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ABHISHEK JAGUESSAR
Learning Objectives
At the end of this presentation, you should: 1-Understand the effects of pregnancy on epilepsy and the complications that epilepsy may have on pregnancy, lactation and neonate. 2-Be able to outline a management plan for an epileptic pregnant woman. 3-Be aware of the different AEDs, their toxic effects and the safest drug that can be used in pregnancy.
Classification Of Epilepsy
A- Partial Seizures (Focal Seizures): This is the commonest type and is subcategorized as : 1-Simple Partial Seizures (Jacksonian epilepsy): The affected woman does not lose consciousness but may experience confusion, tingling, or odd mental and emotional events. Such events may include dj vu phenomenon, mild hallucinations, or extreme responses to smell and taste.
After the seizure, the patient usually has temporary weakness in certain muscles.
Classification Of Epilepsy
2- Complex Partial Seizures (>50% in adults): They can result in loss of judgment, involuntary uncontrolled behavior & loss of consciousness. Prior to the actual seizure, some people may experience a warning aura, which can be an odd odor, a feeling of warmth, or a visual or auditory hallucination. They then may lose consciousness briefly and appear to others as motionless with a vacant stare. After a few seconds, some may begin to perform repetitive movements, such as chewing or smacking of lips. Episodes usually last no more than two minutes. Ocassionally a simple or complex partial seizures evolve into secondarily generalized seizures. The progress may be so rapid that the partial stage is not even noticed.
Classification Of Epilepsy
B- Generalized Seizures They occur in more diffuse areas of the brain and they have more serious effect on the patient. They are further subcategorized as follows: 1-Tonic-Clonic (Grand Mal) Seizures: a-The tonic phase: muscles suddenly contract, causing the patient to fall and lie rigidly for about 10 to 30 seconds. Some people experience aura; most, lose consciousness without warning. If the throat or larynx is affected, stridor occurs when the patient inhales. b-The clonic phase: Seizure is said to enter this phase when the muscles begin to alternate between relaxation and rigidity. After this phase, the patient may lose bowel or urinary control. The seizure usually lasts a total of two to three minutes, after which the patient remains unconscious for a while and then awakens to confusion and extreme fatigue.
Classification Of Epilepsy
2- Absence (Petit Mal) Seizures: Petit mal or absence seizures are brief (three to 30 seconds) losses of consciousness and may consist of only a short cessation of physical movement and loss of attention. Such seizures may pass unnoticed by others. About 25% of patients with petit mal develop grand mal seizures
Classification Of Epilepsy
C- Other Seizures: 1- Atonic (Akinetic) Seizures. A person who has an atonic (or akinetic) seizure loses muscle tone. Sometimes it may affect only one part of the body so that, for instance, the jaw slackens and the head drops. At other times, the whole body may lose muscle tone, and the person can suddenly fall.
2- Simply Tonic or Clonic Seizures. Seizures can also be simply tonic or clonic. In tonic seizures, the muscles contract and consciousness is altered for about 10 seconds, but the seizures do not progress to the clonic phase. Clonic seizures, which are very rare, occur primarily in young children, who experience spasms of the muscles but not their tonic rigidity.
3- Myoclonic. Myoclonic seizures are a series of brief jerky contractions of specific muscle groups, such as the face or trunk.
Classification Of Epilepsy
4-Gestational epilepsy: Some patients experience their first seizures during pregnancy. This can be a result of true gestational epilepsy, a rare syndrome of seizures occurring only during pregnancy. Patients with this syndrome have a variable presentation with single or multiple seizures in one or more of their pregnancies. It can also be a manifestation of epilepsy that may extend beyond the pregnancy.
The workup of these patients should involve a neurologic examination, consultation with a neurologist, CBC count, chemistry panel (particularly for electrolytes), head MRI versus CT scan, and EEG. The differential diagnosis should include eclampsia and any possible etiology considered in the nonpregnant patient, including stroke, electrolyte abnormalities, tumor, trauma, drugs/withdrawal, and epilepsy
Increased incidence of IUGR, dysfunction, microcephaly and mortality (1.2 - 3 times normal).
cognitive perinatal
Breast feeding should be stopped if obvious sedation develops in an infant and is likely to relate to the presence of AED in breast milk.
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AED Breast milk/maternal conc Adult half-life NN half-life ______________________________________________________________________ Carbamazepine 0.40.6 825 828
Phenytoin Phenobarbital Ethosuximide Primidone Valproic acid Lamotrigine Topiramate Zonisamide Levetiracetam
II-Antenatal Care
A-Investigations: Metabolic: serum glucose, urea, electrolytes, Ca & Mg EEK MRI/CT scan of the head.
B-Drugs: Monotherapy at the lowest effective dose should be employed. If large daily doses are needed, use frequent smaller doses or extended-release formula to avoid high peak levels. Monitoring of serum AEDs level is mandatory.
Usually, women don't suspect they are pregnant until their fourth to sixth week of pregnancy. By that time, if there are any harmful effects from their AEDs, most of these effects would have already occurred.
II-Antenatal Care
C-Selenium supplementation: in a dose of 200 /day may be important to minimize the free radical mediated damage. D-Folic acid supplements. E-Morning sickness: If hyperemesis gravidarum, consider giving alternative route if vomiting is severe or prolonged. F-Antenatal diagnosis: of congenital malformations (screening should be done by detailed ultrasound and measurement of fetoprotein at 18 weeks).
Oral 20mg daily is prescribed from 36 weeks until delivery to mothers taking hepatic enzyme-inducing drugs (phenytoin, phenobarbitone, primidone, carbamazepine and topiramate - Not necessary with sodium valproate).
Be aware of the nature of the AED you are using whether it is a hepatic enzyme inducing or not. Most of the newer AEDs are not enzyme inducers).
Benzodiazepines, in large doses, can cause neonatal cardiac and respiratory depression; therefore, close monitoring for these neonates is mandatory.
IV-Postnatal Care
A-Infant: - Inspected for malformation. -Vitamin k 0.1mg/kg IM at birth reduces risks of hemorrhagic disease. B-Bathing: never should be performed alone, as a brief lapse in attention can result in a fatal drowning. Wet sponge not water bath. Changing diapers and clothes are performed best on the floor rather than on an elevated changing table. C-Breast Feeding: encouraged in suitable position. If excessive infant sedation is encountered, as may be seen with phenobarbital or primidone, the infant should be weaned slowly with monitoring for signs and symptoms of withdrawal and infant drug levels.
IV-Postnatal Care
D- The following safety issues must be taken into account: If the mother is likely to drop objects she is holding but remain upright, then she should use a harness when carrying the baby.
IV-Postnatal Care
E- Sleep: If the mother is breastfeeding, sleep deprivation may be unavoidable. The mother should make up any missed sleep during the infant's daytime naps, whenever possible.
F-Anticonvulsant: Any increase in drugs during pregnancy will need to be decreased slowly to pre-pregnancy doses over 3-4 weeks to avoid toxicity. G-Contraceptions: Barriers and IUDs are recommended. Many AEDs induce the hepatic cytochrome P-450 system, which is the primary metabolic pathway of the sex steroid hormones. This leads to rapid clearance of steroid hormones and allow ovulation in women taking OCPs or other hormonal forms of birth control.
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Lower hormone level No significant effect _______________________________________________ Phenobarbital Ethosuximide Phenytoin Valproate Carbamazepine Gabapentin Primidone Lamotrigine Topiramate Tiagabine Oxcarbazepine Levetiracetam Zonisamide
Anti-Epileptic Drugs
I-Monitoring
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.
Anti-Epileptic Drugs
I-Monitoring
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.
Table 3: Therapeutic Levels of Anti-Epileptic Drugs (AEDs) Dichter MA, Brodie M.1996., Brodie M, Dichter MA 1996., Johannessen SI et al 2003., LaRoche SM et al 2004
Drug Carbamazepine
Doses qd-qid
Gabapentin
Lamotrigine Levetiracetama Oxcarbazepine Phenobarbital
300 mg
25-30 mg 5001500 mg 300600 mg 120 mg
Qd
Qd bid bid qd-bid
70-120 mol/L
10-60 mol/L 35120 mol/L 50140 mol/L 1040 /mL
Phenytoin
Primidone Valproic acid
300 mg
500 mg 1000 mg
qd-bid
qd-bid qd-bid
1020 /mL
515 /mL 50100 /mL
Anti-Epileptic Drugs
II-Teratogenicity
Antiepileptic drugs (AEDs) have the potential to produce both anatomic and behavioral teratogenesis.
Mechanisms:
1-Direct drug toxicity: due to accumulation of the drug metabolites (reactive intermediates) which are embryotoxic. 2-Antifolate effect: Phyntoins, carbamazepine & barbiturates impair folic acid absorption. Valproic acid interferes with the production of folinic acid. 3-Genetically determined deficiency of the detoxifying enzyme epoxide hydroxylase. 4-Possible genetic link between maternal epilepsy and malformations.
Screening for NTD: by combination of Maternal serum 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 -fetoprotein and acetylcholineesterase.
1-Fetal Hydantoin Syndrome: 11% of infants exposed will have the syndrome. There is pre and postnatal growth deficiency, dysmorphic facies and mental retardation.
A prospective Finnish study found the mean verbal IQ score following in utero exposure to valproate was 82 compared with 96 for carbamazepine and 95 for healthy controls.
In a retrospective UK study of school-aged children exposed to in utero AEDs, 30% of children exposed to valproate monotherapy had additional educational needs compared with 3.2% of children exposed to carbamazepine monotherapy and 6.5% for other ani-epileptics.
Anti-Epileptic Drugs
III-Mono Versus Polytherapy
It is better to prescribe the lowest possible dose of a single drug to prevent and control fits. Studies have shown higher incidence of malformations with polytherapy compared to montherapy. If large daily doses are needed, then frequent smaller doses or extended-release formula may be helpful to avoid high peak levels. Dose should be divided into 3-4 doses/day. This is because high peak plasma levels of the drug is more teratogenic.
Findings
Malformation rates were 6.5% &15.6% for monotherapy & polytherapy (p = 0.01)
Comparison of 2 Major malformations decreased prospectively from 24.1% to 8.8% (p < 0.01), followed cohorts paralleling an increased no. of patients receiving monotherapy. Prospective study Malformations was higher in of effects of AEDs infants exposed to poly (15%) compared to monoth. (5%) (p < 0.01)
Table 5: Comparison of Malformation Rates During Pregnancy Monotherapy Versus Polytherapy (Cont.)
Study design
Holmes al. 2001 et Frequency of embryopathy in control infants not exposed to AEDs (n = 508) and in infants exposed to AED monotherapy (n = 223) and AED polytherapy (n = 93) were compared
Findings
Frequency of embryopathy was higher in infants exposed to AED monotherapy vs. nonexposed controls (20.6% vs. 8.5%; OR 2.8; 95% CI 1.1 to 9.7). The frequency was also higher in infants exposed to AED polytherapy vs. nonexposed controls (28.0% vs. 8.5%: OR 4.2; 95% CI 1.1 to 5.1)
Table 5: Comparison of Malformation Rates During Pregnancy Monotherapy Versus Polytherapy (Cont.)
Study design Findings
et Influences of changes in prescribing practices analyzed by comparing 2 cohorts, 19721979 and 19801985, in the Netherlands
Mean no. of drugs used during pregnancy decreased from 2.2 in the 70s to 1.7 in the 80s. Rates of anomalies were 9.9% & 7.6% in 70s and 80s cohorts, respectively. The difference did not reach stat significance
Samrn et al. Pooled data from 5 For the AED-exposed 1997 prospective European studies children, the RR for a major malformation was 2.3 (95% CI 1.2 to 4.7) vs controls
6-Toxicity. 40% of patients experience toxic effects from older AEDs which often causes them to withdraw. Among the most distressing are sleepiness, problems in coordination and weight gain.
Differential Diagnosis
1-Eclamptic Seizures:
HTN & Ptnuria are always present. Urine output is diminished & anuria may develop. Hemoglobinuria is common. Fever of 39 C or more indicates impending CNS hemorrhage.
2-Migraine headaches, particularly migraine with auras, may sometimes be confused with epilepsy. With epileptic seizure, the preceding aura is often seen as multiple, brightly colored, circular spots, while migraine sufferers tend to see black, white, or colorless lined or zigzag flickering patterns. Typically the migraine pain expands gradually over minutes toward one side.
4-Narcolepsy: a sleep disorder that causes a sudden loss of muscle tone & excessive daytime sleepiness, can be confused with epilepsy.
6-Pheochromocytoma: Clinically, there is hypertensive crisis, seizure disorder or anxiety attacks. Diagnosis is by 24 hrs VMA, metanephrines or unconjugated catecholamines. Adrenal localization is usually successful with CT or MRI.
9-Fulminant hepatic failure: Due to acute fatty liver of pregnancy or acute viral hepatitis.
Conclusions
1 Epileptic woman can get pregnant. They are not
different than other women population. 2-Epilepsy and its medications increases the incidence of malformations 2-3 times normal. However; there is 90% chance of having a normal child. 3-The most common malformations are cleft lip, left palate and congenital heart diseases.
Conclusions (Cont.)
4-A woman should not stop AED unless she has not had seizures for 2 years; gradual discontinuation can then be attempted. 5-A pregnant should not stops her AED Since most malformations develop during the 1st trimester. 6-Current AEDs are considered to be a necessary evil until newer drugs become available. However, the safest are: Phenobarbital and phenytoins.
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