1129

the T.S.H. response to T.R.H.,’ whereas bromocriptine lowersthe raised T.S.H. found in hypothyroid patients6 but does notinfluence T.S.H. in normal people.’ We have examined theT.S.H. response to T.R.H. stimulation in nine severe postence-phalitic Parkinson’s disease patients before and after threemonths of bromocriptine therapy (mean dosage 45 mg daily).The pretreatment T.S.H. was normal. Although the T.S.H. res-ponse to T.R.H. after bromocriptine treatment suggested a par-tial suppression, this was not statistically significant. The nor-mal thyroid function in parkinsonism and the negligible effectof bromocriptine on T.S.H. secretion suggest that direct dopa-minergic mechanisms within the hypothalamus and pituitarydo not greatly influence the regulation of T.S.H. release andthat the effects of levodopa and dopamine probably involve in-termediate mechanisms.3

Departments of Endocrinology and Neurology,University College Hospital,London WC1E 6AU

K. M. SHAW

A. J. LEESG. M. STERN

HYPOTHYROIDISM FOLLOWED BYHYPERTHYRODDISM

SiR,—The case described by Dr Turner and his colleagues(Aug. 20, p. 410) shows that hyperthyroidism can recur afterl2SI-induced hypothyroidism. A confirmed primary hypothyr-oidism,is usually permanent, but progression to thyrotoxicosishas been reportedl.2 and we have seen two such cases.

Case 1

A 38-year-old man had bilateral proptosis in March, 1975.Serum-thyroxine (T4) was 2-9 g/dl (normal 4-5-10), resin-T3test 0.72 (normal 0-80-1-25), serum thyroid-stimulating hor-mone (T.S.H.). 49 U/ml (normal <2), and long-acting thyroidstimulator (L.A.T.S.) 1-7 units (normal <1-5). A positive reac-tion for thyroid microsomal and thyroglobulin antibodies (titre1/250) was recorded. He had no goitre and was clinically euth-yroid. L-thyroxine (150 g daily) and prednisone (30-10 mgdaily) were prescribed but 4 months later he presented withsymptoms of hyperthyroidism: T4 13 {g/dl, T3 (radioim-munoassay) 311 ng/dl (normal 106-182), resin-T3 test 1.25,r.S.H. <0-2 U/ml. L-thyroxine was withdrawn and 2 monthslater he was clinically and biochemically euthyroid (T 7-0 0g/dl, T3 186 ng/dl). 4 months later and 1 month after predni-sone was stopped he again had symptoms of thyrotoxicosis(tachycardia, weight loss, nervousness) and the followingserum values: T4 9 g/dl, T3 228 ng/dl, resin-T3 test 0-9, T.s.H.<0.2 U/ml. His clinical condition and biochemical valueswere unchanged 1 month later, and propylthiouracil wasstarted. He improved and has remained euthyroid on this

regimen. His exophthalmos has improved from a Hertel mea-sure of 26-27 mm (104) to 24-24 mm (104).

Case 2

A 42-year-old woman with a history of chronic pyeloneph-ritis since 1958 (serum-creatinine 272 &micro;mol/l) presented in1972 with severe hyperthyroidism with diffuse goitre but noexophthalmos. Basal metabolic rate 168%, T4 19 p.g/dl, T3 469ng/dl, resin-T3 test 1-43. No thyroid antibodies. L.A.T.S. notmeasured. She received propylthiouracil and became euthyr-oid ; a subtotal thyroidectomy was done in September, 1973.The microscopic diagnosis was colloid goitre with Graves’ dis-ease. 3 months after the operation she presented with clinically

5. Cooper, D. S., Jacobs, L. S. ibid. 1977, 44, 404.6. Miyai, K., Onishi, T., Hosokawa, M., Ishibashi, K., Kumahara, Y. ibid.

1974, 39, 391.7. Fluckiger, E. in Pharmacological and Clinical Aspects of Bromocriptine

(edited by R. I. Bayliss, P. Turner, and W. P. Maclay); p. 12. M.C.S.Consultants, Tunbridge Wells, 1976.

1. Gavras, I., Thomson, J. A. Acta endocr. 1972, 69, 41.2. Hochstein, M. A., Nair, N., Nevins, M. J. Am. med. Ass. 1972, 20, 2222.

gross hypothyroidism. T4 4.4 &micro;g/dl, T.s.H. 88 p.U/ml.-L-thyrox-ine (200 p.g daily) was started and she became euthyroid. 6months later she was clinically and biochemically hyperthyroid(T4 15 p.g/dl, resin-T3 test 1.44). L-thyroxine was withdrawn,but after 3 months she was still hyperthyroid (T4 11 g/dl T3 3268 ng/dl, resin-T3 test 1.24). Propylthiouracil therapy was re-established and she has remained euthyroid on this treatment.The presentation of case 1 with hypothyroidism and raised

thyroid autoantibodies but no goitre indicates that he mighthave had atrophic autoimmune thyroiditis. The connectionbetween autoimmune thyroiditis and Graves’ disease is well

known,3.4 but thyrotoxicosis rarely develops after hypothyr-oidism.2 That hypothyroidism after thyroidectomy can be tem-porary has been reported by Toft et al., but none of theircases seem to have proceeded to hyperthyroidism. Our case 2suggests that this can happen. The development of hyperthyr-oidism must be kept in mind when following up patients whoare hypothyroid after autoimmune thyroiditis or thyroidec-toms

Department of Internal Medicineand Endocrinology,

Herlev Hospital,Copenhagen, Denmark.

H. PERRILD

J. M&Oslash;LHOLM HANSEN

HYPERTHYROIDISM AND A PARATHYROIDADENOMA COMPLICATING LITHIUM TREATMENT

SiR,&mdash;The thyroid and parathyroid glands are embryologi-cally closely related, and both can be affected by lithium. Com-pensatory changes usually allow normal secretion, and the10% of cases who have hypothyroidism presumably had pre-existing thyroiditis.’ The drug interferes with thyroid secre-tion, and more iodine collects in the gland.6 This may be why10 patients have had hyperthyroidism." They also probablyhad previous thyroid disease, reactivated by the drug. A simi-lar immune process may have caused the parathyroidadenomas found in 5 lithium-treated cases.9,10 This complica-tion was almost certainly more than fortuitous, because 14 outof 96 other treated cases had biochemical hyperparathy-roidism 1’ Hyperparathyroidism is at first asymptomatic, and20% of cases have shown thyroid abnormalities!’Although 33cases of hyperthyroidism have been reported with parathyroidhypersecretion, no reason was found for the association.’3,’4Hypersecretion, and sometimes later gland failure, occurs insarcoidosis, when the granulomas infiltrate the thyroid orparathyroid glands. 15-17 The infrequent endocrinopathies seenin lithium-treated cases, apparently arise from an earlier andsimilar immune process. The patient described below had bothcomplications, and hypermagnesxmia.A woman aged thirty-nine had electroconvulsant treatment

(E.C.T.) for depression in 1968. A year later, she started lithiumtreatment. Her weight fell after five years’ treatment and herserum-thyroxine (T 4) was 201 mmol/1. Her hands became tre-mulous and she showed lid-lag in June, 1975, but she had nogoitre or circulating antibodies. Her serum-T4 was 210

3. Anderson, J. R., Buchanan, V. W., Goudie, R. B. (editors) Autoimmunity;p. 217. Springfield, Illinois, 1967.

4. Doniach, D., Roitt, I. in Clinical Aspects of Immunology (edited by P. G. H.Gell, R. R. A Coombs, and P. J. Lachmann); p. 1355. Oxford, 1975.

5. Toft, A. D., Irvine, W. J., McIntosh, D., Seth, J., Cameron, E. H. D., Lid-gard, G. P. Lancet, 1976, ii, 817.

6. Rosser, R. Br. J. Psychiat. 1976, 128, 61.7. Turner, J. G., Brownlie, B. E. W. Lancet, 1976, ii, 904.8. Merry, J. Br. med. J. 1977, ii, 765.9. Garfinkel, P. E., Ezrin, C., Stancer, H. C. Lancet, 1973, ii, 332.

10. Christenssen, T. A. T. ibid. 1976, ii, 144.11. Christiansen, C., Baastrup, P. C., Transb&oslash;l, I. ibid. p. 969.12. Goldsmith, R. E., Gall, E. A., Altemeier, W. A. Ann. intern. Med. 1971, 73,

395.13. Parfitt, A. M., Dent, C. E. Q. Jl Med. 1970, 30, 171.14. Richards, A. J. Postgrad. J. Med. 1970, 46, 440.15. Karlish, A. J., MacGregor, G. A. Lancet, 1970, ii, 330.16. MacGregor, G. A. Br. med. J. 1977, i, 233.17. MacGregor, G. A. Lancet, 1969, i, 730.

1130

mmol/1, and the serum calcium, phosphate, and magnesiumwere, respectively, 3.07, 0-88, and 0-85 mmol/1. The lithiumwas discontinued and carbimazole was prescribed. Althoughher symptoms improved, the hyperthyroidism recurred. 60 mgcarbimazole daily was then given for three weeks, and in

November, 1975, she was euthyroid. She showed no long-act-ing thyroid stimulator (L.A.T.S.) or L.A.T.S. protector, but shewas still hypercalcxmic. A selenomethionine scan suggested aparathyroid adenoma in the left inferior gland, but her im-munoreactive parathyroid hormone was normal. No renalstones or evidence of osteitis fibrosa were found radiologically,but a single parathyroid adenoma was excised from the rightinferior gland (Mr P. S. Boulter). Her serum calcium, phos-phate, and magnesium returned to normal, and the carbi-mazole was discontinued in September, 1976. She remains

euthyroid, but she required more E.c.T. in April, 1977.I thank Dr L. S. Dirmikis for the L.A.T.s. assay, Dr J. L. H. O’Rior-

dan for the parathyroid assay, and Dr J. Coleman for referring thiscase.

St Luke’s Hospital,Guildford, Surrey GU1 3NT GERALD A. MACGREGOR

TOXICITY OF PERTUSSIS VACCINE

SIR,-The Ombudsman’s report, summarised in your Nov.5 issue (p. 990), concludes that information about adversereactions to pertussis vaccine was not conveyed to parents butthat doctors, nurses, and health authorities were and are fullyinformed. Well informed about what? The report gives no indi-cation of what information about the nature, frequency, or im-plications of the adverse reactions was obtained or disclosed.The fact that an injection of pertussis vaccine may be fol-

lowed by screaming fits, convulsions, apnaeic attacks, andother alarming symptoms has been on record for some time.1,2A temporal relationship is not necessarily a causal one, so someexperts prefer to regard these symptoms as fortuitous: the babywho has a convulsion, screams all night, or stops breathing afew hours after an injection was going to do so anyway,because of some pre-existing disturbance, recognised or unre-cognised.3 And it has to be acknowledged that, if 3 in a 1000infants have convulsions independently of vaccination duringthe first year of life, the observed frequency (1:2500 to

1:10 000) of convulsions immediately after vaccination in thatage-group4-6 might be attributable to chance.The position is entirely different if similar symptoms or

aggravated symptoms recur after a second or third injection.The chance of recurrence, independently but within a day ortwo of injection, is very much lower, perhaps as low as one inseveral millions. In recurrences after vaccination the patternsobserved (repeated convulsions, screaming like nothing else,loss of responsiveness to parents, paralytic or other motor dis-orders) suggest either a sudden intensification of a processalready started at the time of the earlier injection or else aunique predisposition in a given child to react adversely tovaccine.

I have records of 265 children who were reported to me ashaving reacted in this fashion to one or more injections of per-tussis vaccine. In 57 of these children, the main disturbancefollowed a second or subsequent injection. All but 2 are nowmentally defective. In at least 70 there was evidence of predis-position to neurological disturbance in the form of a familyhistory, birth trauma, or genetic or coincident disease, all ofwhich are accepted contraindications to giving pertussis vac-cine. In all cases, medical information has been obtained inde-

pendently of any submissions by their parents, and I am grate-

1. Madsen, T. J. Am med. Ass. 1933, 101, 187.2. Miller, H. G., Stanton, J. B. Q. Jl Med. 1954, 23, 1.3. Prensky, A. L. Dev. Med. Child Neurol. 1974, 16, 539.4. Str&ouml;m, J. Br. med. J. 1967, iv, 320.5. Ehrengut, W. Dt. med. Wschr. 1974, 99, 2273.6. Lenard, H. G., Fest, U., Scholtz, W. Mschr. Kinderheilk, 1977, 125, 660.

ful to many doctors all over the U.K. for patiently andcarefully supplying me with detailed information from theirrecords. In the past I have attempted to convey details of someof these cases to the Joint Committee on Immunisation andVaccination of the D.H.S.S. More recently, by agreement withSir Eric Scowen, the entire file of about 600 cases now heldin the computer of the University of Glasgow has been madeavailable to the Committee on the Safety of Medicines toenable them to prepare a confidential report for the Secretaryof State.

Between 1950 and 1973 I was on the whole convinced, asmany people still are, that pertussis vaccine was reasonably,safe and effective. I was aware of reports to the contrary butdiscounted these because of "information" received from theD.H.S.S. and other health authorities in the U.K. and else-where. No "information" to the contrary reached me.

Department of Community Medicine,University of Glasgow,Ruchill Hospital,Glasgow G20 9NB GORDON T. STEWART

GROWTH-HORMONE DEFICIENCY INCONGENITAL RUBELLA

SiR,-Dr Preece and his colleagues (Oct. 22, p. 842) havemade a significant contribution to helping us understand theextensive disorders that may be associated with congenitalrubella. They report two cases of associated congenital rubellaand alleged idiopathic growth-hormone deficiency.

There is good evidence for growth-hormone deficiency in thefirst patient, and this report should make clinicians aware thatcongenital rubella and idiopathic growth-hormone deficiencymay be associated. However, in the second case the diagnosisof growth-hormone deficiency is less certain. The patient hada peak serum-growth-hormone of 10-4 mi.u./1, 90 min after in-sulin. This response is compatible with a normal response inmany laboratories. To prove growth-hormone deficiency inthis patient, additional tests (preferably with the addition ofpropranolol) should have been done. Perhaps further data willbe obtained, so that these two patients will stimulate investiga-tion of growth-hormone deficiency in other children with con-genital rubella and growth retardation

Department of Pediatrics,University of Virginia

School of Medicine,Charlottesville, Virginia 22901, U.S.A. ROBERT M. BLIZZARD

RUBELLA VACCINE (HPV-77 DE5 STRAIN) FAILS TOSUSTAIN ANTIBODY TITRES

SIR,-In our study of the persistence of immunity aftermeasles, mumps, rubella, and oral poliovirus vaccination wehave become concerned by the apparently high failure-rate ofrubella vaccine. From children previously vaccinated at onesuburban Minneapolis private clinic blood-samples were col-lected at a routine paediatric examination. Of the 119 vaccineestested to date, 40 (33.6%) lacked detectable rubella immunity,having rubella hxmagglutination-inhibiting (H.I.) titres <8. In

contrast, 13 children (10-9%) lacked measles antibodies (H.I.titres <2) and all had neutralising antibodies to poliovirustypes 1-3.The rubella vaccine used was HPV-77 DEs; 69 children had

received it in combination with measles and mumps, 13 were

given it with mumps vaccine, and 37 received the rubella vac-cine alone. The median age at vaccination was 16 months

(mode, 1 year) and the mean period from vaccination to serolo-gical testing was 5 years (median, 4-5 years). 26 (46%) of 56children vaccinated when less than 15 months old had rubellaH.I. titres <8, whereas 14 (22%) of 63 children vaccinated at15 months or older were seronegative. These differences arestatistically significant (corrected chi-square 7-2, P<0.01).