Neurology India Medknow Publications on behalf of the Neurological Society of India ISSN: 0028-3886 EISSN: 1998-4022 Vol. 50, Num. 1, 2002, pp. 106-107

Neurology India, Vol. 50, No. 1, March, 2002, pp. 106-107

Preliminary Observations on Valproate and Cystic Ovaries : Letter to Editor

A. Chakravarty

Division of Neurology, Vivekananda Institute of Medical Sciences, Calcutta, India.

Code Number: ni02030

Women with epilepsy continue to pose special therapeutic problems and dilemmas to their physicians. The latest is the scare about development of polycystic ovarian disease (PCOD) with valproate.¹ The clinical features of PCOD include oligoamenorrhea, infertility, centripetal obesity, hirsutism and raised plasma testosterone level along with bilateral ovarian enlargement and multiple cysts. Recent reports suggested on increased incidence of PCOD amongst women on valproate for epilepsy.^2-9 The author's personal experience with this condition and a critical analysis of the problems at hand is presented.

Between January and February 2000, 20 consecutive young women with epilepsy, attending the author's clinic, who had been on valproate monotherapy for more than two years were advised to have pelvic ultrasound examination. Of these, 14 patients complied. The USG examinations were performed by two experienced ultrasonologists and the results were cross checked. Clinical and EEG diagnoses of patients included : typical absence seizure (1), juvenile myoclonic epilepsy (JME) (7) and idiopathic generalised tonic clonic seizures (IGTCS) (6). All patients were on valproate monotherapy (dosage 600- 1200 mg) for over two years with nearly 100% seizure control. 13 patients were in the age range 16-20 years. Only one young girl was aged 5.5 years.

The USG findings in the 14 patients showed normal ovaries in six patients. Three patients had enlarged ovaries with bilateral 6-8 mm cysts (PCOD). Mild ovarian enlargement (< 6 mm) cysts was seen in 2 cases (probable PCOD). Three patients had normal size ovaries with tiny cysts (<4 mm) bilaterally (possible early PCOD).

The present report is of a preliminary nature based on observations on a relatively small number of patients. It was felt that the pros and cons of such serial screening need to be discussed and views exchanged with professional colleagues across the country, before pursuing further work in this field. Hence the need for this early communication.

Five out of 14 subjects studied had definite/probable PCOD (about 35%) and a further 3 had USG evidence of polycystic changes without any clinical stigmata of PCOD. The latter group may include some follicular ovarian cysts but these are usually unilateral and would be highly unlikely in a pre-pubertal girl aged only 5.5 years. Conversely, these may well represent early PCOD changes in ovaries before overt clinical disease manifests. Including all, more than 50% of subjects had cystic changes in ovaries while continuing on valproate therapy. As mentioned earlier, the results must be interpreted with extreme caution and implications carefully judged.

PCOD is not a very uncommon disease but we are unaware of its exact incidence in our population; nor are we aware how often cystic changes in ovaries may be detected in young women in the population in routine USG screen (preferebly by vaginal USG) is undertaken. In the west, the incidence of PCOD has been quoted to be around 19% amongst healthy women.¹⁰ PCOD is now thought to be a primary hypothalamic disease with dysregulated LH secretion. Such type of abnormal LH pulse frequencies, of course, has been described in drug free women with epilepsy and may cause anovulatory cycles. Hormonal effects of valproate have recently been discussed and may be implicated in the pathogenesis of PCOD.⁴ Dysregulated insulin release may cause obesity and lipid abnormalities in some such individuals. Judging simply by the frequency of occurrence (64% PCOD in the series of Isojarvi et al,³ over 50% abnormal USG in the present series), the issue of association of valproate and cystic ovaries, seems to be a real one and would call for reviews of management strategies in women with epilepsy.

References

1. Isojarvi JI, Laatikainen TJ, Pakarinen AJ et al. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med 1993; 329 : 1383-1388.
2. Popovic V, Spremovic S : The effect of sodium valproate on luteinizing hormonal secretion in women with polycystic ovary disease. J Endocrinol Invest 1995; 18 : 104-108.
3. Isojarvi JI, Laatikainen TJ, Knip M et al. Obesity and endocrine disorders in women taking valproate for epilepsy. Ann Neurol 1996; 39 : 579-584.
4. Garland EJ, Behr R : Hormonal effects of valproic acid? J Am Acad Child Adolesc Psychiatry 1996; 35 : 1424-1425.
5. Murialdo G, Galimberti CA, Women with epilepsy on antiepileptic therapy. J Endocrinal Invest 1997; 9 : 519-526.
6. Sharma S, Jacobs HS : Polycystic ovary syndrome associated with treatment with anticonvulsant sodium valproate. Curr Opion Obstet Gynecol1997; 6 : 391-392.
7. Irwin M, Masland P : Valproate and polycystic ovaries. J Am Acad Child Adolesc Psychiatry1998; 1 : 9-10.
8. Eberle AJ : Valproate and polycystic ovaries. J Am Acad Child Adolesc Psychiatry1998; 10 : 1009.
9. Johnston HF : More on valproate and polycystic ovaries. J Am Acad Child Adolesc Psychiatry1999; 4 : 354.
10. Franks S : Polycystic ovary syndrome. N Engl J Med 1995; 333 : 853-861.

Editor's note : The answer to the problem lies in follow up of patients, regular ultrasound scans, before and after start of valproate in women, along with hormonal studies and ultrasound of epileptic females on other anti convulsants. The editor is aware of two such detalied planned studies being carried out in India at present.

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