Three cases of right frontal megalencephaly: Clinical characteristics and long-term outcome

Three cases of right frontal megalencephaly: Clinical characteristics and long-term outcome

Brain & Development xxx (2015) xxx–xxx Original article Three cases of right frontal megalencephaly: Clinical chara...

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Brain & Development xxx (2015) xxx–xxx

Original article

Three cases of right frontal megalencephaly: Clinical characteristics and long-term outcome Yoichi Ono a, Yoshiaki Saito a,⇑, Yoshihiro Maegaki a, Jun Tohyama b, Hesham Montassir a, Shinya Fujii c, Kenji Sugai d, Kousaku Ohno a a

Division of Child Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Yonago, Japan b Department of Pediatrics, Epilepsy Center, Nishi-Niigata Chuo National Hospital, Niigata, Japan c Division of Radiology, Faculty of Medicine, Tottori University, Yonago, Japan d Department of Child Neurology, National Center of Neurology and Psychiatry, Kodaira, Japan Received 1 August 2015; received in revised form 8 September 2015; accepted 11 September 2015

Abstract Aim: To delineate the clinical and neuroimaging characteristics of localized megalencephaly involving the right frontal lobe. Method: Data from three patients aged 14–16 years at the last follow-up were retrospectively reviewed. Results: All the patients were normal on neurological examination with no signs of hemiparesis. Enlargement of the right frontal lobe with increased volume of subcortical and deep white matter, as well as thickening of the ipsilateral genu of the corpus callosum was common. The onset of epilepsy was 4–7 years of age, with seizure types of massive myoclonus in two and generalized tonic-clonic in two, which could be eventually controlled by antiepileptics. Interictal electroencephalography showed frontal alpha-like activity in one, and abundant spike–wave complexes resulting in diffuse continuous spike–wave activity during sleep in two patients even after suppression of clinical seizures. Psychomotor development appeared unaffected or slightly delayed before the onset of epilepsy, but became mildly disturbed during follow-up period of 7–11 years. Conclusion: Certain patients with right frontal megalencephaly can present with a milder epileptic and intellectual phenotype among those with localized megalencephaly and holohemispheric hemimegalencephaly, whose characteristic as epileptic encephalopathy was assumed from this study. Ó 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Keywords: Hemimegalencephaly; Frontal lobe; Localized megalencephaly

1. Introduction Hemimegalencephaly (HME) is a rare type of congenital brain malformation, characterized by the enlargement of either cerebral hemisphere. HME is accompanied by dysplasia of the cerebral cortex with ⇑ Corresponding author at: Division of Child Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, 36-l Nishi-cho, Yonago 683-8504, Japan. E-mail address: [email protected] (Y. Saito).

structures of polymicrogyria, agyria/pachygyria, and white matter heterotopia, which results in intractable epilepsy and profound disabilities [1,2]. For such cases, early surgical intervention, including hemispherectomy, is warranted to achieve a better outcome in the control of epilepsy and to promote psychomotor development [2]. Localized megalencephaly is now recognized as an enlargement limited to a small part of one cerebral hemisphere [3,4]. The occipital-lobe-predominant type, 0387-7604/Ó 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

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or posterior quadrantic dysplasia, is the most common type of localized megalencephaly. Although psychomotor developmental delays appear less severe in the posteriorly localized megalencephaly than the HME with holohemispheric involvement, complication of infantile spasms and/or daily, intractable seizures are common, and surgical resection of the megalencephalic region is often necessary for the control of epilepsy [3]. The occurrence of frontally localized megalencephaly is rare, and there is very little clinical information available on this condition [3]. Here we report three cases of the latter group for further recognition and characterization. 2. Method Three patients (age 14–16 years, all males) with findings of localized, frontal megalencephaly on magnetic resonance imaging (MRI) (Fig. 1) were recruited from three medical institutes specialized in epilepsy management, and the clinical information was retrospectively

reviewed. The study protocol was approved by the institutional review boards. Familial and perinatal histories and initial psychomotor development were unremarkable in all the patients. There was no consanguinity among parents of any of the patients. No evidence of macrocephaly, hemihypertrophy, or neurocutaneous syndromes was found in any patient. The age at diagnosis of focal megalencephaly ranged from 3 to 7 years, and in each case, the diagnosis occurred when the patient was receiving medical attention for the treatment of their epilepsy. Clinical details during follow-up period of 7–11 years are summarized in the following sections (see also Table 1). Genetic examinations such as G-band chromosomal analysis were not conducted for any patient. For the quantitative assessment of the enlargement of the unilateral frontal lobe, an axial T1-weighted image was chosen from each patient, wherein the anterior horn of the lateral ventricles was the largest. In addition, the right and left frontal lobes as well as the frontal white

Fig. 1. Magnetic resonance imaging of patients with unilateral frontal lobe megalencephaly (A, E, G, H: T2-weighted images, B: fluid-attenuation inversion recovery image, C: T1-weighted image, D: T1 inversion recovery image, F: fraction anisotropy map) (A–C: patient 1, D–F: patient 2, G and H: patient 3) Right frontal lobes appear larger than left frontal lobes in these patients. Blurring gray-white matter boundary (D), cortical thickening with polymicrogyric contour (arrowheads in C), and increased volume of ipsilateral frontal white matter and genu of the corpus callosum (A, D, E, G), are noted. In F, increased signal intensity of the callosal genu, and enlarged frontal white matter (arrows) are noted in the right hemisphere.

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Patient Age Sex Age at Epilepsy diagnosis onset

Seizure type

EEG pattern

Effective AEDs


Generalized myoclonus

Theta/ alpha-like activity


16 y M


4 y9 m

HC at Cutaneous birth findings (cm, SD)

Walking Words DQ/IQ

Seizure 35.6 Salmon1 y11 m free for (+1.6SD) pink nevus 2 years at forehead

18 m

VIQ PIQ ADHD- Educational support RS

88 (5 y, Tanaka-Binet)


76 (8 y, WISC- 76 III) 2

14 y M

3 y7 m

3 y7 m

Generalized clonic/tonic

Triphasic, CSWSlike


Seizure NA free for 5 years




100 (4 y, Enjoji developmental scale for children) 50 (5 y5 m, 55 WIPPSI)

14 y M



Generalized myoclonus, rare clonic/tonic

Triphasic, CSWSlike


Seizure 34 N free for (+0.5SD) 2 years

1 y4 m

24 m

15 y special education at high school


38 (7 y)



5 (14 y)

64 (8 y, WISC- 77 III)


22 (8 y)

59 (11 y10 m, WISC-III) 3


Learning disability during late childhood

6 y support by attendance of caretaker at school 9 y special educational class

79 (7 y, Tanaka-Binet)

9 y special educational class due to attention deficits and learning difficulty

Y. Ono et al. / Brain & Development xxx (2015) xxx–xxx

ADHD-RS, rating scale for attention deficits and hyperactivity disorders, AEDs, antiepileptics; CLB, clobazam; CSWS, continuous spike–wave during slow sleep; DQ, developmental quotient; EEG, electroencephalography; HC, head circumference; IQ, intelligence quotient; LTG, lamotrigine; N, normal findings; N/A, not applicable; NA, information not available; PIQ, performance intelligence quotient; VIQ, verbal intelligence quotient; VPA, valproate; WPPSI, Wechsler preschool and primary scale of intelligence; WISC, Wechsler intelligence scale for children; ZNS, zonisamide.


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Table 1 Characteristics of the patients with frontal hemimegalencephaly.


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matter comprising the corpus callosum of two rostrocaudally neighboring 3-mm-thick slices with slice gaps of 1.5 mm were measured. For analysis, the frontal lobe was posteriorly demarcated at the Sylvian fissure, between the base of frontal operculum and the lateral edge of anterior horn of the lateral ventricle, and medially at the midline of callosal genu. The areas were manually measured on the monitor (EV Insite; PSP, Tokyo, Japan). Magnetoencephalography (MEG) in patients 1 and 3 was performed using a neuromagnetometer (Neuromag 204; Elekta-Neuromag, Oy, Finland) comprising 204 planar type gradiometers as previously described [5]. Magnetoencephalographic data were recorded for more than 20 min, and were analyzed using a band-pass filter of 3–45 Hz. An equivalent current dipole was calculated for the initial peak of each interictal spike discharge in a spherical model. Equivalent current dipoles with a goodness of fit >80% and physiologically realistic current magnitude (Q < 500 nA) were accepted and superimposed onto T1-weighted 3-dimensional brain MRIs of the patients’ brain using a 1.5-T system (MAGNEX EPIOS 15; Shimadzu, Kyoto, Japan). Diffusionweighted imaging for patient 2 was performed using single-shot spin echo echo-planar imaging. The parameters were as follows: data matrix = 96, field of view = 29 cm, section thickness = 3 mm without gap, TE = 73.7 ms, TR = 1000 ms, ASSET factor = 2, number of acquisitions = 4, and b = 1000 s/mm2 with 6 directions. 3. Results 3.1. Evolution of epilepsy and outcome At the age of four years, patient 1 developed myoclonic jerks, which appeared during wakefulness and sometimes resulted in dropping objects from his hands. The myoclonic jerks disappeared after seven months of daily episodes, but remerged thereafter. Electroencephalography (EEG) at the age of five years revealed epileptiform activity with right frontal predominance, and treatment with valproate (VPA) 400 mg was initiated. Following this treatment, generalized myoclonus decreased in frequency, but appeared for a period of a few days at intervals of several months until age 14. After increasing the dose of VPA to 600 mg, the patient has been seizure-free for 2 years. Patient 2 first experienced a generalized clonic seizure during sleep at the age of three years. While being treated with carbamazepine, clonazepam, VPA, sultiame, zonisamide, and clobazam (CLB) in varying combinations, the patient’s generalized seizures appeared at a frequency of once per year until the age of nine years. A regimen of zonisamide (180 mg) and lamotrigine (up to 275 mg) resulted in a seizure-free period of 5 years.

Patient 3 manifested generalized myoclonus repetitively during febrile illness since two months of age. Right frontal spikes were revealed using EEG at the age of one year, but no medication was initiated since these myoclonia appeared exclusively at pyrexia. The patient was diagnosed with febrile myoclonus until the age of seven years, when he experienced massive myoclonia in clusters during sleep. He also experienced generalized clonic seizures at age 7, and generalized tonic-clonic seizures at the age of 11 years. The patient was treated with VPA 500 mg and CLB 20 mg, which resulted in complete seizure control, and the patient has been seizure-free for two years. 3.2. Neuroimaging Enlargement of the right frontal lobe with an increased volume of white matter in this region, as well as a broad genu of the corpus callosum on the same side, was common in all three patients (Fig. 1). The ratio of the left and right frontal lobe parenchyma was 1.05, 1.19, and 1.09 for each patient. The ratio of frontal white matter was 1.01, 1.86, and 1.13 (Supplementary Table 1). Mild cortical thickening and/or findings suggestive of polymicrogyria were noted in patients 1 and 2 (Fig. 1C–E). No intracranial calcification was present on computed tomography of each patient. MEG analysis in patients 1 and 3 identified current dipoles in the right frontal lobe, either anteriorly within the cortex and subcortical white matter (Fig. 2A and B) or posteriorly in the periphery of the dysplastic frontal lobe including the deep white matter (Fig. 2C and D). Diffusion tensor imaging in patient 2 revealed increased signal intensity of right callosal genu, and enlarged frontal white matter on fractional anisotropy (FA) map (Fig. 1F). 3.3. Interictal EEG findings All patients showed frequent epileptiform discharges with right frontal predominance at the onset of epilepsy (Fig. 3). In patient 1, a mixture of theta waves and bursts of 8–15 Hz activity appeared continuously during wakefulness and sleep (Fig. 3A and B). This pattern persisted at follow-up EEGs, even after complete control of epileptic seizures. In patient 2, a triphasic spike–wave complex predominated at the onset of epilepsy (Fig. 3C). These discharges were aggravated and mixed with theta activity, resulting in semi-continuous diffuse epileptiform discharges during sleep at the age of five years (Fig. 3E). Widespread delta activity of 1.5–2 Hz predominated during wakefulness at this period (Fig. 3D). These abnormalities were attenuated with age, resulting in rather localized epileptic activity by 11 years of age (data not shown). In patient 3, right frontal predominant spikes and spike–waves were

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Fig. 2. Magnetoencephalography of patients. (A and B: patient 1, C and D: patient 3). Dipole sources are plotted on T1-weighted images with yellow filled circles.

already abundant at six years of age and were markedly augmented during sleep (Fig. 3F and G). The continuous, diffuse spike–wave activity during sleep persisted thereafter, although epileptic activity during wakefulness somewhat ameliorated during wakefulness (data not shown). 3.4. Long-term prognosis of motor and cognitive functions There have been no signs of hemiparesis or other abnormalities on neurological examination in any of the patients to date (age 14–16 years). Stagnation of intellectual development was common in all the patients, and developmental level was assessed as mild to moderately delayed in late childhood in all patients (Table 1). Each patient attended a special educational class. Patient 1 has attended this class since high school, patient 2 has attended this class since primary school, and patient 3 has attended this class since the 3rd grade of primary school. Attention deficits and hyperactivity were significant in patients 2 and 3 since early childhood, but these conditions ameliorated after the patients were medicated with lamotrigine and methylphenidate, respectively. 4. Discussion Localized unilateral megalencephaly of the frontal lobe has been scarcely recognized in the literature. In a report regarding a series of posterior quadrant dysplasia, the authors mentioned an unreported patient with right fronto-parietal megalencephaly in their experience, who had intractable partial epilepsy, mild hemiparesis, and a learning disability [3]. Otherwise, several cases of localized megalencephaly involving the frontal lobe have been described in some reports [4,6,7]; among the six probable cases belonging to this category, three had right-sided lesions and the remaining had left-sided lesions, and at least four of them developed epilepsy before 2 months of age. Surgical intervention was conducted in at least two subjects. Apart from these brief descriptions, the present report is the first to delineate the course of epilepsy, EEG findings, and

results of cognitive assessments of this type of megalencephaly. It remains unclear whether the characteristics of our patients could be generalized to the unilateral frontal megalencephaly; however, the results of this study are interesting in following points. Besides the localized enlargement of the frontal lobe, some imaging characteristics of the three patients were consistent with those in HME involving the whole hemisphere: thickening of cortex with findings of polymicrogyria, blurring of the gray-white matter boundary, increased volume of white matter, and a broadened genu of the corpus callosum [1]. In addition, increased signal intensity of callosal genu on FA map, observed in patient 2, is in contrast to the decreased FA in the white matter of argyria/pachygyria and focal cortical dysplasia [8,9]. This is rather reminiscent of the increase in the FA value with maturation of white matter, i.e., myelination reduces the axial diffusivity and axonal maturation increases the radial diffusivity during development in early childhood. Therefore, the increased FA signal intensity in this patient may represent an accelerated myelination in HME [10]. In terms of differential diagnosis, focal cortical dysplasia does not show the broadening of corpus callosum, increased white matter volume, or lobar enlargement. Tuberous sclerosis can result in focal megalencephaly [11], but the findings of cortical tuber or cutaneous macules were absent in the present patients. There is a group of patients diagnosed with focal transmantle dysplasia [12], which includes cases with lobar involvement of unilateral frontal or parieto-occipital areas. However, the ipsilateral hemisphere was described as smaller in the case of frontal lobe involvement. The authors assumed abnormal stem cell development in transmantle dysplasia, similar to that in HME. This concept may include the frontal megalencephaly; however, the term may be better limited for the cases of small dysplasia with radial, transmantle white matter signals. Paladin et al. [13] classified EEG patterns in HME as alpha-like activity, triphasic complexes, and a suppression-burst pattern. The EEG patterns of the three patients in the present study were consistent with these characteristics, and persistence of same EEG

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Fig. 3. Electroencephalography (EEG) of the patients (A and B: patient 1 at the age of 5, C–E: patient 2 at the age of 3 (C) and 5 (D and E), F and G: patient 3 at the age of 6). In patient 1, rhythmic theta activity and fast activity of 8–15 Hz persistently appear with right frontal predominance during wakefulness (A) and sleep (B). In patient 2, a frontal predominant spike–wave complex at the onset of epilepsy (D) emerged into semi-continuous diffuse epileptiform discharges during sleep at the age of 5 (E), accompanied by widespread delta activity of 1.5–2 Hz during wakefulness (D). In patient 3, a widespread spike–wave complex was aggravated during sleep, resulting in continuous emergence of diffuse spike–wave activity.

pattern in individual HME patient with age [13] was also common to the three patients. Although patients with the triphasic pattern showed the poorest prognosis in

their series, correlation between EEG patterns and a particular outcome was difficult to analyze in this study because of the limited number of subjects. Regarding the

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age of onset of epilepsy in patients with unilateral frontal megalencephaly, it was notable that the three patients developed epilepsy later than what is usually seen in those with HME. In contrast, the onset of epilepsy in patients with posterior quadrant megalencephaly is usually during infancy [3]. This trend may be common to the cases of focal cortical dysplasia, whereby seizure onset occurs at an earlier age if the dysplasia is located posteriorly than if the dysplasia is located frontally [14,15]. Certain factors including postnatal evolution of synaptogenesis may explain this difference between locations of dysplastic lesions. In general, the pathology of HME has been reported to be more severe in the posterior regions [2]. This may correlate with the fact that localized megalencephaly in a posterior location appears to be more common. In terms of laterality, one study found that eight out of eleven patients with localized megalencephaly had lesions on the left side of the brain [4]. They speculated that this was because right-sided lesions may result in less severe manifestations and the patients do not need a medical referral for surgical intervention. A better control of epilepsy with antiepileptics in the present patients may support this assumption. Generalized myoclonus predominated in two patients, which has been also recognized in holohemispheric HME [2,3,16] and may not be specific to frontal megalencephaly. The distribution of dipole sources in the periphery of the dysplastic lesion in patient 3 was similar to that seen in HME [17]. Innervation with glutamatergic afferents at the periphery of lesions has been observed in cases with polymicrogyria [18], which may explain the similar findings in HME. We could not determine the exact mechanism of better control of epilepsy in the frontal megalencephaly in this study. Meanwhile, cognitive impairment was common in the present patients, though less severe than that seen in HME or posteriorly localized megalencephaly. This may result from the abundant or continuous epileptiform discharges in the three patients, considering the better developmental outcome in children with HME after hemispherectomy [2]. However, surgical intervention was not applicable for the present patients since their epilepsy was well controlled by medication. In this point, it is interesting that steroid therapy [13] and intravenous gammaglobulin [17] showed excellent effects on the infantile spasms in some patients with HME. The EEG findings in patients 2 and 3 could be regarded as continuous spike–wave during slow sleep (CSWS), for which these immunotherapies have been claimed as efficacious. In conclusion, localized megalencephaly in the unilateral frontal lobe can manifest in epilepsy during childhood later than usual HME often with a seizure type of generalized myoclonus. Cortical lesions of polymicrogyria, increased white matter volume, thick callosal


genu, and accelerated myelination characterized unilateral frontal megalencephaly, and these features are similar to those seen in HME. EEGs showed alpha-like patterns in one patient, and continuous, diffuse spike–wave activity during sleep in two patients. Epileptic seizures were well controlled by antiepileptic medications, but mild to moderate impairment in cognitive function of these patients may represent a type of epileptic encephalopathy. Conflict of interest This study was not industry-sponsored. None of the authors report any disclosures. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at 1016/j.braindev.2015.09.005. References [1] Flores-Sarnat L. Hemimegalencephaly: Part 1. Genetic, clinical, and imaging aspects. J Child Neurol 2002;17:373–84. [2] Di Rocco C, Battaglia D, Pietrini D, Piastra M, Massimi L. Hemimegalencephaly: clinical implications and surgical treatment. Childs Nerv Syst 2006;22:852–66. [3] D’Agostino MD, Bastos A, Piras C, Bernasconi A, Grisar T, Tsur VG, et al. Posterior quadrantic dysplasia or hemi-hemimegalencephaly: a characteristic brain malformation. Neurology 2004;62:2214–20. [4] Nakahashi M, Sato N, Yagishita A, Ota M, Saito Y, Sugai K, et al. Clinical and imaging characteristics of localized megalencephaly: a retrospective comparison of diffuse hemimegalencephaly and multilobar cortical dysplasia. Neuroradiology 2009;51:821–30. [5] Tohyama J, Akasaka N, Ohashi T, Kobayashi Y. Acquired opercular epilepsy with oromotor dysfunction: magnetoencephalographic analysis and efficacy of corticosteroid therapy. J Child Neurol 2011;26:885–90. [6] Barkovich AJ, Chuang SH. Unilateral megalencephaly: correlation of MR imaging and pathologic characteristics. AJNR Am J Neuroradiol 1990;11:523–31. [7] Adamsbaum C, Robain O, Cohen PA, Delalande O, Fohlen M, Kalifa G. Focal cortical dysplasia and hemimegalencephaly: histological and neuroimaging correlations. Pediatr Radiol 1998;28:583–90. [8] Widjaja E, Zarei Mahmoodabadi S, Otsubo H, Snead OC, Holowka S, Bells S, et al. Subcortical alterations in tissue microstructure adjacent to focal cortical dysplasia: detection at diffusion-tensor MR imaging by using magnetoencephalographic dipole cluster localization. Radiology 2009;251:206–15. [9] Kao YC, Peng SS, Weng WC, Lin MI, Lee WT. Evaluation of white matter changes in agyria-pachygyria complex using diffusion tensor imaging. J Child Neurol 2011;26:433–9. [10] Kamiya K, Sato N, Saito Y, Nakata Y, Ito K, Shigemoto Y, et al. Accelerated myelination along fiber tracts in patients with hemimegalencephaly. J Neuroradiol 2014;41:202–10. [11] Griffiths PD, Gardner SA, Smith M, Rittey C, Powell T. Hemimegalencephaly and focal megalencephaly in tuberous sclerosis complex. AJNR Am J Neuroradiol 1998;19:1935–8.

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