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Reasons for uncontrolled seizures in children: the impact of pseudointractability

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / y e b e h Reasons for uncontrolled seizures in children: The impact of pseudointractability Ali A. Asadi-Pooya , Mehrdad Emami a Neurosciences Research Center, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iranb Jefferson Comprehensive Epilepsy Center, Department of Neurology, Thomas Jefferson University, Philadelphia, USA Purpose: We investigated the various possible reasons for uncontrolled seizures in patients under 18 years of age to determine the impact of pseudointractability. We also investigated the various forms of pseudointractability in children with uncontrolled seizures.
Methods: In this cross-sectional retrospective chart review study, all patients under 18 years of age with their first seizure occurring at least 6 months prior to the referral date, taking at least one antiepileptic drug (AED),and having at least one seizure in the past 3 months were studied. The presumed reason for uncontrolled sei- zures was arbitrarily considered to be one of these five categories: poor adherence; wrong medication; wrong Uncontrolled seizuresPseudointractability dose of the correct medication; diagnosis other than epilepsy; and finally, medically refractory epilepsy. Statisti- cal analyses were performed using Chi‐square and Fisher's Exact tests to determine potentially significant differ- ences, and a P value less than 0.05 was considered significant.
Results: During the study period, 198 patients were referred to us due to uncontrolled seizures. Ninety patients (45%) were taking one AED, 55 (28%) were taking two AEDs, and 53 (27%) patients were taking more thantwo AEDs at the time of referral. Four percent of these patients did not have epilepsy. Forty‐seven percent ofthe children with uncontrolled seizures had medically refractory epilepsy; 37% were taking the wrong AEDs;10% were taking suboptimal doses of AEDs; and 2% had poor drug adherence.
Conclusion: Uncontrolled seizures in children are a commonly encountered problem, particularly at epilepsy clinics.
One should consider all possible reasons for these uncontrolled seizures, including non-epileptic seizures,pseudointractability, and medically refractory epilepsy. The mainstay for making a correct diagnosis is a detailedclinical history.
2012 Elsevier Inc. All rights reserved.
the impact of pseudointractability. We also tried to determine the vari-ous forms of pseudointractability in these patients.
Epilepsy is defined as a condition characterized by chronic recurrent epileptic seizures due to a primary disturbance of brain function Ep- ilepsy is a common chronic neurological disorder in children Themainstay of treatment in children with epilepsy is antiepileptic drug In this cross-sectional retrospective chart review study, all patients (AED) therapy. In the past two decades, many new AEDs have been in- under 18 years of age who were referred (either as self-referral or re- troduced to the market, so that there are now more than 20 medications ferred by another physician) to the outpatient epilepsy clinic at Shiraz available to treat epilepsy. The physician, therefore, has many choices University of Medical Sciences from January 2009 through October and can tailor therapy. However, having many alternatives also allows 2009 due to presumably uncontrolled seizures were studied. Inclusion for the possibility of choosing an inappropriate or suboptimal agent criteria were as follows: age below 18 years at the time of referral; that may result in uncontrolled seizures (pseudointractability) with the first seizure occurring at least six months prior to the referral On the other hand, more than one-third of individuals with epilepsy date; taking at least one AED since the presumed diagnosis; and finally, have persistent seizures despite taking appropriate AEDs: these are having at least one seizure in the past three months. A clinical diagnosis of the child's disorder was made based on clinical grounds, and all In this study, we investigated the various possible reasons for patients had to be under the care of the epileptologist at our institution.
uncontrolled seizures in patients under 18 years of age to determine Outpatient electroencephalography (EEG) was performed in all pa-tients at the time of referral. Study time for EEG was 10 min, and weperformed intermittent photic stimulation in all patients. Hyperventila-tion was typically performed in children above five years of age if they ⁎ Corresponding author at: Neurosciences Research Center, Shiraz University of Medical were cooperative. Inpatient video-EEG monitoring study was performed when considered necessary for the diagnosis. The study time for the 1525-5050/$ – see front matter 2012 Elsevier Inc. All rights reserved.
A.A. Asadi-Pooya, M. Emami / Epilepsy & Behavior 25 (2012) 341–344 Table 1Final diagnosis of patients who were referred with uncontrolled seizures.
Focal epilepsy (other than temporal lobe epilepsy) video-EEG monitoring was 120 min, and it was required to record both standard deviation) at the time of referral was 9 years (±5). The mini- wakefulness and sleep (either normal or drug induced) in all patients.
mum age was 8 months and the maximum age was 17.5 years. Seizure Other tests (i.e., blood tests, imaging studies, etc.) were requested frequency in the past three months (up to the referral time) was reported to be daily in 93 patients (47%), weekly in 28 (14%), and We studied the demographic and clinical findings. Age, gender, monthly or occasionally in 77 patients (39%). Final diagnoses of these seizure type(s), seizure frequency, medication(s), other clinical findings patients are summarized in . Ninety patients (45%) were taking (i.e., EEG, imaging studies, blood tests, etc.), and final diagnosis of all one AED, 55 (28%) were taking two AEDs, and 53 (27%) patients were patients were registered routinely. Relevant clinical variables were taking more than two AEDs at the time of referral. The patterns of taking summarized descriptively to characterize the study population. The AED(s) among different diagnoses are summarized in . Sex dis- presumed reason for uncontrolled seizures was arbitrarily considered tribution among various diagnoses was not different statistically, in to be one of these five categories: 1. Poor adherence, defined as more two-by-two comparisons. Electroencephalogram findings in patients than one missed dose per week; 2. Wrong (suboptimal) medication, de- with uncontrolled seizures are summarized in Normal routine fined as inappropriate AED for the syndromic diagnosis (e.g., carbamaz- EEGs were sometimes observed in patients with idiopathic generalized epine for childhood absence epilepsy or ethosuximide for frontal lobe epilepsy or focal epilepsy, but EEG was almost always abnormal in pa- seizures ; 3. Wrong (suboptimal) dose of the correct medication; tients with symptomatic generalized epilepsy (P= 0.0001). Long-term 4. Diagnosis other than epilepsy (e.g., psychogenic non-epileptic sei- video-EEG monitoring was often abnormal in patients with epilepsy.
zures, syncope, movement disorder, or breath‐holding spells); and fi- Brain MRI findings in patients with uncontrolled seizures are summa- nally, 5. Medically refractory epilepsy, defined as failure of adequate rized in . Brain MRI was more often abnormal in patients with trials of two tolerated, appropriately chosen, and used AED schedules focal epilepsy or symptomatic generalized epilepsy compared with to achieve sustained seizure freedom . For example, if a patient that in patients with idiopathic generalized epilepsy (Pb 0.02). However, with childhood absence epilepsy had received reasonable doses of the results were similar in patients with idiopathic generalized epilepsy both valproate and ethosuximide (whether as monotherapies or in compared with that in patients with non-epileptic paroxysmal seizure- combination) in his drug history, he was considered to have medically like attacks (P= 0.5); non-specific findings such as atrophy or cyst (among other possibilities) could be seen in both conditions. Blood Statistical analyses were performed using Chi‐square and Fisher's tests were not performed in most patients, and they were not conclusive exact tests to determine potentially significant differences, and a P in others who had them done (irrespective of the final diagnosis). Pre- value less than 0.05 was considered significant. This study was con- sumed reasons for having uncontrolled seizures among all patients are ducted with the approval of the Shiraz University of Medical Sciences Re- summarized in . Presumed reasons for having uncontrolled sei- zures among patients with a confirmed epilepsy syndrome are summa-rized in . The most common reason for having uncontrolledseizures in patients with idiopathic generalized epilepsy was considered During the study period, 198 patients under 18 years of age were re- ferred to us due to uncontrolled seizures. One hundred twenty‐seven Results of EEG studies in patients referred with uncontrolled seizures.
(64%) were males and 71 (36%) were females. The mean age (± Pattern of AED usage among patients with uncontrolled seizures.
SGE: symptomatic generalized epilepsy; TLE: temporal lobe epilepsy; IGE: idiopathic AED: antiepileptic drug; SGE: symptomatic generalized epilepsy; TLE: temporal lobe generalized epilepsy; UE: unclassified epilepsy.
epilepsy; IGE: idiopathic generalized epilepsy; UE: unclassified epilepsy.
a In some patients routine EEG was not done due to financial reasons.
A.A. Asadi-Pooya, M. Emami / Epilepsy & Behavior 25 (2012) 341–344 Results of brain MRI study in patients referred with uncontrolled seizures Presumed reasons for having uncontrolled seizures among patients with confirmedepilepsy syndrome.
Presumed reasons for having uncontrolled seizures [number (%)] SGE: symptomatic generalized epilepsy; TLE: temporal lobe epilepsy; IGE: idiopathic generalized epilepsy; UE: unclassified epilepsy.
a In some patients (other than patients with idiopathic epilepsy syndromes) MRI was not done due to financial reasons.
AED: antiepileptic drug; SGE: symptomatic generalized epilepsy; TLE: temporal lobeepilepsy; IGE: idiopathic generalized epilepsy; UE: unclassified epilepsy.
to be taking the wrong AED. However, in patients with focal epilepsy orsymptomatic generalized epilepsy, true medically refractory epilepsy(defined as failure of adequate trials of at least two tolerated, appropri- further testing and diagnostic information. Electroencephalography is ately chosen, and used AED schedules (whether as monotherapies or the most valuable ancillary test compared with the other diagnostic stud- in combination) to achieve sustained seizure freedom, evident in the ies including brain imaging studies (e.g., MRI) or blood tests patient's history ) was considered to be the most common reason.
). One valuable option is to obtain long-term video-EEG monitoring, al- These differences were statistically significant (Pb0.04). It should be though often one must simply wait and observe a patient over an extend- mentioned again that 55% of the patients were receiving two or more ed period of time before reaching a diagnosis.
AEDs at referral and 16% had received two or more AEDs before, in Once epilepsy has been diagnosed, an antiepileptic drug appropriate their drug history (in total, 71% of the patients had two or more AEDs for that condition may be prescribed. The goal of treatment is to prevent in their dug history). Those patients [58 patients (29%)], who were treat- future seizures from recurring. Treatment is typically started with one ed with only one AED in their drug history were most often those with of the first line AEDs. First-line drugs should be effective and well toler- non-epileptic disorders or those with poor drug adherence or were cat- ated. For localization-related epilepsy (partial onset seizures), these egorized as receiving the wrong medication or suboptimal dose of AED.
drugs include carbamazepine, lamotrigine, and oxcarbazepine among In other words, in order to comply with the new definition of medically others . For generalized epilepsies, first-line drugs include valproate, refractory seizures , we mentioned uncontrolled seizures for referral of lamotrigine, levetiracetam, and topiramate among others . If a the patients to our clinic and then categorized the patients into five clas- first-line drug controls seizures and does not cause side effects, thera- ses including those with medically refractory seizures (if we observed peutic adjustments are not needed. Should seizures persist, the medica- failure of adequate trials of at least two tolerated, appropriately chosen, tion regimen should be adjusted. One should aim for treatment with a and used AED schedules in the patient's drug history).
single agent (monotherapy) to lessen the chances of adverse effectsand drug interactions Despite all efforts, many individuals with ep-ilepsy have persistent seizures. In our study, about half of the children with uncontrolled seizures indeed had medically refractory epilepsy.
Medically refractory epilepsy was particularly common among patients Uncontrolled seizures are a commonly encountered problem, partic- with symptomatic generalized epilepsy and focal epilepsy (specifically, ularly at epilepsy clinics. First, rigorous attempts should be made temporal lobe epilepsy) ). However, if an appropriate treatment to verify the diagnosis of epilepsy and to ensure that the patient does approach has not been implemented or the patient is adherent, they not have non-epileptic seizures or some other disorders. In this study, might experience uncontrolled seizures (pseudointractability). In our we observed that a minority of patients (4%) who were treated for study, pseudointractability was observed in more than half of the chil- uncontrolled seizures indeed had other diagnoses. The differential diag- dren referred with uncontrolled seizures to our clinic. Interestingly, nosis in children and adolescents includes psychogenic non-epileptic more than one-third of the children were experiencing uncontrolled seizures, syncope, and breath‐holding spells, among other possibilities seizures while taking inappropriate AED(s) for their condition. This (night terror, colic, tics, etc.). Clinicians should never forget to inquire was particularly common among patients with idiopathic generalized about drugs, particularly in adolescents. Some drugs such as tramadol epilepsy ). In a previous study, only 32% of patients with juve- may cause seizures . A correct diagnosis of epilepsy needs a standard- nile myoclonic epilepsy (JME) were correctly diagnosed at referral.
ized approach, particularly with regard to taking a detailed clinical his- The main factors responsible for misdiagnosis were failure to elicit a his- tory. The routine use of a standard pro forma minimizes the risk of tory of myoclonic jerks and misinterpretation of myoclonic jerks In missing clinical findings, including seizure types, and most of the time another study, a considerable delay of approximately five years was ob- leads to a correct diagnosis An incorrect diagnosis may indeed served in the diagnosis of juvenile myoclonic epilepsy when physicians have many negative consequences; the patient is then taking unneces- were possibly not familiar with this syndrome .
sary antiepileptic drugs with the potential for significant adverse effects.
Consumption of a suboptimal dose of an appropriate AED or poor If the diagnosis of epilepsy cannot be established, one should obtain drug adherence is another possible cause for pseudointractability in pa-tients with epilepsy. In a previous study from the same region, it was ob- served that about one-fourth of the children with epilepsy did not have Presumed reasons for uncontrolled seizures among all patients.
optimal drug adherence . Paying more attention to medicationeducation for patients and parents and decreasing the complexity of the treatment regimen might increase drug adherence .
This was a cross-sectional study. A follow-up study is necessary to as- certain the exact number of the patients with true medically refractory A.A. Asadi-Pooya, M. Emami / Epilepsy & Behavior 25 (2012) 341–344 epilepsy. In other words, it is necessary to show that in follow-up revised [2] Huseyinoglu N, Ozben S, Arhan E, Palanci Y, Gunes N. Prevalence and risk factors of epilepsy among school children in eastern Turkey. Pediatr Neurol 2012;47(1): treatment schedules did in fact lead to seizure remission in those who were considered as having received poor treatment schedules or those [3] Asadi-Pooya AA, Sperling MR. Antiepileptic drugs: a clinician's manual. Oxford Uni- who had poor drug adherence (if the situation is corrected).
versity Press; 2009. 264 pages; ISBN13: 978-0-19-536821-5; ISBN10: 0-19-536821-5.
[4] Kwan P, Schachter S, Brodie MJ. Drug-resistant epilepsy. N Engl J Med 2011;365: [5] Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342: [6] Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: Uncontrolled seizures in children are a commonly encountered prob- consensus proposal by the ad hoc Task Force of the ILAE Commission on Thera- lem, particularly at epilepsy clinics. When facing a child with uncontrolled peutic Strategies. Epilepsia 2010;51(6):1069-77.
seizures, the health-care provider should consider and investigate all pos- [7] Thundiyil JG, Kearney TE, Olson KR. Evolving epidemiology of drug-induced seizures reported to a poison control center system. J Med Toxicol 2007;3(1):15-9.
sible etiologies, including non-epileptic seizures and seizure mimickers, [8] Asadi-Pooya AA, Emami M, Sperling MR. Age of onset in idiopathic (genetic) general- pseudointractability, and medically refractory epilepsy. The mainstay for ized epilepsies: clinical and EEG findings in various age groups. Seizure 2012;21(6): making a correct diagnosis is having a detailed clinical history.
[9] Marson AG, Al-Kharusi AM, Alwaidh M. The SANAD study of effectiveness of carbamaz- epine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomized controlled trial. Lancet 2007;369:1000-15.
[10] Marson AG, Al-Kharusi AM, Alwaidh M. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalized and unclassifiable epilepsy: We appreciate the Neurosciences Research Center, Shiraz University an unblinded randomized controlled trial. Lancet 2007;369:1016-26.
of Medical Sciences for financially supporting this study.
[11] Montalenti E, Imperiale D, Rovera A, Bergamasco B, Benna P. Clinical features, EEG findings and diagnostic pitfalls in juvenile myoclonic epilepsy: a series of 63 patients.
J Neurol Sci 2001;184:65-70.
[12] Mehndiratta MM, Aggarwal P. Clinical expression and EEG features of patients with juvenile myoclonic epilepsy (JME) from North India. Seizure 2002;11:431-6.
[1] Blume WT, Luders HO, Mizrahi E, Tassinari C, van Emde Boas W, Engel Jr J. Glossary of [13] Asadi-Pooya AA. Drug compliance of children and adolescents with epilepsy. Seizure descriptive terminology for ictal semiology. Epilepsia 2001;49(2):1212-8.

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