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Agyria-pachygyria complex: MR findings and correlation with clinical features
Agyria-Pachygyria Complex: MR Findings and Correlation With Clinical Features Semra Kurul, MD*, Handan C ¸ akmakc¸i, MD†, and Eray Dirik, MD* The aim of this study was to determine the spectrum of clinical abnormalities in the agyria-pachygyria complex, to identify possible causes, and to correlate the clinical features with the extent of the lesions on magnetic resonance imaging. On the basis of the magnetic resonance imaging findings, 37 patients (22 males, 15 females; mean age 21.1 ⴞ 31.2 months) with agyria-pachygyria complex were separated into two groups: Group 1 (18 children) manifested generalized or bilateral gyral malformation, and Group 2 (19 children) manifested localized or unilateral gyral malformation. The ratio of generalized seizures in Group 1 was significantly higher, whereas partial seizures were more common in Group 2. Group 1 patients had seizures significantly more frequently than Group 2 patients. Diffuse electroencephalographic abnormalities were significantly more common in Group 1, as were the localized abnormalities in Group 2. Hemipareses were the most frequent neurologic deficit among Group 2 patients. Spastic quadriparesis and microcephaly were more common in Group 1. In conclusion, the extent of agyria-pachygyria complex varies widely and the clinical features are accordingly diverse. Patients with bilateral or generalized gyral anomalies have poor prognosis for outcome of epilepsy and neurologic disability. The recognition of these lesions with higher-resolution techniques of magnetic resonance imaging is important for planning proper treatment and genetic counseling. © 2004 by Elsevier Inc. All rights reserved. Kurul S, C¸akmakc¸i H, Dirik E. Agyria-Pachygyria complex: MR findings and correlation with clinical features. Pediatr Neurol 2004;30:16-23.
From the *Departments of Pediatric Neurology and †Radiology, Dokuz Eylu¨l University Faculty of Medicine, I˙zmir, Turkey.
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Introduction The term “agyria-pachygyria” is applied to several disorders of neuronal migration anomalies that result in total or subtotal absence of cortical sulci and severely disturbed architectonics of the cortical plate [1,2]. Agyria means mainly absent cortical gyri. In fact, most “agyric” brains have at least small areas of gyral formation. These areas of flat, broad, and shallow gyri are referred to as areas of pachygyria [3]. Pathologic descriptions have demonstrated that agyria and pachygyria are part of a continuum of gyral defects. The term “lissencephaly” is sometimes used as a synonym for agyria. Clinically, gyral cortical defects cause seizures, developmental retardation, and motor deficits [4,5]. Modern neuroimaging techniques have permitted the diagnosis of generalized neuronal migration disorders while the patient is alive [6]. The severity and extent of associated abnormalities vary greatly. The clinical features of lissencephalies have been well described [1,2,4]. However, information about partial gyral anomalies is scarce. The aim of this study was to determine the spectrum of clinical findings in agyriapachygyria complex, to identify possible causes, and to correlate the clinical features with the extent of the lesions on magnetic resonance imaging.
Patients and Methods The study group comprised 37 patients in whom agyria-pachygyria complex was recognized by magnetic resonance imaging in the Department of Pediatric Neurology of Dokuz Eylu¨l University. Magnetic resonance imaging scans were performed with a number of different techniques, because they were performed at many institutions. All of the printed films were reviewed by a pediatric neuroradiologist in our institution without knowledge of detailed clinical evaluation. Imaging sequences were performed at 1 or 1.5 Tesla and included T1-weighted, T2-weighted, and more recently, inversion recovery sequences in some patients. The images were evaluated with specific attention to the severity, location, and size of the anomaly (involved lobes). Side of the lesion and extent of lobar involvement were assessed by examination of
Communications should be addressed to: ¨ niversitesi Tıp Faku¨ltesi; C¸ocuk Sag˘lıg˘ı ve Dr. Kurul; Dokuz Eylu¨l U Hastalıkları AD; C¸ocuk No¨rolojisi BD; 35340 I˙nciraltı I˙zmir, Turkey. Received February 11, 2003; accepted May 14, 2003.
© 2004 by Elsevier Inc. All rights reserved. doi:10.1016/S0887-8994(03)00312-6 ● 0887-8994/04/$—see front matter
Table 1.
Summary of the clinical data of the patients in Group 1 (generalized or bilateral gyral malformation)
No.
Sex
Age at Presentation
Presenting Symptoms
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
M M M M M M M M F M M M M F M F F M
7 days 1 mo 1 yr 4 mo 3 mo 1 yr 14 days 4 mo 1 yr 5 mo 6 mo 3.5 yr 2 yr 9 mo 2 mo 1 yr 3y 15 mo
Seizures Seizures, dev. delay Seizures, dev. delay Seizures, dev. delay Microcephaly, dev. delay Dev. delay Seizures, dev. delay Microcephaly Microcephaly, dev. delay Microcephaly Microcephaly, seizures Microcephaly Dev. delay Microcephaly Seizures, motor deficit Microcephaly, motor deficit Seizures Seizures
Abbreviations: ⫹ ⫽ Present ⫺ ⫽ Absent CMV ⫽ Cytomegalovirus dev. delay ⫽ Developmental delay DTRs ⫽ Deep tendon reflexes EEG ⫽ Electroencephalographic F ⫽ Female FR ⫽ Frontal FP ⫽ Frontoparietal
FTP GT GTC HP hypsar. IS M MF mic.
⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽
Location of Lesion Diffuse Diffuse Diffuse Diffuse Diffuse Diffuse Diffuse Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral
Family History
Associated Syndrome
Prenatal Events
Consanguinity
⫺ ⫺ ⫺ ⫹ ⫹ ⫺ ⫺ ⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫹ ⫺
⫺ ⫺ ⫺ ⫹ Miller-Dieker ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺
⫺ ⫺ ⫺ Febrile illness Intrauterine CMV inf. Psychologic trauma ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ Febrile illness ⫺ ⫺ ⫺ ⫺
⫺ ⫺ ⫺ ⫺ ⫹ ⫺ ⫹ ⫺ ⫺ ⫺ ⫹ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫹
FTP FP FP FTP FP FP FTP FTP FTP FP FP
Frontotemporoparietal Generalized tonic Generalized tonic clonic Hemiparesis Hypsarrhythmia Infantile spasm Male Multifocal Microcephaly
a combination of sagittal, axial, and coronal images. On the basis of magnetic resonance imaging features, the patients were separated into two groups according to the classification of Barkovich [7]: Group 1 (18 children) manifested generalized or bilateral gyral malformation; Group 2 (19 children) manifested localized or unilateral gyral malformation. Clinical findings of Group 1 patients were compared with those of Group 2. Patients were excluded if they had type II lissencephaly or severe cerebellar involvement, schizencephaly, hemimegalencephaly, holoprosencephaly, and gray matter heterotopias. Patients with other complex cerebral anomalies were also excluded from the study because those anomalies could cause neurologic symptoms, obscuring the effects of agyria-pachygyria complex. Patients with agenesis or hypogenesis of the corpus callosum as the only associated anomaly were included in the study. The patients were referred for imaging because of seizures, mental retardation, developmental delay, or microcephaly. All patients underwent physical and neurologic examination. A standard detailed questionnaire had been used, emphasizing pregnancy and in utero factors, development, associated malformations, presenting complaints, and family history. Special attention was paid to the following: presence or absence of seizures, age at onset, type, frequency, response to treatment, course of epilepsy, presence or absence of motor deficit, type of deficit (spastic or flaccid), body areas involved (quadriparesis, hemiparesis, or monoparesis), electroencephalographic results, developmental level in patients younger than 6 years of age (assessed by the Ankara Developmental Screening Test), and intelligence quotient in patients older than 6 years of age (assessed by the Wechsler Intelligence Scale for ChildrenRevised). Extracranial electroencephalographic investigations were performed using the international 10-20 system. Recordings were obtained during both wakefulness and sleep. Epileptiform discharges were divided into two categories: “localized” with a maximum confined to one or two
myoclon. O P PC PG PS QP Spast.
⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽
Myoclonic Occipital Parietal Partial complex Partial with generalization Partial simple Quadriparesis Spasticity
adjacent electrodes; and “diffuse” with multifocal independent spikes or bilateral discharges. Seizure types were classified according to the criteria of the International League Against Epilepsy as being “generalized” or “partial.”[8]. Seizure frequency was divided into three groups: daily, weekly, and monthly, an average of at least one seizure per day, week, or month respectively. Outcome classification of the seizures was performed as follows: “good response,” either the patient was seizurefree or reduction of seizure frequency was greater than 50%; “poor response,” either seizures were worse or the same or reduction of seizure frequency was less than 50%. Intelligence quotient according to the Wechsler Intelligence Scale for Children-Revised was divided into the following categories: “normal”— either verbal or performance intelligence quotient more than 90; “retarded”— both verbal and performance intelligence quotient under 69; and “low normal”—the range between the former two. Developmental level assessed by the Ankara Developmental Screening Test was divided as follows: if the score was less than 10% of the mean score obtained by normal children, it was assessed as “retarded.” If the score was equal to or greater than 10% of the mean score obtained by normal children, it was assessed as “normal.” Differences between the study groups were tested using the Fisher exact test and Mann-Whitney U-Wilcoxon rank sum test. A P value of less than 0.05 was considered significant.
Results Clinical data of the patients in Groups 1 and 2 are summarized in Tables 1 and 2. Magnetic resonance imaging characteristics of the brains of the patients are summarized in Table 3. Some representative magnetic resonance images of the patients are presented in Figures
Kurul et al: MRI Findings in Agyria-Pachygyria Complex 17
Table 1. (Continued)
Neurologic Findings
Cognition/ Development
Seizure Type
Age of Seizures
Seizure Frequency
EEG Findings
Response to Medication
Spast., QP, mic. Spast., QP, mic. Spast., QP, mic. Spast., QP, mic. Spast., QP, mic. Spast., QP Spast., QP Mic. Spast., QP, mic. Mic., bilateral brisk DTRs Spast., QP, mic. Mic., bilateral brisk DTRs Mic. Spast., QP, mic. Spast., QP, mic. Spast., QP, mic. Bilateral brisk DTRs Spast., QP, mic.
Retarded Retarded Retarded Retarded Retarded Retarded Retarded Retarded Retarded Low normal Retarded Retarded Retarded Retarded Retarded Retarded Retarded Retarded
IS, GT IS, GTC IS, GTC GT ⫺ GTC IS, GTC ⫺ ⫺ ⫺ GT ⫺ ⫺ GT IS, GTC GT, myoclon. GTC GTC, myoclon.
7 days 7 mo 1y 4 mo ⫺ 5y 14 days ⫺ ⫺ ⫺ 4 mo ⫺ ⫺ 1.5 y 2 mo 2y 3y 15 mo
Daily Weekly Daily Daily ⫺ Weekly Weekly ⫺ ⫺ ⫺ Daily ⫺ ⫺ Weekly Monthly Daily Monthly Daily
Diffuse (MF) Diffuse (MF) Diffuse (hypsar.) Diffuse Diffuse Diffuse (MF) Diffuse (MF) Diffuse Diffuse Diffuse Diffuse Normal Normal Localized (left) Diffuse (hypsar.) Diffuse (MF) Diffuse Diffuse (MF)
Good Good Poor Poor ⫺ Good Poor ⫺ ⫺ ⫺ Good ⫺ ⫺ Good Good Poor Good Poor
1-4. A comparison of clinical manifestations of the two groups is presented in Table 4. The patients’ ages ranged from 1 day to 15 years (mean 21.09 ⫾ 31.24 months of age) at the time of presentation. In Group 1, the mean age at presentation was 11.05 ⫾ 11.94 months of age (1 day-3.5 years) and in Group 2, it was 30.60 ⫾ 40.26 months (1 month-15 years). There was no significant difference between the two groups with regard to the mean age at presentation, although it was much earlier in Group 1 (P ⫽ 0.233). Twenty-two patients (59.5%) were male, and 15 (40.5%) were female. In Group 1, 14 patients (77.8%) were male and 4 patients (22.2%) were female. In Group 2, 8 patients (42.1%) were male and 11 patients (57.9%) were female. The number of male patients was significantly higher in Group 1 compared with Group 2 (P ⫽ 0.045). Pregnancies were normal in the mothers of all but 11 patients (29.7%): 4/18 patients (22.2%) in Group 1, 7/19 patients (36.8%) in Group 2. These events were maternal serious upper airway infection with fever (two patients), excessive smoking (two patients), vaginal bleeding (two patients), drug exposure (three patients), serious psychological trauma in the first trimester of pregnancy (one patient), and in utero cytomegalovirus infection (one patient). There was no significant difference between the two groups with regard to prenatal events (P ⫽ 0.476). Associated genetic syndromes were present in 5 patients (13.5%). One patient in Group 1 manifested facial anom-
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alies leading to the diagnosis of Miller-Dieker syndrome. In Group 2, four patients were diagnosed with various genetic syndromes including glutaric aciduria type II, oral-facial-digital syndrome, Angelman syndrome, and Klippel-Trenaunay-Weber syndrome. No significant difference was observed between the two groups (P ⫽ 0.340). Karyotype was performed for 10 patients, but manifested no abnormalities. The rate of consanguinity in all study patients was 27%. Family history of neurologic diseases, such as mental retardation of unknown etiology and seizure disorder, was positive in 7 patients (18.9%). There were no significant differences between the two groups with regard to the rate of consanguinity (P ⫽ 1.000) and family history of neurologic disorders (P ⫽ 0.692). The symptoms at presentation were seizures in 25 patients (67.6%), developmental delay in 13 patients (35.1%), microcephaly in 9 patients (24.3%), and motor deficits in 4 patients (10.8%). Patients in Group 1 presented significantly more frequently with microcephaly (8/18 [44.4%] in Group 1 vs 1/19 [26.3%] in Group 2; P ⫽ 0.008). Patients in Group 2, however, presented significantly more frequently with seizures (16/19 [84.2%] in Group 2 vs 9/18 [50%] in Group 1; P ⫽ 0.038). Developmental delay as presenting symptom was much more common in Group 1, but there was no significant difference between the two groups (8/18 [44.4%] in Group 1 vs 5/19 [26.3%] in Group 2; P ⫽ 0.313). Motor deficits were
Table 2.
Summary of the clinical data of the patients in Group 2 (localized or unilateral gyral malformation)
No.
Sex
Age at Presentation
Presenting Symptoms
19 20 21 22 23 24 25 26 27 28 29 30 31
F F F F F M M M M F F M F
1 mo 15 yr 12 yr 5 yr 1 yr 8 yr 6 mo 2 mo 1 yr 1.5 yr 5 yr 15 mo 2 mo
Seizures Seizures, mic., dev. delay Seizures Seizures Seizure, motor deficit Dev. delay Seizures, dev. delay Seizures Motor deficit Seizures Seizures Seizures Seizures
Unilateral Unilateral Unilateral Unilateral Unilateral Unilateral Unilateral Unilateral Unilateral Unilateral Unilateral Unilateral Unilateral
right P right FTP right FR right FP right FP right O right P right FP right FP left O right P right FP left P
⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺
32 33 34 35 36 37
M M F M F F
Seizures Dev. delay Seizures Seizures, dev. delay Seizures Seizures
Unilateral Unilateral Unilateral Unilateral Unilateral Unilateral
left left left left left left
⫹ ⫺ ⫹ ⫺ ⫺ ⫺
2 2 3 3 4 1
mo yr mo yr mo yr
Location of Lesion
FP FR P P FP FR
Family History
Associated Syndrome ⫹ Glutaric aciduria II ⫺ ⫺ ⫺ ⫺ ⫹ Oral-facial-digital syndrome ⫹ Angelman syndrome ⫺ ⫺ ⫺ ⫺ ⫺ ⫹ Klippel-Trenaunay-Weber syndrome ⫺ ⫺ ⫺ ⫺ ⫺ ⫺
Prenatal Events Drug exposure Vaginal bleeding Excessive smoking ⫺ ⫺ ⫺ Vaginal bleeding Drug exposure ⫺ ⫺ ⫺ ⫺ Excessive smoking ⫺ ⫺ ⫺ ⫺ ⫺ Attempt to criminal abortus
Abbreviations as in Table 1.
observed in two groups with almost equal frequency (2/18 [11.1%] in Group 1 and 2/19 [10.5%] in Group 2; P ⫽ 1.000). In follow-up, seizure disorders were present in 28 (75.7%) patients. Eighteen (64.3%) had generalized seizures and the remaining 10 (35.7%) patients had partial seizures. The ratio of generalized seizures in Group 1 was significantly higher than in Group 2. Partial seizures were more common in Group 2 compared with Group 1 (P ⫽ 0.001). Age at onset of seizures ranged from birth to 15 years (mean 25.67 ⫾ 42.94 months). In Group 1, it was from birth to 5 years (mean 14.58 ⫾ 18.20 months) and in Group 2, from birth to 15 years (mean 34.00 ⫾ 53.88 months). The difference between the two groups was not statistically significant (P ⫽ 0.478). The patients in Group 1 had seizures significantly more frequently than in Group 2 (P ⫽ 0.009). Of the 28 patients with seizures, 21 (75%) were good responders to antiepileptic treatment. In the remaining 7 (25%) patients, the seizures were not reduced or were reduced less than 50% despite excessive and adequate antiepileptic treatment. Five of these patients were in Group 1, and two patients were in Group 2. There was no significant difference between the two groups (P ⫽ 0.103). Regarding the electroencephalographic findings, 18 (48.6%) patients manifested diffuse epileptiform abnormality, 15 (40.5%) manifested localized epileptiform activity, and the remaining 4 (10.8%) patients had normal electroencephalographic findings. Diffuse abnormalities were significantly more common in Group 1 (15/18; 83.3%), and localized abnormalities were significantly more common in Group 2 (14/19; 73.7%) (P ⫽ 0.001).
The percentage of neurologic deficits in all study patients was 75.7% (28/37). Neurologic deficits in Group 2 patients were observed as frequently as in Group 1 patients (15/19, 78.9% and 13/18, 72.2%, respectively) (P ⫽ 0.713). However, hemiparesis contralateral to the affected side was the most frequent neurologic deficit in Group 2 patients (P ⫽ 0.001). Spastic quadriparesis and microcephaly were more common in Group 1 compared with Group 2 (P ⫽ 0.001, P ⫽ 0.001, respectively). In the first year of their life, it has been observed that patients with neurologic deficits in Group 1 exhibited hypotonia. Thereafter, hypotonia transformed into spasticity. All study patients but two in Group 2 manifested developmental delay or mental retardation, mild to severe in degree, without any significant difference between the two groups (P ⫽ 0.486). Discussion Advances in neuroimaging techniques have resulted in an increasing recognition of the cortical lesions as the etiology of a number of epilepsies that were previously defined as cryptogenic. It has been reported that modern neuroimaging methods allowed analysis of gross features of the entire brain in all patients, whereas neuropathology was invasive and available for only a highly selected group of patients [4,7]. However, the classification of cortical developmental abnormalities poses a problem to the clinician despite advances in the fields of neuroradiology and molecular genetics. There are reports proposing radiologic, anatomic, or embryologic classification systems [1-3], but such systems often fail because of the extensive variety of these malformations. Barkovich et al.
Kurul et al: MRI Findings in Agyria-Pachygyria Complex 19
Table 2. (Continued)
Consanguinity
Neurologic Findings
Cognition/ Development
Seizure Type
⫹ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫹ ⫺ ⫹ ⫺ ⫺
Mic. Mic., left HP Brisk DTRs (left) Normal Left HP Normal Left HP Mic., left HP Left HP Mic. Left HP Brisk DTRs (left) Right HP
Retarded Retarded Low normal Normal Retarded Low normal Retarded Retarded Retarded Retarded Normal Retarded Retarded
PG GT, atonic GTC GTC GTC ⫺ IS, GTC PC ⫺ PC PS PC PC
⫺ ⫺ ⫺ ⫹ ⫺ ⫺
Right HP Normal Right HP Right HP Right HP Normal
Retarded Retarded Retarded Retarded Retarded Low normal
PG ⫺ PS PG GT PC
proposed a classification system for the malformations of cerebral cortex based on fundamental embryologic and genetic principles and a combination of neuroimaging, gross pathologic, and histologic criteria [7]. Because pathologic descriptions have demonstrated that agyria and pachygyria are part of a continuum of gyral defects, a system for grading the severity of gyral malformations expanding to include pachygyria has been reported by Dobyns et al. [9]. However, their report described only bilateral and diffuse lesions. In our study, because patients with unilateral involvement were included, the classification system of Barkovich was used.
Age of Seizures
Seizure Frequency
EEG Findings
1 mo 15 yr 12 yr 5 yr 1 yr ⫺ 3 mo 2 mo ⫺ 1.5 yr 5 yr 15 mo 2 mo
Daily Monthly Monthly Monthly Monthly ⫺ Monthly Daily ⫺ Monthly Monthly Monthly Daily
Localized Diffuse Normal Localized Localized Normal Diffuse Localized Localized Localized Localized Localized Diffuse
2 mo ⫺ 3 mo 2.5 yr 4 mo 1 yr
Weekly ⫺ Monthly Monthly Monthly Monthly
Localized Localized Localized Localized Localized Localized
(right)
(right) (right)
(right) (right) (left) (right) (right)
(left) (left) (left) (left) (left) (left)
Response to Medication Good Good Good Good Good ⫺ Good Poor ⫺ Good Good Good Good Poor ⫺ Good Good Good Good
Most patients with cortical gyral abnormalities present with epilepsy and mental retardation. However, the severity and extent of these manifestations varies greatly [1-3,10]. Attempts to correlate clinical findings with the severity and location of cortical malformation have met with variable success. Although the clinical course of patients with severe neuronal migration anomalies is well established, information regarding the clinical features and prognosis of partial lissencephalies, namely focal pachygyric lesions, is scarce [11,12]. It is well known that patients with lissencephaly are presenting with symptoms
Table 3. MR characteristics of the brains of patients in Groups 1 and 2 Study Group
Location of Lesion
n
Total
Group 1 (generalized or bilateral agyriapachygyria complex)
Diffuse Bilateral FTP Bilateral FP (Other findings) Corpus callosum agenesis Lateral ventricul dilatation
7 5 6
18
Group 2 (localized or unilateral agyriapachygyria complex)
FTP FP FR P O (Other findings) Corpus callosum agenesis Lateral ventricular dilatation
Total
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1 7 3 6 2
19
(3) – 37
Abbreviations as in Table 1.
20
(3) (4)
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Figure 1. Case 3. T1-weighted axial image demonstrates bilateral diffuse cortical thickening, reduced cortical sulci, and enlargement of the subarachnoid space.
Figure 2. Case 9. T1-weighted axial image demonstrates bilateral frontoparietal cortical thickness, decrease in cortical sulci, and enlargement of the ventricles.
early in life. It has been reported that 60-83% of patients with lissencephaly presented in the first two years of life [4,11,13]. In accordance with previous reports, patients with generalized or bilateral gyral malformation in our study were often symptomatic in the first year of life. The patients with unilateral or focal gyral malformations were symptomatic much later than the patients in Group 1, albeit without any significant difference between the two groups. In our study, the percentage of male patients in Group 1 was significantly higher than in Group 2. All the patients who exhibited diffuse gyral malformations in Group 1 were male. Genetic analysis could not be performed for these patients. However, we conclude that these patients could have X-linked lissencephalies. Previous reports have documented that environmental and teratogenic factors during the first 4 months of the pregnancy may lead to the genesis of gyral abnormalities [2-4]. In our study, some of the pregnancies were complicated by vaginal bleeding and severe febrile illness lasting more than one week during the first trimester. However, we believe that it is not always objective to assert that these prenatal events were in distinct relationship with migrational abnormalities, because it is not possible to demonstrate them and not a small number of pregnancies are complicated by such events. Neuronal migration abnormalities have been reported in a variety of genetic syndromes [4,14]. In our study group, five patients manifested clinically well-defined genetic syndromes. Case 4 in Group 1 exhibited clinical features of Miller-Dieker syndrome. This male died when he was two years old, and a genetic analysis could not be performed for this patient. The other four patients were all in Group 2. Their syndromes diagnosed were glutaric aciduria type II (Case 19), oral-facial-digital syndrome (Case 24), Angelman syndrome (Case 25), and Klippel-
Figure 3. Case 19. T2-weighted axial image demonstrates abnormal thickening of cortical gray matter in the right parietal lobe.
Trenaunay-Weber syndrome (Case 31). The association of these syndromes with neuronal migration abnormalities has been reported previously in literature [2-4,14,15]. Genetic counseling has been offered to the families of our patients. Dobyns et al. reported the consanguinity rate in lissencephalic children as 4.8% [11]. In our study, the consanguinity rate was 27% without any significant difference between the groups. The overall consanguinity rate in Turkey ranges between 10-20%. We consider the rates of consanguinity and family history of neurologic diseases such as seizure disorder and mental retardation that were detected in our study to be high. These results suggest that gyral abnormalities could be due to genetic
Figure 4. Case 30. T2-weighted axial image reveals focal thickening of the right frontoparietal cortex.
Kurul et al: MRI Findings in Agyria-Pachygyria Complex 21
Table 4.
Comparison of clinical manifestations of the patients Variable
Total
Group 1
Group 2
P
n Sex (M/F) Age at presentation (mo) Age at magnetic resonance imaging (mo) Follow-up (yr) Prenatal events Associated syndromes Consanguinity Family history Presenting signs Seizures Developmental delay Microcephaly Motor deficits Seizure Age at seizure onset (mo) Type of seizure Partial Generalized Seizure frequency Daily Weekly Monthly Response to medication Good Poor Electroencephalographic findings Normal Localized Diffuse Neurologic abnormalities Hemiparesis Quadriparesis Microcephaly Developmental/cognitive delay
37 22/15 21.09 ⫾ 31.24 49.91 ⫾ 57.72 4.18 ⫾ 2.80 11/37 5/37 10/37 7/37
18 14/4 11.05 ⫾ 11.94 27.94 ⫾ 44.23 4.83 ⫾ 2.83 4/18 1/18 5/18 4/18
19 8/11 30.60 ⫾ 40.26 70.73 ⫾ 62.26 3.56 ⫾ 2.71 7/19 4/19 5/19 3/19
0.045 0.233 0.094 0.081 0.476 0.340 1.000 0.692
25/37 13/37 9/37 4/37 28/37 25.67 ⫾ 42.94
9/18 8/18 8/18 2/18 12/18 14.58 ⫾ 18.20
16/19 5/19 1/19 2/19 16/19 34.00 ⫾ 53.88
10/28 18/28
0/12 12/12
10/16 6/16
14/28 6/28 8/28
10/12 1/12 1/12
4/16 5/16 7/16
21/28 7/28
7/12 5/12
14/16 2/16
4/37 15/37 18/37 28/37 11/37 13/37 19/37 35/37
2/18 1/18 15/18 13/18 0/18 13/18 15/18 18/18
2/19 14/19 3/19 15/19 11/19 0/19 4/19 17/19
0.038 0.313 0.008 1.000 0.269 0.478 0.001
0.009
0.103
0.001
0.713 0.001 0.001 0.001 0.486
Note: significant P values in italics.
defects more than the prenatal environmental and teratogenic events. In accordance with previous reports, the most frequent presenting symptom in both of the groups was seizure disorder. As first complaint, seizure was significantly more common in Group 2 patients. The mean age of seizure onset in lissencephalic children has been reported as 6.1 months [16]. In focal cortical malformations it has been determined to be much later, mean 3.5 years [17]. Our results were also similar. Because not all of the patients in Group 1 demonstrated severe lissencephalies in our study, we believe that the mean age of seizure onset in Group 1 had been determined much later than documented in the literature. Epilepsies associated with cortical malformations are typically severe, but not all patients present with seizures. Although the epilepsies are often chronic, seizures are easily controlled in some cases. Types of seizures are rarely specific. It has been reported that patients with generalized cortical malformations most often exhibited generalized seizure patterns and infantile spasms, but partial seizures could occur. Patients with localized cortical malformations exhibit partial or generalized seizures or
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infantile spasms [2-4]. Regarding the seizure type, generalized seizures were observed significantly more frequently in Group 1 patients and partial seizures were observed significantly more frequently in Group 2 patients in our study. Similarly, diffuse epileptiform electroencephalographic abnormalities were significantly more common in Group 1 patients and localized abnormalities in Group 2 patients. We believe that these results are in accordance with the anatomic reflection of the lesions. Despite intensive antiepileptic treatment, five patients in Group 1 continued to have frequent seizures. This situation, however, could not lead to consideration of any resective surgery, because these patients were all lissencephalic. It has been reported that corpus callosotomies have helped patients with double cortex, but patients with lissencephaly usually achieved no benefit [18]. Response to antiepileptic treatment of two patients in Group 2 was also poor, one with left, one with right frontoparietal agyria-pachygyria complex. Resective surgery was not possible in these patients because of the extent of the epileptogenic zone. Hemispherectomy was a consideration, but both of the patients exhibited only mild hemiparesis.
For all types of cortical dysplasias, it has been reported that motor manifestations varied from mild hemiplegia to severe spastic quadriparesis [16,19]. Mental manifestations were also variable, from normal intelligence or minimal learning problems to severe mental retardation [1-3]. In a study by Barkovich, the clinical manifestations correlated roughly with the extent and location of radiographic involvement. Patients with diffuse involvement presented earliest and did most poorly. Patients with bilateral focal involvement were older at presentation and manifested less severe motor and cognitive dysfunction. Those with unilateral focal involvement had the fewest motor, cognitive, and speech problems [20]. Although the patients in their study were not lissencephalic, these results are in accordance with those of the present study. No significant difference between the two groups was observed with regard to neurologic deficits. In regard to developmental or cognitive functions, all of the Group 1 patients were retarded to some degree. In Group 2, two patients were not retarded and three patients were only low normal. These results are in accordance with other reports emphasizing that the extent of convolutional abnormalities correlates with the severity of developmental retardation [16,21]. Because of its relatively high spatial resolution, positron emission tomography has been particularly useful in cortical dysplasias [22]. It has been reported that 18F-deoxyglucose positron emission tomography studies of classical lissencephaly provided a different perspective in the analysis of brain gyral anomalies than those with traditional neuroanatomic imaging techniques [23]. We performed single-photon emission computed tomographic analysis of eight patients in our study but could not perform any studies using positron emission tomography. To summarize, the magnetic resonance scans and clinical features of 37 patients with a diagnosis of agyriapachygyria complex were analyzed. The results indicate that the sizes and locations of these lesions vary greatly and the agyric-pachygyric abnormalities represent a broad spectrum rather than one distinct entity. They may be diffuse or focal, and unilateral or bilateral. These gyral abnormalities demonstrate different clinical and radiologic features, and each case has to be analyzed individually to establish the prognosis and risk recurrence. Genetic factors are likely important in some forms of agyria-pachygyria complex independent of the size and location of the lesion. The recognition of these lesions is important for further understanding of these heterogeneous disorders, as well as for planning proper treatment and genetic counseling. References [1] Lammens M. Neuronal migration disorders in man. Eur J Morphol 2000;38:327-33. [2] Ashwal S. Congenital structural defects. In: Swaiman KF, Ashwal S, eds. Pediatric neurology, 3rd ed. St. Louis: Mosby Inc., 1999:234-300. [3] Aicardi J, Ogier H. Malformations of the central nervous system.
In: Aicardi J, ed. Diseases of the nervous system in childhood, 2nd ed. London: Mac Keith Press, 1998:69-130. [4] Whiting S, Duchowny M. Clinical spectrum of cortical dysplasia in childhood: Diagnosis and treatment issues. J Child Neurol 1999;14: 759-71. [5] Golden JA. Cell migration and cerebral cortical development. Neuropathol Appl Neurobiol 2001;27:22-8. [6] Guerrini R, Dravet C, Bureau M, et al. Diffuse and localized dysplasias of the cerebral cortex: Clinical presentation, outcome, and proposal for a morphologic MRI classification based on a study of 90 patients. In: Guerrini R, Andermann F, Canapicchi R, et al., eds. Dysplasias of cerebral cortex and epilepsy. Philadelphia: LippincottRaven, 1996:255-69. [7] Barkovich AJ, Kuzniecky RI, Dobyns WB, Jackson GD, Becker LE, Evrard P. A classification scheme for malformations of cortical development. Neuropediatrics 1996;27:59-63. [8] 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. [9] Dobyns WB, Andermann E, Andermann F, et al. X-linked malformations of neuronal migration. Neurology 1996;47:331-9. [10] Aicardi J. The agyria-pachygyria complex: A spectrum of cortical malformations. Brain Dev 1991;13:1-8. [11] Dobyns WB, Elias ER, Newlin MS, Pagon RA, Ledbetter DH. Causal heterogeneity in isolated lissencephaly. Neurology 1992;42:137588. [12] Palmini A, Andermann F, Olivier A, Tampieri D, Robitaille Y. Focal neuronal migration disorders and intractable partial epilepsy: Results of surgical treatment. Ann Neurol 1991;30:750-7. [13] Barkovich JA, Koch TK, Carrol CL. The spectrum of lissencephaly: Report of ten patients analyzed by magnetic resonance imaging. Ann Neurol 1991;30:139-46. [14] Sarnat HB, Flores-Sarnat L. A new classification of malformations of the nervous system: An integration of morphological and molecular genetic criteria as patterns of genetic expression. Eur J Paediatr Neurol 2001;5:57-64. [15] Barkovich AJ, Chuang SH. Unilateral megalencephaly: Correlation of MR imaging and pathologic characteristics. AJNR 1990;11:52331. [16] Se´ bire G, Goutrie`res F, Tardieu M, Landrieu P, Aicardi J. Extensive macrogyri or no visible gyri: Distinct clinical, electroencephalographic, and genetic features according to different imaging patterns. Neurology 1995;45:1105-11. [17] Hirabayashi S, Binnie CD, Polkey CD. Surgical treatment of epilepsy due to cortical dysplasia: Clinical and EEG findings. J Neurol Neurosurg Psychiatry 1993;56:765-70. [18] Stephen LJ, Kwan P, Brodie MJ. Does the cause of localisation-related epilepsy influence the response to antiepileptic drug treatment? Epilepsia 2001;42:357-62. [19] Barkovich JA, Koch TK, Carrol CL. The spectrum of lissencephaly: Report of ten patients analyzed by magnetic resonance imaging. Ann Neurol 1991;30:139-46. [20] Barkovich AJ, Kjos BO. Gray matter heterotopias: MR characteristics and correlation with developmental and neurologic manifestations. Radiology 1992;182:493-9. [21] deRijk-van Andel JF, Arts WF, Barth PG, Loonen MC. Diagnostic features and clinical signs of 21 patients with lissencephaly type 1. Dev Med Child Neurol 1990;32:707-11. [22] Chugani HT. Functional imaging in cortical dysplasias: Positron emission tomography. In: Guerrini R, Andermann F, Canapicchi R, et al., eds. Dysplasias of cerebral cortex and epilepsy. Philadelphia: Lippincott-Raven, 1996:169-74. [23] Pfund Z, Chugani HT, Juha´ sz C, et al. Lissencephaly: Fetal pattern of glucose metabolism on positron emission tomography? Neurology 2000;55:1683-88.
Kurul et al: MRI Findings in Agyria-Pachygyria Complex 23
From the *Departments of Pediatric Neurology and †Radiology, Dokuz Eylu¨l University Faculty of Medicine, I˙zmir, Turkey.
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Introduction The term “agyria-pachygyria” is applied to several disorders of neuronal migration anomalies that result in total or subtotal absence of cortical sulci and severely disturbed architectonics of the cortical plate [1,2]. Agyria means mainly absent cortical gyri. In fact, most “agyric” brains have at least small areas of gyral formation. These areas of flat, broad, and shallow gyri are referred to as areas of pachygyria [3]. Pathologic descriptions have demonstrated that agyria and pachygyria are part of a continuum of gyral defects. The term “lissencephaly” is sometimes used as a synonym for agyria. Clinically, gyral cortical defects cause seizures, developmental retardation, and motor deficits [4,5]. Modern neuroimaging techniques have permitted the diagnosis of generalized neuronal migration disorders while the patient is alive [6]. The severity and extent of associated abnormalities vary greatly. The clinical features of lissencephalies have been well described [1,2,4]. However, information about partial gyral anomalies is scarce. The aim of this study was to determine the spectrum of clinical findings in agyriapachygyria complex, to identify possible causes, and to correlate the clinical features with the extent of the lesions on magnetic resonance imaging.
Patients and Methods The study group comprised 37 patients in whom agyria-pachygyria complex was recognized by magnetic resonance imaging in the Department of Pediatric Neurology of Dokuz Eylu¨l University. Magnetic resonance imaging scans were performed with a number of different techniques, because they were performed at many institutions. All of the printed films were reviewed by a pediatric neuroradiologist in our institution without knowledge of detailed clinical evaluation. Imaging sequences were performed at 1 or 1.5 Tesla and included T1-weighted, T2-weighted, and more recently, inversion recovery sequences in some patients. The images were evaluated with specific attention to the severity, location, and size of the anomaly (involved lobes). Side of the lesion and extent of lobar involvement were assessed by examination of
Communications should be addressed to: ¨ niversitesi Tıp Faku¨ltesi; C¸ocuk Sag˘lıg˘ı ve Dr. Kurul; Dokuz Eylu¨l U Hastalıkları AD; C¸ocuk No¨rolojisi BD; 35340 I˙nciraltı I˙zmir, Turkey. Received February 11, 2003; accepted May 14, 2003.
© 2004 by Elsevier Inc. All rights reserved. doi:10.1016/S0887-8994(03)00312-6 ● 0887-8994/04/$—see front matter
Table 1.
Summary of the clinical data of the patients in Group 1 (generalized or bilateral gyral malformation)
No.
Sex
Age at Presentation
Presenting Symptoms
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
M M M M M M M M F M M M M F M F F M
7 days 1 mo 1 yr 4 mo 3 mo 1 yr 14 days 4 mo 1 yr 5 mo 6 mo 3.5 yr 2 yr 9 mo 2 mo 1 yr 3y 15 mo
Seizures Seizures, dev. delay Seizures, dev. delay Seizures, dev. delay Microcephaly, dev. delay Dev. delay Seizures, dev. delay Microcephaly Microcephaly, dev. delay Microcephaly Microcephaly, seizures Microcephaly Dev. delay Microcephaly Seizures, motor deficit Microcephaly, motor deficit Seizures Seizures
Abbreviations: ⫹ ⫽ Present ⫺ ⫽ Absent CMV ⫽ Cytomegalovirus dev. delay ⫽ Developmental delay DTRs ⫽ Deep tendon reflexes EEG ⫽ Electroencephalographic F ⫽ Female FR ⫽ Frontal FP ⫽ Frontoparietal
FTP GT GTC HP hypsar. IS M MF mic.
⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽
Location of Lesion Diffuse Diffuse Diffuse Diffuse Diffuse Diffuse Diffuse Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral
Family History
Associated Syndrome
Prenatal Events
Consanguinity
⫺ ⫺ ⫺ ⫹ ⫹ ⫺ ⫺ ⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫹ ⫺
⫺ ⫺ ⫺ ⫹ Miller-Dieker ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺
⫺ ⫺ ⫺ Febrile illness Intrauterine CMV inf. Psychologic trauma ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ Febrile illness ⫺ ⫺ ⫺ ⫺
⫺ ⫺ ⫺ ⫺ ⫹ ⫺ ⫹ ⫺ ⫺ ⫺ ⫹ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫹
FTP FP FP FTP FP FP FTP FTP FTP FP FP
Frontotemporoparietal Generalized tonic Generalized tonic clonic Hemiparesis Hypsarrhythmia Infantile spasm Male Multifocal Microcephaly
a combination of sagittal, axial, and coronal images. On the basis of magnetic resonance imaging features, the patients were separated into two groups according to the classification of Barkovich [7]: Group 1 (18 children) manifested generalized or bilateral gyral malformation; Group 2 (19 children) manifested localized or unilateral gyral malformation. Clinical findings of Group 1 patients were compared with those of Group 2. Patients were excluded if they had type II lissencephaly or severe cerebellar involvement, schizencephaly, hemimegalencephaly, holoprosencephaly, and gray matter heterotopias. Patients with other complex cerebral anomalies were also excluded from the study because those anomalies could cause neurologic symptoms, obscuring the effects of agyria-pachygyria complex. Patients with agenesis or hypogenesis of the corpus callosum as the only associated anomaly were included in the study. The patients were referred for imaging because of seizures, mental retardation, developmental delay, or microcephaly. All patients underwent physical and neurologic examination. A standard detailed questionnaire had been used, emphasizing pregnancy and in utero factors, development, associated malformations, presenting complaints, and family history. Special attention was paid to the following: presence or absence of seizures, age at onset, type, frequency, response to treatment, course of epilepsy, presence or absence of motor deficit, type of deficit (spastic or flaccid), body areas involved (quadriparesis, hemiparesis, or monoparesis), electroencephalographic results, developmental level in patients younger than 6 years of age (assessed by the Ankara Developmental Screening Test), and intelligence quotient in patients older than 6 years of age (assessed by the Wechsler Intelligence Scale for ChildrenRevised). Extracranial electroencephalographic investigations were performed using the international 10-20 system. Recordings were obtained during both wakefulness and sleep. Epileptiform discharges were divided into two categories: “localized” with a maximum confined to one or two
myoclon. O P PC PG PS QP Spast.
⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽
Myoclonic Occipital Parietal Partial complex Partial with generalization Partial simple Quadriparesis Spasticity
adjacent electrodes; and “diffuse” with multifocal independent spikes or bilateral discharges. Seizure types were classified according to the criteria of the International League Against Epilepsy as being “generalized” or “partial.”[8]. Seizure frequency was divided into three groups: daily, weekly, and monthly, an average of at least one seizure per day, week, or month respectively. Outcome classification of the seizures was performed as follows: “good response,” either the patient was seizurefree or reduction of seizure frequency was greater than 50%; “poor response,” either seizures were worse or the same or reduction of seizure frequency was less than 50%. Intelligence quotient according to the Wechsler Intelligence Scale for Children-Revised was divided into the following categories: “normal”— either verbal or performance intelligence quotient more than 90; “retarded”— both verbal and performance intelligence quotient under 69; and “low normal”—the range between the former two. Developmental level assessed by the Ankara Developmental Screening Test was divided as follows: if the score was less than 10% of the mean score obtained by normal children, it was assessed as “retarded.” If the score was equal to or greater than 10% of the mean score obtained by normal children, it was assessed as “normal.” Differences between the study groups were tested using the Fisher exact test and Mann-Whitney U-Wilcoxon rank sum test. A P value of less than 0.05 was considered significant.
Results Clinical data of the patients in Groups 1 and 2 are summarized in Tables 1 and 2. Magnetic resonance imaging characteristics of the brains of the patients are summarized in Table 3. Some representative magnetic resonance images of the patients are presented in Figures
Kurul et al: MRI Findings in Agyria-Pachygyria Complex 17
Table 1. (Continued)
Neurologic Findings
Cognition/ Development
Seizure Type
Age of Seizures
Seizure Frequency
EEG Findings
Response to Medication
Spast., QP, mic. Spast., QP, mic. Spast., QP, mic. Spast., QP, mic. Spast., QP, mic. Spast., QP Spast., QP Mic. Spast., QP, mic. Mic., bilateral brisk DTRs Spast., QP, mic. Mic., bilateral brisk DTRs Mic. Spast., QP, mic. Spast., QP, mic. Spast., QP, mic. Bilateral brisk DTRs Spast., QP, mic.
Retarded Retarded Retarded Retarded Retarded Retarded Retarded Retarded Retarded Low normal Retarded Retarded Retarded Retarded Retarded Retarded Retarded Retarded
IS, GT IS, GTC IS, GTC GT ⫺ GTC IS, GTC ⫺ ⫺ ⫺ GT ⫺ ⫺ GT IS, GTC GT, myoclon. GTC GTC, myoclon.
7 days 7 mo 1y 4 mo ⫺ 5y 14 days ⫺ ⫺ ⫺ 4 mo ⫺ ⫺ 1.5 y 2 mo 2y 3y 15 mo
Daily Weekly Daily Daily ⫺ Weekly Weekly ⫺ ⫺ ⫺ Daily ⫺ ⫺ Weekly Monthly Daily Monthly Daily
Diffuse (MF) Diffuse (MF) Diffuse (hypsar.) Diffuse Diffuse Diffuse (MF) Diffuse (MF) Diffuse Diffuse Diffuse Diffuse Normal Normal Localized (left) Diffuse (hypsar.) Diffuse (MF) Diffuse Diffuse (MF)
Good Good Poor Poor ⫺ Good Poor ⫺ ⫺ ⫺ Good ⫺ ⫺ Good Good Poor Good Poor
1-4. A comparison of clinical manifestations of the two groups is presented in Table 4. The patients’ ages ranged from 1 day to 15 years (mean 21.09 ⫾ 31.24 months of age) at the time of presentation. In Group 1, the mean age at presentation was 11.05 ⫾ 11.94 months of age (1 day-3.5 years) and in Group 2, it was 30.60 ⫾ 40.26 months (1 month-15 years). There was no significant difference between the two groups with regard to the mean age at presentation, although it was much earlier in Group 1 (P ⫽ 0.233). Twenty-two patients (59.5%) were male, and 15 (40.5%) were female. In Group 1, 14 patients (77.8%) were male and 4 patients (22.2%) were female. In Group 2, 8 patients (42.1%) were male and 11 patients (57.9%) were female. The number of male patients was significantly higher in Group 1 compared with Group 2 (P ⫽ 0.045). Pregnancies were normal in the mothers of all but 11 patients (29.7%): 4/18 patients (22.2%) in Group 1, 7/19 patients (36.8%) in Group 2. These events were maternal serious upper airway infection with fever (two patients), excessive smoking (two patients), vaginal bleeding (two patients), drug exposure (three patients), serious psychological trauma in the first trimester of pregnancy (one patient), and in utero cytomegalovirus infection (one patient). There was no significant difference between the two groups with regard to prenatal events (P ⫽ 0.476). Associated genetic syndromes were present in 5 patients (13.5%). One patient in Group 1 manifested facial anom-
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alies leading to the diagnosis of Miller-Dieker syndrome. In Group 2, four patients were diagnosed with various genetic syndromes including glutaric aciduria type II, oral-facial-digital syndrome, Angelman syndrome, and Klippel-Trenaunay-Weber syndrome. No significant difference was observed between the two groups (P ⫽ 0.340). Karyotype was performed for 10 patients, but manifested no abnormalities. The rate of consanguinity in all study patients was 27%. Family history of neurologic diseases, such as mental retardation of unknown etiology and seizure disorder, was positive in 7 patients (18.9%). There were no significant differences between the two groups with regard to the rate of consanguinity (P ⫽ 1.000) and family history of neurologic disorders (P ⫽ 0.692). The symptoms at presentation were seizures in 25 patients (67.6%), developmental delay in 13 patients (35.1%), microcephaly in 9 patients (24.3%), and motor deficits in 4 patients (10.8%). Patients in Group 1 presented significantly more frequently with microcephaly (8/18 [44.4%] in Group 1 vs 1/19 [26.3%] in Group 2; P ⫽ 0.008). Patients in Group 2, however, presented significantly more frequently with seizures (16/19 [84.2%] in Group 2 vs 9/18 [50%] in Group 1; P ⫽ 0.038). Developmental delay as presenting symptom was much more common in Group 1, but there was no significant difference between the two groups (8/18 [44.4%] in Group 1 vs 5/19 [26.3%] in Group 2; P ⫽ 0.313). Motor deficits were
Table 2.
Summary of the clinical data of the patients in Group 2 (localized or unilateral gyral malformation)
No.
Sex
Age at Presentation
Presenting Symptoms
19 20 21 22 23 24 25 26 27 28 29 30 31
F F F F F M M M M F F M F
1 mo 15 yr 12 yr 5 yr 1 yr 8 yr 6 mo 2 mo 1 yr 1.5 yr 5 yr 15 mo 2 mo
Seizures Seizures, mic., dev. delay Seizures Seizures Seizure, motor deficit Dev. delay Seizures, dev. delay Seizures Motor deficit Seizures Seizures Seizures Seizures
Unilateral Unilateral Unilateral Unilateral Unilateral Unilateral Unilateral Unilateral Unilateral Unilateral Unilateral Unilateral Unilateral
right P right FTP right FR right FP right FP right O right P right FP right FP left O right P right FP left P
⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺
32 33 34 35 36 37
M M F M F F
Seizures Dev. delay Seizures Seizures, dev. delay Seizures Seizures
Unilateral Unilateral Unilateral Unilateral Unilateral Unilateral
left left left left left left
⫹ ⫺ ⫹ ⫺ ⫺ ⫺
2 2 3 3 4 1
mo yr mo yr mo yr
Location of Lesion
FP FR P P FP FR
Family History
Associated Syndrome ⫹ Glutaric aciduria II ⫺ ⫺ ⫺ ⫺ ⫹ Oral-facial-digital syndrome ⫹ Angelman syndrome ⫺ ⫺ ⫺ ⫺ ⫺ ⫹ Klippel-Trenaunay-Weber syndrome ⫺ ⫺ ⫺ ⫺ ⫺ ⫺
Prenatal Events Drug exposure Vaginal bleeding Excessive smoking ⫺ ⫺ ⫺ Vaginal bleeding Drug exposure ⫺ ⫺ ⫺ ⫺ Excessive smoking ⫺ ⫺ ⫺ ⫺ ⫺ Attempt to criminal abortus
Abbreviations as in Table 1.
observed in two groups with almost equal frequency (2/18 [11.1%] in Group 1 and 2/19 [10.5%] in Group 2; P ⫽ 1.000). In follow-up, seizure disorders were present in 28 (75.7%) patients. Eighteen (64.3%) had generalized seizures and the remaining 10 (35.7%) patients had partial seizures. The ratio of generalized seizures in Group 1 was significantly higher than in Group 2. Partial seizures were more common in Group 2 compared with Group 1 (P ⫽ 0.001). Age at onset of seizures ranged from birth to 15 years (mean 25.67 ⫾ 42.94 months). In Group 1, it was from birth to 5 years (mean 14.58 ⫾ 18.20 months) and in Group 2, from birth to 15 years (mean 34.00 ⫾ 53.88 months). The difference between the two groups was not statistically significant (P ⫽ 0.478). The patients in Group 1 had seizures significantly more frequently than in Group 2 (P ⫽ 0.009). Of the 28 patients with seizures, 21 (75%) were good responders to antiepileptic treatment. In the remaining 7 (25%) patients, the seizures were not reduced or were reduced less than 50% despite excessive and adequate antiepileptic treatment. Five of these patients were in Group 1, and two patients were in Group 2. There was no significant difference between the two groups (P ⫽ 0.103). Regarding the electroencephalographic findings, 18 (48.6%) patients manifested diffuse epileptiform abnormality, 15 (40.5%) manifested localized epileptiform activity, and the remaining 4 (10.8%) patients had normal electroencephalographic findings. Diffuse abnormalities were significantly more common in Group 1 (15/18; 83.3%), and localized abnormalities were significantly more common in Group 2 (14/19; 73.7%) (P ⫽ 0.001).
The percentage of neurologic deficits in all study patients was 75.7% (28/37). Neurologic deficits in Group 2 patients were observed as frequently as in Group 1 patients (15/19, 78.9% and 13/18, 72.2%, respectively) (P ⫽ 0.713). However, hemiparesis contralateral to the affected side was the most frequent neurologic deficit in Group 2 patients (P ⫽ 0.001). Spastic quadriparesis and microcephaly were more common in Group 1 compared with Group 2 (P ⫽ 0.001, P ⫽ 0.001, respectively). In the first year of their life, it has been observed that patients with neurologic deficits in Group 1 exhibited hypotonia. Thereafter, hypotonia transformed into spasticity. All study patients but two in Group 2 manifested developmental delay or mental retardation, mild to severe in degree, without any significant difference between the two groups (P ⫽ 0.486). Discussion Advances in neuroimaging techniques have resulted in an increasing recognition of the cortical lesions as the etiology of a number of epilepsies that were previously defined as cryptogenic. It has been reported that modern neuroimaging methods allowed analysis of gross features of the entire brain in all patients, whereas neuropathology was invasive and available for only a highly selected group of patients [4,7]. However, the classification of cortical developmental abnormalities poses a problem to the clinician despite advances in the fields of neuroradiology and molecular genetics. There are reports proposing radiologic, anatomic, or embryologic classification systems [1-3], but such systems often fail because of the extensive variety of these malformations. Barkovich et al.
Kurul et al: MRI Findings in Agyria-Pachygyria Complex 19
Table 2. (Continued)
Consanguinity
Neurologic Findings
Cognition/ Development
Seizure Type
⫹ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫹ ⫺ ⫹ ⫺ ⫺
Mic. Mic., left HP Brisk DTRs (left) Normal Left HP Normal Left HP Mic., left HP Left HP Mic. Left HP Brisk DTRs (left) Right HP
Retarded Retarded Low normal Normal Retarded Low normal Retarded Retarded Retarded Retarded Normal Retarded Retarded
PG GT, atonic GTC GTC GTC ⫺ IS, GTC PC ⫺ PC PS PC PC
⫺ ⫺ ⫺ ⫹ ⫺ ⫺
Right HP Normal Right HP Right HP Right HP Normal
Retarded Retarded Retarded Retarded Retarded Low normal
PG ⫺ PS PG GT PC
proposed a classification system for the malformations of cerebral cortex based on fundamental embryologic and genetic principles and a combination of neuroimaging, gross pathologic, and histologic criteria [7]. Because pathologic descriptions have demonstrated that agyria and pachygyria are part of a continuum of gyral defects, a system for grading the severity of gyral malformations expanding to include pachygyria has been reported by Dobyns et al. [9]. However, their report described only bilateral and diffuse lesions. In our study, because patients with unilateral involvement were included, the classification system of Barkovich was used.
Age of Seizures
Seizure Frequency
EEG Findings
1 mo 15 yr 12 yr 5 yr 1 yr ⫺ 3 mo 2 mo ⫺ 1.5 yr 5 yr 15 mo 2 mo
Daily Monthly Monthly Monthly Monthly ⫺ Monthly Daily ⫺ Monthly Monthly Monthly Daily
Localized Diffuse Normal Localized Localized Normal Diffuse Localized Localized Localized Localized Localized Diffuse
2 mo ⫺ 3 mo 2.5 yr 4 mo 1 yr
Weekly ⫺ Monthly Monthly Monthly Monthly
Localized Localized Localized Localized Localized Localized
(right)
(right) (right)
(right) (right) (left) (right) (right)
(left) (left) (left) (left) (left) (left)
Response to Medication Good Good Good Good Good ⫺ Good Poor ⫺ Good Good Good Good Poor ⫺ Good Good Good Good
Most patients with cortical gyral abnormalities present with epilepsy and mental retardation. However, the severity and extent of these manifestations varies greatly [1-3,10]. Attempts to correlate clinical findings with the severity and location of cortical malformation have met with variable success. Although the clinical course of patients with severe neuronal migration anomalies is well established, information regarding the clinical features and prognosis of partial lissencephalies, namely focal pachygyric lesions, is scarce [11,12]. It is well known that patients with lissencephaly are presenting with symptoms
Table 3. MR characteristics of the brains of patients in Groups 1 and 2 Study Group
Location of Lesion
n
Total
Group 1 (generalized or bilateral agyriapachygyria complex)
Diffuse Bilateral FTP Bilateral FP (Other findings) Corpus callosum agenesis Lateral ventricul dilatation
7 5 6
18
Group 2 (localized or unilateral agyriapachygyria complex)
FTP FP FR P O (Other findings) Corpus callosum agenesis Lateral ventricular dilatation
Total
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1 7 3 6 2
19
(3) – 37
Abbreviations as in Table 1.
20
(3) (4)
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Figure 1. Case 3. T1-weighted axial image demonstrates bilateral diffuse cortical thickening, reduced cortical sulci, and enlargement of the subarachnoid space.
Figure 2. Case 9. T1-weighted axial image demonstrates bilateral frontoparietal cortical thickness, decrease in cortical sulci, and enlargement of the ventricles.
early in life. It has been reported that 60-83% of patients with lissencephaly presented in the first two years of life [4,11,13]. In accordance with previous reports, patients with generalized or bilateral gyral malformation in our study were often symptomatic in the first year of life. The patients with unilateral or focal gyral malformations were symptomatic much later than the patients in Group 1, albeit without any significant difference between the two groups. In our study, the percentage of male patients in Group 1 was significantly higher than in Group 2. All the patients who exhibited diffuse gyral malformations in Group 1 were male. Genetic analysis could not be performed for these patients. However, we conclude that these patients could have X-linked lissencephalies. Previous reports have documented that environmental and teratogenic factors during the first 4 months of the pregnancy may lead to the genesis of gyral abnormalities [2-4]. In our study, some of the pregnancies were complicated by vaginal bleeding and severe febrile illness lasting more than one week during the first trimester. However, we believe that it is not always objective to assert that these prenatal events were in distinct relationship with migrational abnormalities, because it is not possible to demonstrate them and not a small number of pregnancies are complicated by such events. Neuronal migration abnormalities have been reported in a variety of genetic syndromes [4,14]. In our study group, five patients manifested clinically well-defined genetic syndromes. Case 4 in Group 1 exhibited clinical features of Miller-Dieker syndrome. This male died when he was two years old, and a genetic analysis could not be performed for this patient. The other four patients were all in Group 2. Their syndromes diagnosed were glutaric aciduria type II (Case 19), oral-facial-digital syndrome (Case 24), Angelman syndrome (Case 25), and Klippel-
Figure 3. Case 19. T2-weighted axial image demonstrates abnormal thickening of cortical gray matter in the right parietal lobe.
Trenaunay-Weber syndrome (Case 31). The association of these syndromes with neuronal migration abnormalities has been reported previously in literature [2-4,14,15]. Genetic counseling has been offered to the families of our patients. Dobyns et al. reported the consanguinity rate in lissencephalic children as 4.8% [11]. In our study, the consanguinity rate was 27% without any significant difference between the groups. The overall consanguinity rate in Turkey ranges between 10-20%. We consider the rates of consanguinity and family history of neurologic diseases such as seizure disorder and mental retardation that were detected in our study to be high. These results suggest that gyral abnormalities could be due to genetic
Figure 4. Case 30. T2-weighted axial image reveals focal thickening of the right frontoparietal cortex.
Kurul et al: MRI Findings in Agyria-Pachygyria Complex 21
Table 4.
Comparison of clinical manifestations of the patients Variable
Total
Group 1
Group 2
P
n Sex (M/F) Age at presentation (mo) Age at magnetic resonance imaging (mo) Follow-up (yr) Prenatal events Associated syndromes Consanguinity Family history Presenting signs Seizures Developmental delay Microcephaly Motor deficits Seizure Age at seizure onset (mo) Type of seizure Partial Generalized Seizure frequency Daily Weekly Monthly Response to medication Good Poor Electroencephalographic findings Normal Localized Diffuse Neurologic abnormalities Hemiparesis Quadriparesis Microcephaly Developmental/cognitive delay
37 22/15 21.09 ⫾ 31.24 49.91 ⫾ 57.72 4.18 ⫾ 2.80 11/37 5/37 10/37 7/37
18 14/4 11.05 ⫾ 11.94 27.94 ⫾ 44.23 4.83 ⫾ 2.83 4/18 1/18 5/18 4/18
19 8/11 30.60 ⫾ 40.26 70.73 ⫾ 62.26 3.56 ⫾ 2.71 7/19 4/19 5/19 3/19
0.045 0.233 0.094 0.081 0.476 0.340 1.000 0.692
25/37 13/37 9/37 4/37 28/37 25.67 ⫾ 42.94
9/18 8/18 8/18 2/18 12/18 14.58 ⫾ 18.20
16/19 5/19 1/19 2/19 16/19 34.00 ⫾ 53.88
10/28 18/28
0/12 12/12
10/16 6/16
14/28 6/28 8/28
10/12 1/12 1/12
4/16 5/16 7/16
21/28 7/28
7/12 5/12
14/16 2/16
4/37 15/37 18/37 28/37 11/37 13/37 19/37 35/37
2/18 1/18 15/18 13/18 0/18 13/18 15/18 18/18
2/19 14/19 3/19 15/19 11/19 0/19 4/19 17/19
0.038 0.313 0.008 1.000 0.269 0.478 0.001
0.009
0.103
0.001
0.713 0.001 0.001 0.001 0.486
Note: significant P values in italics.
defects more than the prenatal environmental and teratogenic events. In accordance with previous reports, the most frequent presenting symptom in both of the groups was seizure disorder. As first complaint, seizure was significantly more common in Group 2 patients. The mean age of seizure onset in lissencephalic children has been reported as 6.1 months [16]. In focal cortical malformations it has been determined to be much later, mean 3.5 years [17]. Our results were also similar. Because not all of the patients in Group 1 demonstrated severe lissencephalies in our study, we believe that the mean age of seizure onset in Group 1 had been determined much later than documented in the literature. Epilepsies associated with cortical malformations are typically severe, but not all patients present with seizures. Although the epilepsies are often chronic, seizures are easily controlled in some cases. Types of seizures are rarely specific. It has been reported that patients with generalized cortical malformations most often exhibited generalized seizure patterns and infantile spasms, but partial seizures could occur. Patients with localized cortical malformations exhibit partial or generalized seizures or
22
PEDIATRIC NEUROLOGY
Vol. 30 No. 1
infantile spasms [2-4]. Regarding the seizure type, generalized seizures were observed significantly more frequently in Group 1 patients and partial seizures were observed significantly more frequently in Group 2 patients in our study. Similarly, diffuse epileptiform electroencephalographic abnormalities were significantly more common in Group 1 patients and localized abnormalities in Group 2 patients. We believe that these results are in accordance with the anatomic reflection of the lesions. Despite intensive antiepileptic treatment, five patients in Group 1 continued to have frequent seizures. This situation, however, could not lead to consideration of any resective surgery, because these patients were all lissencephalic. It has been reported that corpus callosotomies have helped patients with double cortex, but patients with lissencephaly usually achieved no benefit [18]. Response to antiepileptic treatment of two patients in Group 2 was also poor, one with left, one with right frontoparietal agyria-pachygyria complex. Resective surgery was not possible in these patients because of the extent of the epileptogenic zone. Hemispherectomy was a consideration, but both of the patients exhibited only mild hemiparesis.
For all types of cortical dysplasias, it has been reported that motor manifestations varied from mild hemiplegia to severe spastic quadriparesis [16,19]. Mental manifestations were also variable, from normal intelligence or minimal learning problems to severe mental retardation [1-3]. In a study by Barkovich, the clinical manifestations correlated roughly with the extent and location of radiographic involvement. Patients with diffuse involvement presented earliest and did most poorly. Patients with bilateral focal involvement were older at presentation and manifested less severe motor and cognitive dysfunction. Those with unilateral focal involvement had the fewest motor, cognitive, and speech problems [20]. Although the patients in their study were not lissencephalic, these results are in accordance with those of the present study. No significant difference between the two groups was observed with regard to neurologic deficits. In regard to developmental or cognitive functions, all of the Group 1 patients were retarded to some degree. In Group 2, two patients were not retarded and three patients were only low normal. These results are in accordance with other reports emphasizing that the extent of convolutional abnormalities correlates with the severity of developmental retardation [16,21]. Because of its relatively high spatial resolution, positron emission tomography has been particularly useful in cortical dysplasias [22]. It has been reported that 18F-deoxyglucose positron emission tomography studies of classical lissencephaly provided a different perspective in the analysis of brain gyral anomalies than those with traditional neuroanatomic imaging techniques [23]. We performed single-photon emission computed tomographic analysis of eight patients in our study but could not perform any studies using positron emission tomography. To summarize, the magnetic resonance scans and clinical features of 37 patients with a diagnosis of agyriapachygyria complex were analyzed. The results indicate that the sizes and locations of these lesions vary greatly and the agyric-pachygyric abnormalities represent a broad spectrum rather than one distinct entity. They may be diffuse or focal, and unilateral or bilateral. These gyral abnormalities demonstrate different clinical and radiologic features, and each case has to be analyzed individually to establish the prognosis and risk recurrence. Genetic factors are likely important in some forms of agyria-pachygyria complex independent of the size and location of the lesion. The recognition of these lesions is important for further understanding of these heterogeneous disorders, as well as for planning proper treatment and genetic counseling. References [1] Lammens M. Neuronal migration disorders in man. Eur J Morphol 2000;38:327-33. [2] Ashwal S. Congenital structural defects. In: Swaiman KF, Ashwal S, eds. Pediatric neurology, 3rd ed. St. Louis: Mosby Inc., 1999:234-300. [3] Aicardi J, Ogier H. Malformations of the central nervous system.
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