Gender and epilepsy : a Clinician's experience.
Women in India are greatly discriminated against if they happen to have epilepsy. Engagements are often cancelled. The parents of epileptic girls have to give heavy dowry at the time of marriage, even if the boy is handicapped. As a result, many girls do not disclose their problem before marriage. They take the medicine secretly. Epilepsy may sometimes produce problems during pregnancy and delivery, otherwise epileptic women on anti epileptic drugs, can lead a normal married, professional and social life. The stigma of epilepsy should be done away with, as we enter the 21st century.
It has been estimated that 40 million people of the world have epilepsy. The population of India has crossed the 1000 million (100 crore) mark. Prevalence of epilepsy has been estimated from various centres to be about 5.5/1000-7.8/1000 which means there are 5.5 to 7.8 million persons with epilepsy in India, which is about 1/8th of the world population. The Figures in India are not accurate due to the stigma still associated with this disorder. Concealment is the norm, both in urban and rural population. My experience has been mainly from Uttar Pradesh, the most populous state in India with a population of about over 200 million (20 crores).
Gender and Epilepsy
The effects of epilepsy on men and women have been
Presidential oration delivered at Annual Conferences of Indian Epilepsy Association, December 1999, at Hyderabad, India.
observed by clinicians world-wide. Both men and women suffer from epilepsy and both get treated with anti epileptic drugs (AEDs.) The illness in most of the patients is well controlled. There are, however, several features peculiar to women with epilepsy which need special attention, special care and empathy. Both men and women face several social difficulties due to the public image of a person with seizures. Fear, horror, superstition, prejudice and erroneous beliefs hold true even today. This is more so in the case of a girl/woman. Even enlightened educated persons including doctors, whatever they may profess publically, do not accept an epileptic girl as a bride in their own households. This is due to our failure to convince people that epilepsy is like any other illness such as hypertension, diabetes, asthma or heart disease.
The male:female ratio of epileptic patients attending the clinics is also important. Fewer women come to the epilepsy clinics than men. The urban group prefers private consultations. The rural group travels long distances to seek cheap and free medical help at medical colleges, only when they are desperate. Before coming to neurologists, they have already done their rounds with 'ojhas' (exorcists), 'poojas', 'herbal', 'Ayurvedic', 'Unani' and 'Homoeopathy' drugs. Allopathic doctor is consulted as a last resort. They are fearful and afraid, and often do not disclose the real complaint in their daughter, son or spouse. It is only when leading questions are asked, that the diagnosis is made and 'eyewitness' accounts of 'fainting episodes' are described.
The problems with females relate to menstruation, sexual relations, marriage, pregnancy, breast feeding, religious fasts, menopause and profession i.e. housework or cooking. The problems with men are more regarding work aspects i.e. type of jobs, night shift, management, travel, driving and also sexuality, behaviour and cognition. It is well known that there are interactions between cerebral excitability and reproductive hormone secretions. There is an association between epilepsy and endocrine dysfunction. Oestrogen lowers thresholds for seizures whereas progesterone increases it. In men, it has been noticed that there is a decrease in biologically active testosterone. AEDs also reduce biologically active testosterone but control of seizure is not affected as such.
Menstruation and Epilepsy
In women, the term 'catamenial epilepsy' was coined due to seizures occurring at menarche, during or just before menstruation. It was observed that about 1/4th-3/4th of women have an increase in seizures during the premenstrual period. An increase in seizures also occurs during the period prior to ovulation on day 10-14. The data from records of adolescent girls indicate that this was true in 1/3rd of female patients seen at K.G. Medical College, Lucknow. Catamenial epilepsy (in girls immediately or during their menstrual period) was observed in 22% of our cases. This has been attributed to hormonal imbalance, oestrogen/progesterone ratio, fluid retention, electrolyte imbalance, decrease in AED and increase in stress due to premenstrual tension. Clomiphene has been used in such females with anovulatory cycles. We controlled these type of seizures by adjusting AED dosage and adding acetazolamide or clobazam and pyridoxine, with good results.
Pregnancy and Epilepsy
One of the most important aspects of a normal life and aspirations of young men and women is to have a family and children. Yet, persons with epilepsy were denied this fundamental right by prejudiced legislation enacted in this country as late as 1976. It is due to the herculean efforts of Dr. Mani, Dr. B. Ramamurthi and Dr. G. Arjundas, that a public interest litigation was filed in the Supreme court. A bill against discrimination of persons with epilepsy and separating it from mental diseases has been passed by the Parliament. Even more barbaric was the forced sterilization of persons with epilepsy along with Jews and gypsies etc. in Hitler's Germany in the name of eugenics and cleansing of race. In USA, persons with epilepsy in South Carolina, USA, were sterilized and prohibited to marry. Fortunately the situation has changed during the last few decades, and women with epilepsy have become pregnant and borne healthy babies. About 0.4%-0.6% of all children in the world today have been born to women with epilepsy. Nevertheless, it is important to remember that women with epilepsy have more obstetrical complications than women without epilepsy. Pregnancy itself can alter the pharmakokinetics of AEDs. Other important issues include breast feeding (if the mother is on AED), the risk of birth defects in the child and risk of inheriting epilepsy from mother or father.,, The first trimester is the most important period of foetal life when human teratogens can cause problems. This is true not only for AEDs, but also for several other drugs like isotretinoin (for acne), alcohol, non-steroidal estrogen like diethyl stilboesterol (DES), radiation, exposure to xenobiotics, heavy metals, agrochemical agents and drugs used for many infections and psychiatric or mood disorders, which are known to cause similar foetal malformations. The prevention of these problems is possible by (a) good obstetric and antenatal care (b) folic acid supplementation (5mg/day) (c) ultrasound in the 4th or 5th month to ensure that the foetus does not have a birth defect (d) pantothenic acid supplement (e) amniocentesis at 16 weeks for alpha foetoprotein., (f) increase of dose if drug level is reduced as compared to prior control level. The drop in the levels of AED during pregnancy has been attributed variously to reduction of gastric tone and motility, delay in stomach emptying, morning sickness especially in first trimester, and a change in the bioavailability of the drug. Plasma volume increases by 50% and cardiac output by 30%
i.e. total body water increases greatly during pregnancy which also accounts for weight gain. The degree of serum protein binding is a determinant of the drug level concentration in serum. In pregnancy there is a reduction in levels of two major drug binding proteins, albumin and alpha acid glycoprotein, which potentially alter the free drug fraction. Valproic acid and phenytoin are 90% bound to serum proteins. Carbamazepine (CBZ) is only 25% bound and phenobarbitone (PHB) is 50% bound. The decrease in protein binding leads to increased plasma clearance and decrease in blood serum levels.
Birth Defect and AED
The most prominent foetal malformations cited with AED have been cleft palate and foetal hydantoin syndrome, with phenytoin (PHT), neural tube defects e.g. spina bifida occulta with valproic acid (VPA), dysmorphic facies and bleeding disorder with PHB, hip joint dislocation, hernias, hypospadias, congenital heart disease and neural tube defects etc. with CBZ. However, sodium valproate is the only AED in which a dose-response relationship has been recorded in cohort studies., Benzodiazepines like diazepam, clobazam, clonazepam have not yet been specifically implicated. Combination polytherapy in an epileptic mother has been known to produce orofacial defects and neural tube defects in the baby. Use of more than one AED in pregnancy definitely increases the potential of teratogenicity due to epoxide intermediates of CBZ, PHB, PHT and VPA along with hyponatremia.
If a seizure occurs during delivery or during pregnancy, dose of drug has to be adjusted and serum levels monitored. The only serious problem is of status epilepticus during pregnancy or delivery. This can be definitely avoided if pre-pregnancy counselling is done. It has been my practice to always counsel any girl of marriageable age to report immediately when she gets married, or if she becomes pregnant so that the obstetrician and neurologist work in tandem, for a troublefree delivery. Unfortunately this is not possible in rural areas. In such cases the family i.e. mother and girl can be counselled. The practice of sending the bride to parents' home, in Uttar Pradesh, during delivery is very good for such counselling, especially if the girl and parents have not disclosed the seizure disorder to the in-laws which is a common situation in India. If a seizure occurs, one must be alert to pre eclampsia/eclampsia and proper therapy, or termination of pregnancy may have to be done as advised by the obstetrician incharge of the case. Status epilepticus in pregnancy has to be treated as any other case of status, along with proper obstetrical care, as early as possible. In 16 patients who discontinued AED suddenly during 3rd trimester, 14 had status epilepticus. Four of them (28.5%) died. One child was born alive following emergency caesarean section after 6 hours of mother's uncontrolled status epilepticus. All the babies born died in the neonatal period, thereby giving a 100% mortality for the newborn.
The women who survived in hospital had some morbidity i.e. cognitive abnormality and, in some cases, complications such as cortical vein thrombosis, cortical blindness with hemiparesis, which was partially reversible. Out of the 4 deaths, one women had a subarachnoid bleed (CT proved) and possibly had an undiagnosed aneurysm which bled during seizures. Lactic acidosis was also common in such cases and needed correction.
In my experience with 136 young mothers on monotherapy with phenobarbitone, carbamazepine and/or sodium valproate, breast feeding has been quite safe despite reports of 'sleepy babies', hyperexcitability and poor weight gain or inadequate sucking., In rural India, women continue to breast feed their children even after twelve months. The problem of breast feeding babies in epileptic mothers was actually of inadequate breast feeding. The mothers-in-law forcibly discontinued breast feeding of their grand children, as it was felt that epilepsy would be transmitted by milk to the baby. No data is available in mothers on newer AEDs so far. Felbamate is not available in this country. However, it is restricted in other countries during the postpartum period.
Neuropsychological and Psychosocial Aspects of Men and Women on AED
Several authors have commented on cognition and behaviour in epileptic patients on AED and without AED. Six observations were noted as a result of 5 case studies.
Serum folate levels were decreased in 16 out of 28 men on PHT (57.1%) which resulted in antisocial and aggressive behaviour along with mood disorders and memory problems. One case with schizoid behaviour landed in the local jail and was sent to hospital after a withdrawal fit. Addition of folic acid for 6-8 months improved behaviour in these patients. No breakthrough fits occurred.
Non epileptic seizures occur very frequently in women on AED when faced with unpleasant tasks or stress, e.g. extra household work or following arguments with family members.
Neurophysiological studies with P-300 showed increased latency in 97 men who were on AED. None had any problem in work or activities of daily living.
Suicide attempts were commoner in women which involved taking overdose of pills, increased sensitivity, mood changes, depression, excessive anxiety, guilt and minor differences in opinion were magnified. One man attempted suicide as he was hypersensitive when peers discussed his illness. All recovered and none was booked in criminal case after admission in hospital. Sympathetic counselling was given on followup with good response.
Geshwind syndrome was observed in 25 out of 36 cases of temporal lobe seizures. They had hypergraphia, excessive religiousity and complete lack of sexual desire. These11 men and 14 women lived as celibate with episodes of religious ecstacy.
Many workers have commented on decreased sexual function in epileptics. This is multifactorial in cause and appears to be related to decrease in levels of biologically active testosterone. Testosterone in serum exists in three states i.e. free, albumin bound and sex hormone binding globulin (SHBG). Only about 2% of it occurs in free form, 55% is bound to albumin and 43-45% is bound to SHBG. The albumin bound testosterone is not biologically active. Several AEDs induce hepatic synthesis of SHBG and theoretically increase levels of total testosterone, but cause reduction of free and non SHBG testosterone, which are the active forms. Serum testosterone levels of FSH, LH, prolactin may also change. We studied serum testosterone levels in 26 men on VPA monotherapy for 2 years, 9 men on PHT for 4 years, 6 men on CBZ, 4 men on primidone (PM), and 9 on PHB and compared the levels with normal controls and men with epilepsy not on any AED. The results are shown in table I.
Taneja et al examined the semen of 55 patients with epilepsy (42 on PHT and 13 untreated) and compared them with 28 healthy controls. Testosterone, LH and FSH level were studied in 21 out of 55 cases. There was a lower volume of seminal fluid, spermatozoa concentration and the total sperm count in untreated cases and those on PHT as compared to controls. Hormonal analysis showed lower level of testosterone in nine cases. LH was decreased in 7 cases. Adult male epileptics treated with sodium valproate showed a gradual fall of total testosterone levels in plasma, which became significant only after 1 year (20.32+5.7 nmol/L). Adult male epileptics who were on monotherapy with sodium valproate for more than 2 years had lower levels (15.76+10.45 nmol/L), which was also associated with rise of FSH levels (5.9+0.98 IU/L). No overt sexual dysfunction, impotence or feminisation were recorded.
Gender and Social Aspects-Personal experience
The effect of epilepsy on interpersonal relationships in marriage was evaluated in 100 literate women and 13 literate men. Seizures were well controlled from the age of 13-15 years upto 20-23 years. Single bedtime dose or thrice daily doses of PHB, PHT or thrice daily dose of CBZ was used. Age at marriage ranged from 18 years to 28 years (mean 22.3 yrs). All cases were seizure free for 2.8-3 years at the time of marriage. All belonged to urban middle class households (lower and upper). All the 100 women concealed the fact of their having seizures prior to marriage, abetted and instigated by parents. This was despite the medical advice that an informal discussion with a doctor by both parties could help in avoiding the problems later on. 58 women were supplied medication by parents who were fearful of disclosure of epilepsy. Medication was given in dark/cosmetic unlabelled containers and sometimes in B complex bottles or labelled 'headache' medicine'. 3-6 months after marriage, 13% of women disclosed the fact that they were or had been treated for convulsions/epilepsy. The result of this disclosure was that they were sent back to their parents home. Of these 10 out of 13 (22.4%) were pregnant at the time of disclosure. All delivered healthy babies. The husband/family took the custody of the baby boy in three cases. However, baby girls were left at home with mother.
45% of women continued to successfully run their home and do work outside the home (bank, school, office, clerical work) and still had not disclosed the fact of their having epilepsy to their spouse or in-laws (time factor 2.8 years). Till date, 28 are off AEDs as well. When asked about the daily medication they reported that it was prophylaxis for headache, backache or vitamin for sexual vigour. Of the remaining cases 42/100 had GTCS on missing medication or when on ritual fast of 'karwachauth' and 'teej' in Hindu and 'ramzan' in Muslim women. The seizure was disclosed as the 'first seizure' both by the woman and her parents. Men fare better in marriage. 13 men had disclosed the fact of their epilepsy before marriage. No marriage was cancelled as dowry demand was less. Two of these men were impotent (13.4%). Two wives sought separation and went back to parents. One had behavioural dyscontrol state, though seizures were controlled. The wife of this particular patient attempted suicide and later sought legal separation. 10 men continue to have normal marital life and are still on AEDs. Men with epilepsy face greater problems at work and are usually
self-employed at home, earning less than their seizure free peers. They do not have much problems with married life. The wives are given the responsibility of giving medication (AED) in time. The same unfortunately is not true in the case of an affected wife who has to take medication in secret, furtively. Women in India are greatly discriminated against if they happen to have epilepsy. Engagements are often cancelled. The parents of epileptic girls, even when marrying the girl to another handicapped boy, have to give heavy dowry. The woman has to put up with snide comments from in-laws, if not downright cruelty. They are threatened with legal separation, separation from the children and a second wife, which add to their mental tension. We have documented these social aspects, as even if legislation is enforced, old ideas/prejudice die hard, especially in states like UP, where literacy is so low. Each of us has a duty to educate the public about epilepsy and remove prejudices as far as possible.