Periventricular leukomalacia and epilepsy: Incidence and seizure pattern

Neurology Issue: Volume 52(2), 15 January 1999, pp 341-345 Copyright: ©1999 American Academy of Neurology Publication Type: [Articles] ISSN: 0028-3878 Accession: 00006114-199901150-00023 [Articles] Periventricular leukomalacia and epilepsy: Incidence and seizure pattern Gurses, C. MD; Gross, D. W. MD, FRCP(C); Andermann, F. MD, FRCP(C); Bastos, A. MD; Dubeau, F. MD, FRCP(C); Calay, M. MD; Eraksoy, M. MD; Bezci, S. MD; Andermann, E. MD, PhD; Melanson, D. MD Author Information From the Montreal Neurological Institute and Hospital (Drs. Gurses, Gross, Bastos, Dubeau, Andermann, and Melanson), McGill University, Montreal, Quebec, Canada; Istanbul University Neurological Sciences Institute (Drs. Gurses, Calay, and Eraksoy), Department of Neurology, and Turkish Spastic Children's Society (Dr. Bezci), Department of Pediatrics, Istanbul, Turkey. Supported in part by the R. Samuel McLaughin Foundation (D.W.G.). Received March 13, 1998. Accepted in final form November 17, 1998. Address correspondence and reprint requests to Dr. Frederick Andermann, Montreal Neurological Institute and Hospital, 3801 University Street, Montreal, Quebec, Canada H3A 2B4.

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Back to Top Article abstract Objective: To study the incidence and pattern of epilepsy in patients with periventricular leukomalacia (PVLM) in two specialty clinic settings. Background: Motor and cognitive deficit as well as epilepsy are common in patients with PVLM. With modern imaging techniques, PVLM is now easily recognized. Methods: Epileptic seizures and syndromes as well as motor and cognitive deficits were correlated with MRI findings. Two patient populations were studied: Group A-children with cerebral palsy and PVLM presenting to a center for children with motor disability (n = 19); and Group B-epileptic patients with PVLM presenting to a tertiary epilepsy center (n = 12). A single patient with PVLM and epilepsy who underwent extensive investigations, including intracranial EEG telemetry, is reported. Results: In Group A, 47% of patients had epilepsy (9/19). PVLM was found in 1.27% of patients investigated for epilepsy at a tertiary epilepsy center (12/942). The majority of

patients in both groups had multiple seizure types, with complex partial seizures being most common. Of patients with seizures (Groups A and B), 85.7% had intractable epilepsy (18/21). Intracranial EEG in the illustrative case demonstrated a multifocal epileptic process with occipitotemporal predominance. Conclusions: PVLM was an uncommon underlying cause in patients presenting with epilepsy (Group A); however, patients presenting with motor disability and PVLM (Group B) had a high incidence of seizures. PVLM in epileptic patients is associated with multiple seizure types and medically refractory disease.

Patients with periventricular leukomalacia (PVLM) are at increased risk of developing motor neurologic sequelae, delayed cognitive development, visual impairment, and epilepsy.1 MRI is a sensitive and powerful method for assessing cerebral structure and provides insight into the time of insult and nature of the pathology.2-4 We investigated the incidence and type of epilepsy in children presenting at an institution for children with motor disability with PVLM, the type of epilepsy in adults with epilepsy treated at a tertiary epilepsy center, the presence of intractability, and the relationship with the degree of PVLM found on magnetic resonance brain imaging. Finally, a single patient with PVLM and intractable epilepsy who underwent extensive investigations, including intracranial EEG telemetry, is reported. The objectives of this article were to gain a better understanding of the relationship of PVLM and epilepsy and to determine whether the finding of PVLM has localizing and prognostic significance. Methods. Two independent patient populations from the Turkish Spastic Children's Society, Istanbul, and the Montreal Neurologic Institute and Hospital (MNI), Montreal, were studied. The study consisted of the following inclusion criteria. Patients with cerebral palsy who had PVLM on MRI at the Turkish Spastic Society between March and October, 1995, were included as Group A. Reports for all brain MRIs performed on patients with a diagnosis of epilepsy at the MNI from 1990 to 1997 were reviewed. All MRIs with a diagnosis suggestive of PVLM were included in the study representing Group B. MRIs performed at the Turkish Spastic Society were performed using a Philips (Best, the Netherlands) 0.5-Tesla Imaging System. T2-weighted images (2000 to 3000/30 to 120) were conducted. T1-weighted images (400 to 800/20 to 35) were conducted in the axial or sagittal planes. MRIs performed at MNI were done using a 1.5-T Philips Gyroscan (ACS II; Philips). T1-weighted (500 to 550/18 to 20), T2-weighted (3000 to 3300/80 to 120), and proton density (PD) (2800 to 3300/20 to 25) images were obtained in the axial, coronal, and sagittal planes. One neuroradiologist at each center reviewed all MRIs. MRI diagnosis of PVLM was defined as periventricular hyperintensity on T2-weighted images associated with either ventricular irregularities or ventriculomegaly. Patients were separated into two groups based on MRI findings: Group I had PVLM without abnormalities of cortex, and Group II had PVLM with abnormal cortex. Charts were reviewed in all cases. In the Turkish cohort, all patients and families were contacted and were asked questions from a standardized questionnaire. Epileptic seizures and syndromes were assessed according to the International League Against Epilepsy (ILAE) classifications of 1981, 1985, and 1989 and were correlated with MRI findings.57 Other variables that were studied were gestational age; prenatal, perinatal, and postnatal course; presence of motor disability; and cognition. A gestational age of less than 36 weeks was considered preterm. The classification of the motor disability was made according to topography (monoplegia, diplegia, hemiplegia, or tetraplegia) and the nature of the motor disturbance (spastic, hypotonic, dyskinetic, ataxic, mixed, or unclassified). Both

classifications were used concurrently.8 Psychomotor development was studied with the Denver developmental screening test. Five sectors were assessed in relation to the chronological age and to the age corrected for preterm: personal, social, fine motor, gross motor, and language. Intracranial EEG telemetry data are reported in detail on a single patient with PVLM and intractable epilepsy who was extensively investigated at MNI. Data analysis. One-tailed Student's t-test was used for comparison of age at onset of seizures between study groups.9 Fischer's exact test was used for comparisons of all other observations in the study groups.9 Results. Children with motor disability (Group A). Nineteen children with cerebral palsy had evidence of PVLM on MRI at the Turkish Spastic Children's Society in Istanbul. On review by a neuroradiologist, all met study criteria for PVLM. Twelve patients were classified as Group I (PVLM alone), and 7 were classified as Group II (PVLM with cortical involvement). There was 1 pair of affected twins and another twin whose sibling was unaffected. There were 3 female and 9 male patients in Group I and 6 female and 1 male patient in Group II. Seven of 12 patients in Group I and 1 of 7 in Group II were born preterm (difference not statistically significant). Perinatal complications were found in all patients except 1 patient in Group I (table 1). Four of 12 patients in Group I and 5 of 7 patients in Group II had a history of seizures (difference not statistically significant). Mean age at seizure onset was 1.44 years for Group I and 0.77 years for Group II (p = 0.25). Seizure types were multiple in most patients and are outlined in table 1. Seizures were intractable in 3 of 4 patients in Group I and 4 of 5 patients in Group II. All patients had motor abnormalities. Eight of 12 patients in Group I had spastic diplegia; 3 had hypotonic diplegia; and 1 had spastic hemiplegia. In Group II, 2 of 7 had spastic diplegia; 1 had hypotonic diplegia; 2 had spastic hemiplegia; 1 had hypotonic hemiplegia; and 1 had spastic tetrapareisis. Diplegia (either spastic or hypotonic) was significantly more likely to occur in Group I (p = 0.038). Psychomotor development was not assessed in six patients (five from Group I and one from Group II). Three of seven patients tested in Group I and all six patients tested in Group II had abnormal cognitive development (p = 0.049). Patients with PVLM presenting at a tertiary epilepsy center (Group B). Of 942 patients with a diagnosis of epilepsy undergoing brain MRI, 12 (1.27 %) were reported to have PVLM. On review of the MRIs, all 12 met our criteria for PVLM and were included in the study. Five patients were classified as Group I (PVLM alone), and 7 as Group II (PVLM with cortical involvement). All five patients in Group I were male. Group II consisted of three males and four females. One patient in each group was born preterm (28 weeks for the patient in Group I and 29 weeks for the patient in Group II), and all others were born at term. Four of five patients in Group I and six of seven in Group II had prenatal or perinatal complications as listed in table 2. Mean age at seizure onset in Group I was 9.3 years and 5.9 years in Group 2 (p = 0.17). Types of seizures were similar in the two groups, and the predominant seizure type (seen in 11 of 12 patients [91.7%]) was complex partial. Other types included generalized tonicclonic, tonic, atypical absence, prolonged febrile, and drop attacks (as listed in table 2). Seizures were intractable in all but 1 patient from Group II. One patient in Group I had an anterior corpus callosotomy that provided minimal benefit. One patient in Group II

underwent left anterior temporal lobectomy that was associated with a marked improvement in seizure frequency and behavior; however, he died 6 months postoperatively from an anaphylactic reaction. Findings on neurologic examination were as follows. Of all the patients in either group, only one from Group I had spastic diplegia. The most common neurologic finding for both groups was ataxia or dysarthria found in two patients from Group I and in three from Group II. One patient from Group I had brisk reflexes, and one from Group II had a mild hemiparesis. Three of five patients from Group I and four of seven from Group II had with mental retardation. Case report of a patient with PVLM who underwent intracranial EEG investigation. A 37year-old righthanded man presented with intractable epilepsy. His perinatal period was complicated by rhesus antigen (RH) incompatibility requiring blood transfusions along with hypoglycemia. Two days postpartum the patient developed repetitive head movements and clonic leg movements that resolved. At 3 years of age, the patient had a febrile convulsion. At 8 years of age, the patient had onset of his habitual seizure pattern. He had complex partial seizures associated with a warning during which he would have an unusual sensation in the left hand, hear a "scream," and have abdominal pain. He also described seeing colors in the right visual field at the start of some attacks. After the warning, he would become unresponsive for a few minutes. Another type of seizure consisted of left-hand shaking with right eye and face pain without impairment of consciousness, sometimes followed by secondarily generalized convulsions. He had weekly seizures despite multiple medications, occasionally requiring hospitalization for uncontrollable attacks. Examination showed that full-scale intelligence quotient (IQ) was 58 with evidence of diffuse cerebral dysfunction, left spastic hemiparesis, and reduced two-point discrimination on the left hand. Interictal scalp EEG showed active independent epileptic foci in both temporal and frontal regions with right hemisphere predominance. Ictal scalp EEG showed seizure onset in the central, parietal, and temporal regions most often with right hemisphere predominance with clinical manifestations preceding EEG abnormalities. MRI showed diffuse cortical atrophy along with PVLM that was more prominent in the occipital regions. With physical findings and ictal symptomatology suggesting a right hemispheric primary epileptic focus, intracranial electrode implantation was conducted at the Montreal Neurologic Institute and Hospital in an attempt to better clarify the location of seizure onset with the goal of finding a potentially resectable focal epileptic lesion. On depth electrode investigation, interictal epileptic abnormalities were seen predominantly in the hippocampal contacts bilaterally. Twenty-one seizures were recorded. Two were not lateralized; six had onset in the left hippocampus; four had onset in the left temporal neocortex; one had onset in the left frontal; four had onset in the left occipital cortex; three had onset in the right hippocampus; and one had onset in the right occipital region. Discussion. Regulation of cerebral blood flow (CBF) is essential to normal brain development and is easily disturbed even with minor stresses during the prenatal and perinatal period.10-12 Hypotension and cerebral hypoperfusion may induce cerebral ischemia in the arterial watershed zones, particularly the periventricular region. Tweed et al. examined the autoregulation of CBF in utero in normoxic and hypoxic conditions.13 Autoregulation was found to be functionally active in all regions of normal fetuses but to be abolished in the mildly hypoxic fetuses.13 Pyrds et al. found a highly significant correlation between absent arterial pressure/CBF autoregulation and subsequent

PVLM and periventricular hemorrhage.14 Ninety-four percent of the patients in both arms of our study (29/31) had at least one perinatal complication. Marret et al. found that premature infants with PVLM showed positive rolandic sharp waves in the EEG and suggested that these may be an early indicator for PVLM in the neonatal period.15 Conversely, other authors found that positive rolandic sharp waves and moderately abnormal EEG background were associated with grade 3 to 4 intraventricular hemorrhage.16,17 De Vries et al. investigated the EEG of infants with PVLM.18 Initially these were abnormal, but within several weeks they improved when additional subcortical lesions were not present.18 None of our patients had EEG recordings during the neonatal period. Wyllie et al. described a chil with West's syndrome and PVLM who remained seizure free 1 year after a right temporal-parietal-occipital resection.19 Cusmai et al. found that 11 of 12 patients born prematurely and who developed West's syndrome with PVLM became seizure free after 3 to 7 years but their EEGs continued to show multifocal epileptic abnormalities recorded predominantly over occipital or temporo-occipital regions.20 These correlated with the side of the primary brain lesion.20 Okumura et al. reported that patients with severe PVLM and West's syndrome had a worse prognosis than those with mild PVLM and West's syndrome.21 Among children with PVLM on MRI presenting at a specialized center for spastic children, 47% (9/19) were found to have seizures, 78% (7/9) of which were intractable. There was no clear correlation between the extent of the lesions or the severity of motor disability and the presence of epilepsy or time of onset of seizures. There was a trend to occurrence of seizures in those children who had cortical MRI abnormalities in addition to white matter changes. Additionally, children with cortical involvement were significantly more likely to have developmental delay (p = 0.049). Conversely, children who had mainly white matter abnormality were significantly more likely to have the classic motor findings of diplegia (p = 0.038). The second group consisted of patients presenting at a tertiary epilepsy center. Only a small percentage of patients presenting with epilepsy had PVLM (1.27%). Of patients with PVLM 91.7% (11/12) had complex partial seizures. Most also had other types of seizures. There was no statistical correlation between the severity and different types of MRI lesions and the clinical seizure patterns. In these patients, epilepsy was severe and intractable, but this may represent a bias of ascertainment. Because the referral pattern for the two centers in the study is drastically different (the Turkish Spastic Society seeing predominantly cerebral palsy patients, and the diagnosis of epilepsy being used for enrollment in the MNI group), it is not possible to directly compare the two patient cohorts. It would be expected that the differences observed between the two groups regarding age at seizure onset, frequency of epilepsy, motor disability, and prematurity are related to the differences in referral patterns between the two tertiary centers. Although physical findings and ictal symptomatology suggested a lateralized epileptic process in the illustrative patient, extensive scalp and intracranial EEG recordings demonstrated multiple ictal generators without clear predominance. Although it is not possible to draw conclusions form a single case, the multifocality of the seizure disorder in this patient suggests extensively that epileptogenic cortex could be the reason for intractability. One could hypothesize that perinatal anoxic insults could potentially affect neurons, as well as white matter, in such a way that intrinsically irritable cortex is created either through direct effects on the neurons or possibly via disruption of normal subcortical circuitry leading to epileptogenicity. Although PVLM constitutes a relatively small proportion of patients presenting to an

epilepsy center (1.27%) (Group B), a relatively large proportion (47%) of patients with PVLM (Group A) had seizures. The recognition of PVLM is clinically relevant as PVLM was associated with multiple seizure types and medically intractable disease (78% of patients in Group A and 91% of patients in Group B were medically intractable). Although the pattern and extent of PVLM on MRI was useful regarding predicting motor deficit (diplegia) as well as developmental delay, there was no correlation between the MRI and the seizure pattern. Intracranial EEG recordings in a single patient demonstrated multifocal epileptic abnormalities with a predominance of abnormalities in the occipital and temporal lobes. Back to Top References 1. Aicardi J. Diseases of the nervous system in childhood. London: MacKeith Press, 1992. [Context Link] 2. Barkovich AJ. Pediatric neuroimaging. New York: Raven Press, 1990. [Context Link] 3. Volpe JJ. Value of MR in definition of the neuropathology of cerebral palsy in vivo. AJNR Am J Neuroradiol 1992;13:79-83. Serials Solutions 360Link Bibliographic Links [Context Link] 4. Krageloh-Mann I, Petersen D, Hagberg B, Michaelis R. Magnetic resonance imaging in the timing of pathological events-a study in bilateral spastic cerebral palsy children. In: Lou HC, Greisen G, Larsen JF, eds. 37th Alfred Benzon Symposium: brain lesions in the newborn. Copenhagen: Munksgaard, 1994:178-188. [Context Link] 5. Commission on classification and terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489-501. Serials Solutions 360Link Bibliographic Links [Context Link] 6. Commission on classification and terminology of the International League Against Epilepsy. Proposal for classification of epilepsies and epileptic syndromes. Epilepsia 1985;26:268-278. Serials Solutions 360Link [Context Link] 7. Commission on classification and terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389-399. Serials Solutions 360Link [Context Link] 8. Minear WL. A classification of cerebral palsy. Pediatrics 1956;18:841-852. Serials Solutions 360Link Bibliographic Links [Context Link] 9. Fisher LD, Van Belle G. Biostatistics: a methodology for the health sciences. New York: Wiley, 1993. [Context Link] 10. Lou HC. The "lost autoregulation hypothesis" and brain lesions in the newborn-an update. Brain Dev 1988;10:143-146. Full Text Bibliographic Links [Context Link] 11. Lou HC. Perinatal hypoxic-ischemic brain damage and intraventricular hemorrhage. A pathogenic model. Arch Neurol 1980;37:585-587. Serials Solutions 360Link Bibliographic Links [Context Link] 12. DeReuck J, Chattha AS, Richardson EP Jr. Pathogenesis and evolution of periventricular leukomalacia in infancy. Arch Neurol 1972;27:229-236. Serials Solutions 360Link Bibliographic Links[Context Link] 13. Tweed WA, Cote J, Pash M, Lou H. Arterial oxygenation determines autoregulation of cerebral blood flow in the fetal lamb. Pediatr Res 1983;17:246-249. Serials Solutions 360Link Bibliographic Links [Context Link] 14. Pryds O, Greisen G. Effect of PaCO2 and haemoglobin concentration on day to day

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