Original article

Epileptic Disord 2004; 6: 173-80 The roles of electroencephalography and in children with holoprosencephaly

Ming-Tao Yang1, Wang-Tso Lee2, Steven Shinnforng Peng3, Haung-Chi Lin4, Chao-Lin Tseng5, Jao-Shwann Liang1, Peng-Jung Wang6, Yu-Zen Shen2 1. Department of Pediatrics, Far Eastern Memorial Hospital, Taipei ; 2. Department of Pediatrics and 3. Radiology, National Taiwan University Hospital, Taipei ; 4. Department of Pediatrics, En Chu Kong Hospital, San-Shia ; 5. Department of Pediatrics, Taiwan Adventist Hospital, Taipei ; 6. Department of Pediatrics, Tzu Chi Hospital, Hualien, Taiwan. Received February 2nd, 2004 ; Accepted July 28, 2004

ABSTRACT − We analyze the respective roles of neuro-imaging and EEG in the assessment of 11 children with holoprosencephaly and . were present in seven patients (64%) ; six were treated with antiepileptic drugs ; five had intractable epilepsy. Two of the patients with intractable epilepsy became -free under polytherapy. Fourteen EEG recordings were performed in eight patients. The abnormal EEG findings included slow waves, focal epilep- tiform discharges, slow spike-and-wave complexes, , frontal fast activity, fronto-occipital gradients of amplitudes (posterior amplitude attenua- tion), lack of photic driving, periodic discharges, and extremely large ampli- tudes. A fronto-occipital gradient was found only in alobar and semilobar holoprosencephaly (HPE), while hypsarrhythmia only in lobar HPE. Lack of photic driving was found only in alobar HPE. All EEGs showed diffuse slow waves, and all patients had severe developmental delay. The Deep Gray Score (DGS) in neuroimaging studies, thought to predict clinical outcome, was irrelevant given the presence and intractability of the . Patients with higher DGS, nonetheless, tended to have higher mortality rate. In conclusion, EEG evaluation provides additional functional information to neuroimaging studies in the assessment of neurological outcome in patients with HPE. With a more mature and well-formed , as found in the lobar and semilobar types, the possibility of hypsarrhythmia and photic driving increased, while that of fronto-occipital gradients decreased.

KEY WORDS: holoprosencephaly, semilobar HPE, alobar HPE, epilepsy, hypsar- rhythmia, EEG..

Holoprosencephaly (HPE) results from order of decreasing severity: alobar, the failure of the embryonic forebrain, semilobar, and lobar [3]. The patients Correspondence: Dr. Wang-Tso Lee, Department of Pediatrics, the prosencephalon, to separate into with HPE usually present with delayed National Taiwan University Hospital, No. 7, symmetric cerebral hemispheres dur- development, spastic quadriplegia, Chung-Shan S. Road, Taipei, Taiwan. ing the first four weeks of embryogen- failure to thrive and seizures [2]. How- Tel: + 886-2-2312-3456 ext 5134 esis [1, 2]. The deformities of HPE are ever, the neurodevelopmental out- Fax: + 886-2-2393-4749 E-mail: [email protected] categorized into three major types in come cannot always be predicted ac-

Epileptic Disorders Vol. 6, No. 3, September 2004 173 Yang et al.

curately on the basis of DeMyer’s classification (lobar, noncleavage of caudate nuclei, lentiform nuclei, thalami semilobar, and alobar) [4]. The often-cited rule of “face and hypothalamus and the spatial orientation of the predicts the ” was found to be true in approximately thalami, according to the rating scale of Simon EM et al. 80% of cases [5]. Recently, the deep gray score (DGS), [16]. The caudate nuclei, lentiform nuclei and thalami which measures the degree of involvement of the basal were graded on a scale of 0 to 3, with 0 = complete ganglia and thalami (see Methods section for details), was separation, 1 = less than 50% noncleavage or abnormal reported to correlate better with clinical performance and medial location, 2 = 50% to 99% noncleavage, and outcome [6]. 3 = complete noncleavage. The degree of hypothalamic The EEG, as a method of functional evaluation, has been noncleavage was assessed using a scale of 0 to 2, with found to be valuable in evaluating patients with CNS 0 = complete separation, 1 = partial (anterior) noncleav- malformations [7, 8]. The peculiar EEG patterns in cortical age, and 2 = complete noncleavage. The DGS score con- dysplastic lesions, including type I lissencephaly and sisted of the sum of the grades of caudate nuclei, lentiform hemimegalencephaly, are of unusually high amplitude nuclei, thalami and hypothalami, with a maximum score (150-3,000 µV) background activity and unusual alpha of 11 [6]. The higher DGS indicated more severe non- activity at 15-25 Hz, more or less continuous or in bursts cleavage of forebrain. [8]. In most patients, these unusual patterns are age- dependent. However, there are few EEG studies in chil- dren with HPE, and their relationship with the neurologi- Results cal outcome is rarely reported [9-13]. Therefore, in the present study, we analyzed the EEGs and Among the eleven patients with HPE (table 1), four were neuroimages, including DGS, in children with HPE in female and seven were male. Ages at the last follow-up order to examine their value as predictors of the develop- were from ten days (Patient 11), when she expired, to ment and outcome of epilepsy. seven years. HPE was diagnosed by brain imaging studies taken from prenatally to 22 months old. Three patients had lobar HPE; four semilobar HPE; four alobar HPE (figure 1). Methods Patients 7 and 8 were siblings, and patient 3 had a younger brother, who was terminated prenatally as the result of a malformation. We reviewed the medical records of all children diag- Seizures were noted in seven patients (patients 1-7), in- nosed with HPE between 1993 and 2002 at three major cluding three with a lobar type HPE, two with a semilobar medical centers in Taiwan. The functional status of each type and two with an alobar type. The ages at seizure onset patient was updated by direct inquiry, either by interview ranged from one day to two years of age. Patients 4 and 5, or by phone. There were eleven patients with HPE en- alobar type HPE, tended to have earlier seizure onset than rolled in total. Their clinical manifestations, seizure pat- the other patients. Of the seven patients who experienced tern, EEG findings, neuroimaging studies, associated chro- seizures, six (patients 1-6) had epilepsy and were treated mosome abnormalities and long-term prognosis were with antiepileptic drugs. The types of seizures in these six analyzed. patients were: infantile spasms in two; neonatal seizures in The epilepsies were classified according to the revised two; generalized seizures in one; both generalized and classification of epilepsies and (ILAE, partial seizures in one. The remaining patient, patient 7, 1989) [14]. Fourteen EEGs were performed in eight pa- had only one episode of generalized tonic-clonic seizures tients (patients 1 to 8). Follow-up EEGs were available for secondary to central diabetes insipidus with hypernatre- three patients (patients 1, 2 and 6). All EEGs were reviewed mia. Only one of the six patients with epilepsy, patient 3, by two child neurologists. Each record lasted at least had an easy-to-control seizures and was free of seizures 30-40 minutes. Each patient was exposed to photic stimu- under monotherapy with ; the other five lation of a 5-20 Hz flash. Special was given to patients had intractable epilepsies. The risk of intractabil- high-amplitude (more than 50 µV) fast activities and ity was not related to HPE types, DGS, or age of seizure fronto-occipital gradients. Fronto-occipital gradient (or onset. Patients with earlier onset of seizures however, ‘posterior amplitude attenuation’ ording some [15]) is tended to have intractable epilepsy. Two of the five pa- defined as decreasing amplitudes of EEG tracing from the tients with intractable epilepsy (patients 1 and 6) became fronto-temporal leads to the occipital leads, instead of the seizure free-under polytherapy. The remaining three pa- occipital predominance observed in the normal popula- tients still suffer from intractable epilepsies. tion. Fourteen EEG studies were performed in eight patients All patients, except patient 3, had an MRI, coupled or not (tables 1 and 2). The characteristic EEG findings included with a CT scan examination. Patient 3 received only CT. slow background activity in all (8 patients), frontal fast The Deep Gray Score (DGS) was assessed by a neuroradi- activity in 5 out of 8 (figure 2), focal epileptiform dis- ologist on the basis of CT and MRI findings, including the charges in 4 out of 8, modified hypsarrhythmia in two

174 Epileptic Disorders Vol. 6, No. 3, September 2004 plpi iodr o.6 N 6, Vol. Disorders Epileptic Table 1. Clinical presentations in children with HPE.

No. Sex Age* HPE type DGS Presentation Seizure onset Epilepsy type EEG findings Chromosome Outcome SL FS SSW H FFA FOG PD Others # 1 M 6y9m Lobar 2 Dysmorphism 2m Infantile spasms + + + + + 18p deletion -ridden Intractable then seizure-free with o polytherapy ,Spebr2004 September 3, . 2 F 2y3m Lobar, ACC 1 Dysmorphism 2m Infantile spasms + + + + N Bed-ridden Intractable seizures 3 M 6y10m Semilobar, 1 Meningocele 2y9m Generalized + + + N Bed-ridden meningocele (on scalp) seizures Seizure-free with monotherapy 4 M 4m Alobar 11 Prenatal 1d Neonatal + + + + – + N Bed-ridden (with echography seizures Intractable seizures dorsal cyst) 5 F 1y7m Alobar 11 Seizures 3m Neonatal + + – N Expired seizures Intractable seizures 6 M 7y7m Lobar Spastic 1y10m Partial and + + + + + N Expired posture generalized Intractable then Developmental seizures seizure-free with delay polytherapy 7 M 2y4m Semilobar Seizures 3m + + + + N Bed-ridden Seizure-free after control of DI 8 M 1m Alobar Congenital + + + N Expired (with hydrocephalus dorsal cyst) holoprosencephaly with children in Electroencephalography 9 M 6y3m Semilobar 6 Micropenis N Bed-ridden No seizure 10 F 7m Semilobar, Imperforate N Loss follow-up ACC anus No seizure 11 F 10d Alobar 8 Dysmorphism 18p deletion Expired (with dorsal cyst) ACC = agenesis of ; AED = anti-epileptic drug; DGS = deep gray score (see methods for score evaluation); DI = diabetes insipidus; FFA = frontal fast activity; FOG = fronto-occipital gradient; FS = focal spikes; GTC = generalized tonic-clonic seizure; H = hypsarrhythmia; N = normal; PD = photic driving; SL = slow waves/ slow background activities; SSW = slow-spike-and-wave complexes. [U1] *Age: at the day of the last follow-up (interview, phone, chart records) # Other EEG findings: In patient 4: periodic discharges, lack of normal organization, and in patient 6: extremely high amplitude. 175 Yang et al.

(A) (B) (C)

(D) (E) (F)

Figure 1. Brain imaging studies in patients with HPE. (A) and (B) T1-weighted MRI in patient 4 at the first day of life shows alobar HPE with a huge dorsal cyst. In addition, a cleft palate is also noted in the coronal view (arrow). (C) Brain echography in patient 7, semilobar type, shows fused thalami and lateral ventricles. (D) CT in patient 3 shows semilobar HPE with meningocele. (E) T1-weighted MRI in patient 2 shows agenesis of corpus callosum in the saggital view. (F) T2-weighted MRI in patient 2 shows fusion of the anterior inferior frontal area with agenesis of septum pellucidum and corpus callosum in the coronal view.

(figure 2), slow spike-and-wave complexes in one (figure EEG amplitude and lack of photic driving, mostly in pa- 3), periodic discharges and lack of normal organization in tients with alobar HPE, were noted before one year old. one, and extremely large amplitude in one (figure 3). Follow-up EEGs were performed in patients 1, 2 and Hypsarrhythmia was noted in two patients with lobar HPE. 6 with lobar HPE. Evolutionary changes were noted in A fronto-occipital gradient of EEG amplitude was found in patients 1 and 2, who initially had hypsarrhythmia. Patient two patients with alobar HPE and one with semilobar HPE. 1 presented with infantile spasms and hypsarrhythmia at Photic stimulation to 5-20 cps flickering lights revealed two months of age. Following adrenocorticotropic hor- fundamental driving in all patients with lobar and semilo- mone therapy, the EEG at seven months showed diffuse bar HPE, apart from two patients with alobar HPE, aged slow waves and the pattern of hypsarrhythmia disap- four days and six months respectively. peared. Frontal fast activities and focal spikes on the EEG were noted at five years old. Frontal fast activities became Concerning age-dependent EEG manifestations (figure 4), less apparent after six years, when the seizure pattern slow background activity, focal epileptiform discharges, evolved to focal seizures with eye blinking. Patient 2 also and frontal fast activity were noted in all kinds of HPE presented with infantile spasms at two months, when the patients from birth to six years old. Hypsarrhythmia, noted EEG revealed negative findings. At five months, hypsar- only in patients with lobar type HPE, appeared before two rhythmia developed. Vigabatrin was given initially but years old. Conversely, slow spike-and-wave complexes changed for topiramate at nine months because of lack of appeared after two years old in patient 3 (semilobar type) efficacy. At that time the EEG showed only mild frontal fast and patient 6 (lobar type). A fronto-occipital gradient of activities and diffused slow waves. The EEG at one and a

176 Epileptic Disorders Vol. 6, No. 3, September 2004 Electroencephalography in children with holoprosencephaly

Table 2. Abnormal EEG findings in different types of HPE.

HPE types EEG findings (n) SL FS SSW H FFA FOG PD Non-lobar (5) 5 (100%) 2 (40%) 1 (20%) 0 3 (60%) 3 (60%) 2 (40%) Alobar (3) 3 (100%) 2 (68%) 0 0 2 (68%) 2 (68%) 0 Semilobar (2) 2 (100%) 0 1 (50%) 0 1 (50%) 1 (50%) 2 (100%) Lobar (3) 3 (100%) 2 (68%) 1 (33%) 2 (68%) 2 (68%) 0 3 (100%) FFA = frontal fast activity; FOG = fronto-occipital gradient; FS = focal spikes; H = hypsarrythmia; PD = photic driving; SL = slow waves/ slow background activities; SSW = slow-spike-and-wave complexes.

Fp1-F3 F3-C3 Fp1-F3 F3-C3 F3-C3 C3-O1 C3-P3 C3-P3

P3-O1 O1-T3 P3-O1 Fp2-F4 T3-F3 Fp2-F4 F4-C4 F4-C4 F4-C4 C4-P4 C4-P4 C4-O2 P4-O2 P4-O2 F7-T3 F7-T3 O2-T4 T3-T5 T3-T5 T4-F4 F8-T4 1 sec 50 uV F8-T4 T4-T6 T4-T6 50 uV 1 sec 1 sec 100 uV 9 m/o 10 m/o 18 m/o

Figure 2. The EEG of patient 2 at 9 months old shows mild frontal fast activity, especially over the left hemisphere. The EEG at 10 months old shows more apparent frontal fast activity. The EEG at 18 months old shows random, high-voltage, multifocal spike wave complexes (modified hypsarrhythmia). half years old evolved to slow waves with multifocal Discussion spikes, when the seizure pattern was mainly focal seizures with eye blinking. EEGs of patient 6 showed no apparent Plawner et al. [6] reported that about half (49%) of the changes. patients with HPE have at least one seizure and about half (52%) of them have difficult-to-control seizures. In the Only seven neuroimaging investigations were available present study, 3 patients (43%), among the seven with for DGS grading (table 1). Two out of three patients who seizures, had intractable seizures. As previously reported, had a DGS greater than seven expired, and the remaining our study showed that the severity of the cortical malfor- one is currently four months old[U2], with marked hypo- mation did not correlate with the presence or absence of tonia and developmental delay. Three out of four patients seizures [6]. Nonetheless, in alobar HPE (as in our patients with DGS less than seven lived up to six years old; all had 4 and 5), epilepsy was an early and severe manifestation, developmental delay and were bed-ridden. while patients with semilobar and lobar HPE usually had a later onset of seizures. However, late onset of seizures has For the 11 patients we imposed of a follow-up from ten also been reported in children with alobar HPE [17, 18]. days to seven years. Four died between the age of ten days and seven years. One patient was lost to follow-up. The causes of epilepsy in HPE may be related to the Among the six remaining patients (two with a lobar type, cortical abnormalities [19-21]. The variations in seizure three with a semilobar type, and one with alobar type), severity may be due to a mediolateral gradient in cortical motor development was severely delayed in all. A high or abnormalities, sparing the lateral cortex relatively [6]. This low DG score made no difference. is in contrast with other brain malformations, such as classic lissencephaly. Chromosome studies (karyotyping) were performed in all Some characteristic EEG findings in patients with HPE, patients. Two were found to have an 18p deletion. related to their underlying embryogenic abnormalities,

Epileptic Disorders Vol. 6, No. 3, September 2004 177 Yang et al.

Fp1-F3 Fp1-F7 F3-C3 F7-T3

C3-P3 T3-T5

P3-O1 T5-O1

Fp2-F4 Fp2-F8 F4-C4 F8-T4

C4-P4 T4-T6 P4-O2 T6-O2

F7-T3 F3-C3 T3-T5 C3-P3

F8-T4 F4-C4 T4-T6 C4-P4

100 50 uV uV 1 sec 1 sec 2y4 m/o 6 y/o

Figure 3. The EEG of patient 6 at two years four months old shows intermittent, high-voltage generalized spike-slow wave complexes during . The EEG at six years old shows more frequent high-voltage generalized spike-slow wave complexes. In addition, frontal fast activities and central alpha rhythm are noted.

Abnormal EEG findings

SL FS FFA SSW H FOG PD-

01234567

A ge (years)

Figure 4. Age distribution of abnormal EEG findings in HPE patients. Although there was slow background activity, focal epileptiform discharges, and frontal fast activity were noted all ages, hypsarrhythmia, fronto-occipital gradient of EEG amplitudes and lack of photic driving were noted below two years old. Slow spike-and-wave complexes appeared after two years old. FFA: frontal fast activity; FOG: fronto-occipital gradient; FS: focal spikes; H: hypsarrythmia; PD-: lack of photic driving; SL: slow waves/ slow background activities; SSW: slow-spike-and-wave complexes. have been reported in the literature. The characteristic charges, and isoelectric or relatively flat leads, reflecting EEG abnormalities in alobar HPE include random or re- the poor organization of cerebral cortex in HPE [10]. It was petitive intermixed spikes and slow waves, periodic dis- suggested that because of the poor connections between

178 Epileptic Disorders Vol. 6, No. 3, September 2004 Electroencephalography in children with holoprosencephaly

the bilateral cortices and poor connections between the with lobar HPE had hypsarrhythmia, showing alobar HPE cortex and the subcortical structures, the seizures in pa- no hypsarrhythmia. Furthermore, evolutionary EEG tients with alobar HPE may also present with a Jacksonian- changes in the present study were only found in more type propagation without secondary generalization [22]. mature type HPE and correlated with the maturation of In the present study, however, diffuse slow waves on the brain, a finding compatible with previous studies [12, 13, EEG were found in all patients with HPE, while hypsar- 26]. rhythmia and focal epileptiform discharges were also oc- DGS was suggested to have a better correlation with the casionally found. Our data suggest that the abnormalities severity of clinical problems and developmental out- in HPE are not just the result of non-separation of the comes in patients with HPE, compared to the simpler midline structures, but also of the presence of cortical classification by DeMyer [6]. In the present study, DGS dysplasia. was not closely related to the developmental outcome of Other characteristic EEG changes in HPE are frontal fast the patients: motor development of all patients, whether activities and fronto-occipital gradients of EEG amplitudes their DGSs were high or low, was less than three months . (posterior amplitude attenuation). Frontal fast activities The DGS, nonetheless, correlated with the severity of the and fronto-occipital gradients may be related to the se- brain malformation, and a higher DGS may indicate ear- quence of embryogenesis, caudal to rostral and dorsal to lier mortality in patients with HPE (table 1). In addition, ventral. Because the frontal forebrain is the last to be although DGS may be useful for the prediction of clinical formed and is most commonly involved, fast activity is performance and outcome, in the present study neither the more apparent over the frontal areas. Frontal fast activity DeMyer’s classification nor the DGS could be used to was noted in five of our patients (two in the lobar type, one predict the occurrence and severity of seizures (table 1). in the semilobar and two in the alobar type), including two Conversely, abnormal non-epileptiform EEGs, such as during the neonatal period. The peculiar EEG for neonates triphasic waves or focal polymorphic delta activities, may with semilobar HPE consisted of high-amplitude rhythmic be helpful in determining the severity and, hence, the fast activity, which was continuous during wakefulness prognosis of cerebral dysfunction [27]. As shown in the and became discontinuous during sleep [13], and a fronto- present study, despite their DGS, all our patients with occipital gradient. In comparison, continuous high- developmental delay had diffuse delta activities. It indi- voltage (more than 50 µV) rhythmic fast activities in other cated that the severity of non-separation of deep gray cortical dysplasias, such as type I lissencephaly, are sel- nuclei cannot be used as the only factor for predicting dom observed in the neonatal period [8, 23], do not show neurological outcome in patients with HPE. Functional asynchronous discontinuity in sleep and have no anterior- investigations such as EEG may be of some help. posterior voltage gradient. Frontal fast activity beyond the neonatal period appeared intermittently. Fronto-occipital gradients or posterior amplitude attenua- Conclusion tion were noted in alobar HPE [10], as was the case for our patients 4 and 8, and was correlated with the presence of Characteristic EEG findings, including a fronto-occipital a dorsal cyst [15]. However, patient 7, with semilobar HPE gradient, frontal fast activities and lack of photic driving, not associated with a dorsal cyst, also showed a fronto- could be found in patients with HPE and were related to occipital gradient. In our patients, a fronto-occipital gra- the severity of the brain malformation. With a more mature dient of EEG amplitudes was noted only in alobar or and well-formed cerebrum, as found in the lobar and semilobar HPE, indicating that the more mature the brain, semilobar type, the possibility of hypsarrhythmia and the less the fronto-occipital gradient or the less high- photic driving increases, while that of a fronto-occipital amplitude frontal activities. gradient decreases. EEG evaluation gives additional func- tional information to neuroimaging studies in the assess- In our study, only patients 1 and 2 with lobar type HPE ment of neurological outcome in patients with HPE. M showed evolutionary EEG changes. They both presented with infantile spasms, but only patient 2 suffered from difficult-to-control seizures. In Watanabe’s series, only one of the three patients with semilobar HPE presented References with a generalized seizure during the neonatal period, evolving to a West syndrome and later a Lennox-Gastaut 1. Golden JA. Towards a greater understanding of the pathogen- syndrome [24]. The age of onset of infantile spasms in our esis of holoprosencephaly. Brain Dev 1999; 21: 513-21. patients was earlier than been previously reported in Tai- 2. Ashwal S. Congenital structural defects. In: Swaiman KF, Ash- wan [25]. Furthermore, other studies [12, 13] showed that wal S. Pediatric – principles & practice. 3rd ed. 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