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Congenital Perisylvian Syndrome: MRI and Glucose PET Correlations
Congenital Perisylvian Syndrome: MRI and Glucose PET Correlations Aimee F. Luat, MD*†, Bruno Bernardi, MD*†‡, and Harry T. Chugani, MD*†‡ Congenital perisylvian syndromes are late migration/ cortical organization disorders associated with distinctive clinical and imaging features. The clinical, magnetic resonance imaging, and 2-deoxy-2-[18F] fluoroD-glucose (FDG) positron emission tomography scan findings of six children (age range: 3.2-16.7 years; 5 males) with congenital perisylvian syndrome were evaluated. The patients presented with heterogenous neurologic impairments, depending upon the involved hemisphere and the extension of perisylvian malformation. Two manifested bilateral malformation and four manifested unilateral. The characteristic MRI finding consisting of a vertically oriented sylvian fissure continuous with the central and postcentral sulcus was associated with variable extension of bordering polymicrogyric cortex. The positron emission tomography scans of all patients revealed perisylvian metabolic abnormalities corresponding to the magnetic resonance imaging– defined abnormality. Variable extent of abnormal glucose metabolism was also observed in areas with normal magnetic resonance imaging features. All patients with unilateral magnetic resonance imaging abnormality exhibited abnormal glucose metabolism also in the contralateral side. The two patients with bilateral malformation had more extensive positron emission tomography abnormalities than the morphologic anomalies on MRI. Although MRI remains the diagnostic gold standard to detect the lesion, positron emission tomography scan is helpful to evaluate the full functional extension of the cortical anomaly, thereby contributing to the definition of the clinical severity of the syndrome. © 2006 by Elsevier Inc. All rights reserved. Luat AF, Bernardi B, Chugani HT. Congenital perisylvian syndrome: MRI and glucose PET correlations. Pediatr Neurol 2006;35:21-29.
From *The Carman and Ann Adams Department of Pediatrics, and the Departments of †Neurology and ‡Radiology, Childrens Hospital of Michigan, Wayne State University, Detroit, Michigan.
© 2006 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2005.11.003 ● 0887-8994/06/$—see front matter
Introduction Progress in brain imaging, particularly magnetic resonance imaging (MRI), has enabled the detection of a large spectrum of developmental brain malformations [1-7]. Correlation of clinical and magnetic resonance imaging features has identified several cortical developmental anomalies associated with specific neurologic syndromes [8-12], one of which is bilateral perisylvian polymicrogyria. Congenital bilateral and unilateral perisylvian syndromes are late migration/cortical organization disorders associated with distinctive clinical and imaging features. Bilateral perisylvian polymicrogyria is characterized by pseudobulbar palsy, cognitive deficits, seizures, and bilateral perisylvian cortical abnormalities readily detected with magnetic resonance imaging [13-16], whereas the unilateral malformation is associated with hemiplegia and pyramidal signs and symptoms contralateral to the identified cortical malformation on magnetic resonance imaging [17]. High-definition magnetic resonance imaging is considered the best imaging modality for revealing the presence of cortical malformations, for describing their morphologic findings, and for evaluating their extension and boundaries. The MRI features are characterized by the presence of a slightly enlarged and almost vertically oriented sylvian fissure in continuity with the central or postcentral sulcus. The gray matter bordering the abnormal sylvian fissure appears thicker than normal with increased number of thin gray/white matter interdigitations overlaid by small densely packed gyri, suggesting polymicrogyria. There is a broad spectrum in the magnetic resonance imaging extent of the cortical malformation, ranging from unilateral subtle gyral or sulcal abnormalities to large bilateral cortical infolding [18,19]. Particularly when high-resolution magnetic resonance imaging is not available and sequences not suitable for gray/white matter differentiation are used, the cortex can appear normal. In this situation, the correct diagnosis is suggested only by
Communications should be addressed to: Dr. Chugani; Pediatric Neurology/PET Center; Children’s Hospital of Michigan; 3901 Beaubien Blvd.; Detroit, MI 48201. E-mail: [email protected] Received June 7, 2005; accepted November 14, 2005.
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the abnormal shape and orientation of the sylvian fissure [19], without the possibility to fully define the anatomical extent of the abnormality. The study of brain glucose metabolism using 2-deoxy2-[18F]fluoro-d-glucose (FDG)–positron emission tomography (FDG-PET) provides a unique, functional neuroimaging tool allowing detection of cytoarchitectural disturbance in malformations of cortical development. In fact, positron emission tomography has the ability to reveal abnormal metabolic activity in the dysplastic cortex as well as in gray matter heterotopias [20-24]; positron emission tomography is a useful complement to magnetic resonance imaging in the evaluation of cortical developmental disorders. It may confirm strong clinical suspicion in the presence of subtle magnetic resonance imaging findings, define the metabolic extent of the malformation, and identify potential metabolic abnormalities contralateral to the side of the MRI-detected malformation. In this study, we evaluated the relationship between the clinical features; magnetic resonance imaging and brain FDG-PET scan findings in six children with congenital perisylvian syndrome in order to determine whether PET scanning provided further characterization of the malformation. Patients and Methods Six children (age range 3.2-16.7 years; 5 males and 1 female) with congenital perisylvian syndrome identified from our clinical records and positron emission tomography scan database were included in the study. Clinical records, magnetic resonance imaging and FDG-PET scan studies of these patients were analyzed to determine the relationship between neurologic features, MRI, and PET scan findings.
Clinical Records Developmental history, clinical presentation, and neurologic examination of the six patients were reviewed. Complete data on maternal, perinatal, and family history were available for all patients. Only patients with both magnetic resonance imaging and FDG-PET scans were included. Other investigations performed, such as electroencephalogram, genetic and metabolic tests were also noted.
Positron Emission Tomography Scan Procedure FDG-PET studies were performed using the CTI/Siemens EXACT/HR whole-body positron tomograph (Knoxville, TN). This scanner has a 15-cm field of view and generates 47 image planes with a slice thickness of 3.125 mm. The reconstructed image in-plane resolution obtained is 6.5 ⫾ 0.35 mm at a full-width-at-half maximum and 6.0 ⫾ 0.49 mm in the axial direction (reconstruction parameters: Shepp-Logan filter with a 1.1 cycles per centimeter cutoff frequency and Hanning filter with a 0.20 cycles per pixel cutoff frequency). All patients fasted for 4 hours before positron emission tomography scanning. A venous line was established for the injection of the tracer FDG (0.143 mCI/kg). The patients were asked to close their eyes if they were able to cooperate. External stimuli were minimized by dimming the lights and discouraging interaction so that studies reflected the resting awake state during the uptake period (0 to 30 minutes postinjection). Sedation with intravenous pentobarbital (Nembutal) or midazolam (Versed) was used during the scanning period, if necessary, only after the tracer uptake period was completed. Scalp electroencephalographic recordings were performed during the uptake period of the positron emission tomography scan in all six patients in order to record clinical and subclinical epileptiform activity, which may contribute to the pattern of glucose metabolism. The electroencephalogram was recorded for 30 minutes after the FDG injection, using Nicolet Voyageur Digital electroencephalography equipment (Nicolet Biomedical Inc., Madison, WI). All positron emission tomography studies were accomplished without clinical seizures. The scanning phase lasted 20 minutes, and all PET slices were oriented parallel to the canthomeatal plane. Calculated attenuation correction was performed as previously described [25]. All positron emission tomography images were analyzed by one of the investigators (H.T.C.).
Results Clinical Features The clinical history of the two patients with magnetic resonance imaging evidence of bilateral perisylvian malformation (Patients 1 and 2) was characterized by parental consanguinity and grade III intraventricular hemorrhage with hydrocephalus, respectively. None of these patients had abnormal findings on genetic and metabolic evaluations. Further clinical details on these six patients are provided in Table 1. Magnetic Resonance Imaging Findings
Magnetic Resonance Imaging Magnetic resonance studies of six patients were acquired, between 1995 and 2004, with a 1.5 Tesla scanner (GE, Signa). Only one study (Patient 1) underwent MRI scan in another institution using a different magnet. For each patient, the following sequences were acquired: axial and coronal fast spin echo T2-weighted imaging (TR 2500-3000, TE 70-120 ms) 5-mm slice thickness, axial fluid-attenuated inversionrecovery T2-weighted (TR 9600; TE 160 ms), sagittal and axial spin-echo T1-weighted imaging (TR 400-600; TE 11-20 ms). In Patients 2, 4, and 6, three-dimensional spoiled gradient recalled echo T1-weighted imaging and coronal fluid-attenuated inversion-recovery images were also performed. The magnetic resonance imaging scans were initially evaluated, and the diagnosis made, by different radiologists. At the time of this study, all MRI scans were reevaluated by two of the investigators (H.T.C. and B.B.) and assigned a diagnosis of either bilateral or unilateral perisylvian syndrome. In addition, the presence of other cortical developmental abnormalities was observed.
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Initially, magnetic resonance imaging findings were interpreted as normal in one case (Patient 1), as atrophy due to a possible vascular insult in another (Patient 4), and as nonspecific gyral malformations in two (Patients 3 and 6). Our magnetic resonance imaging review of these four patients identified the perisylvian malformations with polymicrogyric-appearing cortex, thus allowing the diagnosis to be made. The abnormal cortex bordering the sylvian fissure was particularly visible on parasagittal slices (Fig 1), exhibiting increased white/gray matter interdigitations overlaid by small densely packed gyri, suggesting polymicrogyria. The extent of polymicrogyria varied from the involvement of the perisylvian region alone to involvement of almost the entire cerebral hemispheres with sparing of the occipital lobes.
Table 1.
Summary of clinical, PET-EEG, MRI, and FDG-PET scan findings of the six patients
Patient No. Age at PET Scan Time Sex
Clinical Features
PET EEG/Spike Frequency
MRI
FDG-PET Scan
Cognitive delay. Speech delay. Pseudobulbar palsy. Intractable epilepsy. Motor and ocular apraxia. Micrognathia. Parental consanguinity Cognitive delay. No words. Intractable epilepsy. Spastic quadriparesis. Cortical blindness. History of intraventricular hemorrhage.
Normal BA. Multifocal, independent S/W right and left hemispheres 8/minute
Bilateral, abnormally prolonged and verticalized sylvian fissure. Bilateral, perisylvian polymicrogyric cortex extending to the opercular regions.
Diffusely slow for age. Multifocal independent S/W right and left hemispheres 5/minute
3. 16.7 years old. Male
Cognitive delay. Speech delay. Intractable epilepsy. Dysarthria
Normal BA S/W left central region 5/minute
4. 14.4 years old. Male
Congenital left hemiparesis. Cognitive delay. Intractable epilepsy.
Normal BA Focal slowing in the right temporal occipital region. Multifocal S/W right and left hemispheres. 30/minute
5. 3.2 years old. Male
Cognitive delay. Language and fine motor delay.
Normal EEG
Bilateral, abnormally prolonged and verticalized sylvian fissure, fused with the rolandic fissure. Bilateral, perisylvian polymicrogyric cortex extending to almost the whole cerebral hemispheres, with partial sparing of the occipital lobes, bilaterally. Left abnormally prolonged sylvian fissure fused with the rolandic fissure. Subtle gyral malformation in the contralateral right perirolandic and opercular regions. Polymicrogyria in the posterior perisylvian region, frontal, parietal-insular, and temporal regions on the left side. Left hemispheric hypoplasia. Right abnormally prolonged sylvian fissure fused with the Rolandic fissure. Polymicrogyria in the right perisylvian, right frontal and right parietal regions. Right hemispheric hypoplasia. Right abnormally prolonged sylvian fissure fused with the rolandic fissure. Polymicrogyria in the right perisylvian and parietal regions. Right hemispheric hypoplasia.
Increased: Bilateral perisylvian regions. Bilateral inferior parietal cortex. Decreased: Left superior parietal cortex, bilateral middle and inferior temporal cortex Increased: Bilateral perisylvian regions. Medial occipital cortex Decreased: Left frontal cortex. Bilateral posterior temporal and lateral occipital cortex.
6. 13 years old. Male
Congenital left hemiparesis with hemiatrophy. Features of both Sturge-Weber and Klippel-Trenaunay syndrome right port wine stain, left cataract, right somatic hemihypertrophy. Cognitive delay. Intractable epilepsy.
Diffusely slow for age Focal slowing in the right temporo-parietal-occipital region. Multifocal S/W in the right temporo-parietal-occipital region and in the left temporal region. 3/minute
1. 7.9 years old. Male
2. 6 years old. Female
Right abnormally prolonged sylvian fissure fused with the rolandic fissure. Polymicrogyria in the right perisylvian and frontoparietal regions. Venous angioma in the right sylvian region with ipsilateral deep venous system anomalies.
Decreased: Bilateral perisylvian regions and temporal cortex, left more than right. Increased: Left posterior parietal cortex. Left frontal cortex. Right frontal cortex.
Increased: Right perisylvian region. Right parietal-temporal cortex. Right frontal cortex. Left superior temporal cortex. Increased: Right perisylvian region. Right parietal cortex. Right frontal cortex. Decreased: Left superior temporal cortex. Left parietal cortex. Decreased: Right perisylvian region. Right parietal cortex. Right temporal and occipital cortex. Right frontal cortex. Left parietal cortex.
Abbreviations: BA ⫽ Background activity EEG ⫽ Electroencephalography FDG ⫽ 2-deoxy-2-[18F] fluoro-d-glucose MRI ⫽ Magnetic resonance imaging PET ⫽ Position emission tomography S/W ⫽ Spike and wave
Luat et al: Congenital Perisylvian Syndrome 23
magnetic resonance imaging abnormality identified in this patient as unilateral. In the remaining three unilateral malformations, no other magnetic resonance imaging abnormalities were observed in the contralateral side. In Patient 6 with right side unilateral involvement, ipsilateral abnormal veins with a large venous angioma were observed. PET Scan Findings In all patients, positron emission tomography scan disclosed abnormal gyral metabolism in the affected perisylvian region. Two patients (Patients 1 and 2) with bilateral perisylvian malformation on magnetic resonance imaging, had increased glucose metabolism in the bilateral perisylvian regions. Patients 4 and 5 with unilateral malformation had increased glucose metabolism in the affected perisylvian region, whereas Patients 3 and 6 had decreased glucose metabolism. In addition, variable areas of increased and decreased glucose metabolism were observed beyond the perisylvian malformation in all the patients (Table 1). Correlation of Clinical, Magnetic Resonance Imaging, and Positron Emission Tomography Scan Findings
Figure 1. Magnetic resonance imaging of Patient 1. T1-weighted (TR/TE ⫽ 516/14 ms) sagittal image revealing the wide and vertically oriented sylvian fissure lined by polymicrogyric-like cortex and fused with the rolandic fissure.
Among the cases with unilateral involvement, one had involvement of the left hemisphere (Patient 3) and three of the right (Patients 4, 5, and 6). Patient 3 manifested a subtle gyral pattern abnormality in the contralateral right perirolandic region with opercular asymmetry not clearly morphologically defined (Fig 2a). We considered the
All six patients manifested cognitive dysfunction and developmental delay of varying severity. Patient 1 had motor and oculomotor apraxia in addition to the pseudobulbar palsy suggesting involvement of the sensorimotor association cortex. Patient 2 had cortical blindness that could not be explained solely by the magnetic resonance imaging– defined morphologic abnormalities. Positron emission tomography scan revealed hypometabolism in the lateral occipital cortex and hypermetabolism in the medial occipital cortex. Despite having unilateral MRIdefined malformation, Patients 4 and 6 displayed multifocal epileptiform activities involving the left and right hemispheres independently. In these two patients, FDG-
Figure 2. Fast spin echo T2-weighted axial magnetic resonance imaging (TR/TE⫽ 3000/104 ms) (a) and FDG-PET scan (b) findings of Patient 3. Magnetic resonance imaging (a) disclosed clear perisylvian gyral abnormality in the left and a subtle gyral abnormality in the contralateral side. Positron emission tomography scan (b) indicated decreased glucose metabolism (arrows) in the bilateral temporal regions.
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Figure 3. Axial T1-weighted (TR/TE⫽ 450/11 ms) magnetic resonance imaging and FDG-PET scan findings of Patient 5. Magnetic resonance imaging (a) identified the abnormality in the right perisylvian region. FDG-PET scan (b) also revealed increased glucose metabolism in the right frontal region (arrow head) and decreased glucose metabolism in the contralateral left superior temporal parietal cortex (arrow).
PET disclosed involvement of the contralateral hemisphere. In all patients, the location of the abnormal gyral metabolism observed in the positron emission tomography scan was consistent with the abnormal perisylvian cortex evident on magnetic resonance imaging. In addition, multifocal areas of increased and decreased glucose metabolism were observed in areas beyond the sylvian malformation, also consistent with the extent of gyral abnormalities documented on magnetic resonance imaging. However, there were additional areas of abnormal glucose metabolism without magnetic resonance imaging evidence of structural abnormality. These were identified either in the hemisphere with known morphologic anomaly, or in the contralateral hemisphere. In all four patients with magnetic resonance imaging indicating unilateral perisylvian involvement, positron emission tomography scans disclosed contralateral areas of abnormal glucose metabolism. The magnetic resonance imaging of Patient 3 detected subtle gyral abnormality contralateral to the well-defined malformation on the left side, whereas positron emission tomography scan clearly revealed areas of decreased glucose metabolism in the bilateral temporal regions (Fig 2b), thus allowing the bilateral anomaly definition. Patient 4 manifested increased glucose metabolism in the contralateral superior temporal gyrus. Patients 5 and 6 had decreased glucose metabolism in the contralateral left superior temporal-parietal (arrow in Fig 3b) and left parietal regions, respectively. Furthermore, these two patients also had more extensive positron emission tomography scan abnormalities on the side where magnetic resonance imaging abnormality was observed: Patient 5 manifested increased glucose metabolism in the right frontal region (arrow head in Fig 3b), whereas Patient 6 had decreased glucose metabolism in the right temporal and occipital cortex (Fig 4b). Likewise, in two patients with bilateral involvement (Patients 1 and 2), positron emission tomography scan abnormalities were more ex-
tensive than the gyral abnormalities evident in the magnetic resonance imaging. Glucose metabolic abnormalities were detected in the left superior parietal cortex in Patient 1. Decreased glucose metabolism in the bilateral lateral occipital cortex and increased glucose metabolism in the medial occipital cortex were observed in Patient 2 (Table 1). Discussion Different pathogenic mechanisms are likely responsible for the cortical anomalies characterizing congenital perisylvian syndrome. Evidence exists that the cortical abnormalities present in this disorder may be secondary to fetal hypoxic-ischemic event [26], intrauterine infection [27], or to genetic causes [13,15,28,29], producing a disturbance of normal cortical development during the last phase of neuronal migration or the ensuing period of cortical organization. No defined etiology could be detected for each of the six patients. In one patient (Patient 1), a genetic cause could be suspected owing to the history of parental consanguinity and the presence of dysmorphology such as micrognathia. Because Patient 2 had a history of Grade III intraventricular hemorrhage, one might speculate that a hypoxic-ischemic brain insult was responsible for this case. All six patients presented the characteristic clinical features of perisylvian syndromes. Developmental delay, pseudobulbar palsies, and seizures were present in children with bilateral malformations, whereas hemiplegia/ hemiparesis and seizures were present in those with unilateral lesions. The severity of the neurologic manifestations varied depending upon the abnormal magnetic resonance imaging as well as positron emission tomography scan findings. The type and severity of neurologic impairments were related to unilateral or bilateral involvement, side affected, extent of the magnetic resonance imaging features, and
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Figure 4. Spoiled gradient recalled echo T1-weighted (TR/TE⫽ 450/9 ms) axial reformatted magnetic resonance imaging and FDG-PET scan findings of Patient 6. Magnetic resonance imaging (a) revealed exposure of the right insula and wide right sylvian fissure with perisylvian polymicrogyria. Positron emission tomography scan (b) also disclosed decreased glucose metabolism (arrows) in the right temporal and occipital cortex.
presence of positron emission tomography abnormalities outside the detected magnetic resonance imaging features (Table 1). Generally, patients with more extensive cortical involvement seemed to have the most severe clinical course. A common finding in all six patients was the presence of cognitive dysfunction; language delay was present in four. The two patients with bilateral involvement exhibited severe language dysfunction; one with pseudobulbar palsy and the other spoke no words. One of the four patients with unilateral malformation manifested involvement of the left hemisphere and three of the right. The patient with left perisylvian involvement and contralateral equivocal gyral malformation on magnetic resonance imaging had clear bitemporal hypometabolism on positron emission tomography (Fig 2b). The majority of the patients presented with epilepsy. Kuzniecky et al. [30] have reported the epileptic spectrum of congenital perisylvian syndrome. In their series, the most frequent type of seizure was atypical absence and generalized tonic-clonic seizures, whereas partial seizures were less frequent. Seizures were poorly controlled in 65%. In our series, the majority of patients presented with complex partial seizures with secondary generalization. One patient had epileptic spasms. The observation that seizures were intractable in all of the patients in the present study may be related to the referral pattern to our epilepsy surgery center. The four patients with unilateral involvement presented with diverse clinical manifestations, ranging from mild speech and fine motor delay (Patient 5) to congenital hemiplegia contralateral to the brain defect and intractable epilepsy (Patients 4 and 6), which is similar to the clinical features of the six patients reported by Sebire et al. [17], while Patient 3 had right arm drift and dysarthria. Patient 6 manifested features of both Klippel-Trenaunay and Sturge-Weber syndrome. To our knowledge, the association between perisylvian polymicrogyria and these two syndromes has not been reported. Whether this association in a single patient is fortuitous or may be a clue to an etiologic relationship remains to be determined.
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Among the two patients with bilateral perisylvian malformation, Patient 1 satisfied the main clinical features of the syndrome as originally described by Kuzniecky et al. [14,15]; these are dysarthria, pseudobulbar palsy, cognitive deficits, intractable seizures, and micrognathia. In addition, Patient 1 manifested significant motor as well as ocular-motor apraxia suggesting involvement of association cortex as well. The clinical presentations of our patients are related to the widespread extent of the brain dysfunction defined by both magnetic resonance imaging and positron emission tomography scans. The wide spectrum of their clinical manifestations indicates that the clinical findings in children with congenital perisylvian syndrome are more heterogeneous than in the original description of the syndrome and is reflective of more extensive structural and functional brain involvement. This suggestion has also been made by other investigators [16,31,32]. Magnetic Resonance Imaging Findings in Congenital Perisylvian Syndrome Magnetic resonance imaging findings of the patients disclosed the well known features of congenital perisylvian syndrome, characterized by widening and verticalization of the sylvian fissure, polymicrogyric-like cortex in the sylvian and perisylvian regions [13-17,19] with wide variability in the extent of the malformations. In addition, in this series, a reduction in the adjacent subcortical and periventricular white matter was evident in the cases presenting large extension of the cortical abnormalities (Table 1). In two patients (Patients 3 and 6), the diagnosis of nonspecific gyral malformation was initially made. In Patient 4, the hemispheric hypoplasia with larger than normal periencephalic cerebrospinal fluid spaces, due to the developmental anomaly, was initially considered as cerebral hemiatrophy secondary to an old cerebrovascular accident. This finding is consistent with the volume loss in the affected hemisphere reported in all patients in Sebire’s
series [17]. The findings of the present study support the notion that perisylvian dysgenesis may appear on magnetic resonance imaging as a spectrum of malformations ranging from unilateral subtle gyral or sulcal abnormalities with abnormally oriented sylvian fissure to bilateral extensive cortical infolding bordered by polymicrogyric-like cortex [18].
Brain Glucose Metabolism in Congenital Perisylvian Syndrome In all six patients, the positron emission tomography scans revealed characteristic findings of either hypometabolism or hypermetabolism in the area of gyral malformation. In addition, all patients had variable areas of decreased or increased glucose metabolism in areas beyond the perisylvian malformations. These abnormalities are presumably secondary to both structural and functional derangement of the abnormal cortex presenting disordered cortical cytoarchitecture, associated with disorganized lamination. The resulting disturbance of glucose metabolism is typically represented by hypometabolism on FDGPET [33,34]; this was observed in two of our patients (Patients 3 and 6). Conversely, hypermetabolism of the perisylvian region was evident in four of six patients (Patients 1, 2, 4, and 5). There are several possible explanations for hypermetabolism on FDG-PET scans. First, areas of hypermetabolism may be detected if seizures occur during the “uptake period” after tracer injection, or if there is persistent epileptiform activity without clinical seizures during uptake [35-37]. This phenomenon is likely the result of the intrinsic epileptogenicity of dysplastic cortex [38-40]. However, none of our patients manifesting hypermetabolism had an ictal event during the uptake period (Table 1), although Patient 4 did manifest frequent interictal spiking (30 spikes/ minute) on the electroencephalogram during the uptake. Second, Palmini et al. [41] reported that patients with refractory epilepsy associated with cortical dysplasia may exhibit continuous epileptiform activity on intracranial recordings, and these are not always detected on the scalp electroencephalogram. This finding is another potential explanation for the hypermetabolism because all of our patients had intractable epilepsy. Third, it is known that heterotopias appear as relatively hypermetabolic nodules or bands when compared with the surrounding white matter, presumably because of the dense accumulation of neurons and their connections [23,42,43]. Furthermore, heterotopic malformations, when focal or unilaterally diffuse, may result in functional reorganization of the brain regions close to the heterotopia or in the contralateral hemisphere [34]. This phenomenon has been demonstrated using 15O-water positron emission tomography in a number of studies [44-46]. Thus, it is also possible that the hypermetabolism, observed in our patients on the same side but far from the detected malformation or contralat-
eral to it, may be the result of such functional reorganization. In the study of van Bogaert et al. [19] on “perisylvian dysgenesis”, two types of metabolic pattern were observed in the abnormal perisylvian cortex. The first was a pattern of metabolic activity not significantly different from that of normal gray matter, whereas the second was a heterogeneous pattern with areas of preserved and decreased metabolism. These authors proposed that the heterogeneous metabolic pattern observed was related to the presumed polymicrogyric cytoarchitecture of perisylvian dysgenesis. Depending on the timing of the brain injury (postmigratory or during neuronal migration), the number of synaptic connections in the cortical layers will vary, resulting in the variable degree of metabolism evident on positron emission tomography scans. The hypometabolism observed in cortical regions, which appeared normal on magnetic resonance imaging, was also presumably related to the presence of microdysgenesis. Correlation of Magnetic Resonance Imaging and Positron Emission Tomography Scan Findings In all four patients with unilateral perisylvian involvement on magnetic resonance imaging (Patients 3, 4, 5, and 6), FDG-PET scan also disclosed areas of abnormal glucose metabolism in the contralateral hemisphere. The lesions in the involved hemisphere were more extensive than depicted on magnetic resonance imaging in two patients. In Patient 3, whose magnetic resonance imaging revealed definite structural abnormality only in one side and possible abnormality in the contralateral side, clearly defined bitemporal hypometabolism was observed on the positron emission tomography scan. Moreover, in two patients with bilateral involvement, positron emission tomography scan abnormalities were more extensive than morphologic abnormalities detected on magnetic resonance imaging. The locations of these positron emission tomography abnormalities corresponded to areas of independent epileptiform discharges observed in the electroencephalogram (Table 1). In Patient 2, the bilateral occipital cortex, appearing normal on magnetic resonance imaging, presented severe decreased glucose metabolism on positron emission tomography. This finding could explain the cortical blindness observed in this patient. The widespread positron emission tomography abnormalities not identified by magnetic resonance imaging could therefore explain the wide spectrum of the clinical manifestations of the patients reported herein. The positron emission tomography results of this study were similar to those of van Bogaert et al. [19], who reported metabolic changes detected outside the polymicrogyric-like cortex. Our findings again demonstrate that functional neuroimaging with positron emission tomography can provide invaluable information on the full extent and severity of congenital perisylvian syndrome. Similarly, in the study of Lee et al. [23], positron emission tomography abnormalities assisted
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magnetic resonance imaging in the identification of neuronal migration disorders and provided supplementary information on the extent of the cortical abnormalities. Aside from the abnormal glucose metabolic pattern evident in cerebral dysgenesis, abnormalities in the binding of 11C-flumazenil to the central benzodiazepine receptors in areas beyond the MRI-detected morphologic lesions have been reported [47,48]. This finding again reflects the widespread functional abnormalities in cerebral dysgenesis. The present study has demonstrated new findings. In congenital perisylvian syndrome, positron emission tomography scan can add to magnetic resonance imaging and provide evidence of functional abnormalities that could further explain the broad clinical spectrum of the syndrome. It is true that these two tests evaluate two different aspects of the brain: structural and functional. The present study, however, demonstrated that in congenital perisylvian syndrome, positron emission tomography scanning can be a useful complementary test to magnetic resonance imaging by further identifying and characterizing the syndrome. This study has confirmed the variable clinical features of congenital perisylvian syndrome and has compared the magnetic resonance imaging and positron emission tomography findings. Although the diagnosis relies on the magnetic resonance imaging morphologic information, functional neuroimaging with positron emission tomography is a complementary diagnostic tool in the recognition of the syndrome as well as in the full definition of its severity.
This work was supported by NIH grant NS34488 (to H.T.C.). We are grateful to the staff of the PET Center and the magnetic resonance imaging department at Children’s Hospital of Michigan, Wayne State University for the collaboration and assistance in performing the studies described above.
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dysplasia, or the ‘double cortex’ syndrome: The clinical and epileptic spectrum in 10 patients. Neurology 1991;41:1656-62. [9] Hashimoto R, Seki T, Takuma Y, Suzuki N. The ‘double cortex’ syndrome on MRI. Brain Dev 1993;15:57-9. [10] Dubeau F, Tampieri D, Lee N, et al. Periventricular and subcortical nodular heterotopia. A study of 33 patients. Brain 1995;118: 1273-87. [11] 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. [12] Barkovich AJ, Kuzniecky RI, Jackson GD, Guerrini R, Dobyns WB. Classification system for malformations of cortical development Update 2001. Neurology 2001;57:2168-78. [13] Graff-Radford NR, Bosch EP, Stears JC, Tranel D. Developmental Foix-Chavany-Marie syndrome in identical twins. Ann Neurol 1986;20:632-5. [14] Kuzniecky R, Andermann F, Tampieri D, Melanson D, Olivier A, Leppik I. Bilateral central macrogyria: Epilepsy, pseudobulbar palsy, and mental retardation—a recognizable neuronal migration disorder. Ann Neurol 1989;25:547-54. [15] Kuzniecky R, Andermann F, Guerrini R. Congenital bilateral perisylvian syndrome: Study of 31 patients. The congenital bilateral perisylvian syndrome multicenter collaborative study. Lancet 1993;341: 608-12. [16] Gropman AL, Barkovich AJ, Vezina LG, Conry JA, Dubovsky EC, Packer RJ. Pediatric congenital bilateral perisylvian syndrome: Clinical and MRI features in 12 patients. Neuropediatrics 1997;28:198203. [17] Sebire G, Husson B, Dusser A, Navelet Y, Tardieu M, Landrieu P. Congenital unilateral perisylvian syndrome: Radiological basis and clinical correlations. J Neurol Neurosurg Psychiatry 1996;61:52-6. [18] Raymond AA, Fish DR, Sisodiya SM, Alsanjari N, Stevens JM, Shorvon SD. Abnormalities of gyration, heterotopias, tuberous sclerosis, focal cortical dysplasia, microdysgenesis, dysembryoplastic neuroepithelial tumour and dysgenesis of the archicortex in epilepsy. Clinical, EEG and neuroimaging features in 100 adult patients. Brain 1995;118:629-60. [19] van Bogaert DP, Gillain CA, Wikler D, et al. Perisylvian dysgenesis: Clinical, EEG, MRI and glucose metabolism features in 10 patients. Brain 1998;121:2229-38. [20] Chugani HT, Shewmon DA, Peacock WJ, Shields WD, Mazziotta JC, Phelps ME. Surgical treatment of intractable neonatal-onset seizure: The role of positron emission tomography. Neurology 1988;38: 1178-88. [21] Chugani HT, Shields WD, Shewmon DA, Olson DM, Phelps ME, Peacock WJ. Infantile spasms: I. PET identifies focal cortical dysgenesis in cryptogenic cases for surgical treatment. Ann Neurol 1990;27:406-13. [22] Khanna S, Chugani HT, Messa C, Curran JG. Corpus callosum agenesis and epilepsy: PET findings. Pediatr Neurol 1994;10:221-7. [23] Lee N, Radtke RA, Gray L, et al. Neuronal migration disorders: Positron emission tomography correlations. Ann Neurol 1994;35:290-7. [24] Morioka T, Nishio S, Sasaki M, et al. Functional imaging in periventricular nodular heterotopia with the use of FDG-PET and HMPAO-SPECT. Neurosurg Rev 1999;22:41-4. [25] Bergstrom M, Litton J, Eriksson L, Bohm C, Blomqvist G. Determination of object contour from projections for attenuation correction in cranial positron emission tomography. J Comput Assist Tomogr 1982;6:365-72. [26] Barkovich AJ, Rowley HA, Bollen A. Correlation of prenatal event with the development of polymicrogyria. AJNR 1995;16:822-7. [27] Zucca C, Binda S, Borgatti R, et al. Retrospective diagnosis of congenital cytomegalovirus infection and cortical maldevelopment. Neurology 2003;61:710-2. [28] Brunelli S, Faiella A, Capra V, et al. Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly. Nat Genet 1996;12:94-6.
[29] Borgatti R, Triulzi F, Zucca C, et al. Bilateral perisylvian polymicrogyria in three generations. Neurology 1999;52:1910-3. [30] Kuzniecky R, Andermann F, Guerrini R. The epileptic spectrum in the congenital bilateral perisylvian syndrome. CBPS Multicenter Collaborative Study. Neurology 1994;44:379-85. [31] Guerrini R, Dravet C, Raybaud C, et al. Neurological findings and seizure outcome in children with bilateral opercular macrogyric-like changes detected by MRI. Dev Med Child Neurol 1992;34:694-705. [32] Miller SP, Shevell M, Rosenblatt B, Silver K, O’Gorman A, Andermann F. Congenital bilateral perisylvian polymicrogyria presenting as congenital hemiplegia. Neurology 1998;50:1866-9. [33] Rintahaka PJ, Chugani HT, Messa C, Phelps ME. Hemimegalencephaly: Evaluation with positron emission tomography. Pediatr Neurol 1993;9:21-8. [34] Chugani HT. Role of PET in detection of cerebral dysgenesis. In: Kotagal P, Luders H, editors. The epilepsies: Etiologies and prevention. New York: Spectrum, 1999:29-36. [35] Chugani HT, Shewmon DA, Khanna S, Phelps ME. Interictal and postictal focal hypermetabolism on positron emission tomography. Pediatr Neurol 1993;9:10-5. [36] Bruehl C, Witte OW. Cellular activity underlying altered brain metabolism during focal epileptic activity. Ann Neurol 1995;38:414-20. [37] Bittar RG, Andermann F, Olivier A, et al. Interictal spikes increase cerebral glucose metabolism and blood flow: A PET study. Epilepsia 1999;40:170-8. [38] Redecker C, Lutzenburg M, Gressens P, Evrard P, Witte OW, Hagemann G. Excitability changes and glucose metabolism in experimentally induced focal cortical dysplasias. Cereb Cortex 1998;8:623-34. [39] Benardete EA, Kriegstein AR. Increased excitability and de-
creased sensitivity to GABA in an animal model of dysplastic cortex. Epilepsia 2002;43:970-82. [40] Chitoku S, Otsubo H, Harada Y, et al. Characteristics of prolonged afterdischarges in children with malformations of cortical development. J Child Neurol 2003;18:247-53. [41] Palmini A, Gambardella A, Andermann F, et al. Intrinsic epileptogenicity of human dysplastic cortex as suggested by corticography and surgical results. Ann Neurol 1995;37:476-87. [42] Bairamian D, Di Chiro G, Theodore WH, Holmes MD, Dorwart RH, Larson SM. MR imaging and positron emission tomography of cortical heterotopia. J Comput Assist Tomogr 1985;9:1137-9. [43] Falconer J, Wada JA, Martin W, Li D. PET, CT, and MRI imaging of neuronal migration anomalies in epileptic patients. Can J Neurol Sci 1990;17:35-9. [44] Calabrese P, Fink GR, Markowitsch HJ, et al. Left hemispheric neuronal heterotopia: A PET, MRI, EEG and neuropsychological investigation of a university student. Neurology 1994:44;302-5. [45] Hatazawa J, Sasajima T, Shimosegawa E, et al. Regional cerebral blood flow response in gray matter heterotopia during finger tapping: An activation study with positron emission tomography. Am J Neuroradiol 1996;17:479-82. [46] Muller RA, Behen ME, Muzik O, et al. Task-related activations in heterotopic brain malformations: A PET study. Neuroreport 1998;9: 2527-33. [47] Richardson MP, Koepp MJ, Brooks DJ, Fish DR, Duncan JS. Benzodiazepine receptors in focal epilepsy associated with cortical dysgenesis: An [11-C] Flumazenil PET study. Ann Neurol 1996;40:188-98. [48] Hammers A, Koepp MJ, Richardson MP, et al. Central benzodiazepine receptors in malformations of cortical development: A quantitative study. Brain 2001;124:1555-65.
Luat et al: Congenital Perisylvian Syndrome 29
From *The Carman and Ann Adams Department of Pediatrics, and the Departments of †Neurology and ‡Radiology, Childrens Hospital of Michigan, Wayne State University, Detroit, Michigan.
© 2006 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2005.11.003 ● 0887-8994/06/$—see front matter
Introduction Progress in brain imaging, particularly magnetic resonance imaging (MRI), has enabled the detection of a large spectrum of developmental brain malformations [1-7]. Correlation of clinical and magnetic resonance imaging features has identified several cortical developmental anomalies associated with specific neurologic syndromes [8-12], one of which is bilateral perisylvian polymicrogyria. Congenital bilateral and unilateral perisylvian syndromes are late migration/cortical organization disorders associated with distinctive clinical and imaging features. Bilateral perisylvian polymicrogyria is characterized by pseudobulbar palsy, cognitive deficits, seizures, and bilateral perisylvian cortical abnormalities readily detected with magnetic resonance imaging [13-16], whereas the unilateral malformation is associated with hemiplegia and pyramidal signs and symptoms contralateral to the identified cortical malformation on magnetic resonance imaging [17]. High-definition magnetic resonance imaging is considered the best imaging modality for revealing the presence of cortical malformations, for describing their morphologic findings, and for evaluating their extension and boundaries. The MRI features are characterized by the presence of a slightly enlarged and almost vertically oriented sylvian fissure in continuity with the central or postcentral sulcus. The gray matter bordering the abnormal sylvian fissure appears thicker than normal with increased number of thin gray/white matter interdigitations overlaid by small densely packed gyri, suggesting polymicrogyria. There is a broad spectrum in the magnetic resonance imaging extent of the cortical malformation, ranging from unilateral subtle gyral or sulcal abnormalities to large bilateral cortical infolding [18,19]. Particularly when high-resolution magnetic resonance imaging is not available and sequences not suitable for gray/white matter differentiation are used, the cortex can appear normal. In this situation, the correct diagnosis is suggested only by
Communications should be addressed to: Dr. Chugani; Pediatric Neurology/PET Center; Children’s Hospital of Michigan; 3901 Beaubien Blvd.; Detroit, MI 48201. E-mail: [email protected] Received June 7, 2005; accepted November 14, 2005.
Luat et al: Congenital Perisylvian Syndrome 21
the abnormal shape and orientation of the sylvian fissure [19], without the possibility to fully define the anatomical extent of the abnormality. The study of brain glucose metabolism using 2-deoxy2-[18F]fluoro-d-glucose (FDG)–positron emission tomography (FDG-PET) provides a unique, functional neuroimaging tool allowing detection of cytoarchitectural disturbance in malformations of cortical development. In fact, positron emission tomography has the ability to reveal abnormal metabolic activity in the dysplastic cortex as well as in gray matter heterotopias [20-24]; positron emission tomography is a useful complement to magnetic resonance imaging in the evaluation of cortical developmental disorders. It may confirm strong clinical suspicion in the presence of subtle magnetic resonance imaging findings, define the metabolic extent of the malformation, and identify potential metabolic abnormalities contralateral to the side of the MRI-detected malformation. In this study, we evaluated the relationship between the clinical features; magnetic resonance imaging and brain FDG-PET scan findings in six children with congenital perisylvian syndrome in order to determine whether PET scanning provided further characterization of the malformation. Patients and Methods Six children (age range 3.2-16.7 years; 5 males and 1 female) with congenital perisylvian syndrome identified from our clinical records and positron emission tomography scan database were included in the study. Clinical records, magnetic resonance imaging and FDG-PET scan studies of these patients were analyzed to determine the relationship between neurologic features, MRI, and PET scan findings.
Clinical Records Developmental history, clinical presentation, and neurologic examination of the six patients were reviewed. Complete data on maternal, perinatal, and family history were available for all patients. Only patients with both magnetic resonance imaging and FDG-PET scans were included. Other investigations performed, such as electroencephalogram, genetic and metabolic tests were also noted.
Positron Emission Tomography Scan Procedure FDG-PET studies were performed using the CTI/Siemens EXACT/HR whole-body positron tomograph (Knoxville, TN). This scanner has a 15-cm field of view and generates 47 image planes with a slice thickness of 3.125 mm. The reconstructed image in-plane resolution obtained is 6.5 ⫾ 0.35 mm at a full-width-at-half maximum and 6.0 ⫾ 0.49 mm in the axial direction (reconstruction parameters: Shepp-Logan filter with a 1.1 cycles per centimeter cutoff frequency and Hanning filter with a 0.20 cycles per pixel cutoff frequency). All patients fasted for 4 hours before positron emission tomography scanning. A venous line was established for the injection of the tracer FDG (0.143 mCI/kg). The patients were asked to close their eyes if they were able to cooperate. External stimuli were minimized by dimming the lights and discouraging interaction so that studies reflected the resting awake state during the uptake period (0 to 30 minutes postinjection). Sedation with intravenous pentobarbital (Nembutal) or midazolam (Versed) was used during the scanning period, if necessary, only after the tracer uptake period was completed. Scalp electroencephalographic recordings were performed during the uptake period of the positron emission tomography scan in all six patients in order to record clinical and subclinical epileptiform activity, which may contribute to the pattern of glucose metabolism. The electroencephalogram was recorded for 30 minutes after the FDG injection, using Nicolet Voyageur Digital electroencephalography equipment (Nicolet Biomedical Inc., Madison, WI). All positron emission tomography studies were accomplished without clinical seizures. The scanning phase lasted 20 minutes, and all PET slices were oriented parallel to the canthomeatal plane. Calculated attenuation correction was performed as previously described [25]. All positron emission tomography images were analyzed by one of the investigators (H.T.C.).
Results Clinical Features The clinical history of the two patients with magnetic resonance imaging evidence of bilateral perisylvian malformation (Patients 1 and 2) was characterized by parental consanguinity and grade III intraventricular hemorrhage with hydrocephalus, respectively. None of these patients had abnormal findings on genetic and metabolic evaluations. Further clinical details on these six patients are provided in Table 1. Magnetic Resonance Imaging Findings
Magnetic Resonance Imaging Magnetic resonance studies of six patients were acquired, between 1995 and 2004, with a 1.5 Tesla scanner (GE, Signa). Only one study (Patient 1) underwent MRI scan in another institution using a different magnet. For each patient, the following sequences were acquired: axial and coronal fast spin echo T2-weighted imaging (TR 2500-3000, TE 70-120 ms) 5-mm slice thickness, axial fluid-attenuated inversionrecovery T2-weighted (TR 9600; TE 160 ms), sagittal and axial spin-echo T1-weighted imaging (TR 400-600; TE 11-20 ms). In Patients 2, 4, and 6, three-dimensional spoiled gradient recalled echo T1-weighted imaging and coronal fluid-attenuated inversion-recovery images were also performed. The magnetic resonance imaging scans were initially evaluated, and the diagnosis made, by different radiologists. At the time of this study, all MRI scans were reevaluated by two of the investigators (H.T.C. and B.B.) and assigned a diagnosis of either bilateral or unilateral perisylvian syndrome. In addition, the presence of other cortical developmental abnormalities was observed.
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Initially, magnetic resonance imaging findings were interpreted as normal in one case (Patient 1), as atrophy due to a possible vascular insult in another (Patient 4), and as nonspecific gyral malformations in two (Patients 3 and 6). Our magnetic resonance imaging review of these four patients identified the perisylvian malformations with polymicrogyric-appearing cortex, thus allowing the diagnosis to be made. The abnormal cortex bordering the sylvian fissure was particularly visible on parasagittal slices (Fig 1), exhibiting increased white/gray matter interdigitations overlaid by small densely packed gyri, suggesting polymicrogyria. The extent of polymicrogyria varied from the involvement of the perisylvian region alone to involvement of almost the entire cerebral hemispheres with sparing of the occipital lobes.
Table 1.
Summary of clinical, PET-EEG, MRI, and FDG-PET scan findings of the six patients
Patient No. Age at PET Scan Time Sex
Clinical Features
PET EEG/Spike Frequency
MRI
FDG-PET Scan
Cognitive delay. Speech delay. Pseudobulbar palsy. Intractable epilepsy. Motor and ocular apraxia. Micrognathia. Parental consanguinity Cognitive delay. No words. Intractable epilepsy. Spastic quadriparesis. Cortical blindness. History of intraventricular hemorrhage.
Normal BA. Multifocal, independent S/W right and left hemispheres 8/minute
Bilateral, abnormally prolonged and verticalized sylvian fissure. Bilateral, perisylvian polymicrogyric cortex extending to the opercular regions.
Diffusely slow for age. Multifocal independent S/W right and left hemispheres 5/minute
3. 16.7 years old. Male
Cognitive delay. Speech delay. Intractable epilepsy. Dysarthria
Normal BA S/W left central region 5/minute
4. 14.4 years old. Male
Congenital left hemiparesis. Cognitive delay. Intractable epilepsy.
Normal BA Focal slowing in the right temporal occipital region. Multifocal S/W right and left hemispheres. 30/minute
5. 3.2 years old. Male
Cognitive delay. Language and fine motor delay.
Normal EEG
Bilateral, abnormally prolonged and verticalized sylvian fissure, fused with the rolandic fissure. Bilateral, perisylvian polymicrogyric cortex extending to almost the whole cerebral hemispheres, with partial sparing of the occipital lobes, bilaterally. Left abnormally prolonged sylvian fissure fused with the rolandic fissure. Subtle gyral malformation in the contralateral right perirolandic and opercular regions. Polymicrogyria in the posterior perisylvian region, frontal, parietal-insular, and temporal regions on the left side. Left hemispheric hypoplasia. Right abnormally prolonged sylvian fissure fused with the Rolandic fissure. Polymicrogyria in the right perisylvian, right frontal and right parietal regions. Right hemispheric hypoplasia. Right abnormally prolonged sylvian fissure fused with the rolandic fissure. Polymicrogyria in the right perisylvian and parietal regions. Right hemispheric hypoplasia.
Increased: Bilateral perisylvian regions. Bilateral inferior parietal cortex. Decreased: Left superior parietal cortex, bilateral middle and inferior temporal cortex Increased: Bilateral perisylvian regions. Medial occipital cortex Decreased: Left frontal cortex. Bilateral posterior temporal and lateral occipital cortex.
6. 13 years old. Male
Congenital left hemiparesis with hemiatrophy. Features of both Sturge-Weber and Klippel-Trenaunay syndrome right port wine stain, left cataract, right somatic hemihypertrophy. Cognitive delay. Intractable epilepsy.
Diffusely slow for age Focal slowing in the right temporo-parietal-occipital region. Multifocal S/W in the right temporo-parietal-occipital region and in the left temporal region. 3/minute
1. 7.9 years old. Male
2. 6 years old. Female
Right abnormally prolonged sylvian fissure fused with the rolandic fissure. Polymicrogyria in the right perisylvian and frontoparietal regions. Venous angioma in the right sylvian region with ipsilateral deep venous system anomalies.
Decreased: Bilateral perisylvian regions and temporal cortex, left more than right. Increased: Left posterior parietal cortex. Left frontal cortex. Right frontal cortex.
Increased: Right perisylvian region. Right parietal-temporal cortex. Right frontal cortex. Left superior temporal cortex. Increased: Right perisylvian region. Right parietal cortex. Right frontal cortex. Decreased: Left superior temporal cortex. Left parietal cortex. Decreased: Right perisylvian region. Right parietal cortex. Right temporal and occipital cortex. Right frontal cortex. Left parietal cortex.
Abbreviations: BA ⫽ Background activity EEG ⫽ Electroencephalography FDG ⫽ 2-deoxy-2-[18F] fluoro-d-glucose MRI ⫽ Magnetic resonance imaging PET ⫽ Position emission tomography S/W ⫽ Spike and wave
Luat et al: Congenital Perisylvian Syndrome 23
magnetic resonance imaging abnormality identified in this patient as unilateral. In the remaining three unilateral malformations, no other magnetic resonance imaging abnormalities were observed in the contralateral side. In Patient 6 with right side unilateral involvement, ipsilateral abnormal veins with a large venous angioma were observed. PET Scan Findings In all patients, positron emission tomography scan disclosed abnormal gyral metabolism in the affected perisylvian region. Two patients (Patients 1 and 2) with bilateral perisylvian malformation on magnetic resonance imaging, had increased glucose metabolism in the bilateral perisylvian regions. Patients 4 and 5 with unilateral malformation had increased glucose metabolism in the affected perisylvian region, whereas Patients 3 and 6 had decreased glucose metabolism. In addition, variable areas of increased and decreased glucose metabolism were observed beyond the perisylvian malformation in all the patients (Table 1). Correlation of Clinical, Magnetic Resonance Imaging, and Positron Emission Tomography Scan Findings
Figure 1. Magnetic resonance imaging of Patient 1. T1-weighted (TR/TE ⫽ 516/14 ms) sagittal image revealing the wide and vertically oriented sylvian fissure lined by polymicrogyric-like cortex and fused with the rolandic fissure.
Among the cases with unilateral involvement, one had involvement of the left hemisphere (Patient 3) and three of the right (Patients 4, 5, and 6). Patient 3 manifested a subtle gyral pattern abnormality in the contralateral right perirolandic region with opercular asymmetry not clearly morphologically defined (Fig 2a). We considered the
All six patients manifested cognitive dysfunction and developmental delay of varying severity. Patient 1 had motor and oculomotor apraxia in addition to the pseudobulbar palsy suggesting involvement of the sensorimotor association cortex. Patient 2 had cortical blindness that could not be explained solely by the magnetic resonance imaging– defined morphologic abnormalities. Positron emission tomography scan revealed hypometabolism in the lateral occipital cortex and hypermetabolism in the medial occipital cortex. Despite having unilateral MRIdefined malformation, Patients 4 and 6 displayed multifocal epileptiform activities involving the left and right hemispheres independently. In these two patients, FDG-
Figure 2. Fast spin echo T2-weighted axial magnetic resonance imaging (TR/TE⫽ 3000/104 ms) (a) and FDG-PET scan (b) findings of Patient 3. Magnetic resonance imaging (a) disclosed clear perisylvian gyral abnormality in the left and a subtle gyral abnormality in the contralateral side. Positron emission tomography scan (b) indicated decreased glucose metabolism (arrows) in the bilateral temporal regions.
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Figure 3. Axial T1-weighted (TR/TE⫽ 450/11 ms) magnetic resonance imaging and FDG-PET scan findings of Patient 5. Magnetic resonance imaging (a) identified the abnormality in the right perisylvian region. FDG-PET scan (b) also revealed increased glucose metabolism in the right frontal region (arrow head) and decreased glucose metabolism in the contralateral left superior temporal parietal cortex (arrow).
PET disclosed involvement of the contralateral hemisphere. In all patients, the location of the abnormal gyral metabolism observed in the positron emission tomography scan was consistent with the abnormal perisylvian cortex evident on magnetic resonance imaging. In addition, multifocal areas of increased and decreased glucose metabolism were observed in areas beyond the sylvian malformation, also consistent with the extent of gyral abnormalities documented on magnetic resonance imaging. However, there were additional areas of abnormal glucose metabolism without magnetic resonance imaging evidence of structural abnormality. These were identified either in the hemisphere with known morphologic anomaly, or in the contralateral hemisphere. In all four patients with magnetic resonance imaging indicating unilateral perisylvian involvement, positron emission tomography scans disclosed contralateral areas of abnormal glucose metabolism. The magnetic resonance imaging of Patient 3 detected subtle gyral abnormality contralateral to the well-defined malformation on the left side, whereas positron emission tomography scan clearly revealed areas of decreased glucose metabolism in the bilateral temporal regions (Fig 2b), thus allowing the bilateral anomaly definition. Patient 4 manifested increased glucose metabolism in the contralateral superior temporal gyrus. Patients 5 and 6 had decreased glucose metabolism in the contralateral left superior temporal-parietal (arrow in Fig 3b) and left parietal regions, respectively. Furthermore, these two patients also had more extensive positron emission tomography scan abnormalities on the side where magnetic resonance imaging abnormality was observed: Patient 5 manifested increased glucose metabolism in the right frontal region (arrow head in Fig 3b), whereas Patient 6 had decreased glucose metabolism in the right temporal and occipital cortex (Fig 4b). Likewise, in two patients with bilateral involvement (Patients 1 and 2), positron emission tomography scan abnormalities were more ex-
tensive than the gyral abnormalities evident in the magnetic resonance imaging. Glucose metabolic abnormalities were detected in the left superior parietal cortex in Patient 1. Decreased glucose metabolism in the bilateral lateral occipital cortex and increased glucose metabolism in the medial occipital cortex were observed in Patient 2 (Table 1). Discussion Different pathogenic mechanisms are likely responsible for the cortical anomalies characterizing congenital perisylvian syndrome. Evidence exists that the cortical abnormalities present in this disorder may be secondary to fetal hypoxic-ischemic event [26], intrauterine infection [27], or to genetic causes [13,15,28,29], producing a disturbance of normal cortical development during the last phase of neuronal migration or the ensuing period of cortical organization. No defined etiology could be detected for each of the six patients. In one patient (Patient 1), a genetic cause could be suspected owing to the history of parental consanguinity and the presence of dysmorphology such as micrognathia. Because Patient 2 had a history of Grade III intraventricular hemorrhage, one might speculate that a hypoxic-ischemic brain insult was responsible for this case. All six patients presented the characteristic clinical features of perisylvian syndromes. Developmental delay, pseudobulbar palsies, and seizures were present in children with bilateral malformations, whereas hemiplegia/ hemiparesis and seizures were present in those with unilateral lesions. The severity of the neurologic manifestations varied depending upon the abnormal magnetic resonance imaging as well as positron emission tomography scan findings. The type and severity of neurologic impairments were related to unilateral or bilateral involvement, side affected, extent of the magnetic resonance imaging features, and
Luat et al: Congenital Perisylvian Syndrome 25
Figure 4. Spoiled gradient recalled echo T1-weighted (TR/TE⫽ 450/9 ms) axial reformatted magnetic resonance imaging and FDG-PET scan findings of Patient 6. Magnetic resonance imaging (a) revealed exposure of the right insula and wide right sylvian fissure with perisylvian polymicrogyria. Positron emission tomography scan (b) also disclosed decreased glucose metabolism (arrows) in the right temporal and occipital cortex.
presence of positron emission tomography abnormalities outside the detected magnetic resonance imaging features (Table 1). Generally, patients with more extensive cortical involvement seemed to have the most severe clinical course. A common finding in all six patients was the presence of cognitive dysfunction; language delay was present in four. The two patients with bilateral involvement exhibited severe language dysfunction; one with pseudobulbar palsy and the other spoke no words. One of the four patients with unilateral malformation manifested involvement of the left hemisphere and three of the right. The patient with left perisylvian involvement and contralateral equivocal gyral malformation on magnetic resonance imaging had clear bitemporal hypometabolism on positron emission tomography (Fig 2b). The majority of the patients presented with epilepsy. Kuzniecky et al. [30] have reported the epileptic spectrum of congenital perisylvian syndrome. In their series, the most frequent type of seizure was atypical absence and generalized tonic-clonic seizures, whereas partial seizures were less frequent. Seizures were poorly controlled in 65%. In our series, the majority of patients presented with complex partial seizures with secondary generalization. One patient had epileptic spasms. The observation that seizures were intractable in all of the patients in the present study may be related to the referral pattern to our epilepsy surgery center. The four patients with unilateral involvement presented with diverse clinical manifestations, ranging from mild speech and fine motor delay (Patient 5) to congenital hemiplegia contralateral to the brain defect and intractable epilepsy (Patients 4 and 6), which is similar to the clinical features of the six patients reported by Sebire et al. [17], while Patient 3 had right arm drift and dysarthria. Patient 6 manifested features of both Klippel-Trenaunay and Sturge-Weber syndrome. To our knowledge, the association between perisylvian polymicrogyria and these two syndromes has not been reported. Whether this association in a single patient is fortuitous or may be a clue to an etiologic relationship remains to be determined.
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Among the two patients with bilateral perisylvian malformation, Patient 1 satisfied the main clinical features of the syndrome as originally described by Kuzniecky et al. [14,15]; these are dysarthria, pseudobulbar palsy, cognitive deficits, intractable seizures, and micrognathia. In addition, Patient 1 manifested significant motor as well as ocular-motor apraxia suggesting involvement of association cortex as well. The clinical presentations of our patients are related to the widespread extent of the brain dysfunction defined by both magnetic resonance imaging and positron emission tomography scans. The wide spectrum of their clinical manifestations indicates that the clinical findings in children with congenital perisylvian syndrome are more heterogeneous than in the original description of the syndrome and is reflective of more extensive structural and functional brain involvement. This suggestion has also been made by other investigators [16,31,32]. Magnetic Resonance Imaging Findings in Congenital Perisylvian Syndrome Magnetic resonance imaging findings of the patients disclosed the well known features of congenital perisylvian syndrome, characterized by widening and verticalization of the sylvian fissure, polymicrogyric-like cortex in the sylvian and perisylvian regions [13-17,19] with wide variability in the extent of the malformations. In addition, in this series, a reduction in the adjacent subcortical and periventricular white matter was evident in the cases presenting large extension of the cortical abnormalities (Table 1). In two patients (Patients 3 and 6), the diagnosis of nonspecific gyral malformation was initially made. In Patient 4, the hemispheric hypoplasia with larger than normal periencephalic cerebrospinal fluid spaces, due to the developmental anomaly, was initially considered as cerebral hemiatrophy secondary to an old cerebrovascular accident. This finding is consistent with the volume loss in the affected hemisphere reported in all patients in Sebire’s
series [17]. The findings of the present study support the notion that perisylvian dysgenesis may appear on magnetic resonance imaging as a spectrum of malformations ranging from unilateral subtle gyral or sulcal abnormalities with abnormally oriented sylvian fissure to bilateral extensive cortical infolding bordered by polymicrogyric-like cortex [18].
Brain Glucose Metabolism in Congenital Perisylvian Syndrome In all six patients, the positron emission tomography scans revealed characteristic findings of either hypometabolism or hypermetabolism in the area of gyral malformation. In addition, all patients had variable areas of decreased or increased glucose metabolism in areas beyond the perisylvian malformations. These abnormalities are presumably secondary to both structural and functional derangement of the abnormal cortex presenting disordered cortical cytoarchitecture, associated with disorganized lamination. The resulting disturbance of glucose metabolism is typically represented by hypometabolism on FDGPET [33,34]; this was observed in two of our patients (Patients 3 and 6). Conversely, hypermetabolism of the perisylvian region was evident in four of six patients (Patients 1, 2, 4, and 5). There are several possible explanations for hypermetabolism on FDG-PET scans. First, areas of hypermetabolism may be detected if seizures occur during the “uptake period” after tracer injection, or if there is persistent epileptiform activity without clinical seizures during uptake [35-37]. This phenomenon is likely the result of the intrinsic epileptogenicity of dysplastic cortex [38-40]. However, none of our patients manifesting hypermetabolism had an ictal event during the uptake period (Table 1), although Patient 4 did manifest frequent interictal spiking (30 spikes/ minute) on the electroencephalogram during the uptake. Second, Palmini et al. [41] reported that patients with refractory epilepsy associated with cortical dysplasia may exhibit continuous epileptiform activity on intracranial recordings, and these are not always detected on the scalp electroencephalogram. This finding is another potential explanation for the hypermetabolism because all of our patients had intractable epilepsy. Third, it is known that heterotopias appear as relatively hypermetabolic nodules or bands when compared with the surrounding white matter, presumably because of the dense accumulation of neurons and their connections [23,42,43]. Furthermore, heterotopic malformations, when focal or unilaterally diffuse, may result in functional reorganization of the brain regions close to the heterotopia or in the contralateral hemisphere [34]. This phenomenon has been demonstrated using 15O-water positron emission tomography in a number of studies [44-46]. Thus, it is also possible that the hypermetabolism, observed in our patients on the same side but far from the detected malformation or contralat-
eral to it, may be the result of such functional reorganization. In the study of van Bogaert et al. [19] on “perisylvian dysgenesis”, two types of metabolic pattern were observed in the abnormal perisylvian cortex. The first was a pattern of metabolic activity not significantly different from that of normal gray matter, whereas the second was a heterogeneous pattern with areas of preserved and decreased metabolism. These authors proposed that the heterogeneous metabolic pattern observed was related to the presumed polymicrogyric cytoarchitecture of perisylvian dysgenesis. Depending on the timing of the brain injury (postmigratory or during neuronal migration), the number of synaptic connections in the cortical layers will vary, resulting in the variable degree of metabolism evident on positron emission tomography scans. The hypometabolism observed in cortical regions, which appeared normal on magnetic resonance imaging, was also presumably related to the presence of microdysgenesis. Correlation of Magnetic Resonance Imaging and Positron Emission Tomography Scan Findings In all four patients with unilateral perisylvian involvement on magnetic resonance imaging (Patients 3, 4, 5, and 6), FDG-PET scan also disclosed areas of abnormal glucose metabolism in the contralateral hemisphere. The lesions in the involved hemisphere were more extensive than depicted on magnetic resonance imaging in two patients. In Patient 3, whose magnetic resonance imaging revealed definite structural abnormality only in one side and possible abnormality in the contralateral side, clearly defined bitemporal hypometabolism was observed on the positron emission tomography scan. Moreover, in two patients with bilateral involvement, positron emission tomography scan abnormalities were more extensive than morphologic abnormalities detected on magnetic resonance imaging. The locations of these positron emission tomography abnormalities corresponded to areas of independent epileptiform discharges observed in the electroencephalogram (Table 1). In Patient 2, the bilateral occipital cortex, appearing normal on magnetic resonance imaging, presented severe decreased glucose metabolism on positron emission tomography. This finding could explain the cortical blindness observed in this patient. The widespread positron emission tomography abnormalities not identified by magnetic resonance imaging could therefore explain the wide spectrum of the clinical manifestations of the patients reported herein. The positron emission tomography results of this study were similar to those of van Bogaert et al. [19], who reported metabolic changes detected outside the polymicrogyric-like cortex. Our findings again demonstrate that functional neuroimaging with positron emission tomography can provide invaluable information on the full extent and severity of congenital perisylvian syndrome. Similarly, in the study of Lee et al. [23], positron emission tomography abnormalities assisted
Luat et al: Congenital Perisylvian Syndrome 27
magnetic resonance imaging in the identification of neuronal migration disorders and provided supplementary information on the extent of the cortical abnormalities. Aside from the abnormal glucose metabolic pattern evident in cerebral dysgenesis, abnormalities in the binding of 11C-flumazenil to the central benzodiazepine receptors in areas beyond the MRI-detected morphologic lesions have been reported [47,48]. This finding again reflects the widespread functional abnormalities in cerebral dysgenesis. The present study has demonstrated new findings. In congenital perisylvian syndrome, positron emission tomography scan can add to magnetic resonance imaging and provide evidence of functional abnormalities that could further explain the broad clinical spectrum of the syndrome. It is true that these two tests evaluate two different aspects of the brain: structural and functional. The present study, however, demonstrated that in congenital perisylvian syndrome, positron emission tomography scanning can be a useful complementary test to magnetic resonance imaging by further identifying and characterizing the syndrome. This study has confirmed the variable clinical features of congenital perisylvian syndrome and has compared the magnetic resonance imaging and positron emission tomography findings. Although the diagnosis relies on the magnetic resonance imaging morphologic information, functional neuroimaging with positron emission tomography is a complementary diagnostic tool in the recognition of the syndrome as well as in the full definition of its severity.
This work was supported by NIH grant NS34488 (to H.T.C.). We are grateful to the staff of the PET Center and the magnetic resonance imaging department at Children’s Hospital of Michigan, Wayne State University for the collaboration and assistance in performing the studies described above.
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