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Diagnosis and Treatment of Epilepsy

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 Epilepsia,  45 (Suppl. 8):13–16, 2004 Blackwell Publishing, Inc.  C  International League Against Epilepsy

Educational Lecture

Diagnosis and Treatment of Epilepsy Hirokazu Oguni  Department of Pediatrics, Tokyo Women’s Women’s Medical U niversity, Tokyo, Tokyo, Japan

Summary: Purpose:  The correct diagnosis of epilepsy leads to an appropriate treatment. Thefirst step step is to distin distingui guish sh epilept epileptic ic seizur seizures es from from  Methods: Thefirst nonepi nonepilept leptic ic attacks attacks,, and to make make a precis precisee seizur seizuree diagno diagnosisand sisand classification. The next step is to identify the etiology or basic disorders underlying the epilepsy by physical and neurologic examinations, laboratory tests, including EEGs and neuroradiologic examinations. Although the EEG is the most important laboratory examination for the diagnosis of epilepsy, limitations of EEG interpretations must be recognized. syndromic classificatio classification n of the patients, patients, to deterdeter Results:  A syndromic mine whether they fit known syndromes, should be attempted.

If patients do not match a described syndrome, a neurobiologic approach, utilizing genetic, neurophysiological, and neuropharmacologic knowledge, alternatively provides useful information to understand the neurobiologic background of epilepsy. Conclusions:   Both approaches have advantages and disadvantages for diagnosing and treating epilepsy. Both approaches can be used used interc interchang hangeab eably ly with with patien patients ts with with seizur seizuree disdisorders, depending upon their condition. The epilepsy diagnosis, etiology, and seizure-type diagnosis should be reevaluated when seizur seizuree contro controll is insuf insuffi ficie cient nt with with first first-- and second second-line antiepileptic drugs. Key drugs.  Key Words: Words: Diagnosis Diagnosis of epilepsy—  epilepsy—  Syndromic approach—Neurobiologic approach.

Diagnosis and treatment of epilepsy cannot be separated; appropriate treatment can only be performed without a precise diagnosis of epilepsy. It is rare to observe a seizure directly at the first medical examination or at an outpatient clinic. Thus, the confirmation and diagnosis of  the seizure types usually rely heavily on the history taken from the parents or caregivers. The first requirement is to distinguish epileptic seizures from the nonepileptic attacks, such as syncopal attacks, atonic attacks caused by moyamoya moyamoya disease, and psychogen psychogenic ic seizures, seizures, etc. Syncope includes breath-holding spells in infancy, infancy, orthostatic dysregulation during childhood, and a noxious vasovagal reflex at any age. In distinguishing a syncopal attack from an epilep epileptic tic seizur seizure, e, we must must pay attent attention ion to the feelin feeling g of  “blackouts” or sensation of faintness immediately before loss loss of consci conscious ousnes nesss and the presen presence ce of a provo provokin king g facfactor, such as standing for a long time, sudden unexpected pain, or noxious stimuli. Next, we must ask the following questions directly to the patients or indirectly to the parents to make a precise seizure diagnosis including the aura content, clouded consciousness, understanding and production of language during the seizure if the patient

is conscious (the involvement of a dominant hemisphere), asymmetry of the seizures, presence of automatism, deviations of the eyes and head, and a dystonic arm posture. The clinical manifestation of ictal automatism may differ among young children and older children or adults. Young children may have an automatic seizure characterized by sudden rushing and holding their mother with a fearfu fearfull expres expressio sion n as if they they were were frighte frightened ned of attack. After we confirm that the attacks are of epileptic origin, we must ask the parents when the attacks most often occur; during during wakefulnes wakefulness, s, sleep, sleep, awakeni awakening, ng, or  drowsiness. In idiopathic generalized epilepsy, generalized tonic–clonic seizures (GTCSs) commonly occur during awakening or wakefulness, but during sleep or during wakefulness and sleep in partial epilepsy or symptomatic generalized epilepsy, respectively. We must ask carefully about the provoking factors of the attacks. In idiopathic generalize generalized d epilepsy epilepsy,, such as juvenile juvenile myoclonic myoclonic epilepsy epilepsy,, a lack of sleep provokes the attacks. The next step is to identify the etiology or basic disorders underlying the epilepsy, so we ask about family histories histories of convulsi convulsive ve disorders disorders and neurologica neurologicall diseases. eases. In Japan, Japan, a family family histor history y of invo involun luntar tary y movem movement ent,, late-onset dementia, or ataxia in adult relatives may suggest that children with intractable generalized epilepsy with with a slowly slowly progre progressi ssing ng clinic clinical al course course will will have have

Address Address correspond correspondenc encee and reprint reprint requests requests to Dr. Dr. H. Oguni Oguni at Department Department of Pediatrics Pediatrics,, Tokyo Women’ Women’ss Medical Medical Universit University, y, 8-1 Kawada-cho Kawada-cho,, Shinjuku-ku, Shinjuku-ku, Tokyo 162, Japan. Japan. E-mail: E-mail: [email protected] [email protected] twmu.ac.jp




dentatorubr dentatorubral-pa al-pallidol llidoluysia uysian n atrophy atrophy.. Questions Questions about the history, including febrile convulsions during infancy, developmental delay, and central nervous system infection should be asked. Physical and neurological examinations should be performed carefully to identify the localization and lateralization of minor neurological deficits. The dermatological findings should be carefully checked to rule out the presence of a neurocutaneous syndrome. Laboratory examinations should include blood sugar, calcium, calcium, phosphorus phosphorus,, magnesium, magnesium, creatine creatine kinase, kinase, and lactic acid, especially in children. In cases of intractable epilepsy, CSF lactate, urinary organic and amino acids, or  other specific tests may be required. The routine EEG should be recorded during wakefulness, sleep, photic stimulation, and hyperventilation. The EEG is the most important laboratory examination for the diagnosis of epilepsy, for the following reasons: a. Electroence Electroencephalo phalography graphy is able to identify identify epilepepileptiform tiform EEG activ activity ity,, suppor supportin ting g the diagno diagnosis sis of  epilepsy. Also worthy of attention is localized slowwave wave activ activity ity,, which which maysuggest maysuggest an underl underlyin ying g cerecerebral abnormality. abnormality. b. The The pres presen ence ce of a spec specif ific ic EEG EEG patt patter ern, n, such such as 3-Hz 3-Hz spike–wa spike–wave ve complexe complexess or rolandic rolandic discharge discharges, s, points points toward a specific epileptic syndrome and prognosis. c. The localization localization and lateralization lateralization of the epileptoepileptogenic genic EEG foci foci can expla explain in the clinic clinical al manife manifesta statio tion n of the aura aura and seizur seizuree manife manifesta statio tions ns of the patien patients. ts. In candidates for epilepsy surgery, the localization and lateraliza lateralization tion of epileptoge epileptogenic nic foci should be properly properly evaluat evaluated. ed. EEG examinatio examinations, ns, including including special special EEG electrodes electrodes such as sphenoidal sphenoidal,, zygomatic, and supraorbital electrodes should be considered. In contra contrast,we st,we also also must must know know thelimits thelimits forinterpre forinterpretin ting g the EEG findings for the following reasons: d. The epileptiform EEG abnormality abnormality may not be identifi tified ed in the the firs firstt EEG exam examin inat atio ion. n. In addi additi tion on,, a few few patients do not show any epileptiform EEG abnormalities on repeated EEG examinations (1). In such cases, we must make a diagnosis of epilepsy based solely on the clinical history of the seizures. e. The presen presence ce of an epilep epileptif tiform orm EEG abnorm abnormalality itself does not necessarily indicate the presence of epileptic seizures. Genetically determined epileptic EEG abnormalities, including rolandic spike discharges, generalized fast or 3-Hz spike–wave complexes plexes and photosensit photosensitivit ivity y are incidental incidentally ly identified identified in children without seizure disorders. A family history of convulsive disorders in close relatives may explain the presence of these epileptic EE G findings.  Epilepsia, Vol. Vol. 45, Suppl. 8, 2004


f. A localized localized epileptic epileptic EEG focus may shift in locallocalization, become multifocal, or spread diffusely with age in children with epilepsy (2). g. The EEG may include include both both focal focal and generali generalized zed epileptiform activity, which sometimes makes it difficult to classify epilepsy into either partial or generalized if the seizure type also is undetermined. One of the examples is symptomatic partial epilepsy with secondary bilateral synchrony, which is sometimes encountered during childhood (3). As a routine neuroimaging study for seizure disorders, a head computed tomography (CT) scan gives us information about the structural abnormality of the brain. In cases of symptomatic epilepsy, brain magnetic resonance imaging (MRI) provides more detailed information than does a CT scan. In patients with complex partial seizures, brain MRI is especially useful to identify temporal lobe abnormalities, because CT imaging is disturbed by temporal bone. A neuropsychological examination also gives us information with regard to selective higher cognitive dysfunction in patients with localization-related epilepsy. We must must make make a seiz seizur uree-ty type pe diag diagno nosi sis, s, then then an epilepsy diagnosis, and follow a treatment strategy based on the analysis of the aforementioned information obtained on an outpatient basis. It is now more common for  epilep epileptol tologi ogists sts to take take a syndro syndromic mic approa approach, ch, in which which the clinical and EEG characteristics, including the onset age, seizur seizuree types, types, circad circadianrhythmof ianrhythmof theseizures theseizures,, and qualit quality y of epileptic EEG abnormalities, are analyzed in detail (4). Then Then we look look for known known syndro syndromes mes sharin sharing g these these featur features es of the patients. The advantage of syndromic classification is to give us practically useful information regarding a precise diagnostic, prognostic, and therapeutic approach (5). However, not all patients fit into the described syndromes on an outpatient basis, although many epileptic syndromes have been proposed. In addition, these syndromes vary in specificity from some that represent broad concepts to others that are highly specific. Conversely, a neurobiological approach, with genetic, neurophysiologic, and neuropharmacological knowledge, provides useful information to understand the neurobiologic ological al backgr backgroun ound d of epilep epilepsy sy that that does does not fit into specific syndromes (5). Based on accumulated clinical and experimental evidence, Gloor (6) proposed a concept of generalized cortico-reticular epilepsy. Idiopathic epilepsy produced by genetically determined cortical hyperex perexcit citabi abilit lity y reside resided d at one end of a spectr spectrum, um, and symptomatic epilepsy produced by acquired diffuse gray matter pathology resided at the other end. Intermediate cases were determined by mixtures of the genetic and acquired factors. Conversely, Doose (7) proposed a concept of hereditary impairment of brain maturation, in which he considers that genetically determined multifocal sharp



Schematic tic FIG. FIG. 1.   Schema

drawin drawing g of the neuneurophysiologic mechanism underlying generalized spike-and-wave complexes. The neurophysiologic mechanisms underlying absence seizures and generalized spikeand-wa and-wave ve comple complexe xes s based based on variou various s exexperimental perimental studies (10–14) (10–14) are summasummarized and illustrated. This mechanism can apply apply in part to that that of spike-a spike-andnd-wa wave ve complexes produced by the secondary bilateral synchrony (12) and of focal spikeand-wave and-wave complexes. complexes. The generalize generalized d and focal spike-and-wave spike-and-wave complexes have been shown to give rise to atonic seizures, epileptic-negative myoclonus, absence or atypical atypical absence absence seizures, seizures, and transient transient interference with cognitive function. Ethosuximide suximide is considered to suppress suppress the spike-andspike-and-wav wave e complex complexes es by blocking blocking the T-type calcium channel and thus abolishing the rhythmic sustaining mechanism mechanism (14).

waves produce various clinical symptoms, and thus various epileptic syndromes, depending on the localization of  sharp waves in childhood partial epilepsy. epilepsy. These epileptic syndromes, including benign epilepsy with centrotemporal spike foci, benign occipital epilepsy, Landau–Kleffner  syndrome, syndrome, and epilepsy epilepsy with continuous continuous spike–wa spike–waves ves during slow sleep, etc., are thus recognized as a clinical phenotype or clinical spectrum of this genetically determined epilepsy epilepsy with multifocal multifocal sharp waves. waves. This conceptua conceptualizalization more easily can explain borderline cases. Atypical or  borderline cases are always identified, even in a discrete epileptic syndrome with homogeneous clinical and EEG charac character terist istics ics.. We should should consid consider er these these atypic atypical al cases cases as valuable examples giving us clues to the neurobiological background of the syndrome itself, rather than excluding them from the syndrome as heterogeneous epilepsy cases. If we do not, we may subdivide a small number of  patients into more and more subentities by rigid definitions, and this may be a never-ending story described by Doose (8). We have have shown shown a dramat dramatic ic effec effectt of ethosu ethosuxim ximide ide (ESM) (ESM) on childr children en with with atypic atypical al benignpartia benignpartiall epilep epilepsy sy,, or  cryptogenic partial epilepsy with secondary bilateral synchrony first seen with partial seizures, epileptic–negative myoclonus, and atypical absence seizures (9). The basic neurophysi neurophysiologic ological al mechanisms mechanisms underlying underlying spike-andspike-andwave wave discha discharge rgess helps helps in part part to expla explain in how how these these seizur seizures es are generated in the cortex and why they respond to ESM (Fig. 1). The neurobiological approach provides a global view of the factors underlying epilepsy, but it does not provide a precise diagnosis, prognosis, or therapeutic regimen, as does the syndromic approach (5). Thus, both approaches have advantages and disadvantages for ma king a diagnosis and treating epilepsy. At present, we should use both approachesinterchan approachesinterchangeabl geably y with patients patients with seizure seizure disorders, depending upon their condition.

Treatment decisions must consider recent advances in first unprovoked seizure studies. The recurrence rate of a first unprovoked seizure has been reported to range from 27 to 71%, depending on various factors (14). The recurrence rate reaches ∼30% in children with cryptogenic generalized seizures when no EEG abnormality is present (14). Antiepilep Antiepileptic tic drug (AED) treatment treatment decisions decisions should should be based upon the balance of risks and benefits of treatment, and the views of the patient or parents in the case of  a first seizure. seizure. A first-line first-line AED should be prescribed prescribed for  patients based on the seizure type and syndromic classifications. cations. The epilepsy epilepsy diagnosis, diagnosis, etiology etiology,, and seizure-ty seizure-type pe diagnosis should be reevaluated when seizure control is insufficient with first- and second-line AEDs.

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8. Doose H. Myoclonic-astat Myoclonic-astatic ic epilepsy. Epilepsy Res  1992;6(suppl): 163–8. 9. Oguni Oguni H, UeharaT, UeharaT, Tanaka anaka T, et al.Dramaticeffe al.Dramaticeffect ct of ethosu ethosuxim ximide ide on epileptic negative myoclonus. Neuropediatrics @ 1998;29:29–  34. 10. Weir Weir B, Sie PG. Extracellula Extracellularr unit activity in cat cortex during the spike-wave complex.  Epilepsia  1966;7:30–43. 11. 11. Elge Elgerr CE, CE, Spec Speckm kman ann n E-J, E-J, Proh Prohas aska ka O, et al. al. Patt Patter ern n of intracortical tracortical potential potential distribution distribution during focal interictal interictal epileptiepileptiform discharges (FIED) and its relation to spinal field potentials Electroencephalogr Clin Neurophysiol   1981;51:393–  in the rat. rat.   Electroencephalogr 402.

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12. Gloor P. Generalized Generalized epilepsy with spike and wave wave discharges: discharges: a reinterpreta reinterpretation tion of its electrographi electrographicc and clinical clinical manifestati manifestations. ons.  Epilepsia 1979;20:571–88. 13. Gloor Gloor P. Elec Electr trop ophys hysio iolo logy gy of gene genera rali lize zed d epil epilep epsy sy.. In: In: Schwartzkroin PA, Wheel H, eds.   Electrophysiology of epilepsy . New York: Academic Press, 1984:107–36. 14. Coulter DA, Huguenard JR, Prince DA. DA. Specific petit mal anticonvulsants reduce calcium currents in thalamic neurons.  Neurosci Lett  1989;98:74–8. 15. Shinnar S, Berg AT, AT, Moshe SL, et al. The risk of seizure seizure recurrence after a first unprovoked unprovoked afebrile seizure in childhood: childhood: an extended extended follow-up. Pediatrics  1996;98:216–25.

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