A first seizure is a frightening event for families and friends, but for patients it may engender a certain degree of confusion and reluctance to seek attention. They are often amnestic for the event, and the consequences of a diagnosis of "epilepsy" are serious. In one's approach to diagnosis and management one must not only draw upon our collective knowledge of the pathophysiology of seizures but upon our abilities to humanely guide and counsel anxious patients. The consequences of a diagnosis and treatment must be weighted against the risks of recurrent seizures.

This review will cover the following areas:
	- Definitions, and prevalence - Risk of recurrence - Predictors of recurrence - Patient evaluation - Initiation of treatment

A seizure is a paroxysmal self limited event caused by an excessive electrical discharge of the central nervous system. Epilepsy is a disorder characterized by recurrent seizures (Hauser & Kurland 1975). All of us have a lifetime risk of having a single seizure of approximately 8.8%. The prevalence of epilepsy is however approximately 0.65%. It is clear that most persons with an initial seizure will never have another (Hauser et al. 1990).

Our task is simplified somewhat by the fact that 2/3 of persons presenting to medical attention for initial treatment for seizures will have had multiple episodes and so by definition have epilepsy. Their risk of recurrence is therefore high and most require treatment. Only 1/3 of patients with a new onset seizure will be identified after the first episode (Hauser et al. 1983). Their risk for recurrence is uncertain. Less than half will have another seizure and the benefits and consequences of therapy need to be carefully evaluated (Shinnar et al. 1990, Hopkins et al. 1988).

The concept of provoked (a seizure secondary to a neurological or physiological insult) vs. unprovoked (no clear precipitating insult) seizure has been developed by Dr. Allen Hauser. Prior to this concept the literature on risk of recurrence varied widely and hence was not as helpful. There was a greater risk seen in retrospective studies and for studies of first generalized tonic clonic seizure. Many persons with partial seizures are unrecognized until they have a generalized convulsive episode thus their recurrence rates appeared very high. We now recognize certain features which are predictors of recurrence and which must be searched for in the evaluation of patients presenting with this disorder.

A substantial proportion of persons with an initial seizure will never have another. Treatment of a person with a single seizure is generally not recommended. Exceptions are circumstances in which recurrence risk is high: symptomatic seizure secondary to brain infection or injury, persons with pre-existing neurological deficit, persons with juvenile myoclonic epilepsy. Evidence of injury to cortical gray matter appears to be the best general predictor of risk, but there are exceptions.

There are some persons presenting with multiple seizures who one would not treat. Children with Benign Rolandic Epilepsy probably do not need pharmacologic treatment. Persons whose seizures are the result of alcohol or drug withdrawal are generally not treated. Their risk of recurrence is a function of their risk for recidivism. It is possible however for persons with substance abuse to also have an underlying epilepsy. The rare woman whose seizures only occur during pregnancy gestational epilepsy, probably does not need treatment when no longer pregnant.

The natural history of untreated epilepsy is essentially unknown. Gowers writing in 1881 reported that in 1/3 of patients with an initial seizure a second one occurred within one month. A retrospective study by Elwes et al. (1988), found that in 32% of persons with a first seizure a second attack followed in one month. In 51% it followed in 3 months and by one year 87% of persons developing epilepsy had had their second seizure. It is for this reason that clinically we seldom have to deal with the question of recurrence. following an initial seizure.

History of previous neurologic insult
A person presenting with a history of a previous neurologic insult (severe head injury, stroke, CNS infection, or intracranial lesion) have a 2 to 3 fold risk of recurrence compared to persons without such as history (Hauser, Annegers and Kurland 1991). For those persons with congenital neurological abnormalities who have mental retardation or cerebral palsy prior to the development of their first seizure, the risk of recurrence is virtually 100%.

Abnormal neurologic examination
When a person has a remote neurological insult and presents with an initial seizure the presence of abnormalities on a neurologic examination is a predictor of future recurrence. If no such etiologic event has occurred an abnormal neurologic examination appears to have little predictive value (Hauser 1995).

Electroencephalogram
Following a first unprovoked seizure an abnormal EEG has excellent predictive value. An EEG with epileptiform abnormalities has an 60 - 80% risk of recurrence. If the abnormalities are simply slowing and not epileptiform, the risk of recurrence drops to 30-40%. Persons with a normal EEG have a risk of 10-25% (Von Donselaar et al. 1992).

Seizure type
The evaluation of the predictive value of seizure type is complicated by the difficulty in accurately determining whether the onset is partial or generalized. In children partial onset seizures appear to increase the risk of recurrence. In adults this is not the case (Shinnar et al. 1990, Hirtz et al. 1984, Camfield et al. 1985). Juvenile Myoclonic Epilepsy of Janz or the more modern term, myoclonic epilepsy of adolescence is an unusual disorder occurring in 3 - 4% of persons with epilepsy (Janz & Christian 1957). Characterized by myoclonus upon awakening approximately 85% of patients also have generalized tonic clonic seizures. Affected persons appear to never enter remission. A history of myoclonus upon awakening and the typical EEG with polyspike and slow wave complexes in a patient presenting with a generalized seizure secures the diagnosis.

Family history
Most of the studies evaluating the impact of family history on recurrence have been performed in children. Only one has found an association and that for children in whom a sibling had epilepsy (Hauser et al. 1990).

History of Acute Symptomatic (Provoked) Seizures
By symptomatic seizure one refers to a patient with a previous history of a seizure following a neurological insult such as a head injury, stroke, or CNS infection. Such persons by definition have not had a diagnosis of epilepsy until their recurrence. A history of a seizure following a previous neurological insult increases the risk of recurrence by a factor of 4 (Hauser et al. 1990, Annegers et al 1980, Annegers et al 1988, So et al 1993).

Febrile Convulsions
The seizures are by definition convulsions occurring during a febrile illness in a child between the age of 6 months to 3 years. Their prevalence is 3% in the general population but higher 14% in siblings of children with febrile convulsions and slightly higher in children of parents with epilepsy, 5%. Persons with febrile convulsions are at increased risk for the development of epilepsy, 7% by the age of 26 years. This risk appears to be associated with recurrent febrile convulsions within the same illness, those which last more than 15 minutes, and those with lateralizing features (Wallace 1988). In a study of adults presenting with their first seizure a history of febrile convulsions was associated with a 50% chance of recurrence within 5 years ( Hauser et al. 1990).

Circadian Timing
The time of day of the appearance of a seizure is a predictor of recurrence. Nocturnal seizures have a greater likelihood for recurrence than those occurring while awake (Shinnar et al. 1991).

The extent of an initial evaluation has been the subject of some debate. The yield of neuroimaging studies for example is rather low. Only 10-16% of persons with new onset seizures after age 45 have a cerebral tumor. I would argue however that the physician's responsibility is to the patient first. A patient deserves to know that all reasonable efforts have been made to make a diagnosis and that the risk of something untoward occurring to them in the future has been minimized. I therefore recommend the following initial evaluation.

History: one cannot emphasize enough the importance of a careful detailed history. Additional information from other observers is usually required. The components of the seizure, presence or absence of an aura, the progression of the ictus and characteristics of the post ictal phase may permit one to differentiate between partial and generalized epilepsies and even lateralize a focus. Specifics which ought to be established are:

- Presence of precipitating factors
- Presence and manifestation of auras
- Detailed description of the event and duration
- Post ictal behavior and duration
- Effect on consciousness
- Any history of previous similar events

The presence or absence of historical risk factors should also be determined:

- Pregnancy, birth and developmental history
- Febrile seizures
- CNS infection
- Head trauma with loss of consciousness, skull fracture or cortical contusion
- Drug or alcohol abuse
- Family history of epilepsy
- Concurrent medications
- Birthmarks or skin lesions
- Toxic exposures
- Metabolic disturbances
- Cerebral vascular disease
- Degenerative disease

Spending time on the history is the best single neurologic investment. Though often considered indelicate inquiring about the injudicious use of psychoactive substances is often helpful as this information is rarely volunteered and may have an important bearing on future management.

Examination: look for lateralizing signs, but do not minimize the mental status. Persons with good social skills may mislead one to think that they are intellectually intact when careful questioning often reveals otherwise.

Particularly in children evaluation of the skin is important. Neurocutaneous disorders may present with seizures. Tuberous sclerosis is characterized by the triad of: mental retardation, seizures and adenoma sebaceum. Depigmented nevi, shagreen patches and periungal fibromas are frequent clinical markers. Subependymal calcified tumors are the cause of the seizures in this condition. Neurofibromatosis is characterized by multiple cafe au lait spots and the development of fibromas and neuromas along the course of peripheral nerves. Intracranial neoplasms are common. In Sturge-Weber syndrome a port-wine nevus is seen on the face in the territory of the first division of the trigeminal nerve. It is accompanied by a vascular malformation of the ipsilateral cerebral hemisphere and consequently difficult to control seizures. Hereditary hemorrhagic telangectasia (Osler-Weber-Rendu syndrome) is associated with vascular anomalies and malformations of the CNS hence seizures and strokes. Telangiectasias of the skin and mucus membranes are characteristic.

Laboratory studies: metabolic disturbances are seldom the cause of first onset seizures, and a careful history may guide one in the proper evaluation. If one is not seeing the patient acutely only a CBC, hemoglobin A1C, BUN, creatinine, and liver function tests may be necessary to screen for infection, diabetes, renal or hepatic disease. If the patient has previously been seen in an emergency department obtain the acute labs as they will be more likely to reveal any etiologic abnormality. The utility of urine of blood testing for toxic substances is contingent upon the proximity of the exam to the seizure, but can be very useful.

EEG: though epilepsy is a clinical diagnosis the EEG remains the gold standard. In non acute situations a sleep EEG is more likely to provide useful information and I suggest simply obtaining a sleep deprived or induced study as the initial EEG. A normal waking study is fairly useless for only 1/3 will show epileptiform abnormalities and one will always wonder what sleep would have revealed, so save time and money by getting one in the first place. Provocative techniques such as hyperventilation and photic stimulation should always be included.

Neuroimaging: MRI scanning with thin slices through the hippocampus if partial seizures are suspected is the study of choice. Both T1 and T2 weighted images should be performed. CT scanning has such low resolution it is reserved for evaluating cerebral hemorrhage or in acute situations with persistent neurological findings which cannot be explained and MRI is not available.

Once it has been established that a seizure has occurred one should attempt to classify it. Proper classification will assist one in choosing initial AED therapy and assist the patient and family in determining the prognosis.

The current standard is the International League Against Epilepsy's Classification of epileptic seizures. This scheme uses both clinical and EEG data and a modified version is presented below.

Non epileptic seizures should always be considered in the differential diagnosis. The prevalence is unclear, but 25-33% of patients referred for EEG telemetry obtain this diagnosis. While a large number of such patients are conversion reactions there are a number of other etiologies. Vasovagal attacks, cardiac arrhythmia's, sleep disorders, and intoxications can present as a seizure and need to be ruled out.

The primary question is when do we treat? There is no evidence that anti-epileptic drugs (AED) prevent the occurrence of epilepsy in a person at risk. These medications appear to suppress seizures in a person with the biological substrate in which epileptiform neurons all ready exist.

Initiating treatment and hence establishing the diagnosis of epilepsy will have significant consequences for a person's life. It may restrict their driving privileges and can eliminate them from consideration of certain jobs such as pilot, commercial diving or commercial automobile or truck driving. It will prevent or at best make difficult obtaining health and life insurance. It will attach a social stigma which can have profound negative effects on self esteem and social opportunities. It is for these reasons that we are generally reluctant to treat a first seizure unless the risk of recurrence is high.

Medical treatment with AED unfortunately also carries risks. The dose related side effects of fatigue, ataxia, and confusion are common to all these drugs. Though relatively rare, hepatic failure, aplastic anemia, and severe dermatologic reactions of the Stevens-Johnson Syndrome can occur. With some AED chronic use may also be associated with cerebellar atrophy and attendant ataxia or a peripheral neuropathy. Clearly one must balance the benefits of treatment with the risks. If it is likely that seizures will recur treatment is clearly preferable to non treatment despite the medication risks. This is because persons with epilepsy are at greater risk for injury and death than persons in the general population. The increased morbidity and mortality is associated with seizures.

Persons with epilepsy have standardized mortality ratios (SMR) 2 - 3 times higher than the general population. Their increased risk appears to be limited to the first 10 years after diagnosis. The increased mortality is not simply a function of deaths from the underlying etiology of epilepsy. Patients with cyrptogenic seizures have SMR of 2.4 (Brorson & Wranne 1987). Common causes of death in persons with epilepsy include pulmonary infections, neoplasms and accidents particularly drowning (Klenerman et al. 1993)

Sudden unexplained death in epilepsy (SUDEP) occurs approximately once in every 370 persons with epilepsy. Such patients are generally found dead in bed with no discernible explanation. Risk factors include: male gender, generalized seizures, young age, and subtherapeutic plasma AED concentrations (Leestma et al. 1989).

Prospective studies of newly diagnosed epilepsy are uncommon. In the landmark study by Elwes et al. (1984), 106 patients with newly diagnosed but untreated epilepsy were treated with AED monotherapy, monitored and the dosage adjusted if seizures recurred. The patients were followed for 66 months. The results were good. The proportion of persons seizure free for 2 years was 88% at 4 years, 92% at 8 years.

In another prospective study of 283 newly diagnosed patients who were not monitored only 48% obtained 2 year remissions (Beghi and Tognoni 1988). The effectiveness of therapy appears to be a function of continued and effective monitoring not simply initial diagnosis and treatment.

Initiation of treatment with AED should occur when there is evidence of substantial risk for recurrence. It should be started with a single medication and titrated until seizure control is obtained or unacceptable side effects occur. Seizures being random events make it difficult to know when control has necessarily occurred. Choosing a target dose likely to place the patient in the mid therapeutic range is a good place to start. A useful formula for estimating the proper loading dose is:

Dose in mg/kg = the volume of distribution X the difference between the desired plasma concentration and the current plasma concentration.

Prior to initiation of therapy baseline laboratory determinations of CBC, electrolytes, renal and hepatic function should be drawn to provide a basis of comparison if the patient develops AED related metabolic abnormalities. The routine measurement of these variables is not required. It cannot prevent or protect against idiosyncratic reactions.

Most patients do best with a gradual initiation of their medication which minimizes their risk of developing dose related side effects. Once a patient develops side effects to a medication they may become reluctant to continue it despite its efficacy.

Plasma AED levels should be used sparingly to assist the physician in determining if further titration is necessary, or which of two medications is contributing to toxicity. Levels should attempt to be drawn during a steady state, and if not trough at least know when the last dose was in relation to the sampling.

Dosing schedules should be targeted to coincide with other regular daily activities to improve compliance. The more frequent the dose schedule the greater the likelihood of missed doses. As mentioned above, studies in which patients were monitored demonstrated higher proportions of persons with seizure control than those in which monitoring was not performed. Initiation is only the beginning effective treatment requires a continual relationship between physician and patient.

All currently available AED have anticonvulsant properties. There is also tremendous variation among patients. That said there is an accepted convention of first line usually older less expensive medications and second line AED. They are listed in table 2.

Determining whether to treat a patient with a new onset seizure requires an estimation of the risk of recurrence. Proper evaluation of this risk requires: a history, neurologic examination, sleep EEG, and MRI brain scanning.

In evaluating a person with new onset of seizures :

First confirm the event as a seizure. If a single event, are there significant risk factors: previous neurological deficit, previous acute symptomatic seizure, abnormal neurologic examination, epileptiform abnormalities on EEG. If so initiate treatment with appropriate AED.

If no significant risk factors, educate and observe. If a recurrence is to happen it is likely to do so within the first few months following the first seizure.

If the seizure is recurrent when the patient first presents unless there has been drug or alcohol withdrawal or Benign Rolandic Epilepsy, initiate treatment with appropriate AED. Push in monotherapy until seizures are controlled or side effects become problematic. If unsuccessful start a second AED and taper off the first medication. Reserve polytherapy for persons not controlled on monotherapy after 3 AED.

Persons treated with AED require monitoring and continued follow up if adequate seizure control is to be maintained. The prognosis for persons with epilepsy has improved with more effective medication, but the key factor is better neurological management which requires a partnership between patient and physician.

-End-

Mark S. Yerby M.D., M.P.H.
North Pacific Epilepsy Research
Mother Joseph Plaza
9427 SW Barnes Road - Suite 595
Phone: 503-291-5300
Fax: 503-291-5303

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