Anda di halaman 1dari 6

Agyria-Pachygyria: Clinical, Neuroimaging,

and Neurophysiologic Correlations


Jao-Shwann Liang, MD*, Wang-Tso Lee, MD, PhD*, Chainllie Young, MD, PhD*,
Steven Shinnforng Peng, MD†, and Yu-Zen Shen, MD, PhD*

Agyria-pachygyria complex is a disorder of neuronal thickened cortical mantle [1,2]. Pachygyria is considered
migration and organization. Patients suffer either mo- the less severe form and exhibits a broader spectrum of
tor or intellectual retardation. We report our experi- clinical features than agyria. In many cases, agyria and
ences of 10 patients with agyria-pachygyria complex pachygyria coexist in the same patient [3]. They represent
and evaluate their clinical features, electroencephalog- degrees of the same fundamental disorders in cell migra-
raphy, and evoked potentials. Of nine electroencepha- tion and cortical organization [4]. More and more patients
lography examinations, five patients demonstrated have been documented as agyria-pachygyria since the
characteristically high-amplitude fast activity. One of advent of computed tomography (CT) and magnetic res-
nine patients had an abnormal brainstem auditory- onance imaging (MRI). Although some of these disorders
evoked potential. Three of seven patients had abnor- have a genetic basis, the cause of the migrational arrest is
mal goggled visual-evoked potential. Six patients re- still unknown.
ceived somatosensory-evoked potential examinations, Patients with agyria-pachygyria are always retarded
and five of these were abnormal, including four with in their motor or intellectual function, and seizures are
prolonged central conduction times. Of the 10 patients, common early in life [5]. Some unusual electroen-
eight survived with variable intellectual and motor cephalography (EEG) patterns have been proposed to
retardation; two died of sepsis. Patients with grades 1-4 suggest a diagnosis of agyria-pachygyria [5-7]. However,
agyria-pachygyria had high incidences of somatosen- there are limited studies focusing on the changes of
sory-evoked potential abnormalities and also suffered evoked potentials in these patients. We report our experi-
worse neurologic outcomes. Normal brainstem audito- ences of 10 patients with various types of agyria-
ry-evoked potential but abnormal cortical somatosen- pachygyria and evaluate their clinical features, EEG, and
sory-evoked potential components and prolonged cen- evoked potentials. Additionally, we try to clarify the
tral conduction time in these patients indicate that relationship between clinical presentations, neuroimaging,
agyria-pachygyria is a supratentorial disease. We con- and evoked potential findings in these patients.
clude that somatosensory-evoked potential examina-
tion is supplemental to neuroimaging in predicting the
neurologic prognosis of patients with agyria-pachygyria. Patients and Methods
© 2002 by Elsevier Science Inc. All rights reserved.
We reviewed the medical records of patients with agyria-pachygyria at
Liang J-S, Lee W-T, Young C, Peng SS, Shen Y-Z. the National Taiwan University Hospital from February 1992 to February
2001. Agyria-pachygyria was diagnosed based on clinical and neuroim-
Agyria-pachygyria: Clinical, neuroimaging, and neuro-
aging findings. To correlate the extent of agyria-pachygyria with clinical
physiologic correlations. Pediatr Neurol 2002;27:171-176. findings and evoked potential changes, we modified the classification of
agyria-pachygyria complex into six degrees of severity to include focal
pachygyria, according to radiologic findings from Andel’s classification
[8] (Table 1). Neurophysiologic studies, including EEG and evoked
potentials studies, were performed in these patients except in those
Introduction patients who did not cooperate. A 14-channel Nihon-Kohden EEG
machine was used in the EEG studies. Electrodes were placed according
Agyria-pachygyria is a disease of neuronal migration to the 10-20 system method. Special attention was given to high-
characterized by the total or partial absence of sulci and a amplitude (more than 50 ␮V) fast activities. The multimodality evoked

From the Departments of *Pediatrics and †Radiology; National Taiwan Communications should be addressed to:
University Hospital; Taipei, Taiwan Dr. Lee; Department of Pediatrics; National Taiwan University
Hospital; No 7, Chung-Shan South Road; Taipei 100, Taiwan.
Received September 11, 2001; accepted February 21, 2002.

© 2002 by Elsevier Science Inc. All rights reserved. Liang et al: Analysis of Agyria-Pachygyria Complex 171
PII S0887-8994(02)00401-0 ● 0887-8994/02/$—see front matter
Table 1. Classification of agyria-pachygyria according to Table 2. Four patients were admitted for seizures, and
neuroimaging findings
three were admitted for developmental delays. Of the 10
Grade 1 Complete agyria
patients, nine received MRI examinations, and only Pa-
Grade 2 Agyria with some sulci tient 1 received CT examination. Seven patients had
Grade 3 A mixture of approximately 50% agyria and 50% agyria-pachygyria with neuroimaging grading 1-4 (Fig
pachygyria 1A), and three were grade 5-6 (Fig 1B). All of our grade
Grade 4 Complete pachygyria
Grade 5 Focal pachygyria more than 50% of cortex
1-4 patients were classic type I lissencephaly. Six patients
Grade 6 Focal pachygyria less than 50% of cortex have received chromosome studies, and only Patient 2 was
proven to have Miller-Dieker syndrome. Of the seven
Modified from Andel et al. [8]. patients with grade 1-4 agyria-pachygyria, five patients
had infantile spasms and had seizure onset at less than 1
potentials were recorded with a Bravo EP machine (Nicolet, Madison, year of age. In contrast, only Patient 10, with grade 6
WI) and included goggled visual-evoked potential, brainstem auditory- agyria-pachygyria, developed seizures at 10 years of age.
evoked potential, and somatosensory-evoked potential to the median
nerve stimulation.
Visual-evoked potentials using light-emitting diode goggles were
Neurophysiologic Evaluations
performed. Light-emitting diode stimulus was a red flash presented
monocularly using Nicolet 1015 goggles delivered at 1 flash/second. Electroencephalography was performed in nine patients,
Silver/silver chloride electrodes were positioned using the International seven of whom were grade 1-4 and two of whom were
Electrode system at Oz. All active sites were referred to Cz, and the grade 5-6. Four patients had a neuroimaging grading of
patient was grounded from the FPz. 1-4, and only one patient was a grade 6 with high-
Monaural rarefaction click auditory brainstem responses (ABRs) were
elicited at an 21.1 clicks/second with the contralateral ear masked.
amplitude fast activity (Fig 2). The frequencies of the fast
Recording electrodes were placed on the vertex (Cz) and referred to the activities ranged from 8 to 16 Hz with an amplitude higher
ears ipsilateral and contralateral to the side of stimulation. Waves I, III, than 50 ␮V. The high-voltage tracings were dominant at
and V were identified in the resulting ABR tracing, and the latencies of areas corresponding to the pachygyria, as demonstrated in
these peaks were determined, as well as the I-III, III-V, and I-V interpeak Patient 10 (Fig 1B).
intervals.
In somatosensory-evoked potential studies, the median nerves were
Eight of the nine patients had a normal brainstem
stimulated with electric pulses of 0.1-ms duration at a stimulus frequen- auditory-evoked potential, with the exception of Patient 7
cies of 2.7/seconds. Surface electrodes were placed on the scalp 2 cm who underwent prolonged ventilator usage because of
posterior to C3 and C4 and the cervical spine C7. The reference elec- septic shock and cardiopulmonary dysfunction. Goggled
trode was placed at Fpz. Latencies of the sensory-evoked potential visual-evoked potential was performed in seven patients.
components at the points of C7 (N13) and the cortex (N1) were especially
reviewed. Central conduction time (N1-N13) was compared with the
Three of these findings were abnormal, including Patient 9
normative data for the median nerve sensory-evoked potentials of Taylor who had congenital anomalies of optic nerve hypoplasia,
and Fagan [9]. iris heterochromia, and agenesis of corpus callosum (Table
3). Five of the six patients with somatosensory-evoked
Results potential examinations had abnormal N1 cortical compo-
nents in somatosensory-evoked potentials (Table 4). Four
Ten patients, including six females and four males, with of these patients also had prolonged central conduction
agyria-pachygyria were enrolled (mean age ⫽ 5.4 years; times (Fig 3). The N1 abnormalities included poor wave-
age range ⫽ 1 year-14 years and 8 months). The initial forms or near absence of cortical components. In contrast,
clinical presentations of these patients are presented in latencies of the sensory-evoked potential component at the

Table 2. Clinical manifestations and neuroimaging findings in 11 patients with agyria-pachygyria

Seizure Imaging
Case Initial presentations Age Gender Patterns Imaging Findings Grading

1 Seizure 14 yr 8 mo F G-T-C Complete agyria Grade 1


2 SGA and ventriculomegaly 6 yr F IS Complete agyria Grade 1
3 SGA and DD 1 yr 2 mo F IS Complete agyria Grade 1
4 Seizure 9 yr 5 mo F IS Agyria-pachygyria Grade 2
5 Seizure 3 yr 6 mo M IS Agyria-pachygyria Grade 2
6 DD 3 yr 2 mo F IS Complete pachygyria Grade 4
7 Congenital anomaly with facial dysmorphysm 1 yr 10 mo F G-T-C Complete pachygyria Grade 4
8 DD 2 yr 6 mo M No seizure Focal pachygyria Grade 5
9 SGA and congenital anomaly 1 yr F No seizure Focal pachygyria Grade 5
10 Seizure 10 yr 8 mo M G-T-C Focal pachygyria Grade 6

Abbreviations:
DD ⫽ Developmental delay IS ⫽ Infantile spasms
G-T-C ⫽ Generalized tonic clonic seizure SGA ⫽ Small for gestational age

172 PEDIATRIC NEUROLOGY Vol. 27 No. 3


Figure 2. Electroencephalogram of Patient 10, recorded at 10 years of
age, exhibits the dominant high-voltage tracings at bilateral frontal
areas corresponding to the pachygyric areas demonstrated in Figure 1B.

Clinical Outcome

In all, eight of 10 patients survived and had variable


intellectual and motor retardation. Of the seven patients
with grade 1-4 agyria-pachygyria, two died because of
sepsis, and five patients had profound intellectual and
Figure 1. (A) T2-weighted magnetic resonance imaging of Patient 2 motor retardation with intractable seizures during the
demonstrates smooth brain surface, lack of insular operculation, thick- 9-96-month follow-up period (Table 5). The intellectual
ened cerebral cortex, and enlarged lateral ventricles (TR ⫽ 2,500 ms, TE
⫽ 90 ms). (B) T2-weighted magnetic resonance imaging of Patient 10 and motor outcome of the children who were grade 5-6
displays decreased sulcation and thickened cortex at bilateral middle and was much better than that of children who were grade 1-4
superior frontal areas (TR ⫽ 5,552 ms, TE ⫽ 112 ms).

Table 3. Summary of goggled visual-evoked potential findings in


seven patients with agyria-pachygyria

Imaging
neck point were normal in these patients. Of these five Case Grading Visual-Evoked Potential Findings
patients with abnormal somatosensory-evoked potentials,
four had grade 1-4 agyria-pachygyria, and one patient 2 Grade 1 Poor waveform of goggled visual-evoked potential
(Patient 10) was grade 6. Patient 10, who developed 3 Grade 1 Normal
5 Grade 2 Absence of goggled visual-evoked potential
seizures at 10 years of age, had only mild prolongation of 6 Grade 4 Normal
central conduction time at the left side. Somatosensory- 8 Grade 5 Normal
evoked potentials could not be elicited in Patient 5, who 9 Grade 5 Absence of goggled visual-evoked potential
10 Grade 6 Normal
had seizures at 3 months of age and died of sepsis.

Liang et al: Analysis of Agyria-Pachygyria Complex 173


Table 4. Summary of the somatosensory-evoked potentials to median nerve stimulation in six patients with agyria-pachygyria

Site of Stimulation
Imaging Age at Right (ms) Left (ms) Upper Limit of N1-N13
Case Grading Recording N13 N1 N1-N13 N13 N1 N1-N13 for the Age (ms)

2 Grade 1 5 yr 6 mo 9.8 29.4 19.6 10 30.6 20.6 7.91


3 Grade 1 10 mo 9 31.6 22.6 9 32.2 23.2 10.31
5 Grade 2 3 mo — — — — — —
6 Grade 4 2 yr 9 mo 8.6 31.8 23.2 8.2 34.4 26.2 9.7
8 Grade 5 4 yr 1 mo 8 15 7 8.2 15.2 7 7.91
10 Grade 6 10 yr 4 mo 11 17.6 6.6 10.8 18 7.2 6.92

Note: Bold characters are components with abnormalities.


—, Somatosensory-evoked potential cannot be elicited.

Abbreviation:
CCT ⫽ Central conduction time

agyria-pachygyria. In addition to neuroimaging, neuro- and developed seizures at 10 years of age. In contrast,
physiologic studies provide another tool for predicting the somatosensory-evoked potentials could not be elicited in
neurologic outcome of patients with agyria-pachygyria. Patient 5, who had intractable seizure onset as early as 3
Although Patient 10 had grade 6 agyria-pachygyria, he had months of age and died of sepsis at 3 years and 6 months
mild abnormalities in somatosensory-evoked potentials of age. He had a worse clinical outcome than those

Figure 3. Somatosensory-evoked potentials of Patient 2, recorded at 5 years and 6 months of age, demonstrates prolonged and poor waveform of scalp
sensory-evoked potentials with normal latencies of cervical component.

174 PEDIATRIC NEUROLOGY Vol. 27 No. 3


Table 5. Correlation of imaging grading, age of seizure onset, and neurologic outcomes

Imaging Age of Duration of


Case Grading Seizure Onset Neurologic Outcome Follow-up (mo)

1 Grade 1 12 yr MR with extensive support to maintain basic ADL 32


2 Grade 1 8 mo Bedridden 72
3 Grade 1 8 mo Bedridden 9
4 Grade 2 2 mo Bedridden 96
5 Grade 2 3 mo Expired 42
6 Grade 4 9 mo MR with extensive support to maintain basic ADL 24
7 Grade 4 10 mo Expired 9
8 Grade 5 No seizure MR with limited support to maintain basic ADL 24
9 Grade 5 No seizure Severe psychomotor retardation 8
10 Grade 5 10 yr MR with intermittent support to maintain basic ADL 5

Abbreviations:
ADL ⫽ Activities of daily living MR ⫽ Mental retardation

patients with grade 1-2 agyria-pachygyria. Therefore the mic activity, which is abnormally rapid for age, has
somatosensory-evoked potential evaluation was supple- diagnostic value for agyria-pachygyria [5,7]. As demon-
mentary to neuroimaging in predicting the clinical out- strated in Patient 10, there is a correlation between
come of these patients. high-voltage fast activities and the anatomic configura-
tions of agyria-pachygyria in neuroimaging. These high-
Discussion amplitude fast activities may be caused by the electric
activity of a relatively large part of the cortex picked up by
Agyria-pachygyria complex is a spectrum of cortical a scalp electrode or resulting from denervation supersen-
malformations and a relatively severe form among migra- sitivity caused by deafferentation of cortical neurons [5,7].
tion disorders. Although the exact etiologies remain un- Compared with the EEG findings in agyria-pachygyria,
clear, agyria-pachygyria complex may arise from genetic the experience of the role of evoked potentials in evalu-
factors or more often may be secondary to acquired injury ating patients with agyria-pachygyria is limited [5,11-14].
of the glial guides that direct the migration of neuroblasts Although delayed conduction through the brainstem path-
[10]. As reported in our present study, seizures and way in brainstem auditory-evoked potential studies has
delayed development are often the presenting symptoms in been observed [12], our study did not reveal abnormalities
patients with agyria-pachygyria. Seizure attacks, espe- in brainstem auditory-evoked potentials, except for one
cially infantile spasms, are common early in life for those
patient who required prolonged ventilator usage. Our
with complete agyria. Although all of these patients were
result was similar to that reported by Capua [13].
retarded either in motor or intellectual function, the
Previous studies of visual-evoked potential abnormali-
clinical features and neurodevelopmental dysfunction
ties in agyria-pachygyria are varied [11-12]. Visual-
were diverse and suggest dependence on the extent,
evoked potentials seem unable to identify or distinguish
distribution, and detailed structure of agyria-pachygyria
specific supratentorial cerebral malformations, including
[10]. In previous studies, those patients with predomi-
agyria-pachygyria [12]. Even in patients with holoprosen-
nance of the pachygyria cortex had a lesser degree of
psychomotor disability [3]. However, in our studies the cephaly, callosal agenesis, and colpocephaly, visual-
severity of psychomotor retardation may not completely evoked potentials could be normal [12]. In Coupland’s
correspond to the degree of image abnormalities and may study [12], abnormal flash visual-evoked potential wave-
partially be related to the age at seizure onset. Patients forms and delayed conduction times were observed. How-
with agyria and those who had earlier onset of seizures had ever, normal flash visual-evoked potential results were
the worse outcome in our study. evident in Kriss’ study [11]. The normal visual-evoked
The advent of CT and MRI has made the diagnosis of potential findings in Kriss’ study lead to the conclusion
agyria-pachygyria during life possible in recent years. In that occipital development is better preserved than that of
addition to neuroimaging, EEG abnormalities are also the brainstem in agyria-pachygyria [11]. However, in our
helpful in the diagnosis of agyria-pachygyria [5-7,11]. present study visual-evoked potential abnormalities were
These abnormalities include generalized high-amplitude present in three of the seven patients through visual-
fast activity, high-amplitude sharp- and slow-wave com- evoked potential evaluations, whereas only one of the nine
plexes, and a pattern consisting of bursts of sharp waves patients with brainstem auditory-evoked potential exami-
alternating with periods of electrocerebral depression [5]. nations was abnormal. These results indicate occipital
The most common form is the high-amplitude fast activity. development is also involved in agyria-pachygyria, but the
This unusual pattern of abnormally high-amplitude rhyth- brainstem is much better preserved.

Liang et al: Analysis of Agyria-Pachygyria Complex 175


Somatosensory-evoked potentials may assist in the local- physiologic studies could serve as prognostic factors in
ization of brain dysfunction and may prove helpful in agyria-pachygyria.
formulating a prognostic statement in brain lesions caused by
malformation [15]. Reports on the diagnostic utility of
somatosensory-evoked potentials in agyria-pachygyria are References
rare [5,13-14]. The primary somatosensory fields in agyria- [1] Dobyns WB, Reiner O, Carrozzo R, Ledbetter DH. Lissenceph-
pachygyria patients were restricted to the centroparietal, or aly: A human brain malformation associated with deletion of the LIS1
occasionally the frontal areas. The absence of frontal P20 and gene located at chromosome 17p13. JAMA 1993;270:2838-42.
parietal N1 suggests a hypoplastic central sulcus or function- [2] Ashwal S. Congenital structural defects. In: Swaiman KF,
ally undifferentiated subdivision of the somatosensory cortex Ashwal S, eds. Pediatric neurology, 3rd ed. St Louis: Mosby, 1999:234-
300.
[14]. In our studies the configuration of the cortically gener- [3] Kuzniecky RI. Magnetic resonance imaging in developmental
ated complexes was abnormal; the latencies at the cortex disorders of the cerebral cortex. Epilepsia 1994;35(Suppl 6):S44-56.
(N1) and the central conduction time (N1-N13) were pro- [4] Menkes JH, Sarnat HB. Neuroembryology, genetic program-
longed compared with those of normal children. The poor ming, and malformations of the nervous system. In: Menkes JH, Sarnat
waveforms or absence of the cortical sensory-evoked poten- HB, eds. Child Neurology, 6th ed. Philadelphia: Lippincott Williams &
Wilkins, 2000:277-400.
tial components in our results suggests agyria-pachygyria to
[5] de Rijk-van Andel JF, Arts WFM, Weerd AW. EEG and evoked
be a disease limited to the supratentorial cortex. In the present potentials in a series of 21 patients with lissencephaly type 1. Neurope-
study, patients with grade 1-4 agyria-pachygyria or somato- diatrics 1992;23:4-9.
sensory-evoked potential abnormalities disclosed worse in- [6] Hakada S, Watanabe K, Hara K, Miyazaki S. The evolution of
tellectual and motor disability compared with those with electroencephalographic features in lissencephalic syndrome. Brain Dev
grade 5-6 or without somatosensory-evoked potential abnor- 1979;1:277-83.
[7] Gastaut H, Pinsard N, Raybaud C, Aicardi J, Zifkin B. Lissen-
malities. Therefore somatosensory-evoked potential exami-
cephaly (agyria-pachygyria). Clinical findings and serial EEG studies.
nations can be considered a supplementary tool in predicting Dev Med Child Neurol 1987;29:167-80.
the neurologic outcome of patients with agyria-pachygyria. [8] Andel JFR, Arts WFM, Barth PG, Loonen MCB. Diagnostic
The timing of neuronal migration arrest in agyria- features and clinical signs in 21 patients with lissencephaly type 1. Dev
pachygyria is at approximately 3-4 months of gestation Med Child Neurol 1990;32:707-17.
[3]. Associated brain abnormalities including enlarged [9] Taylor MJ, Fagan ER. SEPs to median nerve stimulation:
Normative data for pediatrics. Electroencephalogr Clin Neurophysiol
ventricles, heterotopias, and cerebellar or callosal agenesis 1988;71:323-30.
have been located in some agyria-pachygyria patients [3]. [10] Aicardi J. The agyria-pachygyria complex: A spectrum of
Normal brainstem-evoked potential, but abnormal cortical cortical malformations. Brain Dev 1991;13:1-8.
sensory-evoked potential components, and prolonged cen- [11] Kriss A, Boyd S, Thompson D, Harris CM. A study of EEG,
tral conduction time in our patients reflect that agyria- electroretinogram, visual evoked potential, and eye movements in clas-
sical lissencephaly. Dev Med Child Neurol 2000;42:48-52.
pachygyria is a supratentorial disease. This result may
[12] Coupland SG, Sarnat HB. Visual and auditory evoked potential
presumably be because our patients did not have any correlates of cerebral malformations. Brain Dev 1990;12:466-72.
cerebellar and brainstem malformations, which are com- [13] Capua MD, Vigevano F, Wisniewski K. Somatosensory
mon in type II lissencephaly. evoked potentials in hemimegalencephaly and lissencephaly: Anatomo-
In conclusion, although agyria-pachygyria cannot be functional correlations. Brain Dev 1993;15:253-7.
diagnosed by using the findings in neurophysiologic stud- [14] Saito Y, Adachi K, Nezu A, Deguchi K, Kimura S. Topograph-
ical features of the sensory-evoked responses in malformed brains.
ies, neurophysiologic studies, especially somatosensory-
Pediatr Nerurol 2000;23:243-9.
evoked potentials, may be a supplemental tool in evaluat- [15] Scher MS. Pediatric neurophysiologic evaluation. In: Swaiman
ing the neurologic prognosis of these patients. Combined KF, Ashwal S, eds. Pediatric neurology, 3rd ed. St Louis: Mosby,
with neuroimaging grading, the abnormalities in neuro- 1999:142-81.

176 PEDIATRIC NEUROLOGY Vol. 27 No. 3