1194
from seizures whereas the doves will advise caution and wait for up to 5 years. In a child with no defined cause for the seizure disorder who has a normal neurological examination and electroencephalogram (EEG), a trial of drug withdrawal can reasonably be contemplated after 2 years. This course of action is all the more important because antiepileptic drug therapy,l1 even with newer agents such as carbamazepine12 and sodium valproate,13 can subtly impair cognition and behaviour. What about an adult in full employment who drives a car and is taking a modest dose of a first-line antiepileptic agent? There are few long-term drug-related side-effects in such patients apart from the increased risk of teratogenesis;14 and drug withdrawal presents a real danger of seizure recurrence, which has physical and psychological implications and inevitably leads to loss of the driving licence. In these circumstances, many patients and doctors will opt for the status quo.
Physicians with an interest in epilepsy have been eagerly awaiting the results of the antiepileptic drug withdrawal trial reported in this issue (p 1175). This trial, coordinated by David Chadwick in Liverpool and funded by the Medical Research Council, is the largest prospective study of antiepileptic drug withdrawal yet undertaken. Patients consenting to randomisation were allocated to slow withdrawal (over 6 months if possible) or to continuation of existing therapy. Both adults and children were included. Recruitment started in February, 1984, and finished on schedule in June, 1988. 125 clinicians from forty centres entered patients. Over 1000 patients accepted randomisation; another 776 were eligible but either declined or their physician was against their entry to the trial. The demographic differences between randomised and non-randomised patients are regrettable but virtually unavoidable-most of the patients who did not consent to randomisation (74%) were unwilling to stop drug therapy, especially if they possessed a driving licence. At the end of 2 years, 78 % of patients remaining on treatment continued free of seizures compared with 59% in whom drug therapy had been slowly withdrawn. Factors increasing the risk of recurrence were more than one antiepileptic drug and a history of tonic-clonic seizures. The latter finding was perhaps unexpected because some previous studies,2-4 but not all,15 had suggested a better outlook for this group. The explanation seems to be the inclusion of some patients with juvenile myoclonic epilepsy, an underdiagnosed syndrome that is usually easy to control and that may recur on drug withdrawal. 16 The
important determinant of a good outcome was the length of the seizure-free period. The prognostic importance of the EEG was not specific enough to be helpful, especially in adults. However, patients with only tonic-clonic seizures, associated with generalised spike and wave on an EEG, had a higher recurrence
most
rate.
The MRC antiepileptic withdrawal study is the first to include a group of patients randomised to continuing therapy. More than 20% of treated patients reported seizure recurrence during the first 2 years of observation. In addition, patients who managed to go 2 years free of seizures after drug withdrawal had a much reduced risk of later relapse. Will the results of this substantial trial bring about improvement in patient care? First, even with a sample of over 1000 patients, specific prognostic factors could not easily be identified and the study provided no new insights in this respect. The trialists intend to develop a statistical program from their data to help predict the risk of seizure recurrence in individual patients. The better outlook reported in children6-9 was borne out by this study. Most patients whose livelihood or lifestyle depends on their being seizure free would, on this evidence, be ill advised to contemplate drug withdrawal. The doves have it. Beghi E, Di Mascio, R, Tognoni G. Drug treatment of epilepsy: outlines, criticism and perspectives. Drugs 1986; 31: 249-65. 2. Annegers JF, Hauser WA, Elverback LR. Remission of seizures and relapse in patients with epilepsy. Epilepsia 1979; 20: 729-37. 3. Wallis WE. Withdrawal of anticonvulsant drugs in seizure-free epileptic patients. Clin Neuropharmacol 1987; 10: 423-33. 4. Pedley TA. Discontinuing antiepileptic drugs. N Engl J Med 1988; 318: 1.
982-84. 5.
Callaghan N, Carrett A, Goggin T. Withdrawal of anticonvulsant drugs in patients free of seizures for two years. N Engl J Med 1988; 318:
942-46. 6. Matricardi M, Brinciotti M, Benedetti P. Outcome of discontinuation of antiepileptic drug therapy in children with epilepsy. Epilepsia 1989; 30: 582-89. 7. Bouma PAD, Peters ACB, Arts RJHM, Stijnen TL, van Rossum J. Discontinuation of antiepileptic therapy: a prospective study in children. J Neurol Neurosurg Psychiatry 1987; 50: 1579-83. 8. Shinnar S, Vining EPG, Mellits ED, et al. Discontinuing antiepileptic medication in children with epilepsy after two years without seizures. a prospective study. N Engl J Med. 1985; 313: 976-80. 9. Arts WFM, Visser LH, Loonen MCB, et al. Follow-up of 146 children with epilepsy after withdrawal of antiepileptic therapy. Epilepsia 1988; 29: 244-50. 10. Chadwick D. The discontinuation of antiepileptic therapy. In: Meldrum BS, Pedley TA, eds. Recent advances in epilepsy 2. Edinburgh: Churchill Livingstone, 1985: 111-24. 11. Hirtz DG, Nelson KB. Cognitive effects of antiepileptic drugs. In: Pedley TA, Meldrum BS, eds. Recent advances in epilepsy 2. Edinburgh: Churchill Livingstone, 1985: 161-81. 12. Gallasi R, Mooreale A, Lorusso S, Rocaccianti G, Lugaresi E, Baruzzi A. Carbamazepine and phenytoin: comparison of cognitive effects in epileptic patients during monotherapy and withdrawal. Arch Neurol
1988; 45: 892-94. 13. Gallasi R, Mooreale A, Lorusso S, Rocaccianti G, Lugaresi E, Baruzzi A. Cognitive effects of valproate. Epilepsy Res 1990; 5: 160-64. 14. Brodie MJ. Management of epilepsy during pregnancy and lactation. Lancet 1990; 336: 426-27. 15. Shafer SQ, Hauser WA, Annegers JF, Klass DW. EEG and other early predictors of epilepsy remission: a community study. Epilepsia 1988; 29: 590-600. 16. Gram L. Epileptic seizures and syndromes. Lancet 1990; 336: 161-63.
Precocious puberty Much has changed lately in our understanding and classification of premature sexual development. It used to be thought that premature sexual maturation of gonadal origin (ie, excluding adrenal disorders) consisted of only two conditions--central precocious
1195
puberty and isolated premature thelarche. Central precocious puberty (often described as gonadotropindependent or idiopathic precocious puberty) is brought about by the premature onset of pulsatile gonadotropin releasing hormone (GnRH) secretion. Consequently the sequence of pubertal development is normal but the advance in epiphyseal maturation eventually compromises adult stature. By contrast, isolated premature thelarche usually starts in girls under the age of two years and the changes are confined to breast development; growth rate is normal and the condition usually resolves spontaneously. The advent of GnRH analogues, used in the suppression of gonadotropin secretion from the pituitary gland,l had two immediate outcomes. It led to an important method of treatment of central precocious puberty, and absence of response indicated that puberty was independent of GnRH secretion. Initial reports of familial testotoxicosis,also described
gonadotropin-independent precocious puberty,33 showed that gonadotropin independence was a common aetiological factor in boys with precocious puberty, and the serum in such cases may contain a testis stimulating factor.4 Central precocious puberty in boys is almost always a serious condition associated with central nervous system space-occupying lesions. Gonadotropin-independent precocious puberty has been described in girls, but only in association with McCune-Albright syndrome,3in which atypical pubertal development is common.5 More is known about the pathophysiology of puberty in girls than in boys because of the use of the non-invasive technique of pelvic ultrasonography.66 as
The clinical classification of premature sexual maturation in girls is not as simple as was once thought—ie, all affected children cannot easily be
placed in the diagnostic categories of central precocious puberty or isolated premature thelarche. Fontoura et all have described clinical subgroups of "central" precocious puberty in girls. More recently, spontaneous gonadotropin secretion1O and ovarian ultrasound findings" led to the suggestion that there is spectrum of conditions of premature sexual maturation with central precocious puberty and isolated premature thelarche at either end, which may also involve gonadotropin-independent precocious puberty. This spectrum may encompass disorders of follicular maturation, with lesions at different stages in the complex process of primordial to mature preovulatory follicle development." In this context, it is interesting that the characteristic periodic changes of breast size in girls with isolated premature thelarche can be correlated with changes in the size of ovarian cystS.6 There is some evidence that variants of
Little is known about the importance of abnormalities of premature sexual maturation with respect to future fertility. Moreover, it is unclear whether the alternative mechanism of gonadotropinindependent precocious puberty is relevant to normal pubertal development. Further investigation into the mechanisms of such variants of premature sexual maturation may enhance our understanding of the onset and maintenance of normal sexual maturation and thereby improve treatment regimens for
infertility. 1.
Crowley WF, Comite F, Vale WW, et al. Therapeutic use of pituitary desensitisation with a long acting LH-RH agonist: a potential new treatment for idiopathic precocious puberty. J Clin Endocrinol Metab 1981; 52: 370-72. SM, Grumbach MM, Kaplan SL. Gonadotropin-
2. Rosenthal
independent familial sexual precocity with premature Leydig and germinal cell maturation (familial testotoxicosis): effects of a potent luteinising hormone-releasing factor agonist and medroxyprogesterone acetate therapy in four cases. J Clin Endocrinol Metab 1983; 57: 571-79. 3. Wierman MB, Beardsworth DE, Mansfield J, et al. Puberty without gonadotropins: a unique mechanism of sexual development. N EnglJ Med 1985; 312: 65-72. 4. Manasco PK, Girton ME, Diggs RL, et al. A novel testis-stimulating factor in familial male precocious puberty. N Engl J Med 1991; 324: 227-31. 5. Foster CM, Feuillan P, Padmanabhan V, et al. Ovarian function in girls with McCune-Albright syndrome. Pediatr Res 1986; 20: 859-63. 6. Stanhope R, Abdulwahid NA, Adams J, Brook CGD. Studies of
gonadotropin pulsatility and pelvic ultrasound distinguish between isolated premature thelarche and central precocious puberty. Eur J Pediatr 1986; 145: 190-94. 7. Schwarz HP, Zuppinger K. Unsustained central sexual precocity in girls. Pediatr Res 1986; 20: 1198 (abstr). 8. Comment on a discussion about abnormal puberty. In: Preece MA, ed. International symposium on growth disorders, San Diego 1987. Princetown: Excerpta Medica, 1987: 84. 9. Fontoura M, Brauner R, Prevot C, Rappaport R. Precocious puberty in girls: early diagnosis of a slowly progressing variant. Arch Dis Child 1989; 63: 1170-76. 10. Pescovitz OH, Hench KD, Barnes KM, Loriaux DL, Cutler GB. Premature thelarche and central precocious puberty: the relationship between clinical presentation and the gonadotropin response to luteinising hormone-releasing hormone. J Clin Endocrinol Metab 1988; 67: 474-79. 11. Stanhope R, Brook CGD. Thelarche variant: a new syndrome of precocious sexual maturation? Acta Endocrinol 1990; 123: 481-86. 12. Vale W, Rivier J, Vaughan J, et al. Purification and characterisation of an FSH releasing protein from porcine ovarian follicular fluid. Nature
1986; 321: 776-79.
a
sexual
maturation
GnRH nocturnal Vale and gonadotropin secretion. 10 have a hormonal mechanism to colleagues12 proposed explain how the gonad may control gonadotropin secretion independently of GnRH. premature
independent,"
despite
are
having However,
Practice imperfect exactitude is the sublimity of the stupid,
the If midwives and obstetricians associated with the Dudley Road Hospital obstetric unit in Birmingham are far from stupid. Perry et aP have investigated the local practice of blood pressure measurement during pregnancy by means of a self-completed questionnaire. 89 % of respondents reported that they usually measured blood pressure with the patient in the sitting position. Nevertheless, 44% regarded the supine position as suitable and 13% approved of the right lateral. Even when available, a large cuff was seldom used for large arms. Respondents were almost equally divided between use of the fourth (point of muffling) or fifth (point of disappearance) phase of Korotkoff sounds for determination of diastolic
from seizures whereas the doves will advise caution and wait for up to 5 years. In a child with no defined cause for the seizure disorder who has a normal neurological examination and electroencephalogram (EEG), a trial of drug withdrawal can reasonably be contemplated after 2 years. This course of action is all the more important because antiepileptic drug therapy,l1 even with newer agents such as carbamazepine12 and sodium valproate,13 can subtly impair cognition and behaviour. What about an adult in full employment who drives a car and is taking a modest dose of a first-line antiepileptic agent? There are few long-term drug-related side-effects in such patients apart from the increased risk of teratogenesis;14 and drug withdrawal presents a real danger of seizure recurrence, which has physical and psychological implications and inevitably leads to loss of the driving licence. In these circumstances, many patients and doctors will opt for the status quo.
Physicians with an interest in epilepsy have been eagerly awaiting the results of the antiepileptic drug withdrawal trial reported in this issue (p 1175). This trial, coordinated by David Chadwick in Liverpool and funded by the Medical Research Council, is the largest prospective study of antiepileptic drug withdrawal yet undertaken. Patients consenting to randomisation were allocated to slow withdrawal (over 6 months if possible) or to continuation of existing therapy. Both adults and children were included. Recruitment started in February, 1984, and finished on schedule in June, 1988. 125 clinicians from forty centres entered patients. Over 1000 patients accepted randomisation; another 776 were eligible but either declined or their physician was against their entry to the trial. The demographic differences between randomised and non-randomised patients are regrettable but virtually unavoidable-most of the patients who did not consent to randomisation (74%) were unwilling to stop drug therapy, especially if they possessed a driving licence. At the end of 2 years, 78 % of patients remaining on treatment continued free of seizures compared with 59% in whom drug therapy had been slowly withdrawn. Factors increasing the risk of recurrence were more than one antiepileptic drug and a history of tonic-clonic seizures. The latter finding was perhaps unexpected because some previous studies,2-4 but not all,15 had suggested a better outlook for this group. The explanation seems to be the inclusion of some patients with juvenile myoclonic epilepsy, an underdiagnosed syndrome that is usually easy to control and that may recur on drug withdrawal. 16 The
important determinant of a good outcome was the length of the seizure-free period. The prognostic importance of the EEG was not specific enough to be helpful, especially in adults. However, patients with only tonic-clonic seizures, associated with generalised spike and wave on an EEG, had a higher recurrence
most
rate.
The MRC antiepileptic withdrawal study is the first to include a group of patients randomised to continuing therapy. More than 20% of treated patients reported seizure recurrence during the first 2 years of observation. In addition, patients who managed to go 2 years free of seizures after drug withdrawal had a much reduced risk of later relapse. Will the results of this substantial trial bring about improvement in patient care? First, even with a sample of over 1000 patients, specific prognostic factors could not easily be identified and the study provided no new insights in this respect. The trialists intend to develop a statistical program from their data to help predict the risk of seizure recurrence in individual patients. The better outlook reported in children6-9 was borne out by this study. Most patients whose livelihood or lifestyle depends on their being seizure free would, on this evidence, be ill advised to contemplate drug withdrawal. The doves have it. Beghi E, Di Mascio, R, Tognoni G. Drug treatment of epilepsy: outlines, criticism and perspectives. Drugs 1986; 31: 249-65. 2. Annegers JF, Hauser WA, Elverback LR. Remission of seizures and relapse in patients with epilepsy. Epilepsia 1979; 20: 729-37. 3. Wallis WE. Withdrawal of anticonvulsant drugs in seizure-free epileptic patients. Clin Neuropharmacol 1987; 10: 423-33. 4. Pedley TA. Discontinuing antiepileptic drugs. N Engl J Med 1988; 318: 1.
982-84. 5.
Callaghan N, Carrett A, Goggin T. Withdrawal of anticonvulsant drugs in patients free of seizures for two years. N Engl J Med 1988; 318:
942-46. 6. Matricardi M, Brinciotti M, Benedetti P. Outcome of discontinuation of antiepileptic drug therapy in children with epilepsy. Epilepsia 1989; 30: 582-89. 7. Bouma PAD, Peters ACB, Arts RJHM, Stijnen TL, van Rossum J. Discontinuation of antiepileptic therapy: a prospective study in children. J Neurol Neurosurg Psychiatry 1987; 50: 1579-83. 8. Shinnar S, Vining EPG, Mellits ED, et al. Discontinuing antiepileptic medication in children with epilepsy after two years without seizures. a prospective study. N Engl J Med. 1985; 313: 976-80. 9. Arts WFM, Visser LH, Loonen MCB, et al. Follow-up of 146 children with epilepsy after withdrawal of antiepileptic therapy. Epilepsia 1988; 29: 244-50. 10. Chadwick D. The discontinuation of antiepileptic therapy. In: Meldrum BS, Pedley TA, eds. Recent advances in epilepsy 2. Edinburgh: Churchill Livingstone, 1985: 111-24. 11. Hirtz DG, Nelson KB. Cognitive effects of antiepileptic drugs. In: Pedley TA, Meldrum BS, eds. Recent advances in epilepsy 2. Edinburgh: Churchill Livingstone, 1985: 161-81. 12. Gallasi R, Mooreale A, Lorusso S, Rocaccianti G, Lugaresi E, Baruzzi A. Carbamazepine and phenytoin: comparison of cognitive effects in epileptic patients during monotherapy and withdrawal. Arch Neurol
1988; 45: 892-94. 13. Gallasi R, Mooreale A, Lorusso S, Rocaccianti G, Lugaresi E, Baruzzi A. Cognitive effects of valproate. Epilepsy Res 1990; 5: 160-64. 14. Brodie MJ. Management of epilepsy during pregnancy and lactation. Lancet 1990; 336: 426-27. 15. Shafer SQ, Hauser WA, Annegers JF, Klass DW. EEG and other early predictors of epilepsy remission: a community study. Epilepsia 1988; 29: 590-600. 16. Gram L. Epileptic seizures and syndromes. Lancet 1990; 336: 161-63.
Precocious puberty Much has changed lately in our understanding and classification of premature sexual development. It used to be thought that premature sexual maturation of gonadal origin (ie, excluding adrenal disorders) consisted of only two conditions--central precocious
1195
puberty and isolated premature thelarche. Central precocious puberty (often described as gonadotropindependent or idiopathic precocious puberty) is brought about by the premature onset of pulsatile gonadotropin releasing hormone (GnRH) secretion. Consequently the sequence of pubertal development is normal but the advance in epiphyseal maturation eventually compromises adult stature. By contrast, isolated premature thelarche usually starts in girls under the age of two years and the changes are confined to breast development; growth rate is normal and the condition usually resolves spontaneously. The advent of GnRH analogues, used in the suppression of gonadotropin secretion from the pituitary gland,l had two immediate outcomes. It led to an important method of treatment of central precocious puberty, and absence of response indicated that puberty was independent of GnRH secretion. Initial reports of familial testotoxicosis,also described
gonadotropin-independent precocious puberty,33 showed that gonadotropin independence was a common aetiological factor in boys with precocious puberty, and the serum in such cases may contain a testis stimulating factor.4 Central precocious puberty in boys is almost always a serious condition associated with central nervous system space-occupying lesions. Gonadotropin-independent precocious puberty has been described in girls, but only in association with McCune-Albright syndrome,3in which atypical pubertal development is common.5 More is known about the pathophysiology of puberty in girls than in boys because of the use of the non-invasive technique of pelvic ultrasonography.66 as
The clinical classification of premature sexual maturation in girls is not as simple as was once thought—ie, all affected children cannot easily be
placed in the diagnostic categories of central precocious puberty or isolated premature thelarche. Fontoura et all have described clinical subgroups of "central" precocious puberty in girls. More recently, spontaneous gonadotropin secretion1O and ovarian ultrasound findings" led to the suggestion that there is spectrum of conditions of premature sexual maturation with central precocious puberty and isolated premature thelarche at either end, which may also involve gonadotropin-independent precocious puberty. This spectrum may encompass disorders of follicular maturation, with lesions at different stages in the complex process of primordial to mature preovulatory follicle development." In this context, it is interesting that the characteristic periodic changes of breast size in girls with isolated premature thelarche can be correlated with changes in the size of ovarian cystS.6 There is some evidence that variants of
Little is known about the importance of abnormalities of premature sexual maturation with respect to future fertility. Moreover, it is unclear whether the alternative mechanism of gonadotropinindependent precocious puberty is relevant to normal pubertal development. Further investigation into the mechanisms of such variants of premature sexual maturation may enhance our understanding of the onset and maintenance of normal sexual maturation and thereby improve treatment regimens for
infertility. 1.
Crowley WF, Comite F, Vale WW, et al. Therapeutic use of pituitary desensitisation with a long acting LH-RH agonist: a potential new treatment for idiopathic precocious puberty. J Clin Endocrinol Metab 1981; 52: 370-72. SM, Grumbach MM, Kaplan SL. Gonadotropin-
2. Rosenthal
independent familial sexual precocity with premature Leydig and germinal cell maturation (familial testotoxicosis): effects of a potent luteinising hormone-releasing factor agonist and medroxyprogesterone acetate therapy in four cases. J Clin Endocrinol Metab 1983; 57: 571-79. 3. Wierman MB, Beardsworth DE, Mansfield J, et al. Puberty without gonadotropins: a unique mechanism of sexual development. N EnglJ Med 1985; 312: 65-72. 4. Manasco PK, Girton ME, Diggs RL, et al. A novel testis-stimulating factor in familial male precocious puberty. N Engl J Med 1991; 324: 227-31. 5. Foster CM, Feuillan P, Padmanabhan V, et al. Ovarian function in girls with McCune-Albright syndrome. Pediatr Res 1986; 20: 859-63. 6. Stanhope R, Abdulwahid NA, Adams J, Brook CGD. Studies of
gonadotropin pulsatility and pelvic ultrasound distinguish between isolated premature thelarche and central precocious puberty. Eur J Pediatr 1986; 145: 190-94. 7. Schwarz HP, Zuppinger K. Unsustained central sexual precocity in girls. Pediatr Res 1986; 20: 1198 (abstr). 8. Comment on a discussion about abnormal puberty. In: Preece MA, ed. International symposium on growth disorders, San Diego 1987. Princetown: Excerpta Medica, 1987: 84. 9. Fontoura M, Brauner R, Prevot C, Rappaport R. Precocious puberty in girls: early diagnosis of a slowly progressing variant. Arch Dis Child 1989; 63: 1170-76. 10. Pescovitz OH, Hench KD, Barnes KM, Loriaux DL, Cutler GB. Premature thelarche and central precocious puberty: the relationship between clinical presentation and the gonadotropin response to luteinising hormone-releasing hormone. J Clin Endocrinol Metab 1988; 67: 474-79. 11. Stanhope R, Brook CGD. Thelarche variant: a new syndrome of precocious sexual maturation? Acta Endocrinol 1990; 123: 481-86. 12. Vale W, Rivier J, Vaughan J, et al. Purification and characterisation of an FSH releasing protein from porcine ovarian follicular fluid. Nature
1986; 321: 776-79.
a
sexual
maturation
GnRH nocturnal Vale and gonadotropin secretion. 10 have a hormonal mechanism to colleagues12 proposed explain how the gonad may control gonadotropin secretion independently of GnRH. premature
independent,"
despite
are
having However,
Practice imperfect exactitude is the sublimity of the stupid,
the If midwives and obstetricians associated with the Dudley Road Hospital obstetric unit in Birmingham are far from stupid. Perry et aP have investigated the local practice of blood pressure measurement during pregnancy by means of a self-completed questionnaire. 89 % of respondents reported that they usually measured blood pressure with the patient in the sitting position. Nevertheless, 44% regarded the supine position as suitable and 13% approved of the right lateral. Even when available, a large cuff was seldom used for large arms. Respondents were almost equally divided between use of the fourth (point of muffling) or fifth (point of disappearance) phase of Korotkoff sounds for determination of diastolic
