies may be better, but again few details areavailable. Are the mothers with epilepsy representative of allsuch mothers? Are all pregnancy outcomes, includingtherapeutic abortions, recorded? In both types of study,there is little information on the severity of the underlyingepilepsy in women who have used valproate, and on othertreatments given concomitantly or in the recent past.Prospective studies are also needed to measure the total riskof severe congenital abnormalities of any type associatedwith different severities of epilepsy and modes of therapy,since this information is essential for clinical management.

Congenital malformation registries have been establishedin many parts of the world for the purpose of detecting newteratogens and local epidemics, often in response to thethalidomide tragedy. These results may show the success ofthe registries in identifying an important new teratogen.However, those concerned have failed to present the

thorough, detailed, and convincing data that are necessaryfor optimum practical action, and have not adequatelyexplored the biological and teratological questions that arise.

DIURNAL VARIATION IN PLATELETAGGREGATION RESPONSES

NUMEROUS studies have shown enhanced plateletaggregation to various agonists, including ADP, adrenaline,and collagen, in thromboembolic conditions. In particular,enhanced aggregation responses and other alterations ofplatelet function have been recorded in patients with acutemyocardial infarction.1-3 Changes include raised plasmalevels of platelet factor 4 and beta-thromboglobulin,increases in thromboxane B2 production and plateletsensitivity to arachidonic acid and ADP, and decreasedplatelet sensitivity to prostacyclin. These fmdings suggestthat in-vivo platelet activation and aggregation may beinvolved in the initiation and extension of myocardialinfarction. Increased circulating levels of thromboxane A2 inthe local microarterial environment will also cause

vasoconstriction and activate platelets directly, therebyincreasing the threshold of the second phase of ADP-induced aggregation. The suggestion that platelets help toinitiate myocardial infarction has led to widespread interestin the use of antiplatelet drugs, particularly aspirin anddipyridamole, in the primary prevention of myocardialinfarction and in secondary prevention programmes.4Data from the MILIS study in the USA showed a

pronounced circadian periodicity in the time of onset ofmyocardial infarction, with a peak incidence in the

morning.’ This periodicity was observed by both timing ofpain onset and increase of plasma creatine kinase MBactivity. Peak onset of pain was between 0800 and 1100 h,with a peak to trough ratio of approximately 2:1 in a study

1. Szcteklik A, Serwanska M, Lukasiewicz W, et al. Arachidonate versus ADP-inducedplatelet aggregation in acute myocardial infarction. Thrombos Haemostas 1979; 42:822-30.

2. Salky N, Dugdale M. Platelet abnormalities in ischaemic heart disease. Am J Cardiol1973; 32: 612-18.

3 Handin RI, McDonough M, Lesch M. Evaluation of platelet factor four in acutemyocardial infarction. J Lab Clin Med 1978; 91: 340-47.

4. Callus AS. The use of antithrombotic drugs in artery disease. Clin Haematol 1985, 15:509-59.

5. Muller JE, Stone PH, Ture ZG, et al. Circadian variation in the frequency of onset ofacute myocardial infarction. N Engl J Med 1985; 313: 1315-22.

group of 8900 patients. Such circadian variation had

previously been recorded in several other studies of acutemyocardial infarction, including two from the UK.6-8 Asimilar diurnal variation has been reported for suddencardiac death and for cerebral infarction, with peak onset ofthrombotic strokes in the early morning.9,10

Several daily rhythm patterns could contribute to theearly morning peak, including those related to thehaemostatic control mechanism of which platelet functionplays an important role. As a follow-up to the MILIS study,Brezinski and colleagues," using the turbidometric

technique, have now shown a morning increase in plateletaggregability to threshold concentrations of ADP andadrenaline in a group of healthy young male volunteers.These results confirm an earlier report by Tofler et al, whofound increased aggregation responses during the morning,when people began to awake and start their daily routineactivities, that were specifically increased upon assuming anupright posture.12 These changes were associated with themaximum increase in the striking daily variations of plasmaadrenaline and noradrenaline levels. The increasedhormone levels are not sufficient to stimulate in-vitro

platelet aggregation directly, but they may have a synergisticeffect on other platelet agonists, including ADP.The clinical relevance of observations of enhanced

platelet aggregation and their relation to thrombotic eventsis uncertain. Reduced platelet reactivity and aggregation isoften directly related to impaired haemostasis in vivo and toclinical haemorrhagic episodes. Conversely, there is noconclusive evidence that increased platelet aggregation invitro is pathologically important in thrombosis. Manyclinical and laboratory variables may affect the degree ofplatelet aggregability-eg, high fibrinogen levels are

associated with increased ADP-induced aggregationresponses, particularly in men.13 Increased aggregationresponses are also noted in association with hyperlipidaemia(particularly hypercholesterolaemia), cigarette smoking,exercise, and emotional stress,14-16 all of which are provenfactors for arterial thrombotic events and vary considerablyduring normal daily activities. The degree of aggregationmeasured in vitro will also be influenced by laboratoryconditions such as platelet concentration, pH, temperature,speed of stirring, and concentration of agonist. 17 To this listone must now add the time of day and whether the subjecthas lately assumed an upright posture. For large

6. Reinberg A, Smolensky MH. Biological rhythms and medicine: cellular, metabolic,physiopathologic and pharmacological aspects. New York: Springer-Verlag, 1983.

7. Myers A, Dewar HA. Circumstances attending 100 sudden deaths from coronaryartery disease with coroner’s necropsies. Br Heart J 1975; 37: 1133-43.

8. Tunstall Pedoe H, Clayton D, Moms JN, Bngden W, McDonald L. Coronaryheart-attacks in East London. Lancet 1975; ii: 833-38.

9. Muller JE, Ludmer PL, Willich SN, et al Circadian variation in the frequency ofsudden cardiac death. Circulation 1987; 75: 131-38.

10. Marshall J. Diurnal variation in occurrence of stokes. Stroke 1977; 8: 20-21.11. Brezinski DA, Tolfer GH, Muller JE, et al. Morning increase in platelet aggregability:

association with assumption of the upright posture Circulation 1988; 78: 35-40.12. Tolfer GH, Brezinski DA, Schafer AI, et al. Concurrent morning increase in platelet

aggregability and the risk of myocardial infarction and sudden cardiac death.N Engl J Med 1987; 316: 1514-18.

13. Meade TW, Vickers MV, Thompson SG, et al. Epidemiological characteristics ofplatelet aggregability. Br Med J 1985; 290: 428-32.

14. McDonald JWD, Dupre J, Rodger NW, et al. Comparison of platelet thromboxanesynthesis in diabetic patients on conventional insulin therapy and continuousinsulin infusion. Thrombosis Res 1982; 28: 705-12.

15. Pittilo RM, Clarke JMF, Harris D, et al. Cigarette smoking and platelet adhesion. Br JHaematol 1985; 58: 627-32.

16. Levine SP, Towell BL, Suarez AM, et al. Platelet activation and secretion associatedwith emotional stress. Circulation 1985; 71: 1129-34.

17. Yardumian DA, Mackie IJ, Machin SJ. Laboratory investigation of plateletfunction—a review of methodology. J Clin Pathol 1986; 39: 701-12.

Page 2: DIURNAL VARIATION IN PLATELET AGGREGATION RESPONSES

1406

epidemiological studies of a thrombotic tendency suchinformation may be helpful, but for individual patientsaggregation responses are difficult to interpret-there is stillno real evidence that hyperreactive or hyperaggregableplatelets exist in vivo.

RECURRENT RESPIRATORYPAPILLOMATOSIS

RECURRENT respiratory papillomatosis (RRP, formerlyknown as juvenile laryngeal papillomatosis) is characterisedby the recurrent appearance of benign squamous papillomason respiratory mucosa. The lesions may be sessile or

pedunculated and occur in clusters. The commonest site isthe larynx but papillomas may extend throughout therespiratory tract. The disorder is associated with highmorbidity and mortality because of airway obstruction.RRP was originally thought to be a disease of childhood, buta bimodal distribution is now recognised: most patientspresent before 5 years of age with a smaller adult-onset

group presenting after 15 years.1RRP is caused by infection with human papillomavirus

types 6 and 11.2 Viral particles are seldom demonstrated inpapilloma specimens, but immunofluorescence studies haveproduced evidence of viral DNA incorporated into thecellular genome.3 The virus is also present in apparentlynormal cells, which may become activated and form therecurrent lesions. The organism cannot be eradicated

simply by removing diseased tissue. There are some

indications that children acquire the disease at the time ofdelivery from a mother with genital warts, andcircumstantial evidence suggests that adult disease may be

acquired by orogenital contact. Nevertheless, thetransmission rate is low. Remission, either spontaneously oras a result of treatment, occurs unpredictably; it does notappear to be related to the thoroughness of removal of visibledisease. The papillomas may also spread, especially after atracheostomy, when the tracheobronchial tree may becomeinvolved. Extension to lung parenchyma with multiple cystformation is rare but is usually progressive and fatal.

Malignant change to squamous carcinoma has been

reported.4RRP usually presents with hoarseness of voice or, in

children, with an abnormal cry. Stridor and upper airwayobstruction may become apparent later and it is the airwaycomplication that necessitates treatment. Endoscopicsurgical removal of papillomas remains the mainstay oftreatment and may be required on many occasions, even adozen times and more. Many techniques have been

used-eg, mechanical forceps removal, cryotherapy,diathermy, and ultrasound. Complications of thesetreatments include troublesome bleeding and postoperativeoedema with risks of inhalation and airway obstruction.Repeated surgical treatment may lead to scarring andcontracture with deformation of the larynx. The CO2 laser is

1. Strong MS. Recurrent respiratory papillomatosis In: Evans JNG. Scott-Brown’sotolaryngology, vol 6 466-70 London: Butterworths, 1987.

2 Mounts P, Shaw KV, Kashima H. Viral aetiology of juvenile and adult onsetsquamous papilloma of the larynx. Proc Natl Acad Sci USA 1982; 79: 5425-29.

3. Steinberg BM, Topp WC, Schneider PS Laryngeal papillomavirus infection duringclinical remission. N Engl J Med 1983, 308: 1261-64.

4. Schnadig VJ, Clark WD, Clegg TJ, Yoo CS. Invasive papillomatosis and squamouscarcinoma complicating juvenile laryngeal papillomatosis. Arch Otolaryngol HeadNeck Surg 1986; 112: 966-71

now the preferred method of endoscopic treatment.5

Complete removal of visible disease can be carried out withlittle bleeding and swelling and very slight damage tounderlying normal laryngeal tissue. The necessity of

tracheostomy, which in itself is associated with morbidity inchildren as well as with the risk of further spread, is reduced.Endoscopic removal is repeated as often as required,possibly within weeks. Management of children requires thecooperation and understanding of parents since hospitaladmission may be required for a considerable time,especially if the airway becomes obstructed.

Because of the inadequacies of endoscopic surgicaltreatment and the difficulties of recognising infection invisually normal tissue, many workers have sought aneffective adjuvant therapy. Hormones, steroids, antibiotics,topical antimitotic agents such as podophyllin and 5-fluorouracil, vaccines, antimetabolites, and cytotoxics7 haveall been tried to prevent a recurrence. No technique has yetgiven consistently good results without harmful effects.Attention has lately turned to the use of interferon. Earlyreports$°9 indicated a clinical response to an alpha humanleucocyte interferon, but relapse on cessation of thetreatment was common. A 3-year follow-up of patientstreated with alpha interferon gave similar results.10 Thepersistence of human papillomaviral DNA in laryngealtissue, even after lengthy interferon treatment, has latelybeen documented;" this observation presumably accountsfor the frequent recurrences. Leventhal et al have now

reported the results of a multicentre randomised cross-overtrial with interferon alfa-nl in 66 patients.12 Half the groupreceived interferon for 6 months followed by 6 months’observation; the other half were observed initially for 6months and then treated. Endoscopic examination andremoval of papillomas was carried out every 2 months toassess disease. There was a statistically significantimprovement in the group receiving interferon but

improvement was not maintained in many patients duringthe subsequent observation period. Patients without

tracheostomy were more likely to respond. The interferonwas administered intramuscularly throughout the trial

period, and toxic effects were encountered—eg, transientfever with influenza-like symptoms, and hepatic andhaematological dysfunction. 19 of the 66 patients wereunable to complete the prescribed treatment.Thus, existing varieties of interferon undoubtedly slow

the growth of respiratory papillomas but they do not seem toeradicate virus from respiratory mucosal tissues. Althoughtemporary remission has been produced in conjunction withendoscopic surgical removal, no form of treatment hasconsistently led to long-term remission of RRP.

5. Strong MS, Vaughan CW, Healy GB, Cooperband SR, Clemente MACP. Recurrentrespiratory papillomatosis: management with the CO2 laser. Ann Otol RhinolLaryngol 1976; 85: 508-16.

6. Dedo H, Jackler RK Laryngeal papillomas: results of treatment with CO2 laser andpodophyllum. Ann Otol Rhinol Laryngol 1982; 91: 425-30.

7. DelVillar R, Echeverna E, DeAcosta V, Dibildox JC, Diaz FL. Laryngealpapillomatosis: its treatment at the Hospital Infantil de Mexico Arch Otolaryngol1956, 64: 480-85.

8 Haglund S, Lundquist P, Cantrell K, Strander H. Interferon therapy m juvenilelaryngeal papillomatosis. Arch Otolaryngol 1981; 107: 327-32.

9. Goepfert H, Sessions RB, Gutterman JU, Cangir A, Dichtel WJ, Sulek M. Leukocyteinterferon in patients with juvenile laryngeal papillomatosis. Ann Otol RhinolLaryngol 1982; 91: 431-36.

10. Lusk RP, McCabe DF, Nixon JH. Three year experience of treating recurrentrespiratory papilloma with interferon. Ann Otol Rhinol Laryngol 1987; 96: 158-61.

11. Steinberg BM, Gallagher T, Stoler M, Abrahamson AL. Persistence and expression ofhuman papillomavirus during interferon therapy Arch Otolaryngol Head NeckSurg 1988; 114: 27-32

12. Leventhal BG, Kashima HK, Weck PW, et al. Randomised surgical adjuvant trial ofinterferon alfa-nl m recurrent papillomatosis. Arch Otolaryngol Head Neck Surg1988, 114: 1163-69.