A Case Study Q&A with Edward Faught, MD

The More You Know: Profiling a Patient With Newly Diagnosed Epilepsy

Patient History

A 37-year-old man was referred to the neurology clinic for evaluation of seizures and options for antiepileptic therapy. Three weeks previously, he had awakened earlier than usual and had gone downstairs. His wife heard a strange noise in the kitchen and found him convulsing on the floor. She called 911, and he was taken to an emergency department (ED), where he arrived approximately 30 minutes after the call. On examination, he was confused and combative, seemed to be moving his left arm less than his right, but had no other apparent neurological abnormalities. An urgent CT scan of the head revealed a small area of encephalomalacia, apparently old, in the anterior right frontal lobe. Laboratory tests were normal except for a mild elevation of serum CPK. He had been given diazepam 5 mg intravenously in the ambulance, and received 15 mg/kg of intravenous fosphenytoin in the ED. Three hours later he was alert and cooperative, had no focal neurological abnormalities, but reported some dizziness and a mild headache. Prior to discharge from the ED, his serum phenytoin level was 12 µg/mL. He was sent home with a prescription for phenytoin capsules at a daily dosage of 300 mg at bedtime.

In the neurology clinic, he provided a past history of a concussion resulting from a motorcycle accident two years previously, after which he had been unconscious for about an hour. He had been hospitalized overnight but did not recall the results of neuroimaging studies. He has been having problems with early awakening from sleep at night. Additional history from his wife revealed that, for about a year, her husband has sometimes been very restless and agitated during sleep. She said that he seemed to awaken from sleep and thrash around in bed for 10 to 15 seconds, after which he would respond verbally and then return to sleep. She told her husband that she thought he had been having nightmares, but he had no recollection of having bad dreams. These events occurred every one to two months, and had not been relieved by taking a benzodiazepine before bedtime every night to help improve his sleep.

Since the ED evaluation and starting phenytoin treatment, he had experienced no further seizures but complained of feeling slightly unbalanced when walking and had mild sleepiness. His general and neurological examinations were normal except for a slight impairment of tandem gait. An EEG revealed intermittent focal slowing, with occasional sharp waves in the right frontal region (F4). His serum phenytoin level was 18.5 µg/mL.

Diagnosis

The patient was given a diagnosis of epilepsy, with complex partial seizures of right frontal lobe origin and one secondarily generalized tonic-clonic seizure. The presumed etiology was brain injury that resulted from the previous head trauma.

Q:

Why had the patient’s seizure disorder been unrecognized for so long and why might this patient have experienced a generalized tonic-clonic seizure?

A:

Frontal lobe complex partial seizures are typically nocturnal and brief, involve hypermotor activity, and produce little or no postictal confusion. They may be mistaken for nightmares or other sleep disturbances. In this case, sleep loss may have contributed to the incidence of a tonic-clonic seizure. Although the EEG is often normal in this syndrome, in this case the abnormal interictal EEG helped to support the the diagnostic impression.

A decision was made to transition from phenytoin to topiramate. He was asked to start with 25 mg of topiramate at bedtime, increasing by 25 mg/wk to a planned dosage of 100 mg BID. Phenytoin was continued at the same daily dosage.

Q:

For this patient, what are some of the considerations when selecting AED therapy?

A:

Antiepileptic drugs (AEDs) that are approved by the FDA for initial monotherapy of partial-onset seizures include the older AEDs, phenytoin, carbamazepine, and valproate, and the newer medications, topiramate and oxcarbazepine. This patient will likely need AED treatment indefinitely because of the fixed structural brain injury and the late occurrence of posttraumatic seizures. In this case, a newer AED was chosen in order to avoid some of the possible long-term side effects and drug interactions associated with medications in the older AED group. Frontal lobe seizures are often refractory to treatment, so there is a good possibility that this patient will need combination drug therapy in the future; newer AEDs generally have fewer drug interactions, therefore they may be better "base drugs," to which other AEDs can be added if necessary. Either of the two newer AEDs approved for initial monotherapy could have been chosen; topiramate was selected partly because of its broad coverage of seizure types.

Two months later, the patient returned for a neurology clinic visit. He had experienced no more convulsions or nocturnal events, but complained of fatigue and slowed thinking.

Q:

What is the most reasonable course of action to address the patient’s side effects?

A:

Although topiramate can cause fatigue and cognitive symptoms, the incidence of these adverse drug reactions (ADRs) is less in topiramate monotherapy than in combination therapy, therefore the ADRs may not be attributable to topiramate alone. Topiramate is a mild inhibitor of the CYP450 isoenzyme 2C19, which is involved in the metabolism of phenytoin, possibly contributing to the high phenytoin serum level of 26.5 µg/mL found during this clinic visit. Based on this his phenytoin was slowly tapered at the rate of 100 µg/wk. On his next clinic visit two weeks later, he felt more alert. He was asked to continue topiramate at 100 mg BID. A serum topiramate level two weeks later was 7.2 µg/mL.

Q:

Is it necessary to measure serum levels of topiramate?

A:

Although determining topiramate serum levels is not required for therapy, it may be useful to obtain a serum level when the target dose of a newly introduced drug is reached; this provides a benchmark for judging future variations in therapeutic response or adverse effects.