Epilepsy: Medical AspectsChapter 1

Seizures/convulsions/fits mean involuntary jerky movements of the body which can occur due to a variety of disorders, e.g. low blood glucose, low calcium, liver failure, kidney failure, etc. They are called provoked seizures (provoked by the various causes listed) and is not epilepsy. The treatment is to treat the underlying cause.

When seizures, convulsions/fits occur without any provocation for two or more times on different days then it is called epilepsy. Seizure is like fever, which can be caused by many conditions, while epilepsy is a definite diagnosis like typhoid, malaria, etc. This means all seizures are not epilepsy and there are some types of epilepsy without seizures also, which will elaborated later on.

Seizure mimics consist of syncope, nonepileptic attack disorder (Pseudoseizure), transient ischemic attacks (TIAs), Panic attacks, hyperventilation, hypnic jerks (Table 1).

Syncope is basically due to hypoxemia of the brain and the person experiences ringing in ears, blurring of vision, pallor and slowly sinks to the ground with rapid recovery once he is flat on the ground. One should realize that the heart is a pumping station, which pumps blood against gravity to the overhead tank—the brain. Nature wants the person to be flat on the ground, so that the brain and heart are on the same level and the blood supply can be restored very quickly. However, the “well wishers” around the person “out of respect” to the person do not allow him to lie flat on the ground and make him sit on a chair which continues the syncopal episode as the blood supply to the brain is not fully restored. This prolonged syncope may lead to frank seizure.

Syncope is the most common cause of misdiagnosis of epilepsy, as any episode of transient loss of consciousness is readily diagnosed as seizure. It is also a common cause for referral for EEG. The types of syncope are shown in Table 2.

Table 3 shows the differences between syncope and seizure.

Table 5 shows the differences between TIA and epilepsy.

In contrast to the general medical causes secondarily involving the brain as explained above, direct involvement of brain, resulting in acute symptomatic seizures are head injury, stroke, neuroinfections, cardiac arrest leading to hypoxic ischemic encephalopathy.

Seizures occurring during the course of viral encephalitis, meningitis are provoked seizures due to structural involvement of brain and require antiepileptic drugs for a period of three months after discharge from hospital. If there are no further seizures the drug can be withdrawn. Seizures due to metabolic disturbances like hepatic/renal dysfunction are controlled by antiepileptic drugs till the underlying cause is treated and do not require antiepileptic drugs at discharge (Table 8).

A large number medications, more than two-hundred and fifty listed, can cause seizures as a side effect. However, medicine induced seizure accounts to only 0.8.%. This group of medicines may be avoided in situations where seizures are part of the clinical picture (Table 9).

During follow-up, after a month, I got the information that another inmate of the same house had chocking sensation while taking bath in the same bathroom and just managed to open the door and come out. This prompted a more detailed history taking and it was found that the bathroom contained a gas geyser for heating water. The cylinder and the geyser were placed in the small bathroom which had ‘no’ ventilation. The geyser was kept on while bathing. In view of poor ventilation and incomplete combustion, carbon monoxide was generated, resulting in hypoxemia to the brain, thus causing unconsciousness.

If anyone gives history of “found unconscious in bathroom”, the first question to be asked is, “Is there a gas geyser in the bathroom?”. 12Adequate precautions to be taken to prevent mishaps, include placement of gas cylinders outside the bathroom, adequate ventilation in the bathroom and bath should be taken after switching off the geyser.

The next step is to identify the type of epilepsy and this is not for academic interest only, but has lots of practical relevance. The choice of drug, investigations and prognosis depends on the type of epilepsy, e.g. Juvenile myoclonic epilepsy (JME) does not need an MRI of the brain, the choice of drug is sodium valproate and the medication should be taken for a long period of time. As against this, consider complex partial seizure (CPS) which requires an MRI scan, and the choice of drug is carbamazepine and prognosis wise 60–70% of these are well controlled, but a good 30–40% will have ‘difficult to treat epilepsy’. The common variety of epilepsy—generalized tonic clonic seizures (GTCS)—is easy to treat and any of the four primary drugs are effective with a good response in 80% of cases and does not need an MRI of the brain in great majority. Having known the importance of identifying the type of epilepsy, let us refer to working classification of epilepsy. ‘Working’, because the International League Against Epilepsy (ILAE) classification is too elaborate and not necessary for practicing primary care physicians (Table 12).

Epilepsy syndromes are electroclinical syndromes comprising of specific clinical settings with characteristic type of seizures and have genetic basis with different prognosis (Table 13).

The GTCS is primary or secondary to CPS, SPS is the most common type of epilepsy. Idiopathic generalized epilepsies have certain characteristic features (Table 14).

However, all these features need not be present in every patient, every time.

In some patients, seizures occur only during sleep, which in a way is an advantage as it will not effect their active life.

Absences seizure occur in pediatric age group, and hence, is not considered in an adult patient (Table 16).

The above description is for the typical absence. However, absence seizures can have other features too. Types of absences are shown in Table 17.

Absence seizure has to be differentiated from complex partial seizure (CPS) in the pediatric age group (see Table 21).

The most striking feature is the number of attacks, i.e. several per day. Diagnosis can be clinched in the outpatient if the child is asked to hyperventilate for four minutes, which produces an attack of absence seizure.

Simple partial sensory seizure consists of sudden sensory symptoms of tingling, numbness or shock, pain, involving one half of the body and lasting for several seconds.

CT scan showed an acute infarct in the right frontoparietal region. Systemic and metabolic causes result only in generalized seizures.

The MRI is clearly the choice of investigation when the time and cost is not an issue as this has much greater resolution and can pick-up minor abnormalities also. If contrast MRI is required the cost further escalates. MRI is mandatory in patients with partial epilepsy, to identify lesions like meningioma, granuloma, glioma, medial temporal sclerosis, cavernoma (Figs 4 to 7).

In the new onset seizure when an imaging is asked for, standard MR sequences like T1, T2 FLAIR may be sufficient. However, “epilepsy protocol” in MR imaging is required in intractable epilepsy to look for subtle structural abnormalities like hippocampal sclerosis and focal cortical dysplasia. Imaging with “Epilepsy protocol” is much more expensive and is not necessary for new onset or well-controlled epilepsy.

In elderly, cerebrovascular diseases are the common cause for symptomatic seizures (Table 26).

In our country, solitary cysticercal lesion causing a flurry of seizures in a short period of 48 hours is well-known. Contrary to popular belief cysticercosis is seen in vegetarians specially due to consumption of uncooked foods, fresh salads, which are handled by infected persons. Simple hygienic principles like washing hands thoroughly while handling food will prevent transmission of the infection (Table 27).

29There is no need for anticysticercal drug as this is caused by a single dying cyst which liberates a chemical that irritates the surrounding cerebral cortex causing a cluster of seizures. If the scan shows several cysts in each slice of the brain, cysticidal drugs should not be given because the toxin liberated on killing the cysts causes intense cerebral edema leading to death. To summarize, single cyst or several cysts do not require treatment. If there are a few live cysts, say about 10 or so, then cysticidal drugs may be given under the cover of steroids to prevent allergic edema of the brain. A repeat CT scan after 3–4 months shows disappearance of the lesion in majority of the cases or healed calcified granuloma or a resolving granuloma. In all these situations, if clinically the person is free from seizures the antiepileptic drugs can be withdrawn.

Often physicians are consulted when the patient is conscious after a head injury (if unconscious, surgeon should be consulted) to 32know whether AED should be started. In such cases, there is no role for prophylactic AED and in provoked seizures there is no need to continue AED (Table 29).

While the yield in GTCS is low, it is significantly high in absences particularly during hyperventilation. EEG is useful in the diagnosis of JME, CPS and Benign Rolandic epilepsy (Table 30).

EEG monitoring in intensive care set-up in an unconscious patient is necessary where electrical status epilepticus is considered, or when a patient in status epilepticus is seizure free, but continues to be unconscious. EEG monitoring is also useful to detect subclinical seizures.

When diagnosis of epilepsy is in doubt, some physicians tend to advise a course of AED for “therapeutic response”!! According to them, if the patient does not get a seizure in the next three months, it means that the patient has epilepsy!. This is not true as the epileptic seizure even without treatment may not occur at all or recur at longer intervals.

Once a firm diagnosis of epilepsy is made, the patient should be informed that the treatment is for a period of 2–5 years of seizure-free period. The patient should periodically consult the physician. If the patient is unwilling to continue medicine for such a long period, there is no point in prescribing the antiepileptic drugs (Table 32).

It is important to emphasize to the patient and the caregiver to maintain a seizure chart which helps the doctor in the revision of AED (Table 33).

The principles of AED therapy is shown in Table 34.

With newer AED aggressively being marketed, there is a tendency to present newer AED as first-line treatment (when it was introduced it was an add on drug!) which increases the cost factor substantially, leading to poor compliance and poor control of epilepsy.

41The dosage schedule depends upon the pharmacokinetics (Table 36). Phenobarbitone and phenytoin have long half-life and are hence, given once a day, preferably at night, while valproate and carbamazepine with shorter half lives are given in two divided doses.

Steady state determines the required time to increase the dose. Drugs requiring prolonged titration—4–6 weeks—are LTG, TOP, OXC, ZON; 1–2 weeks CBZ, GBP, initiate at therapeutic dose VPA, LEV. The AED are steadily increased till seizures are under control; the rate at which the AED are increased varies (Table 37).

As in antibiotics, AED too have narrow and broad spectrum action. When the type of epilepsy is uncertain, broad spectrum AED should be selected (Table 38).

Table 39 shows the mechanism of action of antiepileptic drugs.

There is limited evidence to suggest that mechanism of action is useful in choosing appropriate combination of AED. The combination of drugs in clinical practice are VPA and ESM in Absence.

PB and PHT in GTCS, CBZ and VPA for focal seizures, VPA and LTG have synergistic action and are used in JME. Many AEDs are bound to plasma proteins mainly albumin and it is the unbound fraction which enters from blood into tissues (Table 40).

In presence of hepatic dysfunction the AED which are metabolized in liver are avoided; similarly in renal dysfunction, the AED eliminated by renal route are avoided, or where necessary, drug dosage is reduced appropriately.

The management of epilepsy is like the management of hypertension and diabetes. The dosage has to be steadily increased till the end result is achieved, in epilepsy the end point is no seizures. The dosage is started with the motto “start low, go slow”. In a normal adult, phenobarbitone is started as 30 mg hs and increased to 60 mg after 2–3 weeks with subsequent upward titration once in 2–3 weeks to the maximum tolerable dose or 120 mg.

With phenytoin it is 100 mg hs to be increased to 200 mg after two to three weeks and then subsequent titration once in 2–3 weeks; if seizure recurs, to a maximum of 400 mg hs.

Carbamazepine 200 mg twice a day is the standard adult dose. However, it is better to start with 100 mg in the morning and 200 mg in the night and increase it to 200 mg twice a day after a week with subsequent titration once a week. If seizure recurs, increase by 200 mg every week. Higher doses should be given in the night. Valproate is started as 200 mg twice a day with subsequent titration by 100 mg every 3rd or 4th day, if seizures recur, with higher dose given in the night (Table 45).

As the duration of treatment is 2–5 years of seizure-free period, the cost factor should be taken into consideration while selecting the AED (Table 46).

The list of newer antiepileptic drugs is getting longer with more and more drugs entering into the market (Table 47).

The newer AED entered the market as add-on drugs. Although they are not more effective than the primary drugs and are much costlier, but their side effects are lesser. In senior citizens and pregnant women, newer AED (lamotrigine, levetiracetam) are preferred because of lesser side effects.

Every drug is tried as add-on drug in every patient depending on the treating clinician. More and more newer AEDs are added to the list as no single newer AED is effective as add-on drug.

Hematological evaluation and liver function test are carried out once a year.

Epilepsy may be associated with other illnesses. Instead of adding another drug for that condition, select an AED which is effective for both the conditions. Similarly some AED need to be avoided due to comorbid illness (Tables 50 and 51).

Follow-up once in 3–4 months and hemogram and liver function test to be done once a year.

Table 55 shows the benefits and risks of AED withdrawal.

51A few patients would like to continue AED indefinitely for fear of relapse.

Intractable epilepsy is defined as occurrence of two or more seizures per month for a period of more than two years despite using two or more appropriate AED in the maximum tolerated dose (Table 56).

In case of intractable epilepsy invasive procedures like sphenoidal EEG, placement of electrodes, extradural, subdural or even cortical are resorted to identify seizure focus.

In earlier days, drug resistance was thought of only when all the drugs that were available were tried but failed. Today with increasing knowledge about AED and improved technology and good results after epilepsy surgery, drug resistance is considered when two appropriate drugs are tried for two years which failed to produce a no “seizure” condition. It is better to think of epilepsy surgery at an early date.

It is not as though every patient whose epilepsy is not controlled by drugs can go for surgery. The principle of surgery is very simple, there should be an area in the brain which is clearly identified to have an epileptic focus (i.e. the seizure discharges occur from a particular area) and once this area is identified it should be surgically removed without producing any disability to the patient. To identify this focused area, a neurologist has to work-up the case which may take a few weeks.

The work-up includes dedicated MRI, video EEG, functional MRI, etc. However, once a candidate is deemed fit for surgery, the results of surgery are excellent with 50% of the patients undergoing surgery becoming free from seizures without antiepileptic drugs and another 25% requiring much less dose of antiepileptic drugs. Surgery for medial temporal sclerosis is the most common.

Recent advances, include deep brain stimulation (DBS), targeting subcortical structures and anterior thalamus, responsive stimulation, i.e. stimulation to abort spontaneous seizure which requires implanta­tion of an electrode.

Febrile seizures are defined as seizures occurring between the age of 6 months and 5 years during an episode of febrile illness without neuroinfection and no past history of unprovoked seizures.

Febrile seizures are provoked seizures and not epilepsy. The seizures are provoked by abrupt rise in temperature. Tables 57 and 58 show the characteristic features of febrile seizures.

The long-term effects of single febrile seizure like risk of epilepsy and cognitive dysfunction is nil. In febrile status and atypical febrile seizure there is a possibility of pre-existing neurologic dysfunction which may increase the risk of developing epilepsy later.

Only 30% of children with single febrile seizure have further febrile seizures and do not require AED. Recurrent febrile seizures upset parents who require counseling. Why give the child AED to eliminate the fear and anxiety of parents?

Breath holding spells, seen in children are mistaken for epilepsy. As the term denotes the striking clinical feature is holding the breath, usually while crying (Table 60).

The problem of epilepsy becomes much more difficult in children who have evidence of associated brain damage in the form of cerebral palsy/mental retardation. In these situations, it is the brain damage which is responsible for seizure and not vice versa. The seizures become difficult to control in some patients with brain damage. In school going children, the concern and anxiety of parents is understandable as they are worried whether the child will have a seizure in school resulting in injury to the child or more importantly others will come to know that the child has epilepsy! However, there is no reason to restrain the child from going to school, if the seizures are well-controlled. It is always advisable to inform the class teacher that the child has epilepsy and what the teacher should do in case of an attack and also the teacher should be requested to write a note to the parents if an attack occurs in school. The other concern is about the antiepileptic drugs interfering with memory and learning process, so much so that there are complaints from parents that the child is losing grades in school because of the medicine. The fact is that in the standard dose that is given, most drugs do not interfere with the learning process. However, epilepsy should not stop them from studying or achieving success. Children with epilepsy have the same level of intellectual capacity as others. Epilepsy is often hidden from the child, imposing uncalled for restrictions like not to attend picnics, sports, play, which will make the child rebellious and depressed. This needs to be tackled in a sensitive way. Factually a child with well-controlled seizure can lead a very normal life with normal education, taking part in various sports, picnics, etc.

Incidence of both acute symptomatic seizures and unprovoked seizures is higher in senior citizens above the age of 65 years. Acute symptomatic seizures are more common because of occurrence of brain injury due to stroke, infection, head injury, neoplasm and metabolic disturbances. Cerebrovascular disease is responsible in 40–50% and metabolic disturbance in 10–15%. Fifteen percent of stroke survivors develop epilepsy in first five years. Partial seizures, as expected, are much more common than GTCS. No definite cause could be attributed (idiopathic) in up to 70% in younger age group, while in elderly it is about 50%.

Management of epilepsy in elderly is challenging, both in diagnosis and treatment. In diagnosis because of varied and atypical presentation resulting in either under diagnosis or over diagnosis. It is commonly confused with TIA, TGA, hypoglycemia and other comorbid situations and the falls due to seizure may be wrongly attributed to imbalance, poor vision and cognitive impairment. Treatment is also challenging because of comorbid situations, wherein several drugs are being taken for different disorders resulting in drug-drug interaction, poor compliance, cognitive deficits, decreased absorption, drugs side effects and intolerance.

Generally, the first seizure in younger age group is not treated; but in elderly, the recurrence rate being higher, it is advisable to start AED after the first seizure itself. With reference to AED, there are several factors to be considered like absorption, protein binding, drug metabolism, clearance, pharmacokinetic considerations, comorbid situations, side effect profile and drug interaction tolerability. Among primary AED, the adverse side effects include: PHT causing confusion and ataxia, OXC and CBZ resulting in hyponatremia and VPA resulting 58in hyperammonemic encephalopathy. All of these also affect the bone health which is already brittle in elderly. In this context, the newer AED like LTG, LEV and GBP are better tolerated with less adverse effects and also do not affect the bone health.

Whatever antiepileptic drug is chosen it should be started with a low dose and titrated slowly to avoid toxicity. Phenobarbitone is generally avoided as also phenytoin because of a narrow therapeutic window. Sodium valproate is the drug of choice for generalized epilepsy whereas carbamazepine is given for partial seizures. When primary antiepileptic drugs are not tolerated lamotrigine, levatiracetam may be used (Table 61).

Catamenial epilepsy is a type of epilepsy which is related to menstrual cycles, wherein the seizures occur just before, during or after a period. The first thing is to confirm that the seizures are indeed related to the menstrual cycle by maintaining a diary of the seizures and the first day of the period and this should be maintained for at least 6 consecutive months. If the diary confirms the relationship of the menstrual cycle with occurrence of seizure then an antiepileptic drug, e.g. (Clobazam) during the menstrual phase is added.

Polycystic ovarian syndrome (PCOS) is a fairly common condition with or without epilepsy. This condition is associated with irregular periods and decreased fertility. However, women on sodium valproate are more prone to develop this, particularly when given in large doses. In such a situation, one should change the antiepileptic drug. It is wise to do abdominal ultrasound in young women with epilepsy before starting VPA to assess whether PCOS is already existing.

It is important to realize that neither epilepsy nor the AED will affect the sexual life of the individual. More often the disinterest may be due to depression as a result of the diagnosis and has nothing to do with the illness.

Contraception may be an issue in women taking enzyme inducing antiepileptic drugs, namely, phenobarbitone, phenytoin, carbamazepine and oxcarbazepine. It is not that the seizures increase when oral contraceptive pills are taken with these medicines, rather it is the other way round, that is, these antiepileptic drugs will reduce the estrogen level thus, causing failure of pills resulting in unplanned pregnancy. Drugs like sodium valproate and levitracetam do not interfere and hence, are safe to take. Alternately the estrogen content of the pill should be increased in consultation with the concerned doctor. When not feasible other methods of contraception like barrier contraception, intrauterine contraceptive device (IUCD) can berecommended.

On the other hand, oral contraceptives can decrease lamotrigine levels thus precipitating seizures.

At the time of consultation if already pregnant and seizures are well under control, then no need to change AED.

Though hemodilution brings down the AED level there is no need to increase AED unless there is seizure recurrence. Only in the case of LTG an upward revision may be required anticipating break through seizures.

Minor anomalies are those which do not interfere with function, e.g. low set ears, hypertelorism, digital hypoplasia. Here again it is 2–3 fold higher than in general population.

The anomalies are due to a combination of factors which include effect of epilepsy, AED and genetic causes. The anomalies are seen in normal population in 2–2.5% while in those on AED monotherapy it is seen in 4% and in those on AED polytherapy it is seen in 6.8%. Importantly, higher the dose more the anomalies, particularly for VPA. Hence, it is advisable to keep the dose of VPA to less than 800 mg per day. In recent years, postnatal development of the child has come under attention and it has been reported that fetal exposure to VPA during the antenatal period results in increased incidence of autism, autistic spectrum disorder, lower IQ and poor cognitive development. Hence, it is best to avoid VPA during pregnancy (Table 63).

63Finally, the often asked question is whether the child will inherit the epilepsy. The risk of epilepsy in general population is 1% which is raised marginally to 2–4% if first degree relative is affected that too depending on the type of seizure the woman has.

The required AED in the prescribed dose must be continued through-out pregnancy, delivery and after delivery even while breastfeeding.

It is unfortunate that women with epilepsy have wrong notions regarding continuing the treatment during pregnancy for fear of effects of the drug on the fetus. It is equally disturbing to note that the family physician, as well as the obstetrician, share a similar view resulting in inappropriate suggestions. Time and again I see patients who have been recommended by their obstetricians to terminate the pregnancy as they are on antiepileptic drugs. They are asked to plan for pregnancy/conceive after getting “cured of epilepsy”. Both these advises are incorrect. A woman with epilepsy can certainly marry, conceive, carry on with the pregnancy expect an uneventful delivery and have a healthy child whom she can breastfeed. This is true for more than 90% women with epilepsy.

Today continuous seizures lasting for more than five minutes or two or more seizures without regaining consciousness in between attacks is the practical definition and this also allows to start AED aggressively to prevent further seizures.

Status epilepticus is a medical emergency and is best managed in the intensive care unit. The earlier the status is controlled the better the prognosis.

Status epilepsy can be divided into four stages and the management and prognosis depend on the stage.

The common causes are neuroinfections (e.g. viral encephalitis, pyogenic meningitis) cerebrovascular accidents including cerebral venous thrombosis. In those with prior history of epilepsy, abrupt stoppage of AED can precipitate status epilepticus (Tables 65 to 67).

If alcohol-related status is suspected, IV 100 mg thiamine followed by 50 mL 50% dextrose should be given. Maintenance of vitals, airway, blood pressure should be ensured. Treatment of the cause of status (e.g. infection) should be continued parallely. Prognosis depends on the cause; refractory status is usually due to underlying causative illness like encephalitis/meningitis. Nonconvulsive status is an important consideration in a patient who is unconscious/has altered sensorium and all other common causes being ruled out, continuous EEG monitoring will help to detect non-convulsive status.

66Status epilepticus can result in cerebral damage mainly due to underlying disease causing status, and hypoxemia, The most common cause of status in our country is neuroinfections like viral encephalitis, bacterial meningomeningitis, stroke including cerebral venous thrombosis and metabolic derangements.

In eclampsia, the drug of choice is IV magnesium sulfate 2 g and continue infusion 2 g per hour in 5% dextrose.