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made, a significant proprietary name change should be made too.Recently acquired knowledge is often the first to be lost.

Addenbrooke’s Hospital,Cambridge S. W. B. NEWSOM

M.R.C. Burns Research Group,Birmingham Accident Hospital H. A. LILLY

INCIDENCE OF MATURE FOLLICLES INSPONTANEOUS AND INDUCED OVARIAN CYCLES

SIR,-The number and site of mature follicles which develop ineach ovarian cycle is important information for the management ofinfertility. We have used real-time pelvic ultrasonography to

determine the number of follicles (>18 mm mean diameter) whichoccur in healthy women throughout the menstrual cycle and duringtreatment of anovulatory infertility with clomiphene citrate orhuman menopausal gonadotropins. We have also recorded theincidence of mature follicles occurring simultaneously in bothovaries and the number of multiple pregnancies.Follicular growth was monitored daily during 51 spontaneous

ovarian cycles in forty-five healthy volunteers aged 18-35 yearsfrom day 10 of the menstrual cycle until the mature follicles hadruptured or regressed. Ovulation was defined by a follicle reaching

INCIDENCE AND SITE OF MATURE FOLLICLES IN SPONTANEOUS AND

INDUCED OVARIAN CYCLES

*No. (and 07o of total multiple mature follicles).

a mean diameter of 18-25 mm and subsequently disappearing orchanging in size, shape, or acoustic density. In addition thirty-sixinfertile patients (78 cycles) receiving increasing doses of

clomiphene citrate (’Clomid’) 50-150 mg/day for days 1-5 of themenstrual cycle for the induction of ovulation and thirty-fourpatients (120 cycles) receiving human menopausal gonadotropins(’Pergonal’) and human chorionic gonadotropin (’Pregnyl’)according to the protocol of Sallam et al.2 were studied throughoutthe menstrual cycle until there was morphological evidence that allpossible ovulations had occurred.The incidence and site of two or more mature follicles in the three

groups of women are shown in the table. All mature follicles withinthe same subject and cycle ruptured or regressed over 48 h. Four ofthe patients receiving clomiphene conceived during the study cycle.Three had a single follicle and a singleton pregnancy, while thefourth had two follicles and a twin pregnancy. Multiple maturefollicles were seen during 28 treatment cycles and pregnancy did notoccur. Twelve of the patients receiving gonadotropins conceived.Two had one follicle and subsequently one fetus, four had twofollicles and a single fetus, while six had three or more maturefollicles which ruptured or regressed. Five of these had a single fetusand one had a triplet pregnancy. Multiple mature follicles wereobserved during 64 menstrual cycles and pregnancy did not occur.Our results on the frequency with which two mature follicles

occur during spontaneous ovarian cycles (10%) accord with thefindings of Hackeloer et awl. and Queenan et al.1 The incidence ofmature follicles after the pituitary/ovarian axis of infertile women

1 Queenan JT, O’Brien GD, Simpson J, Bains L, Collins WP, Campbell S. Ultrasoundscanning of ovaries to detect ovulation Fertil Steril 1980; 34: 99-105.

2. Sallam HN, Marinho AO, Collins WP, Rodeck CH, Campbell S. Monitoringgonadotrophin therapy with ultrasound scanning of ovarian follicles. Br J ObstetGynaecol 1982, 89: 155-59

3 Hackeloer BJ, Fleming R, Robinson HP, Adam AH, Coutts JRT. Correlation ofultrasonic and endocrinologic assessment of human follicular development. Am JObstet Gynecol 1979, 135: 122-28

has been stimulated with clomiphene citrate was 37% and althoughthe number of pregnancies in this study was low, the finding mayexplain the generally high success rate reported for this treatmentduring the first few months of use, as well as the slight increase inthe incidence of multiple pregnancies.4 The number of multipleovulations per cycle during treatment with human menopausalgonadotropins was higher (63%), and twelve patients conceived.Although ten pregnancies occurred at the time of multipleovulation, nine patients had a single fetus. Accordingly, the lowincidence of multiple pregnancies during both types of treatmentand the higher frequency of mature follicles suggest either thatfollicular rupture does not invariably signify that ovulation hasoccurred, or that there is high failure rate of fertilisation andimplantation of multiple ova in previously infertile women possiblyas the result of defective function in one of the oviducts.

Alternatively, the sequential release of ova during multipleovulation may reduce the possibility of multiple fertilisation but itmay enhance the possibility of a singleton pregnancy in a subfertilecouple. Moreover, the results from related studies have shown thatthe number of developing follicles is associated with increased

oestrogen production,5 which increases the chance of spermatozoapenetrating through the cervical mucus and so aids conception in apreviously infertile women. Our data are consistent with the

hypothesis that slight overstimulation of the gonads improves theconception rate of previously infertile women, without a markedincrease in the number of multiple pregnancies.

Department of Obstetrics and Gynaecology,King’s College Hospital Medical School,London SE5 8RX

HASSAN N. SALLAMMALCOLM I. WHITEHEADWILLIAM P. COLLINS

HUMAN IMMUNOGLOBULIN FOR CLINICAL USE

SIR,-We should like to comment on your Jan. 15 editorial.First, cold alcohol precipitation is the preferred method of

preparation because it gives an immunoglobulin which does nottransmit hepatitis. The protein is usually 95% or more IgG, with90% a required lower limit. I

Early experience led to the view that it could be given safely onlyby the intramuscular route, and that the product had to be treatedfurther to reduce the frequency and severity of reactions to intra-venous infusions. These reactions are attributed to the high anti-complement activity of immunoglobulin-containing aggregatedprotein,2 though there does not appear to be a simple quantitativerelation between these factors. Modification of IgG by controlledenzymic degradation or by chemical action prevents aggregationand greatly reduces or destroys the effect on complement. Suchtreatments act on the Fc portion of IgG, so that antibody specificityis retained while other properties, including its normal role inactivation of complement, and the catabolic half-life are variablyreduced, thus affecting the frequency of infusions required tomaintain protective antibody levels.Other properties of immunoglobulin preparations may

contribute to reactions associated with infusion or injection.Prekallikrein activator (PKA) is found to a widely varying extent incommercially prepared immunoglobulin.3 There is a similaritybetween the types of reactions reported for plasma protein fraction(U.S. specification), subsequently attributed to batches containinghigh levels of PKA, and to those for immunoglobulin. 3 ’

Unmodified immunoglobulin, retaining fully the integrity andbiological characteristics of native IgG, is an objective for

4. Glass RH. Infertility. In: Yen SSC, Jaffe RB, eds. Reproductive endocrinology.Philadelphia: Saunders, 1978 413-15.

5. Collins WP, Sallam HN, O’Dowd PA, Marinho AO, Branch CM, Campbell S. Simplemethods of monitoring treatment with human gonadotrophins. In Flamigni C,Givens J, eds. The gonadotrophins: Basic science and clinical aspects in females.New York: Academic Press, 1982: 417-27.

1. British pharmacopoeia Vol II. London: British Pharmacopoeia Commission, 1980:854.

2. Barandun S, Kistler P, Jennet F, Isliker H. Intravenous administration of humangamma-globulin. Vox Sang 1962; 7: 157-74.

3. Alving BM, Tankersley DL, Mason BL, Rossi R, Aronson DL, Finlayson JS. Contact-activated factors: contaminants of immunoglobulin preparation with coagulant andvasoactive properties. J Lab Clin Med 1980; 36: 334-46

358

preparative technique. Already there is experience of the intra-venous use of routinely prepared untreated immunoglobulin,diluted in saline and given by slow infusion.4-6 Such a product, freeof preservative and controlled for levels of aggregates, anti-

complement activity, PKA, and kallikrein, is now being preparedfrom large donor pools at the Blood Products Laboratory forintravenous administration, and a trial of its use in hypogamma-globulinaemia will begin shortly at the Clinical Research Centre,Northwick Park Hospital. Other applications, including thetreatment of idiopathic thrombocytopenic purpura, have beeninvestigated elsewhere and this will continue.With regard to specific varicella-zoster immunoglobulin, it may

not be known that sufficient is prepared routinely here to meet thecurrent needs of the Public Health Laboratory Service and theLeukaemia Trials Office.The future clinical applications of IgG may be greatly influenced

by development of hybridoma-derived monoclonal antibodies.7These we would see as providing specificities of a scope far beyondthe possibilities of our present dependence on selected donors; yetnormal immunoglobulin may remain the surest way of providingthe widest range of antibody cover for immune-deficient individualsagainst infections defined and undefined.

Blood Products Laboratory,Elstree,Borehamwood, Herts WD6 3BX

R. S. LANEL. VALLETM. L. KAVANAGH

SIR,-Your Jan. 15 editorial indicates that normal standard IgGmust be modified for intravenous use, mainly because of thepresence of aggregated IgG.! Today, other factors are alsoconsidered relevant. Anti-complementary activity and the presence

PROPERTIES OF STANDARD AND INTRAVENOUS IMMUNOGLOBULIN

*Gel permeation chromatography.tmg protein required to inhibit 1 CH,,, unit (complement required for 50% lysis of 10’sheep red blood cells).method of Alving et al. 1

§ I unit hydrolyses 1’ 8 mmol S-2302 at an initial rate of 1 Nmollmin at pH 7’ 8 and 37°C.

of enzymes from the contact activation system such as prekallikreinactivator and kallikrein are probably the most important2 among themany components that may be involved.3 Therefore it is necessaryto characterise, as fully as possible, those products proposed forintravenous use. You indicate that commercial products are nowavailable, but clinicians should be aware that the quality of these

4. Reed WD, Eddleston ALWF, Cullen H, Williams R, Zuckerman AJ, Peters DK,Williams DG, Maycock W d’A. Infusion of hepatitis B antibodies in antigen-positive active chronic hepatitis. Lancet 1973; ii: 1347—51.

5. Welch AG, McClelland DBL, Watt JG. Some experiences with intravenous

immunoglobulin in Scotland. In: Alving BM, Finlayson JS, eds. Immunoglobulins:characteristics and uses of intravenous preparations (publication no. FDA-80-9005).Washington D.C.: U.S. Government Printing Office, 1979: 195-200.

6. McClelland DBL. Yap PL, Welch AG, Crawford RB. Safety of human

immunoglobulin administered intravenously. XIXth International Society ofHaematology and XVIIth International Society of Blood Transfusion JointCongress (Budapest, 1982): abstr 411.

7. McMichael AJ, Monoclonal antibodies in medicine. In: Nydegger UG, ed. Immuno-hemotherapy. New York: Academic Press, 1981: 195-206.

1. Barundum S, Kistler P, Jeunet F, Isliker H. Intravenous administration of human&ggr;-globulin. Vox Sang 1962; 7: 157-74.

2. Alving BM, Tankersley DL, Rossi F, Aronson DL, Finlayson JS. Contact-activatedfactors: Contaminants of immunoglobulin preparations with coagulant andvasoactive properties. J Lab Clin Med 1980; 96: 334-46.

3. Aronson DL, Finlayson JS. Historical and future therapeutic plasma derivatives. SemThromb Haemost 1979—80; 6: 121-39.

products, including their biological and effector functions, mayvary widely. 4,5In Scotland the standard normal immunoglobulin, prepared here

for intramuscular use, has been administered intravenously to over100 patients with few adverse reactions.6 Nevertheless the need fora higher quality product was recognised and a research and devel-opment programme has been in progress for some time, and aproduct for intravenous use is now being clinically evaluated. Someof the in vitro characteristics of this preparation are shown in thetable, together with similar measurements on our standard product.The intravenous preparation is not significantly more expensive

to manufacture than our standard product. Furthermore, the newmanufacturing procedures have resulted in an increase in

immunoglobulin yield which may be of value in the preparation ofcertain specific immunoglobulins. We are investigating the

application of our process to this area and have prepared humancytomegalovirus immunoglobulin for intravenous use.

Scottish National Blood Transfusion Service,Protein Fractionation Centre,Edinburgh EH17 7QT

ANNE G. WELCHRONALD V. MCINTOSHPETER R. FOSTER

A WEST AFRICAN EPILEPSY FOCUS

SIR,-During some medical-anthropological research in ruralGrand Bassa County in Liberia I came across a serious problem ofepilepsy among the Bassa and Kpelle people.My working definition of epilepsy was: a disease with a regular

appearance of brief lapses of consciousness and/or generalised tonic-clonic convulsions either with or without local onset, occasionallywith biting of the tongue and incontinence.

In districts 3b and 4b of Grand Bassa County I did a survey onselected samples. The total number of people investigated was2733. 134 had epilepsy, according to informants, and 114 of thesepeople were interviewed in detail by me. Within the two districts Idid an in depth study in one smaller geographical unit, the

Whroghbarh clan. The total population in the Whroghbarh clanwas 1673 and 82 individuals had epilepsy, confirmed by me. Theprevalence in both the general survey and the Whroghbarh clan was49 per 1000, which is very high in comparison with other recordedprevalence rates in Africa.The interviewed subjects with epilepsy were physically examined

by doctors, and the diagnosis was based on this examination,together with the medical history, answers to questions about signsand seizures, and observation of absence and grand mal seizures.Diagnosis by EEG was not possible and cardiac, vasovagal, ormetabolic causes could not be strictly excluded.

, Among the epilepsy cases the sex ratio was roughly 1:1. The

epilepsy often manifested around the age of puberty: of the males37% had first had epilepsy at the age of 5-15 and 42% of the femaleswere affected between 10 and 20. I saw not one person who had

epilepsy at the age of 25 or older. According to informants thedisease has prevailed in the area studied for 30 years and may haveincreased during the past five years, an impression confirmed by mydata. Informants mentioned a high death rate among the epilepticsdue to accidents (e.g., burning and drowning), or to fatal seizures.Preventive treatment by traditional healers was ineffective.

Conventional medical care and treatment was not available in thearea studied. People with epilepsy are stigmatised by the

community. The cause of this endemic epilepsy is not known.

J. M Kemperstraat 84 hs,1051 TV Amsterdam, Netherlands CORRY GERRITS

4. Romer J, Morgenthaler JJ, Scherz R, Skvaril F. Characterisation of various

immunoglobulin preparations for intravenous application I: Protein compositionand antibody content. Vox Sang 1982; 42: 62—73.

5. Romer J, Spath PJ, Skvaril F, Nydegger UE. Characterisation of immunoglobulinpreparations for intravenous application II: Complement activation and binding tostaphylococcus protein A. Vox Sang 1982; 42: 74-80.

6. Welch AG, McClelland DBL, Watt JG. Some experiences with intravenous

immunoglobulin in Scotland. In: Alving BM, Finlayson JS, eds. Immunoglobulins:Characteristics and uses of intravenous preparations. Publication (FDA)-80-9005.Washington, D C : US Government Printing Office, 1979: 195-200.