1. Status Epilepticus-Nutshell.pptx
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This slides contains all you need to know about "Status Epilepticus" in a nutshell. It includes definition, investigation, emergency management of status epilepticus. This educational material is suitable for med students, paramedics, nurses & neurology residents.
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1. Status Epilepticus-Nutshell.pptx
- 1. Status Epilepticus & Epilepsy in Pregnancy Dr. Azim Anwar Resident (MD Cardiology) Phase A
- 2. Status Epilepticus Definition: Seizure activity not resolving spontaneously, or Recurrent seizure with no recovery of consciousness in between. (Davidson/22/p1159)
- 3. Status Epilepticus Definition: • Status Epilepticus refers to • Continuous seizures or repetitive, discrete seizures with impaired consciousness in the interictal period. • The duration of seizure activity 15–30 min (Harrison’s Neurology in Clinical Medicine,2nd ed)
- 4. Status Epilepticus Definition: Status epilepticus is broadly defined as • seizure activity that continues for 30 minutes, or recurrent seizures without recovery between attacks. (Bradly/1612)
- 5. Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1). It is a condition, which can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures. ILAE Guideline for status epilepticus,2016
- 6. Contd. This definition is conceptual, with two operational dimensions: • The first is the length of the seizure and the first time point (t1) beyond which the seizure should be regarded as “continuous seizure activity.” • The second time point (t2) is the time of ongoing seizure activity after which there is a risk of long-term consequences.
- 7. Few Words……. • A medical emergency • has a recognised mortality • Diagnosis is usually clinical • As seizure activity becomes prolonged, movements may become more subtle.
- 8. • Cyanosis, pyrexia, acidosis, hypotension, myoglobinuria, Renal failure may occur from myoglobinuria. (Adams & Victor,350) • Complications include aspiration, hypotension, cardiac arrhythmias, renal or hepatic failure, epileptic encepahlopathy.
- 10. • Cause: The etiologies of status epilepticus vary among age groups but all the fundamental causes of seizures are able to produce the syndrome. 1) Fall in AED levels in patients with preexisting epilepsy. 2) Infection: Meningitis, Encephalitis 3) Old trauma 4) Metabolic: Hypoglycemia, Hyponatremia, Hypocalcaemia 5) Stroke and Brain tumor (Davidson 1159+ Adams 350)
- 11. Diagnosis • Can be made on the basis of the description of prolonged rigidity and/or clonic movements with loss of awareness. • The MRI during and for days after a bout of status epilepticus may show signal abnormalities in the region of a focal seizure or in the hippocampi, most often reversible.
- 12. • The MRI changes are most evident on FLAIR and diffusion-weighted sequences. • With regard to acute medical complications, from time to time a case of neurogenic pulmonary edema is encountered during or just after the convulsions, and some patients may become extremely hypertensive, making it difficult to distinguish the syndrome from hypertensive encephalopathy. (Adams/10/350)
- 13. • Management of status epilepticus
- 15. Initial • Ensure airway is patent; give oxygen to prevent cerebral hypoxia • Check pulse, blood pressure and respiratory rate • Secure intravenous access • Send blood for: Glucose, urea electrolytes, calcium magnesium, liver function anti-epileptic drug levels Full blood count and clotting screen Storing a sample for future analysis (e.g. drug misuse)
- 16. If seizures continue for > 5 mins: Give diazepam 10 mg IV (or rectally) or lorazepam 4 mg IV; repeat once only after 15 mins Correct any metabolic trigger, e.g. hypoglycaemia
- 17. If seizures continue after 30 mins IV infusion (with cardiac monitoring) with one of: Phenytoin: 15 mg/kg at 50 mg/min Fosphenytoin: 15 mg/kg at 100 mg/min Phenobarbital: 10 mg/kg at 100 mg/min Cardiac monitor and pulse oximetry Monitor neurological condition, blood pressure, respiration; Check blood gases
- 18. If seizures still continue after 30–60 mins Transfer to intensive care Start treatment for refractory status with intubation, ventilation and general anaesthesia using propofol or thiopental EEG monitor
- 19. Once status controlled • Commence longer-term anticonvulsant medication with one of: Sodium valproate 10 mg/kg IV over 3–5 mins, then 800–2000 mg/day Phenytoin: give loading dose (if not already used as above) of 15 mg/kg, infuse at < 50 mg/min, then 300 mg/day Carbamazepine 400 mg by nasogastric tube, then 400–1200 mg/day • Investigate cause • Mortality-20-30%
- 23. !!! • With failure of aggressive anticonvulsant and anesthetic treatment, there may be a temptation to paralyze all muscular activity, an effect easily attained with drugs such as pancuronium, while neglecting the underlying seizures. The use of neuromuscular blocking drugs without a concomitant attempt to suppress seizure activity is inadvisable. If such measures are undertaken, continuous or frequent intermittent EEG monitoring is essential.
- 25. Epileptic seizures Vs NEAD Non-epileptic attacks Epileptic seizures Duration Often prolonged Seconds or minutes Retained consciousness Common rare Pelvic thrusting common rare Erratic movement, fighting common rare Resisting eye opening common Lids are open or showing clonic movement Tongue biting Rare (usually in front) Common(lateral injury) Incontinence common common Post-ictal confusion rare common Creatine kinase level normal abnormal
- 26. Drug resistant/ refractory Epilepsy C-Slide 26
- 27. Definition: Drug resistant epilepsy may be defined as failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as monotherapy or in combination) to achieve sustained seizure freedom. Seizure freedom is defined as freedom from seizures for a minimum of three times the longest pre intervention inter seizure interval or 12 months, whichever is longer. Treatment failure is defined as recurrent seizure(s) after the intervention has been adequately applied. If a patient has been seizure-free for three times the pre intervention Inter seizure interval but for <12 months, seizure control should be categorized as ‘‘undetermined
- 28. Treatment options Antiepileptic drugs: Further medications trials of AEDs in mono- or polytherapy can be of benefit in individuals with epilepsy with a different mechanism of action than one not previously efficacious may maximize the benefit from subsequent drug trials. Surgery : Non-Drug Treatment:
- 29. Non-Drug Treatment/Lifestyle Modifications Adequate sleep Avoidance of alcohol, stimulants, etc. Avoidance of known precipitants Stress reduction — specific techniques C-Slide 29 American Epilepsy Society 2010
- 31. Epilepsy and Pregnancy 3-4 /1000 pregnancy has epilepsy
- 32. Effects of Pregnancy on Epilepsy Seizure frequency may increase (25%): -hormonal changes of pregnancy (high oestrogen) -associated psychological and emotional stress of pregnancy: all lower threshold for seizures -Nausea and vomiting -↑ AED metabolism & clearance Seizure frequency may decrease (25%): -Improved compliance with drug regimen in some patients Seizure frequency may remain unchanged (50%)
- 33. Effect of Epilepsy On Pregnancy Increased incidence of intra-uterine growth retardation (IUGR), cognitive dysfunction, microcephaly and perinatal mortality (1.2 to 3 times normal) Increased incidence of congenital malformations
- 34. Effects of Pregnancy on AED Enhanced metabolism & increased drug clearance associated with pregnancy can result in decreased serum drug concentration Increased volume of distribution of the AED Increased serum binding proteins Decreased or non-compliance with medication.
- 35. Effects of AED on Pregnancy •Anatomic and behavioral teratogenesis Mechanisms: Direct drug toxicity: due to accumulation of the drug metabolites which are embryotoxic Antifolate effect: Phenytoin, carbamazepine & barbiturates impair folic acid absorption; Valproic acid interferes with the production of folinic acid Genetically determined deficiency of the detoxifying enzyme epoxide hydroxylase Possible genetic link between maternal epilepsy and malformations.
- 36. Approved use of AEDs in pregnancy Drug Focal onset GTCS 1◦/2◦ Absence Myoclonic Carbamazepine Yes Yes No No Phenytoin Yes Yes No No Valproate Yes Yes Yes Yes Lamotrigine Yes Yes Yes Yes Levetiracetam Yes Yes ? ?
- 37. • Management of Epilepsy in Pregnancy
- 38. Pre conceptual : best practice • Prevention of convulsion must get the top priority. AED should not be discontinued or arbitrarily reduced particularly if there have recent convulsion. • Every pregnancy should be preplanned • If a woman discovers she is pregnant while on an antiepileptic drug, changing medications is unlikely to reduce the chances of birth defect, even for valproate but risk of lower IQ of child is retained. • Attempt to decrease pharmacotherapy to monotherapy.
- 39. Pre conception Care • Taper dosages of AEDs to the lowest possible dose • In women who have not had a seizure for 2-5 years, attempt complete withdrawal of pharmacotherapy • Consider pre-conceptual genetic counseling to the woman and her family members • Supplement the diet with folate at 4 mg/d ,2 months prior to conception
- 40. Pre conception Care Counselling: explain to the patient that: – There is a chance of 90% of having normal child – Increased chance of having epileptic child (2-5%) – Increased pregnancy complications – Increased unfortunate outcome if seizures arises during pregnancy – Increased risk of congenital malformations Measurement of the free unbound anti-epileptic drug level in maternal serum Preconception folate supplementation: 5 mg daily at least 2 months before conception
- 41. Antenatal Screening • Follow-up tests Weeks • AED levels (free and total), serum folate level 6-10 • Maternal serum AFP, amniocentesis,* AED levels 15-16 • Ultrasound for neural-tube defects 18-19 • Ultrasound for oral clefts and heart anomalies 22-24 • AED levels 28 • AED levels, maternal vitamin K 34-36
- 43. During pregnancy period • Check total and free levels of AEDs monthly • Consider early genetic counseling • Check maternal serum alpha-fetoprotein (MSAFP) levels and perform a level II fetal survey and ultrasonography at 19-20 weeks' gestation • Consider amniocentesis for alpha-fetoprotein • Fetus exposed to phenobarbiton and certain other drugs cause coagulopathy< • Treated with Vit-K 20mg/day during 08th month Or 10mg I/V before birth & 1mg I/M to neonate
- 44. During labour • Check levels of AEDs • Inform all care providers, Obstretician, anesthesiologists, pediatricians and nurses that the patient has epilepsy • Consider seizure prophylaxis with intravenous benzodiazepines or phenytoin • Manage seizures acutely with intravenous benzodiazepines (1-2 mg of diazepam), then load phenytoin (1 g loaded over 1 h) • Labor management should be based on routine standards of care • Start administration of vitamin K for the infant, and send the cord blood for clotting studies
- 45. Management of a pregnant patient in status epilepticus • Establish the ABCs, and check vital signs, including oxygenation • Assess the fetal heart rate or fetal status • Rule out eclampsia • Administer a bolus of lorazepam (0.1 mg/kg, ie, 5-10 mg) at a rate of no more than 2 mg/min • Load phenytoin (20 mg/kg, ie, 1-2 g) at a rate of no more than 50 mg/min, with cardiac monitoring. • If this is not successful, load phenobarbital (20 mg/kg, ie, 1-2 g) at a rate of no more than 100 mg/min. • Check laboratory findings, including electrolytes, AED levels, glucose, and toxicology screen. • If fetal testing results are nonreassuring, move to emergent delivery
- 46. Use of AED in pregnancy- In brief If a woman has been seizure-free for a satisfactory period, taper and withdraw AEDs at least 6 months prior to becoming pregnant Prescribe the lowest possible dose of a single drug to prevent and control fits
- 47. Contd. If large daily doses are needed, then frequent smaller doses or extended- release formula may be helpful to avoid high peak levels (as high peak plasma levels of the drug is more teratogenic) ALL AED have adverse effect, limited data on newer AEDs, so use when absolutely necessary
- 48. Teratogenecity
- 50. Neural tube defects • 3-9% (Normal 1-3%) • Often skin covered • Anencephaly rare • Spina bifida predominantly – low lumbar or sacral • Low risk if VPA dose <1000 mg/d • Controlled-release formulation to ↓ peak levels
- 51. Fetal Hydantoin Syndrome • 11% of infants exposed to phenytoin or carbamazepine will have the syndrome • There is pre and postnatal growth deficiency, dysmorphic facies and mental retardation
- 52. Fetal Valproate Syndrome • Brachycephaly with high forehead, shallow orbits, small nose, small mouth & low posterior ears • Long overlapping fingers & toes & hyperconvex nails • Cleft palate & congenital heart diseases .
- 53. AED & Breast Feeding
- 54. Catamenial Epilepsy Some women experience a marked increase in seizure frequency around the time of menses. This is thought to reflect either the effects of estrogen and progesterone on neuronal excitability or changes in antiepileptic drug levels due to altered protein binding.
- 55. Contd Some patients may benefit from increases in antiepileptic drug dosages during this time or from control of the menstrual cycle through the use of oral contraceptives. Natural progestins may be of benefit to a subset of women.
- 56. Contraceptive in epileptic Carbamazepine, oxcarbazepine, phenytoin, phenobarbital, primidone, and topiramate (cytochrome P450 enzyme-inducing drugs) decrease blood levels of oestrogen and progesterone Sodium valproate, gabapentin, tiagabine, levetiracetam, zonisamide, lacosamide and pregabalin do not affect levels.
- 57. Epilepsy Comorbidities and AEDs C-Slide 57 American Epilepsy Society 2010
- 58. Depression in Epilepsy Antiepileptic drugs such as phenobarbital, vigabatrin, topiramate, tiagabine, levetiracetam,and clobazam can induce depressive symptoms in patients with epilepsy Carbamazepine, valproate, lamotrigine and pregabalin drugs are associated with mood stabilizing properties, so discontinuation may precipitate depression Suicide rate 5 times higher than that of general population SSRIs and SNRIs may reduce seizures and depressive symptoms Drug of choice-escitalopram and citalopram followed by sertraline. 58 American Epilepsy Society 2010
- 59. Post-stroke seizures • Stroke is the most common cause of seizures and epilepsy in population studies of adults over the age of 35years. • Seizures occurred within 24 hours of the stroke in 43 percent of patients • Low frequency of recurrent seizures after stroke, and an absence of absolute predictors of poststroke epilepsy • The decision of when to treat patients for a poststroke seizure is difficult. • Most physicians empirically treat patients • Drugs of choice- Carbamazepine, Phenytoin, New AEDs
- 60. In case of ICH & SAH For ICH, seizure activity can cause further neuronal injury & coma For cerebellar Hmg & subcortical Hmg- No AED For other cases phenytoin for 1 month can be given. If seizure occurs 2 wks after the event then long time Prophyaxis is needed. Long time prophylaxis of AED is not recommended for SAH without seizure but should be if risk factors present.
- 61. Effect of AEDs on Weight Drug Weight gain Valproate >50% Carbamazepine 15-25% Gabapentin 15% Lamotrigine No Levetiracetam No Topiramate Loss in 45-85%
Editor's Notes
- Although AEDs are the mainstay of treatment, alternative treatment modalities have varying degrees of clinical and experimental support. Lifestyle modifications, particularly avoidance of alcohol and sleep deprivation, can be very important in certain syndromes and individuals. Relaxation, biofeedback, and other behavioral techniques can help a subset of patients, especially those with a reliable aura preceding complex partial or secondarily generalized seizures. Dietary supplements are of unproven value, except for pyridoxine (vitamin B6), which is crucial for treating rare pyridoxine dependency of neonates and infants and for seizures due to antituberculous therapy with isoniazid. Herbal remedies are currently also under investigation.
- Many of our antiepileptic drugs have effects on metabolism that lead to disturbances in reproductive and metabolic health. They do so by altering levels of physiologic steroid hormones; this can affect fertility. They also can affect lipid and carbohydrate metabolism; the end effect of that may be glucose intolerance and obesity, as well as lipid metabolism disturbances. These medications also may affect bone mineral metabolism by multiple mechanisms, including calcium and vitamin D homeostasis, and alter the metabolism of the bone cells themselves. First, let me suggest that the choice of antiepileptic drugs should consider these effects on the body because we want to find the medication that is most likely to achieve effectiveness the first go-around. Second, I am going to show you data supporting this statement. Some AEDs Alter Steroid Hormone Metabolism First, some antiepileptic drugs affect the metabolism of the ovarian sex steroid hormones -- the estrogens, and the progesterones, as well as the androgens, all produced by the ovary. Data from our own group, as well as others, show that the effect of these medications is related to their impact on cytochrome P450 enzymes, or the liver mixed-function oxidase enzymes. We can classify these medications as the inducers; carbamazepine and phenytoin are the most commonly used enzyme inducers and the best studied. The antiepileptic drug that inhibits cytochrome P450 enzymes is represented by valproate. The best-studied medications that have no effect on these enzymes are lamotrigine and gabapentin. There is a great deal of data now showing that women who are taking the inducing antiepileptic drugs have reductions in sex steroid hormones, both the estrogens and androgens. This is not only an effect on the metabolism of these sex steroid hormones, but on the binding because these enzymeinducers increase the levels of sex hormone-binding globulin, which binds to these sex steroid hormones and renders them biologically inactive. Is this relevant to the woman with epilepsy? There are suggestions from our own group that women who have disorders of sexual desire or sexual arousal are those with reductions in androgens and estrogens, those women who are on these enzyme inducers. Similar data have been presented by Herzog showing the same phenomenon with men; that is, that use of these inducers associated with reductions in androgens is associated with erectile dysfunction and reductions in libido in men. Valproate, as an enzyme inhibitor, is associated with elevations in androgens. Dr. Strauss at the University of Pennsylvania has recently shown that valproate induces synthesis of androgens from ovarian thecal cells; so, there is an effect both on synthesis and on metabolism that acts to increase androgen levels. We will speak about what the implications of elevated androgens might be for the woman with epilepsy. In our own study, looking at women with epilepsy receiving lamotrigine and gabapentin, we found no difference between these women and nonepileptic, medically normal controls in any of the parameters of sex steroid hormone levels. So, we must recognize that, based on the antiepileptic drug we are selecting, we may be altering physiologic concentrations of hormones. This may have clinical consequences. Clinical Implications of Weight Gain Is this benign? I think that weight gain in the 50% in whom this develops is not benign. It leads to a number of consequences; one of them is noncompliance with medication. It also leads to longer-term health effects, including elevations in insulin and glucose intolerance. Again, those women who gain weight on valproate are those women who show elevations in fasting and postprandial insulin almost immediately after starting valproate therapy. This can lead to, not only immediate problems with glucose intolerance, but longer term, with diabetes. There also may be psychologic effects associated with the weight gain, and also sleep disturbances, including sleep apnea. The changes in lipid metabolism may predispose to cardiovascular disease. Obesity also is associated with increased risk of certain gynecological malignancies, including endometrial and breast cancer.
- Epilepsy and Pregnancy Issues All of us deal with patients with epilepsy; 50% of the patients we deal with are women, and at least half of that subgroup are women in the childbearing years. Pregnancy issues are a problem to all of us -- how best to advise women from as early as possible to minimize the risks to themselves and to their unborn child. About 3 or 4 of every 1000 pregnancies occurs in women with epilepsy; that is, perhaps slightly less given the prevalence of epilepsy in the population, but that is because women with epilepsy are sometimes worried, or frightened, about becoming pregnant. They have lower rates of getting married, lower rates of having children. The most common reason for this is psychosocial; but there also are, perhaps, difficulties in conceiving, because of infertility issues, issues that surround polycystic ovaries, etc. But, there is this fear that the drugs they take, or the epilepsy that they have, may affect their unborn child. I want to examine this and show how we have been looking at this from our own perspective and from other parts of the world.
- Contraception Issues in Epilepsy Women taking cytochrome P450 enzyme-inducing antiepileptic drugs (AEDs) have a potential 6% failure rate per year for oral contraceptive pills.[34 ]These AEDs increase hepatic metabolism of steroid hormones and increase their binding to sex hormone binding globulin and other serum proteins, both effects that reduce the availability of hormonal contraception. The more potent enzyme inducers (carbamazepine, phenytoin, phenobarbital, primidone) are the most likely to interfere with contraception. Milder inducers (oxcarbazepine, topiramate) appear not to alter contraceptive efficacy significantly when administered at low doses. Lamotrigine, which has one of the most complex interactions with hormones, also potentially reduces the efficacy of contraception. In addition, progesterone and its derivatives have been shown to significantly reduce lamotrigine levels, potentially increasing the risk of seizures. This effect is easily seen during pregnancy with a more than 50% drop in lamotrigine levels due to normal gestational increased progesterone.[35 ] Contraceptives with low doses of estrogen (eg, ethinyl estradiol) or progesterone (eg, norgestrel, norethindrone) may be poorly effective with these AEDs. Triphasic contraceptives, which contain 1 week of very low-dose estrogen immediately following the placebo week, effectively provides no contraceptive benefit until day 14 of the cycle. Such contraceptive regimens may also be particularly ineffective in women taking enzyme-inducing AEDs or lamotrigine. Alternative contraception or adjunctive methods should be considered in these patients. Although neurologists and obstetricians should be familiar with these interactions, a 1996 survey indicates that both specialties are predominantly unaware of these effects and thus unable to provide appropriate contraception counseling to women with epilepsy. Krauss et al found that 27% of neurologists and 21% of obstetricians reported oral contraceptive failures in their patients taking AEDs, but only 4% of neurologists and none of the obstetricians knew the effects of the 6 most common AEDs on oral contraceptives.[36 ] Subdermal levonorgestrel implants (Norplant) have also been shown to have reduced efficacy in women taking enzyme-inducing AEDs.[37 ]It is likely that other forms of hormonal contraception (eg, transdermal patch, Depo-Provera) have potentially reduced efficacy with these drugs, but no literature supports this conjecture. Although the American Academy of Neurology Practice Parameter for Management Issues for Women with Epilepsy states that increasing the estrogenic component of a contraceptive to at least 50 mcg will improve contraceptive effect, reproductive specialists disagree, arguing that the progestin component has a greater effect in preventing ovulation than the estrogen component.[38 ] The literature is not consistent in identifying whether the estrogen or progestin is clinically more important in pregnancy prevention.[39 ] Whether GnRH analogs and other nonovarian hormones have altered efficacy in epilepsy is unknown. Adjunctive contraception by nonhormonal methods or changing antiepileptic therapy to those without hormonal interactions are both reasonable considerations. No impairment of hormonal contraception has been reported with ethosuximide, felbamate, gabapentin, levetiracetam, pregabalin, tiagabine, valproate, or zonisamide.[39 ] No adverse effect on contraception has been reported with implantable stimulators for epilepsy or with epilepsy surgery.
- Contraception Issues in Epilepsy Women taking cytochrome P450 enzyme-inducing antiepileptic drugs (AEDs) have a potential 6% failure rate per year for oral contraceptive pills.[34 ]These AEDs increase hepatic metabolism of steroid hormones and increase their binding to sex hormone binding globulin and other serum proteins, both effects that reduce the availability of hormonal contraception. The more potent enzyme inducers (carbamazepine, phenytoin, phenobarbital, primidone) are the most likely to interfere with contraception. Milder inducers (oxcarbazepine, topiramate) appear not to alter contraceptive efficacy significantly when administered at low doses. Lamotrigine, which has one of the most complex interactions with hormones, also potentially reduces the efficacy of contraception. In addition, progesterone and its derivatives have been shown to significantly reduce lamotrigine levels, potentially increasing the risk of seizures. This effect is easily seen during pregnancy with a more than 50% drop in lamotrigine levels due to normal gestational increased progesterone.[35 ] Contraceptives with low doses of estrogen (eg, ethinyl estradiol) or progesterone (eg, norgestrel, norethindrone) may be poorly effective with these AEDs. Triphasic contraceptives, which contain 1 week of very low-dose estrogen immediately following the placebo week, effectively provides no contraceptive benefit until day 14 of the cycle. Such contraceptive regimens may also be particularly ineffective in women taking enzyme-inducing AEDs or lamotrigine. Alternative contraception or adjunctive methods should be considered in these patients. Although neurologists and obstetricians should be familiar with these interactions, a 1996 survey indicates that both specialties are predominantly unaware of these effects and thus unable to provide appropriate contraception counseling to women with epilepsy. Krauss et al found that 27% of neurologists and 21% of obstetricians reported oral contraceptive failures in their patients taking AEDs, but only 4% of neurologists and none of the obstetricians knew the effects of the 6 most common AEDs on oral contraceptives.[36 ] Subdermal levonorgestrel implants (Norplant) have also been shown to have reduced efficacy in women taking enzyme-inducing AEDs.[37 ]It is likely that other forms of hormonal contraception (eg, transdermal patch, Depo-Provera) have potentially reduced efficacy with these drugs, but no literature supports this conjecture. Although the American Academy of Neurology Practice Parameter for Management Issues for Women with Epilepsy states that increasing the estrogenic component of a contraceptive to at least 50 mcg will improve contraceptive effect, reproductive specialists disagree, arguing that the progestin component has a greater effect in preventing ovulation than the estrogen component.[38 ] The literature is not consistent in identifying whether the estrogen or progestin is clinically more important in pregnancy prevention.[39 ] Whether GnRH analogs and other nonovarian hormones have altered efficacy in epilepsy is unknown. Adjunctive contraception by nonhormonal methods or changing antiepileptic therapy to those without hormonal interactions are both reasonable considerations. No impairment of hormonal contraception has been reported with ethosuximide, felbamate, gabapentin, levetiracetam, pregabalin, tiagabine, valproate, or zonisamide.[39 ] No adverse effect on contraception has been reported with implantable stimulators for epilepsy or with epilepsy surgery.
- Is the diagnosis of epilepsy well established? In some patients, routine EEG recordings or continuous video/EEG monitoring may be warranted to confirm the diagnosis Does the patient require AEDs and if so, is she on the most appropriate medications and the minimum dose to maintain seizure control Many physicians will consider withdrawal of AEDs after a period of two years without seizures. The frequency of seizure recurrence within six and twelve months of discontinuing therapy is 12 and 32 percent, respectively. Thus, if a woman has been seizure-free for a satisfactory period, a taper and withdrawal of AEDs at least six months prior to becoming pregnant is suggested Reproductive counseling All physicians treating women of reproductive potential must discuss pregnancy with these patients, and when appropriate, their caregivers. There are few medical conditions in which pregnancy and childbirth do not complicate management. It always is preferable to discuss epilepsy management options before conception occurs. A candid discussion of whether or when pregnancy is desired can help determine the timing of diagnostic tests and medication changes. The Physician's Discussion Checklist for Women with Epilepsy contains helpful clinical printable practice aids for physicians of women with epilepsy in their reproductive years. There are several ways to optimize therapy prior to consideration of pregnancy. First, establish whether the female patient requires antiepileptic therapy at all. Review of history and EEG may show that the diagnosis is unsubstantiated (due to lack of historical documentation or inadequate diagnostic testing) or that the patient is now seizure free for several years. Second, determine if the current regimen is appropriate for the epilepsy syndrome or seizure type. If drug choice or dosing is in question, referral to a comprehensive epilepsy center for a second opinion should be considered. Third, advocate simplification of treatment to monotherapy, or consider whether epilepsy surgery may be beneficial. EEGs and video-EEGs, scrupulously conducted by qualified laboratories and interpreted by qualified epileptologists, may be helpful.
- The ideal AED serum free level must be established for each patient before conception, and should be the level at which seizure control is the best possible for that patient without debilitating side effects. Levels should be repeated at the beginning of each trimester and again in the last 4 weeks of pregnancy. Monitoring should continue until the 6th to 8th week postpartum. In doing so, one may be able to avoid symptoms of toxicity that result from the changes in pharmacokinetics postpartum. Some authors recommend monthly monitoring, given the possibility of rapid and unpredictable decreases in AED levels in an individual patient. The frequency with which levels are monitored must be tailored to each situation, including increased monitoring for worsening seizure control, adverse effects, and compliance issues. Transvaginal U/S can be performed at 18-20 weeks to diagnose the most severe defets (face - heart). However, sensitivity is better, for cleft palate and lips, if U/S is repeated between 24-28 weeks. Screening for NTD: by combination of Maternal serum α –fetoprotein at 15-22 weeks and Level II,structural Ultrasound, at 16-20 weeks. If results are equivocal, proceed with amniocentesis with measurements of amniotic fluid α -fetoprotein and acetylcholine-esterase
- Neural Tube Defects One of the worries is that the drugs these people take to control the epilepsy may be teratogenic. The currently perceived wisdom is that women with epilepsy taking antiepileptic drugs have a 2-3 times greater risk of having a child with a major congenital malformation. Background risk in the United Kingdom is about 1% to 3%. That means that women with epilepsy taking antiepileptic drugs have a 3% to 9% risk of having a child with a major malformation. One would like to try to withdraw antiepileptic drugs, if possible; but in many cases, that is not possible either because the epilepsy is still active or because of other reasons, such as effects on driving license, or women not wishing to take the risk. Seizures may increase during pregnancy and in the United Kingdom, epilepsy is now the second most common cause of maternal death due to nonobstetric causes. I do not know why that is -- and it is not disclosed in statistics -- but I suspect it is probably because women may be withdrawing from antiepileptic drugs precipitously. What are we good at? When we are giving women preconceptual advice, we are probably all very good at warning of the risks of major structural abnormalities, such as neural tube defects. We recognize, from previous studies, that there is an increased risk, particularly with valproate, and also perhaps with carbamazepine at a level maybe about 1% or 2%. We are probably not so good at recognizing that the neural tube defects in women taking valproate, in particular, are not the same as the neural tube defects in the general population. They tend to be skin covered; they tend not to be with the other abnormalities, such as anencephaly; they tend to be a lower defect, more sacral, lumbosacral; and it may affect canalization. That might be relevant, because we give folic acid, preconceptually, to all women with epilepsy to protect them from this defect. But, that is because we correlate our women with women in the general population in whom folic acid has been shown to reduce the risk of neural tube defects. But, this neural tube defect is slightly different. We are perhaps not so good at knowing about the other major congenital abnormalities that occur, such as facial clefts, hypospadias; how often do they occur, what type of defects occur; and are they associated with any particular drug. We have not got the information about that.
- Fetal Valproate Syndrome: Facial Features We are probably getting a bit better at knowing about some of the minor anomalies that occur. We have become aware, over the last number of years, that some children maybe have dysmorphic features. This has been associated, particularly, with valproate. The point of these dysmorphic features is not so much that the child has these particular features, but rather, is there some association with behavior, or learning, or cognitive delay?
- Contraception Issues in Epilepsy Women taking cytochrome P450 enzyme-inducing antiepileptic drugs (AEDs) have a potential 6% failure rate per year for oral contraceptive pills.[34 ]These AEDs increase hepatic metabolism of steroid hormones and increase their binding to sex hormone binding globulin and other serum proteins, both effects that reduce the availability of hormonal contraception. The more potent enzyme inducers (carbamazepine, phenytoin, phenobarbital, primidone) are the most likely to interfere with contraception. Milder inducers (oxcarbazepine, topiramate) appear not to alter contraceptive efficacy significantly when administered at low doses. Lamotrigine, which has one of the most complex interactions with hormones, also potentially reduces the efficacy of contraception. In addition, progesterone and its derivatives have been shown to significantly reduce lamotrigine levels, potentially increasing the risk of seizures. This effect is easily seen during pregnancy with a more than 50% drop in lamotrigine levels due to normal gestational increased progesterone.[35 ] Contraceptives with low doses of estrogen (eg, ethinyl estradiol) or progesterone (eg, norgestrel, norethindrone) may be poorly effective with these AEDs. Triphasic contraceptives, which contain 1 week of very low-dose estrogen immediately following the placebo week, effectively provides no contraceptive benefit until day 14 of the cycle. Such contraceptive regimens may also be particularly ineffective in women taking enzyme-inducing AEDs or lamotrigine. Alternative contraception or adjunctive methods should be considered in these patients. Although neurologists and obstetricians should be familiar with these interactions, a 1996 survey indicates that both specialties are predominantly unaware of these effects and thus unable to provide appropriate contraception counseling to women with epilepsy. Krauss et al found that 27% of neurologists and 21% of obstetricians reported oral contraceptive failures in their patients taking AEDs, but only 4% of neurologists and none of the obstetricians knew the effects of the 6 most common AEDs on oral contraceptives.[36 ] Subdermal levonorgestrel implants (Norplant) have also been shown to have reduced efficacy in women taking enzyme-inducing AEDs.[37 ]It is likely that other forms of hormonal contraception (eg, transdermal patch, Depo-Provera) have potentially reduced efficacy with these drugs, but no literature supports this conjecture. Although the American Academy of Neurology Practice Parameter for Management Issues for Women with Epilepsy states that increasing the estrogenic component of a contraceptive to at least 50 mcg will improve contraceptive effect, reproductive specialists disagree, arguing that the progestin component has a greater effect in preventing ovulation than the estrogen component.[38 ] The literature is not consistent in identifying whether the estrogen or progestin is clinically more important in pregnancy prevention.[39 ] Whether GnRH analogs and other nonovarian hormones have altered efficacy in epilepsy is unknown. Adjunctive contraception by nonhormonal methods or changing antiepileptic therapy to those without hormonal interactions are both reasonable considerations. No impairment of hormonal contraception has been reported with ethosuximide, felbamate, gabapentin, levetiracetam, pregabalin, tiagabine, valproate, or zonisamide.[39 ] No adverse effect on contraception has been reported with implantable stimulators for epilepsy or with epilepsy surgery.
- Seizures occurred within 24 hours of the stroke in 43 percent of patients. related to local ion shifts and release of high levels of excitotoxic neurotransmitters in the area of ischemic injury. In contrast, an underlying permanent lesion that leads to persistent changes in neuronal excitability appears to be responsible for late-onset seizures after stroke
- Effects of Commonly Used AEDs on Weight Another effect of these antiepileptic drugs is on metabolism. The most obvious clinical manifestation of changes in metabolism is weight. Here we have classified the antiepileptic drugs as those that are associated with weight gain, those that are weight neutral, and those that are associated with weight loss. They are not all equivalent. Valproate is the medication that we most often think about when we think about weight gain on an antiepileptic drug; this may affect up to 50% of women receiving this medication. Conversely, 50% of women do not gain weight. We will discuss the difference between those who have a disturbance in carbohydrate metabolism and those who do not. We see more modest weight gains with carbamazepine and with gabapentin. Lamatrogine, levetiracetam, and oxcarbazepine have been shown to be weight neutral in the pre- and postmarketing trials. Topiramate is the antiepileptic drug that we recognize as most often associated with weight loss. Depending on the study,this has been reported in anywhere between half and three quarters of the women receiving this medication and in men as well. Zonisamide is associated with weight loss. Clinically we recognize this, although the numbers are not firm as to how often this affects our patients.