Assoc. Prof. Dr.. Ebru Altındağ *, Professor. Dr.. Betul Baykan **
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Istanbul Florence Nightingale Hospital, Department of Neurology
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Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Department of Clinical Neurophysiology and Epilepsy Research and Application Center of Istanbul University (epimers)
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Epileptic seizure is a clinical condition resulting from the temporary abnormal electrical extension in brain cells .Disorders related to functions of consciousness, behavior, emotions, motions or perception are seen clinically  limited to a period of time. The most common type of seizure of epilepsy manifested With a wide variety of clinical conditions is generalized tonic-clonic seizure. Every person suffering a seizure does not mean that he/she has epilepsy. Epilepsy is diagnosed if the attacks recur over  time with certain characteristics for every patient, sometimes spontaneously and sometimes on the basis of triggering factors.
Epilepsy is the most common neurological disorder of childhood and adolescence and the second disorder in adulthood after stroke.  The incidence in developed countries is 20-50/100.000. This disease is seen with equal frequency in men and women in all age groups, but it is mostly seen in the youngest and oldest groups.

Requiring a long-term treatment and monitoring , this disease affects the quality of life significantly. Seizures are controlled with accurate treatment in the majority of patients and patients continue their normal life. Thus it is very important to control the seizures. The cornerstone of treatment of epilepsy is antiepileptic drugs (AEDs). However, AED does not eliminate the underlying cause of epilepsy, does not affect the progression of epilepsy and cannot prevent the progression of epilepsy in people who are at risk. It is known that they can reduce or eliminate seizures only within the time they are used. While deciding to start treatment of epilepsy, seizure type, epilepsy syndrome, the expected natural course of seizures in epilepsy and identifying the risk of recurrence have primary importance.

AED therapy may not be successful in all patients as requested. The most common cause of failure is the patient's adherence to treatment. Therefore, the treatment of epilepsy requires good cooperation between physician and patient. In order to sustain success in the treatment, the physician should talk with the patient about the scope of the treatment, anticipated duration and considerations to take; the patient should answer all the questions in  a patient, understanding and reassuring approach. Patients should be reminded to get adequate amount of sleep each night at the same time, not participate in heavy work and night shifts, not consume much alcohol and stay away from psychological factors which can trigger seizures .  In addition, not driving motor vehicles,  not using dangerous sharp,  electrical appliances   at work places, staying away from risky sports activities  such as swimming should be recommended.

Before starting treatment with AEDs first requirement is to establish the correct diagnosis. In order to make a diagnosis of epilepsy, firstly it needs to be verified whether the seizure  or seizures really occurred with an epileptic nature.  If epileptic seizure is confirmed, then the physician should be sure that acute brain affect which can lead epileptic seizure is not present. While making the differential diagnosis, syncope, arrhythmia, transient ischemic attacks, hypoglycemia, hypocalcemia, hyperventilation syndrome, state of alcohol or drug deprivation and pseudoepileptic (psychogenic nonepileptic seizures) should be considered.
After making sure of the diagnosis, the second step is to decide whether medication is required or not. Against the negative consequences of recurrent seizures, the benefits that AEDs provide,  as well as the harm it can bring should be taken into account. On the other hand, the patient's  possible attitude and behavior, living conditions, psychosocial status and most importantly  his/her  the expectations from the treatment are also important within this treatment process which will take too long.

Treatment Approach in First Seizure

The physicians don’t have a common behavior about whether to start AED treatment after the first seizure or not.  In the first seizure, seizures with  infrequent intervals or in some epilepsy syndromes which are known to be benign (such as benign rolandic epilepsy of childhood) , determining the type and clinical characteristics as well as likelihood of recurrence of seizures  by taking advantage of the findings of electroencephalography (EEG) and neuroimaging and observing the natural course of the disease may be more accurate before starting a treatment which may take long , have side effects or perhaps be unnecessary.

In a recent study, 4000 cases with definite diagnosis of epilepsy in whom the issue of starting AED was not determined; were randomized in two groups as to start treatment immediately or wait and followed for at least 5 years. The risk of new seizures in patients who begin treatment has decreased for the first 1-2 years; but no difference was observed  in terms of long term remission between the group for whom treatment was started and the other group for whom treatment was not started .
Risk of recurrence of the seizures varies according to etiology. Whereas the risk of recurrence of seizures related  to metabolic or toxic reasons is low, the risk of recurrence of seizures related to permanent brain injury like brain abscess are reported to be higher. The risk of recurrence after the first seizure in the presence of EEG abnormalities and neurological disorders reaches to 90%.

The general approach is initiation of therapy after a second seizure. Treatment can be initiated after the first seizure in cases which long lasting seizures  with focal onset are defined, first seizure is in status epilepticus form, neurological symptoms such as hemiparesis, mental retardation or cerebral palsy are present, epilepsy is present in family history, the patient has a high-risk job, the patient himself or his family are unable to accept recurrence, abnormality is present in EEG and neuroimaging examinations.

Principles of  Staring Antiepileptic Drug Treatment

Whether the etiology is known or not, the treatment should be started if the diagnosis of epilepsy is definite and seizures are recurring.  The following cases should be considered before starting the therapy.

* Treatment with a single drug selected according to the  syndrome or type of seizure (monotherapy)
* Starting with the least effective dose and increasing the dose until complete seizure control is provided or side effects appear.
*Checking the medication blood level in case of toxicity or suspected non-compliance of the treatment and not changing the dose only by examining the blood level  
* Certainly informing the patient that the effect of the medication would be lost when used with other drugs (such as antibiotics, oral contraceptives etc) or toxic level would be reached.
*  Explaining the risks of discontinuation or forgetting the use of drug to the patient
* Monotherapy with an appropriate second selection if no response to the first drug is achieved; and following an appropriate drug combination in case of still no response.
* Reminding that the treatment conditions are to improve the quality of patient’s life


AED Selection

Clinicians should choose the most appropriate medication while treating newly diagnosed patients. Seizures and type of syndromes, EEG findings help determining the epilepsy syndrome and choosing the appropriate drug.

While selecting from the available antiepileptics, the drug's spectrum of activity, efficacy, long-and short-term potential side effects, dose titration and ease of use, cost, its effects on reproductive cycle, the patient to be a woman, child or the elderly, systemic diseases and comorbid conditions should be considered . In addition, the metabolism of AEDs, drug-drug interactions must be considered. Selected AEI should prevent seizure activity clinically and electrophysiologically, should be effective and long-lasting protective at the same time, should able to be well tolerated and improve quality of life without drug interactions.

Conventional AEDs called phenytoin (DPH), FB (phenobarbital), carbamazepine (CBZ), valproate (VPA) are preferred mostly due to their low costs, long-term experience of usage and greater information about their side effects. The disadvantages of these drugs are having drug interactions and side effects especially more in women, children and the elderly. New AEDs  are known to be better tolerated, have less side effects and drug interactions. Should be noted that new AEDs may be as effective as conventional AEDs.

3 Hz spike-wave discharge observed during short-term absence seizure in EEG examination of a patient with Idiopathic generalized epilepsy

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FIGURE 1.
3 Hz spike-wave discharge observed during short-term absence seizure in EEG examination of a patient with Idiopathic generalized epilepsy



Today, in epilepsy cases presenting  idiopathic generalized tonic-clonic seizures, (Figure 1) VPA is the first option, lamotrigine (LTG) or levetiracetam (LEV) are used as an alternative. Again, topiramate (TPM) may be used in patients with no response to these options. in partial and secondarily generalized epilepsy, CBZ, oxcarbazepine as an alternative (OXA) and DPH which is the economic option are used. While VPA is effective in Myoclonic and absence seizures, ethosuximide (ESM) can be tried only in absence seizures. In the comparative studies no significant difference between the effectiveness of these drugs have been introduced. DPH, VPA and LEV are to options to be referenced due to their fast loading advantage in cases of status epilepticus and tendency to status. If the type of the seizure has not been defined, VPA, LTG or LEV may be used. It should be noted that CBZ, vigabatrin and gabapentin (GBP) can increase absence and myoclonic seizures. Whereas the first choice in female patients planning pregnancy is LTG, GBP and CBZ may be alternative therapies in partial epilepsy.

AEI interactions and Side Effects

side effects varies and toxicity occurs according to the characteristics of binding of the drugs. The two  drugs highly bound to proteins compete with each other when used. For example when  VPA and DPH are used in combination, VPA increases the level of DPH and lead DPH toxicity. Tiagabine (TGB) from the new antiepileptics bind to protein in high rates whereas lakosamid binds less than 15%, LEV and GBP not only never bind to protein but also have no interaction with any other drug.

Former antiepileptics may have dose-dependent side effects such as headache, dizziness, diplopia, fatigue and ataxia. CBZ causes hyponatremia and benign neutropenia; DPH causes gingival hyperplasia and hirsutism, VPA causes gaining weight, menstrual irregularities and hair loss; ESM causes gastrointestinal irritation; FB causes hyperactivity, irritability and sedation. Dose dependent nausea, headache, dizziness, feeling of fatigue may occur in all new antiepileptics. LTG causes ataxia and insomnia; high dose GBP causes gaining weight; TPM causes mental slowing, word-finding difficulties and weight loss; TGB causes dizziness and weakness; OXA causes hyponatraemia; zonisamide causes the fatigue and weight loss.

Many antiepileptic drugs are excreted from the liver and makes changes in hepatic metabolism. Liver enzyme-inducing drugs expedite hepatic metabolism and  can cause weaker seizure control. enzyme inhibition Builders slow hepatic metabolism , increases serum concentration and may lead drug intoxication. Former antiepileptics such as FB, DPH and CBZ form enzyme induction. In addition, affect the metabolism of agents such as vitamins and estrogen. When enzyme inhibitor VPA is used in polypharmacy doses of other drugs should be considered to be low. Felbamate, TPM, and OXA are specific enzyme inhibitors. The new antiepileptic GBP, TGB and LEV neither form enzyme induction nor enzyme inhibiton and makes this situation advantageous. Pregabalin, Another AED similar to GBP is effective in partial or secondary generalized seizures and this drug also doesn’t bind to protein and interact with liver enzymes.

Exceptions in the medical treatment of epilepsy

While prescribing former or new antiepileptic to young women, many factors such as hormonal balance, infertility, teratogenicity must be considered. Enzyme-inducing AEDs can affect the metabolism of vitamin D, especially during prolonged use can reveal osteomalacia.  Since CBZ, DPH and  FBI interacts with oral contraceptives high-dose estrogen-containing preparations should be used with these drugs. Otherwise contraception may be ineffective. In the use of AEDs in pregnancy, major anomalies such as cardiac defects, microcephaly, growth retardation, neural tube defects and  craniofascial and digital anomalies, minor anomaly such as cleft palate may develop.  

The risk of epilepsy increases in people above  sixty-five years old and the treatment varies. Epilepsy occurring in advanced age may respond low dose drugs. Side effects such as AED dependent sedation, tremor cognitive impairment can occur more easily.Since elderly patients are often combined with other drugs (antihypertensive, antidiabetic, etc.) drugs which have  low drug interaction, not-binding to protein and not forming enzyme induction should be preferred. Cognitive and psychological effect should be positive. 70% of all seizures in the elderly people can be controlled. Although the treatment basically resembles in children, there may be the pharmacokinetic difference, dosing and safety differences. While metabolism in children is rapid, metabolism is the same  with the adults after puberty.

Discontinuation of AED

 In the chronic use of antiepileptic drugs, since there may be side effects and remissions are able to be seen in some caes,  the medications may be discontinued by decreasing the dose gradually 2 years after the last seizure in childhood and 4 to 5 years after the last seizure in adulthood.  Studies show that discontinuation of the drug duplicates the rate of recurrence in patients. In addition to this, duration of remission remission duration until the last seizure, the presence of generalized tonic-clonic seizures, myoclonus may be mentioned among other factors which are effective in relapse. Rather than general criteria about discontinuation of drugs, the most accurate approach  is to act by evaluating the conditions specific to each patient.

Treatment-resistant seizures

Findings consistent with right mesial temporal sclerosis in Cranial MRI of a patient who was examined at our epilepsy center due to treatment-resistant epilepsy


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FIGURE 2.
Findings consistent with right mesial temporal sclerosis in Cranial MRI of a patient who was examined at our epilepsy center due to treatment-resistant epilepsy


While seizures can be controlled  in 60% of patients with initial AED treatment,  alternative treatment is required in 40% of the patients. Despite polytherapy and the use of appropriate drug seizures continue in 25% of patients. If epileptic seizures can not be controlled within 1 to 2 years after medication is started, combined drugs fails, unacceptable side effects occur with antiepileptic medications, a lesion  which is considered to be responsible in brain imaging examinations is present, such cases should be evaluated as candidate for epilepsy surgery. In particular, it gained certainity with the increased knowledge that while  some specific epilepsy syndromes don’t respond to medical treatment in general but benefit from surgical treatment. Mesial temporal sclerosis is the most typical and common example of this situation. (FIGURE 2, FIGURE 3)

Left temporal hypometabolism area detected in PET-CT study of another patient with mesial temporal sclerosis


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FIGURE 3.
Left temporal hypometabolism area detected in PET-CT study of another patient with mesial temporal sclerosis


Patients who are candidate for epilepsy surgery are evaluated by epilepsy neurologists with multiisciplinary approach at epilepsy centers that host infrastructure and specialists (neurosurgeon, neuroradiologist, psychiatrist, neuropsychologist) that medical and surgical treatment require . In these centers, not only the treatment-resistant epilepsy patients who are candidate for epilepsy surgery but also patients having psychological and / or psychiatric disease accompanying to epilepsy, those in whom seizures or epilepsy syndrome type could not be ensured and the patients having diagnosis problems are evaluated, too. In the evaluation of the patients for whom surgical interventions are planned  due to treatment-resistant epilepsy, it is known that 15% of the patient are diagnosed with pseudo-seizure in epilepsy centers. Therefore, following-up and treating such patients at epilepsy centers will be more beneficial for the patient.