Periodic lateralized epileptiform discharges of pediatric patients in Taiwan

Periodic Lateralized Epileptiform Discharges of Pediatric Patients in Taiwan Kuo-Shin Chen, MD*, Meng-Fai Kuo, MD, PhD†, Huei-Shyong Wang, MD‡, and Song-Chei Huang, MD§ Periodic lateralized epileptiform discharges are special electroencephalographic abnormalities present in adults with stroke, brain tumor, intracranial hemorrhage, or other rare etiologies. Few reports focused on the etiologies in pediatric patients. We retrospectively reviewed 8002 of our pediatric electroencephalographic records for the past 12 years and listed all associated illness and their outcomes. Forty-four children with periodic lateralized epileptiform discharges were collected. We found that there was an obvious difference in etiologies of our pediatric patients from those reported in the literature. Nearly two thirds of our patients (28 children) were associated with central nervous system infections. The other etiologies included head injury, encephalopathy, epilepsy, and others. Herpes simplex virus was responsible for two thirds (12) of the 18 children with identified pathogens causing a central nervous system infection. Ten patients failed to have a defined pathogen. Periodic lateralized epileptiform discharges have a different clinical significance in pediatric patients than in adults. In Taiwan, central nervous system infection is the most common etiology of periodic lateralized epileptiform discharges in pediatric patients. Herpes simplex virus, although the most common pathogen, should not be considered to be the only cause of encephalitis in children with periodic lateralized epileptiform discharges. © 2003 by Elsevier Inc. All rights reserved. Chen K-S, Kuo M-F, Wang H-S, Huang S-C. Periodic lateralized epileptiform discharges of pediatric patients in Taiwan. Pediatr Neurol 2003;28:100-103.

From the *Department of Pediatrics, St. Paul’s Hospital, Taoyuan; ‡§ Division of Pediatric Neurology, Chang Gung Children’s Hospital, Taoyuan; Kaohsing §Medical College of Chang Gung University, and the †Division of (Pediatric) Neurosurgery, Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan

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Introduction The term periodic lateralized epileptiform discharges (PLEDs) was first mentioned by Chatrian et al. in 1964. The characteristics of the electroencephalographic (EEG) findings consist of periodic sharp waves or spikes, followed by background of slow waves with regular or near regular intervals of 0.3-5 (mostly 1-2) seconds [1]. This particular EEG abnormality evidences in adults with structural lesions such as acute stroke, which was the most common etiology [2-11], followed in frequency by tumor [11-13] and intracranial hemorrhage or subdural hemorrhage [14]. Other etiologies include encephalitis and metabolic disorders [12,15-17]. However, the studies of PLEDs in pediatric patients are rare [18-21], except in neonates [22-25]. This retrospective study was thus conducted. Materials and Methods From 1989 to 2001, 8002 consecutive EEG examinations were performed in the EEG rooms of Chang Gung Memorial and Children’s Hospitals at Linkou, Taiwan. Patients whose EEGs were found to have PLEDs were enrolled in this study. The recordings were obtained on 8or 16-channel EEG recorders with electrode placement according to the International 10-20 System. All EEG tracings were at least 30 minutes long. PLEDs were defined as a series of focal or lateralized sharp waves or spikes, followed by slow wave background, in a periodic or near periodic pattern with an interval of 0.3-5 seconds [1,2,9,26-28]. The PLEDs must appear for at least 20% of the recording time in patients older than neonates. For neonates the criteria of PLEDs must fulfill the description of Lombroso and Holmes [24]. Those equivocal or transient ones were excluded from this study to avoid the uncertainty of the final result. The EEG findings, patient’s identity, laboratory data, neuroimaging study, final diagnosis, and follow-up results were collected. Particular attention was paid to the etiology and the significance of PLEDs in different underlying diseases. Serologic study for patients with central nervous system (CNS) infections measured paired IgG titers for herpes simplex virus (HSV), cytomegalovirus, Japanese encephalitis virus,

Communications should be addressed to: Dr. Wang; Division of (Pediatric) Neurology; Chang Gung Children’s Hospital 199; Tung-Hwa North Rd.; Taipei 10591, Taiwan. Received April 16, 2002; accepted July 11, 2002.

© 2003 by Elsevier Inc. All rights reserved. doi:10.1016/S0887-8994(02)00493-9 ● 0887-8994/03/$—see front matter

Epstein-Barr virus, varicella, and influenza virus with enzyme linked immunosorbent assay. Virologic study included viral culture for cerebrospinal fluid, throat and rectal swabs, and polymerase chain reaction for HSV, influenza, and enterovirus. We defined patients to have “morbidity” if their follow-up neurologic conditions were worse than their premorbid status, including conditions such as increased focal deficits, intractable seizures, occurrence of involuntary movement or spasticity, need for nasogastric feedings, or being bed-ridden.

Results There were 44 patients (28 boys and 16 girls), ranging in age from 19 days to 14 years (mean 4.5 years and median 3.8 years), fulfilling the criteria of PLEDs described above. Only one neonate was included, a 19-dayold with hypoxic ischemic encephalopathy. The incidence of PLEDs in the unselected pediatric patients was 0.55% (44/8002). There were two cases excluded because of presence of focal periodic change on EEG for less than 10 seconds, which never recurred in the following tracings. Their clinical diagnoses were encephalitis of uncertain virus. The observed periodicity of the PLEDs in this study was 0.5–5 seconds in interval (0.2Hz–2Hz). The PLEDs were seen more frequently on the right hemisphere (28 cases) than on the left hemisphere (16 cases). Seven of the patients (15.9%) had independent PLEDs on bilateral hemispheric foci. The most common cause of PLEDs was CNS infection (28 cases, 63.6%). The second one was traumatic brain contusion or subdural hematoma (four cases, 9.1%). The third cause included metabolic disorders such as Reye syndrome (three cases, 6.8%), and idiopathic epilepsy without status epilepticus (three cases, 6.8%). Other rare etiologies including hypoxic encephalopathy, right middle cerebral artery infarction, arteriovenous malformation, leukodystrophy, status epilepticus without obvious etiology, and acute disseminated encephalomyelitis (ADEM), each accounted for one case (Table 1). The age distribution in different etiologies revealed no significance possibly resulting from the small number of patients. The mortality of patients with PLEDs was 22.7% (10 cases), and the morbidity was 50% (22 cases). The remaining 12 children (27.3%) with PLEDs were normal or had well-controlled epilepsy (only one anticonvulsant was used and successfully tapered after 2 years of treatment). PLEDs have been thought to be pathognomonic for herpes simplex encephalitis (HSE). However, in this series, HSE accounted for only 42.9% (12/28 cases) of the patients with CNS infection. Furthermore, HSV was responsible for two thirds (12 cases) of the 18 children of CNS infection with identified pathogens. Ten patients failed to have defined pathogens. There was a single patient with Japanese encephalitis virus, Epstein-Barr virus, varicella virus, cytomegalovirus, influenza virus, and combined Staphylococcus aureus and Pseudomonas

Table 1.

Etiologies for pediatric patients with PLEDs

Diagnosis CNS infection Head injury (brain contusion or subdural hematoma) Idiopathic epilepsy Metabolic disorder (Reye syndrome) Hypoxic ischemic encephalopathy Infarction (right middle cerebral artery) Arteriovenous malformation Acute disseminated encephalomyelitis Leukodystrophy Total

Case Number

Age Distribution

Good Outcome*

28 (63.6%) 4 (9.1%)

7 mo-12 yr 1-6 yr

8 1

3-14 yr 2-4 yr

2 0

4 (9.1%) 3 (6.8%) 1 (2.3%)

19 d

0

1 (2.3%)

3 mo

0

1 (2.3%) 1 (2.3%)

3 yr 5 yr

0 1

1 (2.3%) 44

7 yr 4.5 yr (mean)

0 12

* Good outcome: normal or well-controlled epilepsy (only one anticonvulsant used, and successfully tapered after 2 years of treatment). Abbreviations: d ⫽ Age in days mo ⫽ Age in months yr ⫽ Age in years

aeruginosa (Table 2). The only patient with mixed bacterial infection was noted to be an open infection after craniotomy. Discussion There are still some small variations on the definition of PLEDs. Chatrian et al. described EEG characteristic of PLEDs, based on 118 EEG tracings performed in 33 patients, as focal sharp waves, spikes or multiple spike complexes, followed by slow waves with the amplitudes of sharp waves or spikes mostly ranging from 50 to Table 2. PLEDs

Etiologies of CNS infection in pediatric patients with

Diagnosis

Case Number

Percentage

Herpes simplex encephalitis Japanese encephalitis Influenza encephalitis Varicella encephalitis Epstein-Barr virus encephalitis Cytomegalovirus encephalitis Mixed bacterial meningoencephalitis* Undefined pathogen Total

12 1 1 1 1 1 1 10 28

42.8 3.6 3.6 3.6 3.6 3.6 3.6 35.6 100

* Staphylococcus aureus and Pseudomonas aeruginosa. Abbreviations: CNS ⫽ Central nervous system PLEDs ⫽ Periodic lateralized epileptiform discharges

Chen et al: PLEDs in Children 101

150 ␮V with the periodicity of each sharp wave and slow wave ranging from 0.3-5 seconds (mostly around one second). The underlying etiologies in their study included brain infarcts, tumors, encephalitis, and various metabolic disorders. It was noted that 87% of their patients experienced seizures in the period of illness [1]. Kuroiwa and Celesia defined PLEDs as complexes persisting for more than 10 minutes or even being continuous in a specific behavioral state. When they applied this definition to 15,202 patients with unselected ages, they found that only 0.4% of the patients fulfilled these criteria [9]. Young et al. found that the incidence of PLEDs was 0.6% among their 3978 unselected patients [26]. The incidence of 0.55% (44/8002) in pediatric patients (⬍17 years old) in this study is similar to that of adults or unselected age groups. As to the laterality of PLEDs, Snodgrass et al. reported that PLEDs were seen more commonly in unilateral hemisphere with right side dominance. Bilateral PLEDs accounted for only 10% [2]. The present study found the same result with right side dominance for 64%. There are variable etiologies responsible for PLEDs in the adult group or unselected-age group with the mean age more than 50 years [2-5,7,11,12]. The most common etiology was acute cerebrovascular accident (CVA) that accounted for 27 (43%). The second most common one was various metabolic disorders that accounted for 15% of patients. Brain tumors accounted for seven (14%). Epilepsy, CNS infection (including brain abscess and Creutzfeldt-Jakob disease), and anoxic encephalopathy each accounted for approximately 10% of patients with PLEDs. Few reports studied PLEDs in pediatric patients. From the limited articles in the English literature and this study, the etiologies of PLEDs in pediatric patients are obviously different from that in adult patients. According to Andriola, in a total of 12 pediatric patients, infection, anoxic encephalopathy, and metabolic disorders accounted for 25%, 25%, and 17% of PLEDs respectively [18]. PLEDs in neonates may be an early indicator of strokes [22,23]. In a study of seven pediatric patients, mass lesions, infection, metabolic disorder, or CVA were found to contribute to the PLEDs [19]. However, Raroque’s report of 18 pediatric patients with PLEDs demonstrated a similar pattern in the etiologies with adult reports [20]. In this series, CNS infection accounted for more than 60% (63.6%) of pediatric patients with PLEDs. Head injury, metabolic disorder, and idiopathic epilepsy were the etiologies after CNS infection. It was reported that PLEDs were associated with infections such as HSE [15,16], syphilis, bacterial meningitis, and even Creutzfeldt-Jakob disease [17]. In our series, HSE accounts for 42.9% of PLEDs in the 28 cases with CNS infection and 67% in the 18 children with identified pathogens. Japanese encephalitis, varicella encephalitis, EBV encephalitis, influenza encephalitis, CMV encephalitis, and mixed Staphylococcus aureus and Pseudomonas aeruginosa surgical infection each account for one case. No pathogen could be defined in 10 cases. In summary,

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HSV is the most common pathogen in pediatric CNS infection associated with PLEDs, but it is not as exclusive as previous studies reported. However, limitations in the virology laboratory before 1994 in this hospital may be a contributing factor to the high percentage of uncertain etiology in our patients with CNS infections. PLEDs were reported to be associated with metabolic disorders, which included alcoholism, hyperglycemia, hypercalcemia, hypoglycemia, hepatic encephalopathy, and syndrome of inappropriate antidiuretic hormone [1,3,29]. Funakawa et al. presented cases of mitochondrial encephalomyopathy associated with PLEDs and found that the presence of PLEDs correlated with the recurrence of strokelike episodes [30]. In this study, only three patients (6.8%) were diagnosed with metabolic disorders (Reye syndrome). Regarding the prognosis or morbidity of the patients with PLEDs, some authors have emphasized the importance of underlying etiologies. According to Bernd et al. the prognosis of patients with PLEDs was mainly determined by the underlying disease processes. Acute stroke appears to be associated with the worst prognosis, with mortality ranging from 28.8-53% [1,5-9,11,13,26]. Walsh et al. reviewed the long-term outcome in patients with acute stroke with PLEDs and found that 40% of the patients died in hospital because of that episode or within 2 months of discharge, and 30% of the survivors had significant morbidity. Presence of PLEDs in patients with acute stroke might be a poor prognostic factor for the adult group [11,27]. In this study, PLEDs seemed to be poor prognostic signs for pediatric patients, with 22.7% of mortality and 50% of morbidity. However, in pediatric patients with idiopathic epilepsy, it was thought that PLEDs might not be an absolutely poor prognostic sign [31]. In conclusion, PLEDs carry a different clinical presentation and significance in pediatric patients than adult patients. CNS infection is the most important etiology in children with PLEDs in Taiwan with a subtropical geographic location. As to the infectious pathogens associated with PLEDs in children, HSV is the most common, although not the only one. Finally, PLEDs could be an important prognostic factor for children with encephalitis. References [1] Chatrian GE, Shaw CM, Leffman H. The significance of periodic lateralized epileptiform discharges in EEG: An electrographic, clinical, and pathological study. Electroencephalogr Clin Neurophysiol 1964;7:177-93. [2] Snodgrass SM, Tsuburaya KT, Ajmone-Marsan C. Clinical significance of periodic lateralized epileptiform discharges: Relationship with status epilepticus. J Clin Neurophysiol 1989;6:159-72. [3] Niedermeyer E, Freund G, Krumholz A. Subacute encephalopathy and seizures in alcoholic: A clinical electroencephlographic study. Clin Electroencephalogr 1981;12:113-30. [4] Nonaka K, Kojima H, Onkawa T, Inanaga K. A case of cerebral infarction showing periodic lateralized epileptiform discharges. Folia Psychiatr Neurol Jpn 1985;39:79-84. [5] Striano S, DeFalco FA, Zaccaria F, Fels A, Natale S, Vacca G. Paroxysmal lateralized epileptiform discharges (PLEDs). Acta Neurol (Napoli) 1986;8:1-12.

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